Virtual Library

Background:
Anti-PD1 therapy has activity in patients with NSCLC, as assessed by RECIST or immune-related response criteria (irRC) on selected index lesions. Baseline tumour size was reported as an independent predictor of response to pembrolizumab in melanoma, but little is known about NSCLC. Tumour burden varies depending on number and size of lesions. We investigate the relationship of treatment response and baseline disease burden using comprehensive lesion-specific analysis on imaging at a single centre from a large multicentre Phase I study.

Methods:
Clinicopathologic characteristics of patients with advanced NSCLC enrolled from May 2012 to April 2014 at Westmead Hospital on the phase I pembrolizumab (MK-3475) KEYNOTE-001 were collected, including age, ethnicity, smoking status, histopathology (squamous or non-squamous), stage and prior treatments. Patients were treated with pembrolizumab until disease progression determined by irRC on index lesions or intolerable toxicity. Bi-dimensional measurements of individual lesions on computed tomography scans at baseline, week 9 and thereafter were performed. Every metastasis ≥5mm (up to 30 lesions per organ, excluding bone) and every lymph node ≥15mm in the short axis were assessed. Overall response was determined by change in sum of the product of longest perpendicular diameters (SPD) and categorised as complete response (CR, 100% reduction SPD), partial response (PR, ≥50% reduction SPD), progressive disease (PD, ≥25% increase in SPD) or stable disease (SD, neither CR/PR/PD) using comprehensive lesion-specific analysis.

Results:
Of 25 evaluable patients with at least one post-baseline imaging, 12 were treatment-naïve, 21 were PD-L1 positive (>1% staining of cells) determined by prototype assay using 22C3 antibody and 4 were unknown. A total of 226 lesions were evaluated, 196 at baseline and 22 new lesions by first scan. Objective response (OR, ≥50% reduction SPD) was achieved in 9/25 patients (36%) by first scan, with 1 out of the 9 patients subsequently achieving CR. The patients with treatment response by first scan had a lower median number of lesions at baseline, 4.0 (range 2-8) vs 8.5 (range 4-30) and a lower median SPD per patient at baseline, 2516 vs 4178.5 Clinical benefit (CR/PR/SD) occurred in 15/25 patients (60%) with median treatment duration of 18.4 months (range 2.8 – 33.5 months). At the time of analysis on 11 April 2015, 10/25 patients were still receiving ongoing treatment. Clinical benefit was seen in 14/17 Caucasians and 1/8 non-Caucasians; 14/16 current or former smokers and 1/9 non-smokers. However, all Asians but one were non-smokers and this ex-smoker was the only Asian patient who achieved SD as best response. No differences were found in histopathology, stage, number of prior treatments or age.

Conclusion:
Fewer lesions or lower tumour burden at baseline as determined by comprehensive lesion-specific analysis may predict treatment response to anti-PD1 in advanced NSCLC. More responses were also observed in Caucasians and current or former smokers. Due to small sample size, these results need to be interpreted with caution and warrant further investigation.

Background:
Treatment of metastatic NSCLC patients with immune-checkpoint medicine is intriguing for the potential efficacy, even in difficult setting such as smokers or squamous-carcinoma; however it may be difficult to evaluate the clinical response due to the lack of reliable immuno-monitoring markers and the possibility of radiological pseudo-progression.

Methods:
not applicable

Results:
Herein we report five cases treated with antiPD-L1(MPDL3280A, Genentech): four patients were male and one female, all of them were ex-smokers, affected by metastatic NSCLC; 4 adeno- and 1 squamous cell carcinoma- in progression after one cycle of platin-based combined chemotherapy, median age 60 yrs (58-64), renal function after cisplatin was normal. They received anti-PD-L1 i.v. every 3 weeks in a clinical trial. Two patients had progression of disease, while 3 patients showed a clinical benefit. Patient #1 had stable disease at the pleural and right lung disease in the CT-scan after 6 weeks of treatment. He had low Magnesium values at basal and at every further control during PD-L1 therapy. Patient #2 showed progression of mediastinal lymph nodes and liver metastases in the CT scan after 6 weeks of treatment and progression was confirmed by CT-scans 4 and 8 weeks later; eventually a biopsy of the liver metastasis confirmed that there was a massive neoplastic invasion with tumor infiltrating lymphocytes (Tils) <5%. His basal Magnesium values were always normal. He stopped anti-PD-L1 therapy due to progression. Patient #3 had a volumetric increase of bilateral lung nodules in the CT-scan after 6 weeks while mediastinal lymph nodes were stable; lung nodules again and lymph nodes were both in progression 12 weeks later. His basal and further on Magnesium values were always normal. Patient #4 showed partial response in the CT-scan after 6 weeks of treatment, and benefit was confirmed later on by CT-scan after 12 weeks; he reported a clinical benefit for decrease of fatigue and chest pain; his basal Magnesium value was lower than normal and it has been always abnormal at every further blood check during PD-L1 treatment. Patient #5 showed partial response in the CT-scan after 6 weeks of treatment; she reported a clinical benefit for decrease of fatigue and increase of appetite; her basal Magnesium value was lower than normal and she continued to have low magnesemia at every further blood check during anti-PD-L1 treatment.

Conclusion:
Conclusion: evaluation of response may be difficult with immune checkpoint inhibitors and in one case we performed a biopsy to study tumor infiltrating lymphocytes to decide whether pseudoprogression or real progression. Data about PDL1 expression were not available because patients in a clinical trial. In our experience lower basal Magnesium value may predict a clinical benefit with anti-PD-L1, although we do not know its possible explanation.

Background:
Recent reports have suggested an association between non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) gene mutations. Other studies have indicated that EGFR signaling can activate PD-L1 expression and immune escape in mutant EGFR driven NSCLC. Furthermore PD-L1 expression is down-regulated by EGFR TKI. In this study, we aim to determine the association between tumoral and immune cell PDL1 expression and clinical characteristics and outcome in EGFR mutant NSCLC patients treated with first line EGFR TKI.

Methods:
Tumors from 90 patients with advanced stage NSCLC with EGFR mutations and treated with first line EGFR TKI were analyzed. Double staining for CD3 and PDL1 was performed by immunohistochemistry. PDL1 expression in tumour membrane, and PDL1 and CD3 expression in tumor and stromal immune cells were segmented and quantified using the Vectra slide imaging system (Perkin Elmer, Waltham, MA).

Results:
The median age of patients was 62 (range 34-88) years, 64 (71%) were female, 69 (77%) were never smokers, and 43 (48%) harbored EGFR exon 19 deletion. Most immune cells were CD3-ve and PDL1-ve in the tumor (median 99%) and stroma (median 86%). PDL1 tumor membrane expression was associated with PDL1 expression in CD3+ve immune in the tumor and stroma. There was no association between PDL1 or CD3 expression with response rate or time to progression.

Conclusion:
This is the first study to characterize PDL1 expression in immune cells in advanced stage NSCLC harboring EGFR mutations. PDL1+ve immune cells are rare in this patient population. PDL1 expression in tumor membrane and immune cells may not be associated with outcome in NSCLC patients harboring EGFR mutations and treated with EGFR TKIs.

Background:
Good efficacy and survival was observed in patients with advanced non-small cell lung cancer harboring epidermal growth factor receptor (EGFR) mutation. And the phase II study treated with gefitinib plus carboplatin and S-1 previously demonstrated the good efficacy in terms of progression free survival (PFS) and response rate (RR) as the first-line treatment of advanced NSCLC harboring activating EGFR mutations.

Methods:
This trial was multi-center, open rabel, single arm trial. All patients had a dvanced non-small cell lung cancer (Stage IIIB / IV) harboring activating mutations.A total of 35 patients received carboplatin on day 1 plus oral S-1 on days 1–14 and gefitinib daily. Updated results and subgroup analysis according to EGFR mutations are presented.

Results:
All patients had lung adenocarcinoma with activating EGFR mutations, namely, deletion (exon 19; n = 22), L858R (exon 21; n = 12), and T790M/L858R (exons 20 and 21; n = 1). Almost all patients had stage IV disease. The updated analysis revealed response rate of 85.7 %, a median PFS of 17.6 months (95% CI: 13.4 - 23.0 months), and a median overall survival (OS) was not reached (95% CI: 27.8 months -). Response rate and median PFS and median OS were 90.9 %, 18.7 months (95% CI: 15.5 - 28.4 months) and not reached (95% CI: 27.8 months -) in the exon 19 del+ arm, and 83.3 %, 13.4 months (95% CI: 6.2 - 18.5 months), and 27.9 months (95% CI: 10.1 - 32.4 months) in the exon 21 (L858R) arm. The common toxicities related to gefitinib were skin rash, elevated transaminase and diarrhea. And the common toxicity in the present trial was neutropenia. No interstitial lung disease or treatment-related deaths occurred.

Conclusion:
This triplet chemotherapy showed good efficacy and prolonged PFS. And this analysis showed the different efficacy in terms of PFS and OS of gefitinib plus carboplatin plus S-1 in patients with advanced NSCLC between EGFR mutation subtypes.

Background:
Brain metastasis (BM) in NSCLC is a negative prognostic indicator. Historically, the median survival from diagnosis of BM has been reported as 6 m. The prognostic significance of BM however, may be altered in the setting of EGFR mutated disease. The timing of BM development may also influence survival outcomes. We evaluated the difference between early (<= 6 months from diagnosis) versus late (> 6 months) BM, in EGFR wild type (WT) and mutant (MT) with respect to radiographic patterns and the impact on survival.

Methods:
The British Columbia Cancer Agency provides cancer care to a population of 4.6 million. A retrospective study was conducted of referred patients with stage IV non squamous NSCLC who underwent whole brain radiotherapy and/or surgical resection of brain metastasis with known EGFR mutation status from Mar 2010 - Dec 2012. The data was analyzed by WT and MT, early and late BM groups to characterize the radiographic patterns and overall survival (OS) from initial NSCLC diagnosis (dx) and BM dx.

Results:
430 patients were identified: 327 WT patients (206 early vs 121 late) and 103 MT (65 early vs 38 late). Pattern of BM in WT early vs late showed no difference in size of largest BM, number of metastases, cerebral edema. Leptomeningeal disease was more frequent in WT late disease (2% vs 8% p=0.01). Pattern of BM in MT early vs late showed no difference in size of largest BM, cerebral edema or leptomeningeal disease. There was a trend to miliary pattern disease in MT late BM (p=0.058). Median OS from initial dx in EGFR WT was early: 7.1 m vs late: 24.9 m (p<0.001) and OS from BM dx early: 6.3 m vs late: 4.9 m (p=0.67). Median OS from initial dx in EGFR MT was early: 19.9 m vs late: 25.6 m (p=0.39) and OS from BM dx early: 19.2 m vs late: 3.9 m (p<0.001). Cox proportional hazards (CPH) model showed in the EGFR WT receipt of chemotherapy and late BM were associated with better survival. CPH in EGFR MT demonstrated that good PS and systemic treatment but not BM timing were predictive of better outcomes.

Conclusion:
Brain metastases in EGFR WT disease is a significant negative prognostic indicator with early dx associated with poor survival. In contrast, in EGFR mutation positive disease, the overall survival from diagnosis is the same regardless of the development of early or late brain metastases. This outcome may reflect the importance of systemic control and the penetrance of EGFR TKIs across the blood brain barrier.

Background:
The efficacy of traditional cytotoxic drugs that treat the Advanced Non-Small Cell Lung Cancer (ANSCLC) has reached a plateau. Recently, the targeted therapy has become a new option for ANSCLC treatment. The most representative targeted therapy is tyrosine kinase inhibitor (TKI) aimed at the genetic mutations of epidermal growth factor (EGFR). Currently, three TKI drugs, namely Gefitinib, Erlotinib, and Icotinib, are available in Chinese market. This article compared the molecular structure，pharmacokinetic parameters, clinical data, adverse reactions, and contraindications of the three drugs to guide the optimal selection in clinical practice.

Methods:
Not Applicable.

Results:
Not Applicable.

Conclusion:
Presently the pros and cons of the three drugs are inconclusive. Taken together, TKI can be used as the first-line drug among patients with EGFR mutations. Of these TKIs, Gefitinib is convenient and safe with fair tolerability, and consequently recommended. Icotinib needs to be administered t.i.d without meal. However, in ICOGEN study, it was safer than Gefitinib, and therefore also recommended. Erlotinib needs to be taken without meal, requires quitting smoke and has narrow therapeutic windows. The occurrence rate and severity of its adverse reactions are relatively high. Therefore Erlotinib is not recommended. Among the non-selective patients, TKI can be used as the second- or third-line treatment. Erlotinib apparently has better survival benefit and therefore is recommended. Icotinib has certain efficacy among the Acian female non-smokers with adenocarcinoma or lung adenocarcinoma. Its safety and tolerability are the best. Therefore, Icotinib is the next recommended drug. Gefitinib only has certain efficacies among the Asian female nonsmoking lung adenocarcinoma patients, and therefore is recommended to only the appropriate population.

Background:
Patients with advanced stage of non small cell lung cancer (NSCLC) have been treated with few platinum-doublets in first-line. Most of them are observed for disease progression wich is followed by second-line therapy in proper patients. Maintenance therapy were introduced, with either biologic or chemotherapeutic agents, given after first line treatment, trying to prevent progression and increasing progression-free survival (PFS). Ten years ago, somatic mutations in epidermal growth factor receptor (EGFR) were identified in patients with NSCLC, those targeted agents, used previously as maintenance, were seen to inactivate specific mutated proteins, and treatment of them has changed. For patients with lung adenocarcinoma and activating EGFR mutations who received EGFR TKIs median overall survival (OS) ranges between 24 and 30 months contrasts with the plateau of 10 months reached with first line platinum-based chemotherapy in populations not selected by molecular profiling.

Methods:
We analyze all patients attended in our hospital with NSCLC, who had received EGFR-TKI since 2010. Continuous variables were summarized as arithmetic means, medians and standard deviations. Categorical variables were reported as proportions with 95% confidence intervals (95% CI). OS were measured from the day of EGFR TKI treatment to the date of death and analyzed with the Kaplan-Meier technique,

Results:
The amount of patients were 53. EGFR mutation was detected in 46 (86,8%) patients. The median patient age was 62.8 ± 19 years, 58.5% were women, 41.5 % had a history of non-smoking and 73% had adenocarcinoma histology. Six types of EGFR gene mutations were found: delection in exon 19, exon 18 (G719), exon 20(T790 and S768I),exon 21 (L861Q and L858R). There were 17 (32%) patients with exon 19 delection, 7 (13.2%) patients with exon 18 G719 mutation, 4 (7.5%) and 13 (24.5%) patients with exon 21 L861Q and L858R respectively, 4 (7.5%) with double mutation (two combinations of G719 and L861Q, one combination of G719 plus S768I, and one combination of delection in 19 exon and T790 mutation). Delection in exon 19 and L858R exon 21 mutations were higher in non-smoking patients (31.8% and 40.9%) and in women (35.5% and 32.3%). Mutations in exon 18 (G719) and delection in exon 19 -also- were higher in patients with smoking history (19.4% and 29%) and in men (18.2% and 22.7%). 79.2% received ITK as first line treatment and 1.9% as maintenance therapy. 50.9% had erlotinib, 43.4% had gefitinib and 3.8% received dacomitinib. 13 patients (24.5%) have recieved further lines of therapy including: chemotherapy, immunotherapy and second generation EGFR TKIs. Prognosis was worse in unkwoun mutations and in wild type tumors. OS was 25.8 months [11.4-40.2; IC 95%]

Conclusion:
Treatment of patients with advanced NSCLC should be individualized, based on the molecular and histological features of tumours. When harbouring an activating EGFR mutation, first-line treatment should be with an EGFR TKI. Any avalilable agent can be used, until data from comparative studies may better guide TKI selection.

Background:
As regards lung cancer patients who have relapse on platinum-based chemotherapy, there is a significant need for effective, well-tolerated treatment. Targeted agents such as orally active epidermal growth factor receptor EGFR tyrosine kinase inhibitor TKI (Erlotinib-Tarceva) and (Gefitinib-Iressa) offered a new therapeutic approach. Discovering of somatic EGFR mutations in some patients with NSCLC was a very significant breakthrough in the understanding of this disease. EGFR mutations occur almost within exons 18-21 of the gene of the receptor. The aim of this study was to evaluate tumor response, QoL and adverse effects of erlotinib, as a second line therapy for patients with EGFR mutation in NSCLC, after failure on previous first line therapy.

Methods:
During the year 2010-2011, 5 patients were enrolled in this study for testing EGFR mutations, after conditions for testing were created in Macedonia. We screened 5 patients for EGFR mutations by direct sequencing of axons 18 to 21, by retrospective analyzed their previous biopsy samples. Three of the patients were men and two of the patients were women. Previous smokers were two of males and one male and both female were never-smokers. All of the patients who were enrolled in the study were with histological proven adenocarcionoma. Patients started with erlotinib 150 mg, one tablet per day, after failure on previous first line platinum based chemotherapy, with or without surgery and radiotherapy. Assessment of tumor response was according RECIST criteria on the follow-up visits every 4 weeks. We analyzed tumor response from the beginning with erlotinib until tumor progression or detected severe toxicity. Assessment was performed only for those patients with EGFR mutations. Assessment of QoL was performed by patient’s subjective answers, as subjective improvement and without subjective improvements. Adverse effects were performed according to WHO criteria.

Results:
Tissue was available for all 5 cases, two (40%) of which were found to harbor an EGFR mutation, identified axon 19 deletions. The both two patients responded to therapy. Complete response was seen in female patient for 37 months. Progressive disease was reason to stop with erlotinib after 37 mounts and start with third line therapy. Partial response in male patient was assessed for 30 mounts and is still in follow up. This patient is still alive with good condition. The two patients reported subjective improvements during treatment with erlotinib. Skin rash was grade 2-3, and diarrhea was grade1-2. Both patients complained for hair loss, but without complete alopecia.

Conclusion:
Considering our clinical results, we recommend target therapy with erlotinib for patients with NSCLC and EGFR mutations as a second line treatment. Our excellent results encouraged to require prospective tissue procurement for all patients in Macedonia. This may in fact require a shift in diagnostic practice, from the current emphasis on fine-needle aspiration, which often provides insufficient material for molecular analysis, to obtaining more substantial biopsies and to provide this treatment as a first line for selected patients.

Background:
Several randomized clinical trials have shown that erlotinib and Bevacizumab combination improved the survival of patients with EGFR mutation-positive Non-small cell lung cancer（NSCLC）. The aim of this study was to evaluate the clinical activity of another angiogenesis inhibitor Endostar (rh-endostatin) in combination with continued EGFR-TKIs (including erlotinib, gefitinib and Icotinib) for advanced NSCLC patients who have developed acquired resistance to prior EGFR-TKIs treatment.

Methods:
Advanced NSCLC patients with disease progression who had partial or complete response to prior EGFR-TKIs treatment received 2-8cycles of Endostar plus EGFR-TKIs. Endostar was administered at a dose of 15mg q.d intravenously for 14 days, each at 3-week intervals; combined with continued EGFR-TKIs (erlotinib 150mg PO daily, or gefitinib 250mg PO daily or Icotinib 125mg PO t.i.d); until unacceptable toxicity or disease progression. The response was assessed using Southwest Oncology Group (SWOG) criteria after 6 weeks.

Results:
A total of 17 NSCLC evaluable patients were enrolled, including 9 women and 8 men. The presence of EGFR status were exon 21 L858R point mutation in 7 cases, exon 19 deletion in 5 cases, wild type in 2 cases and unknown in 3 cases. Median number of treatment cycles was four. It showed a 76.47% (13/17) disease control rate and had a prolonged stabilization of disease (>6 months). Median PFS was 6.9 Months. Treatment benefit and overall survival was noted both in activating EGFR mutation patients, EGFR stated unknown patients and even in wild type patients. One stage VI patient with EGFR wild type, developed resistance after 6 months 2nd line erlotinib treatment, received 8 cycles of Endstar and erlotinib combination, and had 46 months overall survival time. Endostar in combination with EGFR-TKIs were generally well tolerated. The most common adverse events were rash 35.29% (6/17), decreased appetite 29.41% (5/17), dry skin29.41% (5/17). No grade 3 or greater adverse events were seen in this study.

Conclusion:
Endostar with the addition of continuation of EGFR-TKIs has demonstrated promising clinical activity in NSCLC patients selected for acquired resistance to previous use of EGFR-TKIs. Treatment with this combination exhibited a good safety profile. Our results strengthen the evidence that angiogenesis inhibitor may be a valid option for NSCLC patients who have progressed on EGFR-TKIs. The optimal clinical combination and activity warrants further investigation.

Background:
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are now key agents in EGFR-mutant non-small-cell lung cancer (NSCLC). In gefitinib or erlotinib monotherapy, its efficacy could be predicted by development of skin rash, however, it has not been fully evaluated if this is similarly the case with afatinib monotherapy.

Methods:
We retrospectively studied consecutive 49 patients with EGFR-mutant NSCLC who received afatinib therapy between 2009 and 2015. Relationship with several toxicities and tumor response was examined.

Results:
Figure 1Figure 2The Grade 2 or worse common adverse events (AEs) included skin rash in 17 patients (35%), diarrhea in 19 (39%) and mucositis in 15 (31%). Of these, number of patients who developed ≥ Grade 2 AEs within the first week was 5 (10%; skin rash), 12 (25%; diarrhea) and 4 (8%; mucositis). As for objective response, 21 (43%) of the 49 had partial response. In association with AEs and antitumor effect, those who had Grade 2 or worse skin rash within the first week tended to have better tumor response as compared with those who did not have (80% vs. 39%; p = 0.077).





Conclusion:
Our small study demonstrated that early development of skin rash might predict the response to afatinib monotherapy.

Background:
Erlotinib is an EGFR tyrosine kinase inhibitor (TKI) which is approved as a first line treatment in patients with metastatic lung cancer with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Here we are reporting use of erlotinib in a patient with a rare double EGFR mutation

Methods:
Case history: Patient is a 52 years old Hispanic female with12 packs/year history of smoking who quit few years prior to diagnosis. She was evaluated for gradually worsening vision of one year duration and regular headaches for one month. MRI brain showed a 2 cm cystic lesion in right posterior temporal /parietal region. She underwent surgical resection which showed metastatic adenocarcinoma cells positive for CAM 5.2, CK 7, napsin and TTF-1 and negative for CK 20 consistent with lung primary. Staging PET/CT scan showed increased FDG uptake in a left upper lobe 2.5 cm perihilar mass (SUV 12.3) with several satellite lesions and hilar nodal metastasis giving her a final stage of T3N2M1. Next generation sequencing: Resected metastatic brain lesion was sent for next generation sequencing which showed presence of EGFR p.L858R and p.H870R mutations and increased EGFR copy number. Other mutations identified included Tp53 p.R175H and CDKN2Ap.H83Y. Tumor was negative for KRAS mutation. EML4-ALK and ROS1 rearrangement were also negative by FISH.

Results:
Treatment: Patient received adjuvant gamma knife to the tumor bed of resected brain lesion and in consideration of her oligometastatic disease was started on concurrent thoracic chemo-radiotherapy. She received a total of 60 Gy radiation to the chest with 2 cycles of cisplatin-etoposide. At the completion of chemo-radiotherapy re-staging CT scan chest and abdomen showed no improvement in chest disease with appearance of new metastatic lesion in liver. MRI brain done at that time also showed a new metastatic lesion in parietal calvarial bone for which she received whole brain radiation therapy. At that time she was stared on erlotinib at 150mg/day. Initially patient had poor tolerance to erlotinib with excessive vomiting. Erlotinib dose was reduced to 150mg every other day and once tolerance improved the dose was gradually increased back to 150mg/day. Re-stating CT scan at 2 months showed partial response in primary thoracic tumor as well as almost complete resolution of metastatic lesion in liver. Patient remains on erlotinib at 150mg/day and most recent re-staging CT scan chest /abdomen as well as MRI brain performed 7 months after starting erlotinib show stable disease.

Conclusion:
Previous reports have shown poor response to EGFR TKI in patients with double EGFR (L858R + p.H870R) mutation (1,2).This case report shows poor response of platinum doublet chemotherapy but good response to EGFR TKI eroltinib in a patient with double EGFR (L858R + p.870R) mutation. References: 1. Pas TD, et al. Activity of Epidermal growth factor receptor-tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring rare epidermal growth factor receptor mutations. Journal of Thoracic Oncology.2011.6(11)1895-1901 2. Tam IY,et al. Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations. Mol Cancer Ther. (2009); 8(8):2142-51

Background:
Lung cancer is the global leading cause of cancer-related deaths. A significant portion of lung cancer patients harbor kinase domain mutations in the epidermal growth factor receptor (EGFR). While EGFR tyrosine kinase inhibitors (TKI) effectively shrink tumors harboring mutant EGFR, clinical efficacy is limited by the development of TKI resistance. As such, effective alternatives are desperately needed.

Methods:
We have been treating M1a lung cancer patients through intrapleural perfusion with hyperthermic chemotherapy (IPHC) followed by cycles of systemic chemotherapy (we termed this procedure IPHC complete treatment, IPHC-CT). Tumor shrinkage was analyzed in mutant EGFR-positive patients after IPHC-CT treatment. Furthermore, patient-derived cell lines driven by mutant EGFR were treated with hyperthermic chemotherapy to study the mechanisms of effect of IPHC-CT on cancer cells.

Results:
Tumor shrinkage was detected in patients whose tumor harbored EGFR kinase domain mutation. Hyperthermia and cisplatin synergistically downregulated EGFR protein levels in tumor cells, which ultimately elicited apoptosis.

Conclusion:
IPHC-CT is effective in treating EGFR kinase domain mutation positive lung cancer patients.

Background:
Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment. response to Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment.

Methods:
A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed.

Results:
At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 mo. vs. 21 mo.; p =0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 mo. vs 13 mo.; p=0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tirosin-kinase inhibitors (TKI’s) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 mo; p=0.81).

Conclusion:
Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis in first-line treatment of EGFR mutated tumors and, more interestingly, in patients with EGFR wild-type NCSLC receiving EGFR TKIs after progression to chemotherapy. Table 1. Multivariate regression model.

Variable	HR	p
Sex	1.28	0.32
Age	1	0.9
N	1.28	0.06
EGFR	0.24	0.001
TKIs (after progression)	0.44	0.03
Liver metastases at onset	1.5	0.28
Liver metastases during disease	1.28	0.43
Bone metastases at onset	1.6	0.22
Bone metastases during disease	1.19	0.64
Skin metastases at onset	2.2	0.31
Adrenal metastases at onset	1.37	0.29

Background:
Erlotinib (E) has been approved for the management of NSCLC patients (pts) after failure of the first or subsequent line of chemotherapy. Although the efficacy of E is clearly associated with the presence of drivers EGFR mutations, there is a subset of pts with EGFR wild type (EGFR wt) tumors who impressively respond. We retrospectively analyzed the clinical and pathological characteristics of a group of pts with unresectable EGFR wt NSCLC treated for a prolonged period with salvage (≥ 2[nd] line setting) E.

Methods:
Patients with unresectable EGFRwt NSCLC who received ≥ 2[nd] line treatment with E without disease progression for at least 6 months, were sought from the database of HORG. Pts with available tumor material were molecularly (KRAS, BRAF, PI3K, HER2 mutations and ALK-EML4 translocation) characterized.

Results:
Among 1450 pts treated in different HORG’s collaborating centers (from 2004-2013), 44 (3.03%) received E for >6months (median: 10.1 mo; range, 6.0-36.5). 17 were women, 57% had no history of smoking, 42 had a PS (ECOG) of 0-1; 16% had squamous cell histology and 73% adenocarcinoma. KRAS mutations were detected in 20.5% (9/42 tested) of the pts, PI3K mutations in 9% (3/30 tested) and ALK-EML4 translocation in 9.5% (2/21 tested); there was no patient with HER2 or BRAF mutated tumor. 11(25%) pts experienced a partial response and 26 (59%) stable disease (Tumor growth control rate 84%). The median PFS and OS was 10.1 (6.0-40.6) and 24.1 (6.0- 89.1) months, respectively. Pts with KRAS wt tumors had a significantly (p=0.018) better OS compared to pts with KRAS mutant tumors. There was a trend of improved PFS (p=0.083) and OS (p=0.053) in favor of pts with adenocarcinoma compared to pts with squamous cell carcinoma.

Conclusion:
Treatment with E significantly improves the clinical outcome in a subset of NSCLC pts with EGFR wt tumors. Pts with non-squamous pathology and no smoking history seem to benefit most from such therapy. KRAS mutation was the only molecular alteration correlated with the clinical outcome. Further molecular analysis of these pts could help to more appropriately define this particular group of patients.

Background:
Multiple phase III trials have demonstrated the benefit in terms of RR and PFS of the EGFR TKIs versus platinum-based chemotherapy in patients with advanced NSCLC and EGFR mutation. Median PFS of these patients ranges from 9-13 months, time where a new therapy approach is needed, the most commonly chemotherapy nowadays. The main resistance mechanism described in this clinical situation is the development of T790M resistance mutation. There are no comparative efficacy data among chemotherapy and T790M targeted therapies. Our research included data from 15 patients treated in our Institution Phase I Unit with a T790M inhibitor analyzing the effectiveness according to their clinical features and mutational profile (T790M carriers or not)

Methods:
Descriptive clinico-pathological and efficacy analysis from October 2013 to March 2015 of patients with advanced NSCLC and EGFR mutation in progression and receiving T790M targeted therapy in the context of a phase I clinical trial performed in our Clinica Trial Unit.

Results:
Fifteen patients were included. The median age resulted 60 years (range 37-80 years) with a proportion of 8 (55%)/7 (45%) female/men. The entire study population was Caucasian and had an histological diagnosis of stage IV NSCLC with the presence of activating mutation of EGFR (66% L848R and del19 44%). In relation to smoking exposition, most of the patients were past-smokers (55%) or active (13%). All patients received a specific T790M inhibitor, 7 of them (45%) with a confirmed T790M mutation by local and/or local analysis. The average of prior lines of therapy before the experimental T790M inhibitor was 1,9. No grade 3/4 toxicities were reported. After an average follow up of 17 months, PFS of the overall population was 4,73 months, with a statistically significance difference between T790M positive patients (8,14 months) versus negative or unknown (1,8 months). We have no outcome at present of the OS for the active treatment of most the patients.

Conclusion:
Despite the limitation of the number of patients and follow-up time, our research suggested a clear survival benefit with the T790M inhibitor in the context of advanced NSCLC patients harboring T790M resistance mutation versus non in progression after EGFR TKI first line therapy.

Background:
Elderly patients (pts) with lung cancer pose significant challenges in cancer treatment because of concurrent comorbidities and age. We examined treatment patterns and outcomes in elderly pts with advanced lung cancer prior to and after introduction of epidermal growth factor receptor (EGFR) inhibitors into clinical use.

Methods:
Clinical data for pts > 65 yrs derived from two databases, cohort 1(1998-2003) and cohort 2(2004-current), were used. Demographics, clinical characteristics and treatment outcomes were compared between these 2 cohorts with stage III/IV lung cancer. Chi-square and Mann-Whitney-U tests were used to compare differences between cohorts. Overall survival (OS) from the time from diagnosis to death from any cause was estimated using Kaplan-Meier method and differences were defined using the logrank test. Pairwise comparisons were analyzed with Sidak’s adjustment applied to account for multiple testing. The Cox proportional hazards model was used to model the association between survival end-points and patient cohort, with the resulting hazard ratios assessed using the Wald test. The proportional hazards assumption was verified by fitting an alternative model with inclusion of a covariate-by-time interaction term and inspection of the p-value of the interaction term for categorical variables. A 2-sided p-value of <.05 was considered statistically significant.

Results:
There were 397 pts (cohort 1) and 1584 pts (cohort 2) with complete data for analysis. The median age of diagnosis was not significantly different between the cohorts (72.5 yrs vs 72.8 yrs), p: 0.252. Median follow-up times were comparable. Cohort 1 had poorer ECOG at diagnosis, more males and a higher proportion of current smokers. For cohort 1, cytotoxic chemotherapy was standard of care and EGFR TKI use was minimal. In contrast, for cohort 2, 50% of pts received EGFR TKI monotherapy in 1[st] line, 30% of pts in 2[nd ]line and 33.3% of pts in 3[rd] line and beyond. There was a significant difference in OS between the both cohorts (p <.001), HR 0.75 in favor of cohort 2. Specifically women, good ECOG, never smoker status, and adenocarcinoma were associated with significantly reduced hazard of death.

Conclusion:
Routine EGFR TKI use in elderly > 65 yrs of age clinical setting has improved OS over the last decade. This benefit is reflected in the reduced hazards of death for specific patient subsets. Elderly pts where targeted therapies are indicated should not be deprived of therapy.

Background:
Lung tumors with EGFR Exon 20 mutations, particularly insertions between the amino acids Y764 and V774, present a major challenge for treatment. These mutations are known to confer resistance to current EGFR specific tyrosine kinase inhibitors (TKI). The mechanism of this resistance is described by Yasuda et al. as a “wedge” formed by the aberrant amino acids locking the C-helix in an inward, active position. This structural aberration prevents the TKI from accessing the critical pocket within the protein and inhibiting kinase activity. Without the ability to treat these tumors with TKIs, alternate treatments need to be pursued.

Methods:
We present, as index cases, two patients with metastatic lung adenocarcinomas demonstrating TKI unresponsive insertions in exon 20. Both patients had exuberant clinical and radiographic responses to cetuximab, an EGFR specific monoclonal antibody.

Results:
The first patient is a 39 year old male never-smoker with lung adenocarcinoma. The disease had progressed prior to molecular identification of the EGFR mutation, and the patient developed bilateral lung disease and metastatic lymph node and brain lesions. An exon 20 EGFR mutation (p.N771_P772insPHGH c.2313_2314insCCCCACGGGCAC) was identified. Following 4th line therapy with combination chemiotherapy plus cetuximab, the tumor burden was dramatically decreased and the patient had markedly improved functional status with the ability to return to employment. The second patient is a 71 year old male never-smoker with lung adenocarcinoma. The disease progressed and the patient developed widely metastatic disease. An exon 20 EGFR mutation (P770_N771insNPP) was identified. The patient was treated with combination cetuximab and afatinib therapy and experienced a dramatic decrease in lung and metastatic tumor burden with improved functional status.

Conclusion:
Cetuximab-containing therapeutic regimens may be a viable therapy for what previously have been considered treatment resistant molecular insults. Additional cases of these mutations and treatment with cetuximab are needed to demonstrate that these results are reproducible and that they warrant study in prospective clinical trials.

Background:
Crizotinib is an oral small-molecule tyrosine kinase inhibitor, which was approved in the United States (US) in August of 2011 for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). In clinical studies, crizotinib has demonstrated robust response rates and significantly greater efficacy than chemotherapy. However, there is currently limited data on crizotinib treatment and related outcomes in real-world practice settings. The main objective of the current study was to assess the treatment patterns and outcomes of ALK-positive advanced NSCLC patients treated with crizotinib in regular clinical practice.

Methods:
Physicians in the US (N= 107) and Canada (N= 40) were recruited from cancer centers/teaching hospitals (48%) or free standing oncology clinics (47%), to abstract data retrospectively from medical records of adult (≥18 years) patients diagnosed with ALK-positive advanced NSCLC and treated with crizotinib as first or later line therapy between August 1, 2011, and March 31, 2013 (for the US) or April 1, 2012 and March 31, 2013 (for Canada) in non-clinical trial settings. IRB approval was obtained. A secure web-based form was used by physicians to abstract data and all patient data were de-identified and anonymous. Descriptive analyses were conducted to assess treatment patterns and objective response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were descriptively analyzed using the Kaplan-Meier method.

Results:
Data were extracted from 212 patient records in US (N=147) and Canada (N=65). The mean (SD) patient age was 58.9 (9.5) years and a majority were male (69%), Caucasian (79%), current or former smokers (67%), ECOG status 0 or 1 (75%), adenocarcinoma histology (90%) and initially diagnosed at the metastatic stage (71%). Cough, fatigue, and dyspnea were the most common symptoms present (71%, 65%, and 55%, respectively) at the time of metastatic NSCLC diagnosis. Approximately 65% (n=137) of patients initiated crizotinib as first-line therapy and the mean ± SD duration of crizotinib treatment was 8.7 ± 4.9 months. Approximately 37% of the patients were deceased at time of medical record abstraction. Disease progression following initial response was the most frequently reported (59%) reason for treatment discontinuation and 35% received additional systemic chemotherapy post-crizotinib. Approximately 90% of patients had no changes (reduction or escalation) in crizotinib dose. Among patients experiencing progression during crizotinib treatment, the most common sites of progressive metastases were liver (35%), bone (30%), and contralateral lung (28%). The crizotinib ORR was estimated to be 66% for the overall cohort (69% first line and 60% for later line). The median (95% CI) PFS from crizotinib initiation was 9.5 (8.7, 10.1) months in the overall cohort. Median (95% CI) OS from crizotinib initiation was 23.4 (19.5, ‒) months for the overall cohort. Based on Kaplan-Meier estimation, 1- and 2-year survival rates from crizotinib initiation were 82% and 49%, respectively.

Conclusion:
Response rates in patients treated with crizotinib in real world settings seem to align with data reported previously from clinical studies. Median OS in patients treated with crizotinib in the real world settings examined here was approximately 2 years from crizotinib treatment initiation.

Background:
Crizotinib is a highly selective drug used in the treatment of anaplastic lymphoma kinase (ALK) gene re-arrangement positive non-small cell lung cancer (NSCLC). In the Czech Republic it was used in frame of compassionate cases program and now is reimbursed in pretreated tumors with EML 4/ALK gen translocation verified by FISH and/or IHC testing. The recommended dose is 250 mg bid/ day. Crizotinib is used since 2011, data are evaluated according to the National Reference Centre Registry.

Methods:
Present study evaluates 26 patients (pts), 14 males,12 females with mean age 60 (31- 75) years. Out of them 11 (42.3%) were non-smokers, 8 (30.8%) ex-smokers and 7 (26.9 %) smokers. All of them had NSCLC with EML4/ALK gene translocation, 23 had adenocarcinoma, two NOS and one patient had adenosquamous cancer. Stage in the time of treatment was IIIB in 3 and IV in 23 pts. Crizotinib was applied in 2[nd] ĺine in 17 pts, 3[rd] line in 5 pts, 4[th] line in 3 pts, 5[th] in one patient. PS was 0 in 3 pts, 1 in 20 pts and 2 in 3 pts.

Results:
On the date of evaluation, 14 pts continued the treatment, 6 died and 6 stopped treatment due to progression. Crizotinib effectiveness was assessed in 15 pts: CR in 3 (20%) pts, PR in 3 (20%) pts, SD in 5 (33.3 %) pts, DP in 4 (26.7 %) pts. CR was associated with long response duration (10.7, 31.8, 34.1 months). Grade 3 adverse events (gastrointenstinal discomfort and liver disease) were observed in two (7.7 %) pts, grade 2 problems with visus appeared in two patients. Dose of crizotinib was reduced in 3 pts. Median of progression free survival was 15 months, median of overall survival was not reached.

Conclusion:
Interim analysis of present series shows, that crizotinib has very good tolerability and promising effectiveness even in heavily pretreated patients with EML4/ALK gene translocation. Long term survival analysis is running. Supported by national grant IGA MZ ČR NT/13569

Background:
Among patients with ALK+ NSCLC who develop metastases, common metastatic sites include brain, bones, and liver. Although the symptomatic profile of ALK+ NSCLC patients with brain metastases is well documented, information remains limited for patients with bone metastases or liver metastases.

Methods:
Data from 2 large US administrative claims databases—IMS LifeLink Health Plan Claims (01/2001 – 03/2014) and Truven Health Analytics MarketScan (01/2002 – 09/2012)—were pooled for this retrospective study. Among adult patients with a lung cancer diagnosis, ALK+ NSCLC patients were identified based on prescription fills for crizotinib. Patients were analyzed if they had ≥60 days of follow-up before and ≥30 days after the bone metastasis or liver metastasis diagnosis date.

Results:
A total of 231 ALK+ NSCLC patients were selected: 191 had bone metastasis and 104 had liver metastasis. For the bone metastasis sample, median age was 54.9 years, 39.3% were male, and median time from first lung cancer diagnosis to the bone metastasis diagnosis was 30 days. The frequency of symptoms frequently associated with bone metastasis increased after bone metastasis diagnosis compared to before. Common skeletal-related events included pathologic fractures (before: 0.5% vs. after: 12.6%), spinal cord compression (2.6% vs. 5.2%), and bone radiation therapy (12.6% vs. 62.3%).Other common symptoms were weakness/fatigue (before: 24.6% vs. after: 46.6%), anemia (10.5% vs. 33.0%), back pain (8.4% vs. 22.5%), bowel dysfunction (6.8% vs. 20.9%), and neoplasm-related pain (0.0% vs. 14.1%). For the liver metastasis sample, median age was 54.0 years, 42.3% were male, and median time from first lung cancer diagnosis to first liver metastasis diagnosis was 151 days. The frequency of symptoms frequently associated with liver metastasis also increased compared to before liver metastasis diagnosis, where most common symptoms were nausea/vomiting (before: 21.2% vs. after: 42.3%), abdominal pain (20.2% vs. 34.6%), fever/sweating (6.7% vs. 27.9%), edema (6.7% vs. 25.0%), jaundice (0.0% vs. 3.8%), and fatigue (29.8% vs. 46.2%).

Conclusion:
ALK+ NSCLC patients experience an increased symptomatic burden after developing bone metastasis or liver metastasis. Further research is warranted to analyze the impact of the symptomatic burden on patient quality of life and other outcomes as well as the potential benefit of instituting second-generation ALK-inhibitors earlier in the treatment course.

Background:
Anaplastic lymphoma kinase (ALK) is a new tyrosine kinase target that has been validated recently in NSCLC. Crizotinib, an oral, small-molecule, tyrosine kinase inhibitor that targets ALK, MET and ROS-1, has been reported to be particularly effective and to have acceptable toxicity in advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). In a phase 1, open-label, multicenter trial evaluating the efficacy and adverse event profile of crizotinib in a cohort of 82 ALK-positive lung cancer patients, treatment for a mean duration of 6.4 months achieved an overall response rate (ORR) of 57%, and the estimated probability of 6-months’ progression-free survival (PFS) was 72%. Mild gastrointestinal disturbances were the main adverse effects observed in this study. Subsequently, updated data from a study involving 143 patients confirmed the durable response and tolerable adverse effect profile of crizotinib in patients with ALK-positive NSCLC.

Methods:
A total of 72 patients with ALK-positive NSCLC who received crizotinib between June 1, 2013 and October 15, 2014 at Shanghai Chest Hospital, Shanghai JiaoTong University, were prospectively enrolled in the study. All were histologically diagnosed and staged as clinically advanced (stage IV, or stage IIIB with pleural effusion) NSCLC. All patients received oral crizotinib 250 mg twice daily in 28-day cycles. The tumor response was assessed after the first cycle of crizotinib therapy and subsequently after every 2 cycles using the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Tolerability was assessed at least twice per cycle until crizotinib was discontinued.

Results:
The patients tended to be young (mean age 55 years, range 31-83 years), never or light smokers (smoking index <400), and to have an adenocarcinoma histology. Most (49/72; 68.1%) had received previous anticancer treatment before crizotinib therapy. Sixty-seven patients (93%) were able to be assessed for efficacy. The objective response rate (ORR) and disease control rate (DCR) were 52.2% (95% CI 40.5%-63.9%) and 64.2% (95% CI 52.75%-75.7%), respectively. The estimated median progression-free survival (PFS) for all 67 patients was 10.3 months (95% CI 8.6-12.0 months). Mild visual disturbances, nausea, vomiting, diarrhea and constipation were the most commonly reported adverse effects.Figure 1



Conclusion:
crizotinib was well tolerated and showed promising efficacy in Chinese patients with ALK-positive, advanced NSCLC. Further prospective, multicenter studies with a larger sample size are needed to confirm these findings.

Background:
Reportedly, the radiologic features of most primary resectable lung cancers harboring an anaplastic lymphoma kinase (ALK)-fusion do not exhibit a ground-glass opacity (GGO) component when viewed using CT. However, little is known about the features of advanced ALK-rearranged lung cancer.

Methods:
The radiologic features of 21 advanced ALK-positive lung cancers treated at the National Cancer Center Hospital East between January 2012 and June 2014 were retrospectively investigated. ALK-fusion was confirmed using IHC and FISH or RT-PCR methods. The primary tumor’s diameter and characteristics (i.e., presence of a GGO component, notch, spiculation, and pleural indentation) as viewed using CT and the SUVmax observed using PET before treatment were evaluated. The radiologic features of 181 EGFR/ALK-negative non-sq NSCLCs treated during the same period were also evaluated as a control group. In addition, sites of distant metastases were evaluated.

Results:
The median age of patients with ALK-positive lung cancer was 58 years (range, 25-83 years). Of the 21 patients, 8 (39%) were female and 11 (52%) were never-smokers. The proportion of primary tumors smaller than 3 cm was significantly higher among the ALK-positive tumors than among the EGFR/ALK-negative tumors (48% vs. 21%, P = 0.01). Notches (71% vs. 41%, P = 0.01) and pleural indentations (81% vs. 55%, P = 0.03) were significantly more common among the ALK-positive tumors than among the EGFR/ALK-negative tumors. No significant differences in peripheral GGO (4.8% vs. 6.1%, P = 1.00) and spiculation (71.4% vs. 54.7%, P = 0.17) were observed. The median SUVmax values of the primary tumors were not significantly different (9.33 [range 4.56-28.81] vs. 10.54 [range 1.20-38.18], P = 0.91). Regarding the sites of distant metastases, liver (33% vs. 8%, P < 0.03) and pleural dissemination (48% vs. 24%, P = 0.03) were more frequent among patients with ALK-positive tumors than among patients with EGFR/ALK-negative tumors.

Conclusion:
We identified the radiologic features of advanced ALK-positive lung cancer, which include smaller-sized primary tumors and higher frequencies of notch and pleural indentation, compared with EGFR/ALK-negative tumors. These findings might be useful for the selection of patients with advanced ALK-positive lung cancer.

Background:
This study aimed to determine the relationship between ALK status and predominant subtype, according to the IALSC/ATS/ERS classification.

Methods:
A reclassification of 638 surgically resected adenocarcinomas was performed in Shanghai Chest Hospital. ALK Status was detected by immunohistochemistry (Ventana Medical Systems) in these patients.All of the cases were confirmed by two independent pathologists.

Results:
The most prevalent subtype was acinar predominant (46.0%), followed by papillary predominant (25.2%), solid predominant (9.2%), micropapillary predominant (8.7%), variants of invasive adenocarcinoma (5.5%), lepidic predominant(5.3%), minimally invasive adenocarcinoma(2.0%), and adenocarcinoma in situ(1.0%). ALK positive was identified in 29 of 638 tumors (4.5%). The ALK positive frequencies were: 3.0%(8/284) for acinar predominant, 1.9%(3/156) for papillary predominant, 12.3%(7/57) for solid predominant, 5.3%(3/54) for micropapillary predominant, 17.6%(6/34) for variants of invasive adenocarcinoma, 3.0%(1/33) for lepidic predominant, 7.7%(1/13) for minimally invasive adenocarcinoma, and 0%(0/7) for adenocarcinoma in situ, respectively. ALK positive was significantly associated with the solid predominant subtype(p=0.003) and variants of invasive adenocarcinoma(p=0.0002).

Conclusion:
The ALK positive frequencies of solid predominant subtype and variants of invasive adenocarcinoma were higher than other subtypes.

Background:
Severala rates for patients with adenocarcinoma of the lung who cannot be treated with targeted therapies due to lack of EGFR gene mutation or EML4-ALK translocation are relatively poor. Clinical trials with a new compounds pose a chance to improve treatment outcome, but also expose patients to many additional and potentially risky-related diagnostic procedures

Methods:
Case study analysis of 57 - years old male patient diagnosed in 2008 with metastatic adenocarcinoma of lung cT2N0M1. Patient was in good condition without any significant comorbidities.Patient has been qualified to A6181058 clinical trial- he received 6 cycles of Paclitaxel and Carboplatin chemotherapy with subsequent maintenance therapyconsisting of 72 Bevacizumab infusions.Partial remission has been achived with reduction of tumor size by 60%. Subsequently, due to disease progression, patient have been enrolled into another clinical trial - EC-FV-07 - 9 cycles of Docetaxel and 26 injections of folate receptor inhibitor EC145 has been applied. After 71 months since treatment initiationdisease has progressed.Upon disease progression paliative radiotherapy has been started. During treatment period, because of clinical trial scheduling requirements, contrast-enhanced computed tomography ( CE-CT)scans were performed every 6 to 8 weeks. During whole disease course neither lung cancer itselfnor applied treatment did not impaire patient's daily activity. Aim of this report is to analyse a disease course and risks of repeated contrast enhanced computed tomography in patient treated with potentially nepfotoxic drug with long lasting maintenace treatment.

Results:
During seven years of treatment contrast-enhanced chest CT scans has been performed 57 times. Effective radiation dose patient has received was 395mSv and 4560 mg of iodine-based contrast was injected.Cumulative doses of chemotherapeutic agents was as folows- Bevacizumab -87480 mg; EC145(Vintafolide) - 90 mg, Carboplatin 3700 mg, Paclitaxel -2508 mg, Docetaxel -1710 mg. Baseline renal function described by glomerular filtration rate (GFR) was 78 ml/min and during treatment GFR never dropped below ml/min. Patient developped sensory peripheral neuropathy, CTC grade 2.Use of ACE inhibitor therapy due to arterial hypertension has been initiated.No other clinically significant toxicity has been observed, including myelotoxicity and renal toxicity other than non-significant transient proteinuria.

Conclusion:
By presenting this case report we would like to bring attention to long -term survival in patient with metastatic NSCLC treated with two lines of chemotherapy that included taxane and targeted molecular therapy. Despite potentially nephrotoxic regimens and rigorous iodine- based CT disease monitoring scans no significant toxicity has been observed. A matter of discussion is a significance of ACE inhibitor for renal protection in contrast-and chemotherapy -induced toxicity.

Background:
In China, lung cancer is increasing rapidly, of which 80% are non-small cell lung cancer, and most belong to Stage IIIB and IV when diagnosed, losing opportunity of surgery, and the prognosis is worse, the average survival time is about 6-12 months. Recently we perform radical resection for part N3-Stage IIIB non-small cell lung cancer, hope to improve the prognosis of these patients. A typical case is discussed here.

Methods:
Case1: Man, aged 43 in Dec 2012, found right supraclavicular lymph node swollen, CT showed right lower lobe tumor 7X6X5cm3, invading right inferior pulmonary vein and pericardium, regional and mediastinal lymph node 11,10,7,4R,3,2R,1R swollen badly; right supraclavicular lymph node biopsy revealed the diagnosis of lung adenocarcinoma; no other distant metastasis was found in brain, liver, and bone; cT3-4N3M0 Stage IIIB, which is usually contraindication of surgery. Three cycles’ preoperative chemotherapy of Pemetrexed and cisplatin (DDP) was conducted, the lung tumor shrunk 1/3, mediastinal lymph node shrunk significantly, and the right supraclavicular lymph node disappeared. PET-CT showed right lower lobe tumor and part mediastinal lymph node positive, however, showed negative in the neck and other part of the body; cT2aN1-2M0 Stage IIA-IIIA, prepared for operation.

Results:
Standard “large-incision” right posterolateral thoracotomy was performed, pleural adhesion, tissue edema, fragile, easily broken, easy bleeding were encountered. Right lower lobe lobectomy, systematic lymph node dissection including No.2R,3A,3P,4R,7,9,10,11,12 group lymph node and surrounding adipose tissue were en block dissected. Tumor size 4X4X3cm3, postoperative pathology diagnosed as lung adenocarcinoma, No.12 lymph node metastasis, others were negative, pT2aN1M0 Stage IIA. Two cycles’ postoperative chemotherapy was followed. Regular follow-up showed the patient recovered very well. Now he is in his 3rd year postoperatively, living a healthy man’s life. CT, Ultrasound, ECT, and blood tumor markers’ test showed no sign of recurrence and metastasis.

Conclusion:
Part supraclavicular lymph node metastasis N3-Stage IIIB non-small cell lung cancer, if prepared carefully, could gain the opportunity of receiving surgical resection, could achieve a much more better prognosis, even to get cured as usual Stage IA-IIIA lung cancer patients who receive regular radical resection of lung cancer.

Background:
Studies have shown the relationship between cancers and bone diseases. Observations have also shown that the spine, rib and pelvis are more susceptible to cancer for riches in marrow that fosters tumor growth. We particularly examined the relationship with spinal fractures and cancer

Methods:
The medical records of more than 100 lung cancer survivors were assessed from six Teaching Hospitals in Eastern (Ethiopia and Tanzania) and Southern African countries from 2003-2013. We checked for osteolytic lesions and osteoblastic lesion as the patients have undergone several kinds of screening during and after cancer treatment including DXA (Dual-energy X-ray Absorptiometry), plain X-ray or magnetic resonance imaging (MRI) to screen for metastatic bone disease

Results:
We found that an estimated 30-40% of the lung cancer patients developed bone metastases and disrupted the balance between bone breakdown and repair which caused reduction of bone in some areas and increased density in others. As a result, the bone was weakened and became more prone to spinal fracture after treatment

Conclusion:
As lung cancer has spread thereby causing spinal fractures, treatment needs to be focused on disease control with chemotherapy. The treatment of bone metastases will be primarily dependent on an effective treatment against lung cancer itself

Background:
Serum tumor markers CYFRA 21-1, CEA, and squamous cell carcinoma antigen (SCCA) are useful in non-small cell lung cancer (NSCLC) diagnosis and prognosis. Cytologic tumor markers obtained during needle aspiration biopsy (NAB) of lung lesions help in NSCLC diagnosis. This study investigated the incremental prognostic value of cytologic tumor markers compared to serum tumor markers.

Methods:
This prospective study included 253 patients diagnosed with NSCLC by NAB with cytologic tumor marker analysis. Cytologic CYFRA 21-1, CEA, SCCA and serum counterparts were followed up for survival analysis. Optimal cut-off values for each tumor marker were obtained for overall survival (OS) and progression free survival (PFS) analysis.

Results:
All patients were followed up for median 22.8 months. Using cut-off value of 0.44ng/ml for C-SCCA, 2.0ng/ml for S-SCCA, and 3.3ng/ml for S-CYFRA, multivariate analysis revealed that high S-CYFRA (Hazard ratio (HR): 1.573), high S-SCCA (HR: 1.999), and high C-SCCA (HR: 1.744) were independent predictive factors for OS. The 3 year overall survival was 55% vs 80% for high and low C-SCCA.

Conclusion:
Cytologic tumor markers are poor prognostic factor in NSCLC patients as serum tumor markers, with C-SCCA showing a strong prognostic factor for overall survival.

Background:
During 1998 and 2013 at the “Colombian Coffee Zone” (conformed by three states Caldas, Quindio, and Risaralda) had an increase of 105 mortality cases of Bronchi and lung malignant tumors, as reported in death certificates.

Methods:
This is an observational, descriptive study, that was made in patients at Clínica Oncologos del Occidente in the year 2014. Information was taken from the Clinical History Administration System (SAHICO). Thereafter, pending data was collected, by phone calls to patients or patient’s family, according to every case. Patients were interviewed to know their actual performance status and, in case of death, date and basic cause of death was asked

Results:
SAHICO reported 178 patients with lung cancer. From these patients, 33 did not have a correct diagnosis. Basically, they did not have a histology report. This happens in patients that consulted with a clinical presentation compatible with a pulmonary origin neoplasia and radiologist reports concluding thorax tumors, which had a lung dependency. But patients had a very low performance status, because they did not assist to the second appointment or never started treatment; finally they died by the disease. The prevalence of these tumors was slightly more common in men. 50% of the patients were between 60.7 and 74 years old. The median age was 69.1 years for males and 64.1 for women. This age median differences were statistically significant (F=9,121 p value=0,003). Also, 90.8% of the patients were from urban areas. 85.3% of tumors treated during 2014 corresponded to NSCLC, meanwhile 10% were Small Cell lung cancer. It was also observed a relationship of 1.7 patients with Squamous cellular carcinoma for every patient with Adenocarcinoma. 28 patients were tested for the EGFR mutation analysis, from these, 5 were mutated. Squamous cellular carcinoma patients were older than Adenocarcinoma patients. Besides this, patients with Small cell had a Media and Median age higher than the squamous cellular carcinoma. Although, Squamous cellular tumor patients were more frequent, the median survival time was inferior to adenocarcinoma patients and the Non-Small cell lung cancer. And neuroendocrine tumor patients had also a longer survival than Squamous cellular patients.

Conclusion:
Pathological characteristics of Lung cancer patients in Colombian Coffee Zone are in general similar than the other latitudes, predominating the squamous cellular carcinoma and with an incidence around 10% of the small cell carcinoma; it is striking the sex relationship close than 1:1, presumably for the early incorporation of the female population to smoking habit and to others known risk factors like the expose to combustion biomass smoke. The epidermic growth factor receptor (EGFR) mutation was observed in same proportion than in other studies.

Background:
The Dutch Radiotherapy Lung Audit (DLRA) is an outcome registration that provides the local health professionals with an instrument to compare and improve their lung cancer treatments. It ensures transparency regarding clinical outcome, quality and safety of lung cancer treatments in the radiotherapy departments throughout the Netherlands. Patients receiving thoracic radiation treatment with curative intent for (primary or recurrent) stage I-IIIB Non-Small Cell Lung Cancer (NSCLC) were included in the registry. The results of the DLRA on the first fully registered year, 2014, are reported.

Methods:
Information collected included patient, tumor and treatment characteristics, the incidence and severity of acute toxicity, mortality within three months after radical radiation treatment and the time interval between diagnostic work-up and start of the radiotherapy. The adherence to the waiting time (time between referral and start of the irradiation) and throughput time (time between planning CT scan and start of the irradiation) guidelines were registered and analyzed, as well as the use of modern treatment techniques such as stereotactic irradiation and image-guided radiotherapy.

Results:
14 out of 21 radiotherapy institutes included patients in the DLRA database. A total of 1350 patients were entered from January-December 2014. Patients were treated with concurrent (32%) or sequential chemoradiation(20%), radiotherapy only (13%) or stereotactic ablative body radiotherapy (SABR [35%]). On a patient record level, there was a high level of completeness. The mean age was 69 years (range 32-91, 59% males). Charlson comorbidity index ≥ 2 was present in 42% of patients. Most patients (45%) were cN+ with 20% cT4 tumors. Fifty eight percent of all patients started irradiation within 21 days after referral (range 0-89%). For 68% of the patients SABR started within 10 days after the planning-CT scan was acquired (range 17-100%) (fig 1). There was no correlation between the number of patients treated and the throughput times. Most patients received IMRT or VMAT irradiation. All registered patients had position verification during irradiation, mostly 3D (94%). Three-month (calculated from the end of RT) acute esophagus toxicity (grade≥ III) and pneumonitis (grade≥ II) of concurrent treatment were 12.4% and 3.9%, 6.1% and 4.1% for sequential chemoradiation, 3.3% and 4.3% for radiotherapy only, and 0.4% and 2.3% for SABR, respectively. Three-month mortality rates were 8.2%, 8.5%, 9.6%, and 1.7%, respectively. Figure 1



Conclusion:
The Dutch Radiotherapy Lung Audit on outcomes after (chemo)radiotherapy is directed towards an improvement of care for lung cancer patients. There's room for improvement in the waiting and throughput times.

Background:
One third of patients with non-small cell lung cancer present with unresectable stage III disease. The median survival for all stage III(A and B) tumours with optimal chemoradiation in published series ranges 17-24 months. Using platinum doublet neoadjuvant chemotherapy as primary treatment the expected response rate is modest at 30-40%. In patients presenting with bulky T4 tumours with direct extension to diaphragm and beyond into liver, the expected outlook would be extremely poor. We report here a series of four such cases over a five year period in our practice which challenge our understanding of this disease

Methods:
Our regional lung cancer network presents all new patients at multidisciplinary tumour meetings to agree staging and management plan. We record data on all new patients registered with demographic data, performance status, results of staging and pathology investigations, treatment proposed, treatment delivered and outcomes in terms of progression free and overall survival.

Results:
Between January 2009 and end 2013 we recorded four cases of bulky right lower lobe lung cancers which showed radiological evidence of invasion into diaphragm (1 case) or beyond to liver (3 cases). There were 2 men and 2 women with ages 34, 51, 52 and 68. Three had squamous carcinoma and in one tumour was poorly differentiated, no subtype. Two were staged radiologically T4N2 and two were T4N0 but both with gross visible extension into liver. All patients were fit and received induction chemotherapy (2 carboplatin/paclitaxel and 2 cisplatin/vinorelbine). All had extraordinary responses to chemotherapy and proceeded to microscopically complete surgical resection. One patient had no viable tumour at operation including within the necessary liver resection. Another had only necrosis in the liver but small area viable residual tumour at right hilum and proceeded to post-op radiotherapy. All are alive with no evidence of recurrence with follow-up ranging 22, 34, 64 and 71 months

Conclusion:
This series although small is remarkable for the exquisite chemosensitivity of locally very advanced squamous cancers which have been apparently cured by neoadjuvant chemotherapy and surgical resection. We are undertaking additional pathological analysis of these specimens to determine whether there is a linking characteristic.

Background:
Trimodality therapy is one of therapeutic options for local advanced lung cancer. While a posterolateral thoracotomy was used as the standard approach, a median sternotomy　with or without transverse thoracotomy is applied if necessary. In our institution, we have applied median approach for patients who need dissection of contralateral mediastinal lymph nodes or clamp of great vessels, mainly pulmonary artery, for a safe resection. The purpose of this study was to evaluate the feasibility and clinical outcome of median sternotomy approach for locally advanced lung cancer after chemoradiotherapy.

Methods:
Between March 2002 and December 2014, 35 non-small-cell lung cancer patients underwent radical surgery with median sternotomy approach after induction chemoradiotherapy . The medical records were reviewed to investigate clinical outcomes including perioperative complications.

Results:
The median patient age was 59 years (range: 41–77 years). There were 28 men and 7 women in the series. The histological subtype was adenocarcinoma in 21 patients, squamous cell carcinoma in 14. 16 patients had stage IIIA disease, and 19 had stage IIIB disease. The median postoperative hospital stay was 23 days. As notable perioperative complications, 12 patients revealed tachycardia that needs medication, 6 pneumonia, 3 radiation-induced pneumonitis, one wound ablation, one bronchial stump fistula, and one chylothorax. All of them were manageable. There was no treatment-related death in this cohort. As patients’ survival, the 3-year and 5-year overall survival rates were 77.7 % and 67.1 %, respectively. The 1-year and 3-year recurrence-free survival rates were 75.4 % and 63.4 %, respectively.

Conclusion:
Our experience indicates that median sternotomy approach for locally advanced lung cancer after ChRT is feasible procedure after chemoradiotherapy.

Background:
Afatinib, an irreversible ErbB family blocker, has shown superiority to chemotherapy in patients with epidermal growth factor receptor gene (EGFR) mutated non-small cell lung cancer. However, there has been no report about the preoperative Afatinib treatment. We report a case of surgical resection for lung adenocarcinoma after Afatinib treatment.

Methods:
A 33-year-old female with a chronic cough was referred to our hospital because of an abnormality on a chest radiograph. Computed Tomography (CT) displayed consolidation in left lower lobe. On bronchoscopic examination, her disease was diagnosed as adenocarcinoma of the lung, harboring EGFR mutation (exson19 deletions). Contrast-enhanced brain magnetic resonance imaging showed 4 brain metastases. Positron emission topography (PET) revealed abnormal accumulation in left lower lobe, lymph nodes (station 1, 4R, 5) and plevis. Her clinical staging was IV (T4N3M1b). Stereotactic radiotherapy for brain metastases (total 35Gy:7Gy/fraction) was done, and Afatinib was administered for 6 months.

Results:
These treatments resulted in a down-stage (T1aN0M1b) ; CT showed that the consolidation shrank and a single nodule (20mm) remained in S8 of left lower lobe. 3 of the brain metastases lost and the rest one diminished. PET revealed slight FDG uptake only in the nodule in S8 but not regional lymph node or in a distant site. We performed surgical resection for the nodule. Pathological examination revealed no cancer rest. The postoperative course was uneventful. She has been continuing Afatinib for 3 months without any recurrence after the surgery.

Conclusion:
We report the first case, to our knowledge, of a patient who obtained significant response to Afatinib and was proved no cancer rest by surgical resection. Although more observation period for this patient and prospective study are needed, this report provides insight into the efficacy of surgical resection after Afatinib treatment.

Background:
Metastatic spread of cancer to distant organs is the reason for most cancer deaths.Lung cancer frequently metastasize to bone, brain, lung, andliver, causing a shorter survival. Therefore, increased knowledgeof metastatic patterns is crucial in the treatment of patients. In this article, we evaluate the prognostic significance of postoperative metastasis organ in NSCLC.

Methods:
The relationship between postoperative metastasis and survival was investigated. Patients who underwent curative lobectomy and pathologically diagnosed with NSCLC between 2005.1 and 2011.12 were included in our study. SPSS 20.0 software was used for analysis. Survival rates were calculated using Kaplan-Meier survival plots and analyzed using the Cox regression. The variables with statistical significance in univariate analysis were included in multivariate analysis. Significant difference between groups could be found if p value was less than 0.05.

Results:
Finally 94 patients including 53 male and 41 female were enrolled in our study. The average age was 62 years old. Metastasis occurred during early stage (less than 2 years postoperatively) in 45 patients, and during late stage (more than 2 years postoperatively) in 49 patients. Single organ metastasis and multiple organ metastasis were found in 85 and 9 patients separately. the most popular metastatic site was pulmonary, and then bone and brain. The overall survival (OS) of all included patients was 41.5%. The median survival time was 43 months and 29 months for single metastasis and multiple metastasis groups separately. There was significant difference in the OS between GS and GM group (45.9% Vs 0, P＜0.001). The median survival time was 50 months and 32 months for early metastatic patients and late metastatic patients separately. Significant difference could be in the OS between GS and GM group (53.3% Vs 30.6%, COX P=0.130, Breslow P=0.014). Cox regression showed age TNM stage (P=0.003), and single organ metastasis (P＜0.001) were significant prognostic factors for NSCLC.

Conclusion:
Lung, bone, and brain were the most popular metastatic organ for postoperative NSCLC. The presence of multiple organ metastases could be identified as an independent poor prognostic factor in NSCLC.

Background:
Non-small cell lung cancer (NSCLC) is the commonest cause of cancer death globally, with a 5-year survival of 16%. Known prognostic factors include stage, performance status (PS) and gender, but does the choice of physician affect patient outcome? We assessed practice variations of four medical oncologists treating advanced NSCLC, investigating this impact on overall survival (OS).

Methods:
Following ethics approval, a retrospective analysis was undertaken of all newly diagnosed stage 4 NSCLC patients seen in out-patient consultation at our institution between 2009 and 2012. All physicians accepted unselected lung cancer referrals and all patients are included. Baseline demographics, systemic therapy received, reasons for not receiving therapy, and OS data were collected. Cox regression analyses (univariate and multivariate) were employed to assess determinants of OS. The physicians were blinded to the results.

Results:
Overall 528 patients were included. Baseline characteristics are shown in table 1. A significant variation was noted in the proportion receiving any systemic chemotherapy (p≤0.01) [D(60%), L(65%), R(43%), M(52%)] (Figure 1A). However OS was not statistically significantly different among all patients (p=0.47), among treated patients (p=0.18) or among untreated patients (p=0.22)(Table and Figure 1B). In multivariate analysis, factors associated with survival were PS (p<0.01), weight loss (<5%, ≥5%)(p<0.01), WBC (<11, ≥11)(p=0.0588) and platelets (<400, ≥400)(p=0.0374).Figure 1

Demographic	Overall (n=528)	Physician R (n=137)	Physician M (n=118)	Physician D (n=115)	Physician L (n=158)	p-value
Median Age	68	70	68	67	67	0.23
Gender (male)	55%	58%	58%	49%	56%	0.42
PS (0-1)	50%	47%	48%	50%	55%	0.01
Hg (<100)	6%	11%	3%	4%	4%	0.01
LDH (<250)	28%	21%	30%	27%	33%	0.09
Platelets (<400)	71%	64%	75%	78%	70%	0.12
Weight loss (>5%)	48%	49%	48%	46%	49%	0.87
WBC (<11)	62%	56%	68%	68%	60%	0.11
Received ≥ 1 line systemic therapy	55%	43%	52%	60%	65%	<0.01

Conclusion:
While practice size and proportion of patient treated did vary between oncologists, these did not translate into significantly different survival. There were statistically significant differences in the distribution of baseline characteristics between the 4 oncologists and this could cause the differences in proportion of patients treated. We hypothesize that as long as the oncologists are well trained and display good practice, survival is not dependant on the individual. This research does not measure other valuable characteristics or outcomes such as rapport, compassion, and quality of life, which may differ between physicians.

Background:
Primary lung cancer is the most common malignant neoplasm worldwide. In spite of the fact that in Egypt, according to various institutional and hospital-based data, bronchogenic carcinoma is the fifth most common malignancy among males the seventh most common cancer in females, its incidence continues to increase with no improvement in treatment outcome. This study aims to analyze the epidemiological factors and clinicopathological features of NSCLC in egyptian patients and evaluate the various lines of treatment and their impact on survival.

Methods:
This study included the examination and analysis of data collected retrospectively from the medical records of 504 patients diagnosed with NSCLC who were treated at Department of Clinical Oncology and Nuclear Medicine, Ain Shams University, Cairo-Egypt in the period from January 2008 till December 2012.

Results:
The median age of the cohort was 59 years (Range 33-80)with male predominance (74.4%) and 59.1% were of urban residence. The most common symptom at presentation was dyspnea (49.2%). Most patients were stage IV at presentation (73.2%) and adenocarcinoma was the most common histology (52.6%). About 85% of the patients received active treatment. The Median PFS after first,second and third lines was 3, 4 and 2 months respectively and the median OS was 8 months. Factors which were associated with a statistically significant difference in median OS were age <60 years versus ≥ 60 years (10 and 7 months respectively, p<0.001), female versus male gender (10 and 8 months respectively, p<0.001), urban versus rural residence (9 and 8 months respectively , p=0.03), smokers versus non-smokers (8 and 10 months respectively, p<0.001), patients presenting with non-neurological symptoms and those presenting with neurological symptoms (9 and 6 months respectively, p< 0.001) and the receiving treatment versus no treatment (10 and 5 months respectively, , p<0.001). Cox regression analysis showed that the factors that were associated with shorter OS were age≥ 60 years, not receiving any line of treatment, patients presenting with neurological symptoms and male gender.

Conclusion:
This study shows that the active treatment of patients with NSCLC continues to have an important impact on survival. The fact that rural residence could be associated with worse OS warrants further investigation. We recommend large multicentric prospective studies comparing multimodality treatment approaches and including quality of life assessment.

Background:
Painful rib metastasis is common in NSCLC. Pain sometimes was partially or totally refractory to analgesic medications or the side-effects of medication were unacceptable. We report the safety and efficacy of a new method: radiofrequency ablation in treating painful none small cell lung cancer (NSCLC) rib metastasis.

Methods:
treating painful none small cell lung cancer (NSCLC) rib metastasis. Methods radiofrequency ablation procedures were completed in 12 patients with painful rib metastasis. Patient age ranged from 66 to 83 years (mean 74.8 years, Standard Deviation (SD) =5.3).Pathology: squamous-carcinoma 4 cases, adeno-carcinoma 7 cases and large cell carcinoma 1 case. Pain causing neoplasm size, pain levels pre- and post-procedure (as assessed using the Visual Analog Scale), time length and target temperature of radiofrequency ablation (RFA) treatments were documented. Figure 1



Results:
Radiofrequency ablation (RFA) procedures were performed with 100% technical success. The mean pre-procedure and post-procedure pain, as measured by the Visual Analog Scale (VAS), was 7.9 (SD=0.90) and 3.4 (SD=0.99) respectively. No symptomatic complications occurred. Non-symptomatic complications included 1 case of pneumothorax, 1case of hemoptysis.

Conclusion:
RFA appears to be safe, practical and effective in the palliative treatment of none small cell lung cancer (NSCLC) chest wall painful metastasis.

Background:
Erlotinib is the standard of care for epidermal growth factor receptor (EGFR) mutated lung adenocarcinomas in the USA. However, in pregnant patients with lung cancer, chemotherapy is recommended, irrespective of EGFR mutations, given the lack of experience and uncertainty for fetus’ safety with Erlotinib.

Methods:
A patient, with twin pregnancy after in-vitro fertilization, was intentionally treated with Erlotinib. Pharmacokinetics of Erlotinib and its active metabolite (OSI240) were measured in mother’s plasma and twins’ cord blood which were collected at delivery. Times of gestation, fetal growth, transplacental pharmacokinetics of Erlotinib, and cancer outcome were recorded. The pharmacovigilance of Erlotinib during pregnancy was analyzed by accessing Roche/Genentech global database.

Results:
A 47 year old woman, ten-weeks pregnant with twins, was diagnosed with stage 4 lung cancer which harbored an exon 19 deletion. She had brain metastases which were treated with stereotactic surgery during the first trimester. Erlotinib -150 mg daily - was intentionally administered at the start of the second trimester. She was treated for 130 days. Growth retardation was noted in one fetus at week 33 and delivery was planned at week 37 by cesarean section. Drug concentrations in mother's plasma and twins'cord blood are shown in the table. Erlotinib and its metabolite cross the placenta, but only at 10-25% of blood concentrations. Side effects included a lower than expected birth weight (87% of normal) and transaminitis in both newborns that resolved within 3 months. The mother sustains an ongoing partial response to Erlotinib with minor skin rash and fatigue from treatment. The infants are normal at 10 months. Table 1. Erlotinib Concentrations in Mother and Twins

Sample	Erlotinib concentration (ng/mL)	%	OSI-420 concentration (ng/mL)	%	Newborn weight (g)
Mother plasma	54.31	100	16.25	100	-
Newborn A cord	13.67	25.2	2.12	13.0	2353
Newborn B cord	12.18	22.4	1.5	9.2	2438

OSI-420, Desmethyl-Erlotinib.

Conclusion:
Erlotinib administration is feasible during late pregnancy and yields improved cancer outcome.

Background:
Endosonographic staging techniques mainly endoscopic (EUS-FNA) or endobronchial (EBUS-TBNA) with needle aspiration modalities has been increasingly described and used in many established centres since the early year 2000 as 1[st ]line mediastinal staging compared to surgical staging (video / cervical mediastinoscopy) . Its minimally-invasive nature , with low complications rate , excellent diagnostic accuracy and ultimately cost-effectiveness are some of the main deciding factors involved .The aim of this review is to evaluate the diagnostic yield of endosonographic staging compared to surgical staging for mediastinal lymphadenopathy in lung cancer patients.

Methods:
A thorough extensive electronic literature database search in PUBMED ,EMBASE ,MEDLINE and ISI web of Science was conducted systematically , emphasizing endosonographic staging modalities vs surgical staging ,ranging from year 2000 up to April 2015 . These search engines were not confined to English-literature language only . Lung cancer patients were identified as a separate unit of analysis ,as well as these endosonographic staging methods at the level of mediastinum and its diagnostic yield ( positive lymph nodes) were clustered in a different analysis group. In this review , the methodological analysis used was the Quality Assessment of Diagnostic Accuracy Study (QUADAS-2) as a tool to allow transparent rating of potential bias and application of primary diagnostic accuracy study. The primary end-point was the number of positive successful mediastinal nodal biopsies ,which was grouped according to the American Thoracic Society (ATS) classification .

Results:
A total of 10 major trials & reviews pertaining to this topic were extensively reviewed . Approximately nearly 1000 patients were grouped in this study ,who underwent either EUS-FNA staging with or without EBUS-TBNA and mediastinoscopy following diagnosis of lung cancer , either in a small or large , single or multiple centres across the world . The sensitivity , specificity , positive (PPV) & negative predictive values (NPV) and diagnostic accuracy or yield for endosonographic staging vs surgical staging modalities were cross-examined .

Conclusion:
According to the systematic analysis , these groups are moving forward for endosonographic (EUS-FNA or EBUS-TBNA) modalities compared to solely surgical staging (mediastinoscopy) in most cases . It seems to be a more promising ,successful & cost-effective method for sampling mediastinal nodes in lung cancer patients .

Background:
Kidney transplantation has dramatically increased during last decades. As significant progress has been made in the prevention and treatment of infections, cancer has become a major cause of concern. Limited data exist about lung cancer after kidney transplantation.

Methods:
The data from 2003 to 2012 of all transplanted patients with lung cancer in three French kidney transplant centers were retrospectively reviewed. 30 cases were included. Lung cancer incidence was determined in two centers for the 2008-2012 period. Each case was matched with two controls. Controls were patients without solid organ transplantation matched with the cases for age (<30; 30-50; 50-65; >65 years), gender and diagnosis date of lung cancer.

Results:
Lung cancer incidence in renal transplanted patients was 1.89/1000 person-years for the 2008-2012 period. Our cohort was mainly formed of male smokers around 60 years old, all current or former smokers. 43% were diagnosed by routine exams. Histopathological distribution was different with more squamous cell carcinoma. As expected, hypertension and ischemic heart disease were more prevalent but the other comorbidities and characteristics were the same in both groups. 60% had a stage IV cancer. Surgery was performed as often as in controls if the stage allowed it and advanced stage received full dose chemotherapy. Palliative care only was given to 20% of the patients. Hospitalization for infectious complications was somewhat higher in the cases group but global survival was similar.

Conclusion:
Kidney transplant recipients are likely to develop lung cancer. Despite frequent radiologic examinations, the majority of patients had advanced stage disease at diagnosis. Therapeutic management and prognosis did not differ between patients and control. As current or past smoking habit was present in all cases, a screening strategy should focus on smokers in this high-risk population. Our study was not designed to determine if other risks factors could be identified.

Background:
The Victorian Lung Cancer Registry (VLCR) pilot project aims to recruit all lung cancer cases diagnosed across participating Victorian sites. Case ascertainment derives from institutional ICD-10 coding. A quantitative, case finding audit was employed to evaluate the case ascertainment methodology and assess capture completeness at a Victorian public and private metropolitan hospital.

Methods:
Lists of lung cancer patients recorded for the period 01/07/2011 and 30/06/2012 were requested from institutional departments including; Radiotherapy, Palliative Care, Day Procedure Unit, Oncology Lung Multidisciplinary Team Meeting (MDM), Cardiothoracic Surgery (CTS), Pathology and the Victorian Cancer Registry (VCR). Comparisons were made between VLCR administrative capture versus clinical capture achieved by the use of clinical databases compared with mandated VCR capture.

Results:
The VLCR registered 125 new cases in Site A and 100 in Site B. A total of 10 (7.5%) patients in Site A and 13 (11%) patients in Site B had not been recruited by the registry. Investigations indicated that the underreporting of these cases was attributed to: Use of the ICD10 R91 Code (when lung cancer is suspected but not confirmed) Non coded patients (e.g. day admissions, direct admission to palliative care or MDM)

Conclusion:
The completeness of capture of incident cancers occurring in a population and included in a registry database is a vital attribute of a cancer registry. Current capture is approximately 90% and inclusion of the R code and an attempt to capture un-coded patients will ensure registry incidence rates are close to their true value.

Background:
Although the contribution of emphysema to lung cancer risk has been recognized, no study has focused the prognostic impact of CT emphysema score for advanced stage of lung cancer. The aim of our study was to analyze the prognostic value of CT emphysema score in patients with advanced squamous cell carcinoma of the lung (SCCL).

Methods:
We analyzed 84 consecutive patients with advanced stage (stage IIIB and IV) of SCCL who underwent palliative chemotherapy. The severity of emphysema was semi-quantitatively scored using baseline chest CT images according to the Goddard scoring system, ranging from 0 to 24. Data on clinical characteristics and survival were retrospectively collected. Survival was estimated by the Kaplan-Meier method and compared with the log-rank test. A multivariable Cox proportional hazard model was used to identify prognostic factors.

Results:
Most patients were male (89%) and current/ex-smokers (90%). The median CT emphysema score was five (range, 0 to 22). In univariable analysis, patients with higher CT emphysema score (> 6) showed a trend toward poor survival (6.3 months vs. 11.4 months in those with lower score, p=0.076). In the multivariable model, higher CT emphysema score was a significant independent prognostic factor for poor survival (HR,1.85; 95% CI, 1.14 to 3.00; p=0.012) along with response to first-line therapy (p=0.001) and second-line therapy (p<0.001).

Conclusion:
The CT emphysema score is significantly associated with poor prognosis in patients with advanced SCCL.

Background:
Recently, continuation maintenance with Pemetrexed after induction therapy with pemetrexed plus cisplatin for advanced pulmonary adenocarcinoma has been approved in Korea. Therefore we retrospectively evaluated the activity and feasibility of continuation maintenance with Pemetrexed in Korean patients.

Methods:
Stage IIIB/V patients with pulmonary adenocarcinoma were evaluated from 2006 to 2015 April. We analyzed 12 cases with maintenance therapy with Pemetrexed. All patients received an induction phase which consisted of 4-6 cycles of induction pemetrexed (500 mg/m[2]) plus cisplatin (75 mg/m[2]) on day 1 of a 21-day cycle and maintenance therapy with pemetrexed (500 mg/m[2]) every 21 days) plus best supportive care until disease progression.

Results:
Mean age was 61 years; 9 were men. Median number of total pemetrexed cycles was 18 (8-42). The mean overall survival time and the mean progression free survival were 46±12.3 months and 21.1±5.8 months, respectively. The median overall survival time and the median progression free survival were 29±20.8 months and 12±7.1 months, respectively. Discontinuations due to drug-related adverse events occurred in one (8%) patients.

Conclusion:
Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced pulmonary adenocarcinoma with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin in Korea.

Background:
To evaluate prognostic factors in the first-line chemotherapy of advanced non-squamous non-small cell lung cancer patients with Eastern Cooperative Oncology Group(ECOG) performance status(PS) 2.

Methods:
We retrospectively analyzed clinical and laboratory characteristics of patients with advanced non-squamous non-small cell lung cancer patients with ECOG PS 2 who received the first-line chemotherapy in our institute. We examined the various clinical values such as gender, age, clinical stage, histology, immunohistochemistry, chemotherapy regimen, underlying diseases, metastasis sites, data of blood test.

Results:
A total of 31 patients aged 45 to 80 years (median 65) were treated from August 2006 to February 2015(male/female;23/8, adenocarcinoma/non-small cell carcinoma;15/16). They were received single agent or combination chemotherapy(carboplatin and pemetrexed(CP);17, others;14). In univariate analysis, median survival times were 9.56 months in adenocarcinoma vs 3.26 months in non-small cell carcinoma(P=0.0011) , 16.77months in Thyroid Transcription Factor-1(TTF-1) expression positive(n=10) vs 4.96 months in TTF-1 expression negative(n=9)(P=0.0166), 2.59 months in 7.0ng/ml and over of CYFRA21-1 vs 9.56 months under 7.0ng/ml of CYFRA21-1(P=0.0236), 8.53 months in CP vs 2.20 months in others(P=0.0003). Objective response rates were 29.4% in CP and 0% in others.

Conclusion:
Our results show that patients who were diagnosed adenocarcinoma pathologically had significantly better prognosis than the others, and CP may attributes to good prognosis of the patients with advanced non-squamous non-small cell lung cancer patients with ECOG PS 2.

Background:
Platinum-Based chemotherapy is still the cornerstone in the treatment of Non-Small Cell Lung Cancer (NSCLC), in non oncogene-addicted patients (pts). Therapeutic algorithm is established on the basis of patient and disease characteristics, such as histology and radiologic features. Pharmagenomic-driven trials are investigating the role of different markers in predicting efficacy and toxicity in NSCLC pts. A better selection of a right therapy for the right patient would improve outcomes ameliorating tolerability and optimize the resources available. The aim of the present study is to carry out a cost-effectiveness analysis, in order to evaluate the economic efficiency of 1st line chemotherapy within a clinical trial (EPIC eudract N 2012-001194-81), in elderly pts affected from advanced NSCLC, looking at efficacy and tolerability.

Methods:
The study population consisted in Elderly Patients Individualized Chemotherapy (EPIC) trial enrolled at San Luigi Hospital (Orbassano-Italy, coordinating centre) from July 2012 to August 2014. Main recruitment criteria: chemotherapy-naïve pts diagnosed with stage IV NSCLC, aged≥70 years, no activating EGFR mutations. We evaluated 48 pts randomised (2:1 ratio) to receive pharmacogenomics-driven chemotherapy assessed according to the genetic profile of primary tumours based on expression of ERCC1, RRM1 and TS evaluated by “Real-Time PCR” (arm A) or standard chemotherapy (arm B). Costs of treatments were calculated using National Health System (NHS) direct costs and 12 months time-horizon. Effectiveness was estimated as Progression Free Survival (PFS). The Incremental Cost-Effectiveness Ratio (ICER) was calculated and pharma-economic analysis was performed setting the Willingness To Pay (WTP) threshold value at 40,000€ per free-disease month gained. The reliability of results was assessed by a probabilistic sensitivity analysis based on “Monte Carlo” method (10,000 simulations) changing the costs and effectiveness variables simultaneously. Number and grade of adverse events were used to determine the tolerability profile.

Results:
The average cost per patient was 10,278.38€ (arm A) and 8,659.53€ (arm B). Related ICER was 4,496.80€ per free-disease month gained and 53,961.73€ per year gained (over the WTP threshold). The scatterplot generated in the sensitivity analysis indicated that higher densities of ICERs, calculated for each simulation, took place at the cross over of the Cartesian axes indicating that there is no clear prevalence of treatment cost-effectiveness. Moreover, the Cost-Effectiveness Acceptability Curve (CEAC) was calculated. This curve demonstrated that treatment A had 35% of probability to be cost-effectiveness.

Conclusion:
This preliminary evaluation, conducted in a subgroup of pts, suggests the relevance of pharmacoeconomic analysis within a clinical trial looking at the best way to identify a tailored treatment in non-oncogene addicted NSCLC pts. Further data will be collected in a larger simple size. Personalised chemotherapy is a potential method addressing both the optimisation of the effectiveness of therapeutic agents and the minimisation of adverse events, objectives even more relevant for elderly and fragile patients, given the possibility to optimize the use of scarce resources available.

Background:
Fever during cancer chemotherapy is require attention using antibiotics to prevention severe infection. On the other hand, it should be avoid using antibiotics to non-infectious fever such as drug and tumor fever with the object of development of resistant bacteria, exacerbation of drug fever, and medical economics.

Methods:
Retrospectively, 1,016 consecutive cycles of cancer chemotherapy were analyzed. Fever was defined as a temperature of ≥37.5°C. Age, sex, tumor histology, the treatment regimen, the timing of fever onset, the number of days for which the fever persisted, the cause of the fever, and the presence or absence of radiotherapy were examined.

Results:
Seventy-four percent of the patients (748 of 1016) were males, the patients’ median age was 68 years (range: from 29 to 88 years), and lung cancer was the most common disease (93%). Fevers occurred in 36% of cycles (367 of 1016) including 37% of those involving males and 32% of those involving females. There was no difference in the frequency of fever among the sexes (p=0.146). The incidence of fever according to age were 33% (≤60), 41% (61-65), 36% (66-70), 33% (71-75), 41% (76-80), and 33% (≥81); it did not differ significantly with age (p=0.424). In incidence of fever according to the drugs administered, gemcitabine was the drug that was most frequently associated with fever (41%; 43/106), followed by irinotecan (40%; 108/272), amrubicin (39%; 29/75), and docetaxel (36%; 47/131). Post-treatment days 4 (8.3%), 3 (6.8%), and 12 (6.7%) were the days on which fever was most common. The distribution of fever exhibited a bimodal distribution; i.e., whilst it peaked on post-treatment days 3 and 4; otherwise, it generally gradually increased until day 12 and then gradually decreased. The peak on post-treatment days 3-4 was considered to be due to adverse drug reactions, and the latter peak was considered to represent neutropenic or infection-based fevers. Fevers occurred on post-treatment days 3-4 in 11% of all cycles (113 of 1016) including 11% (84 of 748) of the cycles involving males and 11% (29 of 268) of those involving females. The incidence of fever on post-treatment days 3-4 according to age were 12% (≤60), 13% (61-65), 10% (66-70), 8% (71-75), 13% (76-80), and 10% (≥81); however, this parameter did not differ significantly with age (p=0.427). The incidence of fever on post-treatment days 3-4, gemcitabine was the drug that was most commonly associated with fever (20%), followed by docetaxel (18%), nedaplatin (12%), and carboplatin (11%). The patients’ fevers were caused by infections (47%), adverse drug reactions (24%), unknown causes (19%), and tumors (7%). The causative infections included febrile neutropenia (50%), pneumonia (18%), unidentified infections (9%), and colitis (7%). The incidence of fever was significantly higher among the patients treated with radiotherapy than among those that did not receive radiotherapy (46% vs. 34%, p=0.001).

Conclusion:
The febrile episodes that occurred on post-treatment days 3-4 were considered to represent adverse drug reactions after cancer chemotherapy. Physicians should be aware of this feature of chemotherapy-associated fever and avoid unnecessary examination and treatments including prescribing antibiotics.

Background:
Various types of chemotherapies have been extensively investigated in advanced non-small cell lung cancer (NSCLC). Although median survival times have been getting long, the outcomes remain poor. This study aimed to analyze the characteristics of those with complete remission among advanced NSCLC patients.

Methods:
Based on our hospital database, 1,699 patients who were registered as lung cancer between August 2004 and April 2011 were examined, and Stage III or IV NSCLC patients, whose treatment began between September 2004 and April 2011, were retrospectively evaluated at September 2014. We defined complete remission as a continuous complete response observed in spite of the treatment initiation over three years ago, regardless of treatment continuation.

Results:
Seven patients were observed. Two patients were at stage IIIA, one at stage IIIB, and four at stage IV. The treatment modalities included cytotoxic chemotherapy only (one patient), chemotherapy and EGFR-TKI followed by surgery (one patient), radiosurgery for brain metastasis followed by surgery and chemotherapy (one patient), and chemoradiation (four patients). Three patients had adenocarcinoma, three squamous cell carcinoma, and one large-cell carcinoma. The numbers according to survival time since the date of treatment initiation were two (between three and four years), three (between four and five years), and two (over five years). All cases had complications of inflammatory diseases. In case 1, an acquired immunological response against lung cancer was suggested. The patient had rheumatoid arthritis and stage IV adenocarcinoma with massive pleural effusion, treatment was only 1 course of vinorelbine, and sepsis occurred after chemotherapy. After that, complete remission has been achieved. Acquired cancer immunity was also suggested in case 2, who had stage IV adenocarcinoma with cardiac tamponade. Pericardial drainage was done and three courses of cisplatin and gemcitabine were administered, followed by EGFR-TKI. Gefitinib have continuously been used for four years, however the tumor in the right upper lobe had gradually getting large. The tumor was resected, while EGFR mutation was negative and many inflammatory cell infiltrations were observed. In case 3, oligo-metastatic states have been controlled by surgery and radiation. The patient had stage IV large cell carcinoma with a brain metastasis, the primary pulmonary lesion was surgically removed after cyber-knife therapy. Chemotherapies were started. Oligo-metastatic new brain lesions were firstly cyber-knife therapies, and the relapsed or new lesions were removed by brain surgeries. After the brain surgery, encephalitis and meningitis developed. Many inflammatory cells were observed around and inside the brain tumor. Finally, the brain tumors and the pleural dissemination disappeared. In case 4, who had stage IIIA adenocarcinoma with bulky N2, PET-assisted three-dimensional conformal radiation therapy was used to control oligo-metastases. The tissue types of chemoradiation-induced complete remission were squamous cell carcinoma in three patients and adenocarcinoma in one patient.

Conclusion:
These results suggest that complete remission can be achieved for several types of advanced NSCLC by employing combinations of treatment modalities. Oligo-metastatic states could be controlled by surgery and radiation therapies with or without chemotherapies. The acquired immune response against lung cancer might be important to induce complete remission.

Background:
In advanced NSCLC, the goal of maintenance therapy is to prolong overall survival of first line platinum based combination chemotherapy. Maintenance Pemetrexed was associated with statistically and clinically significant improvement in both PFS ans OS. Objective was to determine the response rate, progression-free survival (PFS), overall survival (OS).

Methods:
Between January 2011 until July 2014, Peruvian patients with advanced NSCLC (IIIB, IVA) received four to six cycles of Carboplatin (AUC 6) - Pemetrexed 500mg/m2 day 1. Patients who achieved a complete response (CR), partial response (PR) o stable diase (SD) were to received maintenance Pemetrexed (500mg/m2 day 1) in 21 day cycles until disease progression. All patients recevied vitamin B12, Folic acid supplement.

Results:
83 patients received induction chemotherapy and maintenance therapy, median age was 61 years (26 - 84), > 70 years 15.7%, female:male 1.5, no smoking:smoking 2.6, exposure to wood smoke 25 (30.1%), ECOG 1 98.8%, EC IIIB 8.4%, EC IV 91.6%, hystology Adenocarcinoma 100%. Sites of metastasis: pleural 36 (43.4%), bone 20 (24.1%), brain 7 (8.4%), liver 4 (4.8%). 40 (48.2%) received 4 cycles, 27 (32.5%) 6 cycles of induction chemotherapy; median of cycles of maintenance 5 cycles (1-16). Response to treatment: 4 (4.8%) RC, 42 (50.6%) RP, 30 (36.1%) DS, 7 (8.4%) PD. The median time to progression was 11 months, estimated PFS was 86.5%, 39.6%, 13.8% at 6, 12, 30 months respectively. The estimated OS was 68.8%, 51.4% and 41.5% at 12, 24 and 30 months respectively, median time to OS was 28 months. None variables are significantly associated with OS.

Conclusion:
Induction chemotherapy and maintenance therapy with Pemetrexed improves PFS and OS in patients with advanced lung cancer without compromising the quality of life. There is a need for better ways of identifying patients most likely to benefit.

Background:
Pemetrexed (Pem) is a widespread used drug as standard treatment option in patients diagnosed of nsNSCLC in different settings: first line combined with platinum, maintenance or second line treatment. The aim of this study is to assess the cost-effectiveness of Pem-based chemotherapy in routine clinical practice from the perspective of the Spanish National Health System.

Methods:
We evaluated retrospectively clinical outcomes, in terms of overall survival (OS) and progression free survival (PFS), in patients diagnosed of advanced nsNSCLC from 2005 to 2014 who were treated with Pem-based chemotherapy, and we performed a cost-effectiveness analysis. We assessed the cost-effectivenss of the use of Pem-based treatment in routine clinical practice calculating the cost per life years gained (LYG) from the first time the patient received Pem, based on the price established in Spain and the number of cycles received. We calculated OS from the start date of Pem to the death or last contact with the patient, and PFS from the start date of Pem to first tumor progression after Pem.

Results:
114 patients treated with Pem-based chemotherapy were reviewed, 78.9% men and 21.1% women. Mean age at diagnosis was 64 (range 36-81). 80.7% were smokers or former smokers. 90.4% were stage IV and 9.6% IIIB. The predominant histology was adenocarcinoma (69.3%), followed by large cell carcinoma (22.8%), NSCLC-NOS (7%) and pleomorphic carcinoma (0.9%). 59.6% of patients received Pem in first-line and/or maintenance (1L - Maint.), and 40.3% in second or successive lines. The majority of them had a good functional status; ECOG 0 25,4% and 1 59,6%. Median number of received Pem cycles was 5 (range 1-39). Median number of treatment lines was 3 (range 1-8). Clinical outcomes: 68.6% obtained clinical benefit (46.1% stable disease, 21.5% partial response, and 1% complete response). Median progression free survival (PFS) was 5.16 months in 1L- Maint., and 4.55 months in second or successive lines (p = 0,278). Median OS was significantly better in 1L – Maint. setting than in second or successive lines (17.8 vs 9.8 months (p = 0,033)). The mean cost of Pem-based chemotherapy per LYG was 18988 euros in 1L-Maint. setting and 17095 euros in second or successive lines.

Conclusion:
From the perspective of the Spanish National Health System, Pem-based chemotherapy was cost-effective in both first line and/or maintenance setting, and second or successive treatment lines in our patients. The cost per life year gained (LYG) from treatment with Pem was below the standard threshold of 30000 euros.

Background:
Despite the recent remarkable progress in chemotherapy (CTx) regimens, the application of CTx for non-small cell lung cancer (NSCLC) associated with interstitial lung disease (ILD) remains challenging because of the possibility of acute deterioration of the underlying ILD, which can lead to severe respiratory insufficiency, thus decreasing the life expectancy of the patient. To date, no acceptable CTx regimen for patients with ILD has been established. We herein assessed our series of non-small cell lung cancer patients with ILD treated with cisplatin and etoposide (PE).

Methods:
Unresectable NSCLC patients with ILD detected on chest computed tomography (CT) who received PE at our department between December 2006 and December 2013 were retrospectively reviewed. ILD was defined as interstitial opacity on CT, as confirmed by an independent radiologist. Overall survival (OS) was defined as the time from the start date of any treatment to the date of death from any cause. Progression-free survival (PFS) was defined as the time from the start date of PE to disease progression or cancer-related death.

Results:
A total of 32 NSCLC patients with ILD were evaluated. There were 31 males and one female, with a median age of 66 (53-79) years. The ECOG performance status was 0/1/2 in 17/13/2 patients. Seventeen patients had adenocarcinoma, six patients had squamous cell carcinoma and nine patients had NSCLC. Three patients experienced post-surgical recurrence. The clinical stage was IIB/IIIA/IIIB//IV in 2/5/8/17 patients. The subtypes of ILD classified according to the CT appearance were the usual interstitial pneumonia pattern in 22 patients and a non-specific interstitial pneumonia pattern and previous drug-induced pneumonia in five patients each. Oral steroids were administered concomitant with CTx in two patients. Twenty-four patients received PE as the first-line CTx, while the other eight patients received PE after more than two regimens of CTx. Grade 3/4 hematological toxicity of leukopenia was noted in 15 (46.9%) patients, neutropenia was observed in 24 (75.0%) patients, thrombocytopenia occurred in four (12.5%) patients and anemia was detected in six (18.8%) patients. Grade 3 febrile neutropenia was recorded in six (19.4%) patients, grade 3 and 4 acute myocardial infarction occurred in one patient each and grade 3 cerebral infarction occurred in one patient. Two patients experienced grade 2 worsening of ILD and successfully recovered. The response rate was PR/SD/PD in 10/19/2 patients, and one patient could not be evaluated because of an adverse event. The median PFS was 3.9 months, the one-year PFS was 12.8% and the two-year PFS was 4.3%. Additionally, the median OS for all patients was 11.2 months, the one-year OS was 46.2% and the two-year OS was 14.2%.

Conclusion:
PE treatment for unresectable NSCLC associated with ILD was demonstrated to be relatively safe in our series, with an acceptable tumor response and OS. However, careful patient selection and management during CTx are required. The limitation of the current analysis is its retrospective nature and the fact that there was a single arm of CTx therapy. Hence, future prospective comparisons of other CTx regimens are warranted.

Background:
It has been generally accepted that pemetrexed (PEM) with platinum followed by PEM maintenance therapy is a standard first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC). The number of patients treated with long-term use of PEM is increasing, and thus we should know the clinical features including side effects in those patients. Belen et al. reported that skin toxicities were related to PEM maintenance therapy, while Jean et al. demonstrated that 7.8% of patients receiving maintenance PEM had grade 1/2 edema in the PARAMOUNT trial. Further investigation into clarifying the clinical features of these patients is required.

Methods:
We retrospectively reviewed the charts of 13 patients with advanced NS-NSCLC who had been treated with long-term PEM (10 and more courses) in our hospital between July 2009 and December 2014.

Results:
All patients had adenocarcinoma. The median age was 63 years (range: 39-72). Six patients were male, and six were never-smokers. All but one patient were classified as clinical stage IV. Six patients harbored EGFR mutation and one patient had ALK gene rearrangement. Twelve patients received PEM with platinum (cisplatin; seven patients, carboplatin; five patients), and one patient received PEM alone. The median number of courses of PEM was 16 (range: 10-21). Grade 3/4 non-hematological toxicities observed in the 13 patients were anorexia (8%), nausea (8%), and dizziness (15%). Grade 3/4 hematological toxicities observed were neutropenia (46%), anemia (15%), and thrombocytopenia (15%). Two patients had peripheral skin edema; one patient developed eyelid edema at 21 cycles of PEM, and the other developed limb edema and pleural fluid at 20 cycles of PEM. Four patients underwent PEM beyond RECIST PD following platinum-based doublet chemotherapy regimen (CDDP+PEM; 2, CBDCA+PEM; 2). Initial response by the induction chemotherapy was PR in two patients and SD in two patients. The PD sites were lungs in two patients, bone in one patient and adrenal gland in one patient. The median post progression survival (PPS) of each of the four patients was 205.5 days (range; 68-330). All the four patients underwent PEM until “clinical” PD. Progressive sites were lungs in two patients, bone in one patient and esophagus in one patient. The median duration between RECIST PD and clinical PD was 100.5 days (range; 35-210).

Conclusion:
The differential profile of adverse effects, including dizziness and edema, driven by long-term PEM compared with those by conventional use of PEM suggested that we should cautiously select supportive therapies for NSCLC patients who are being treated with long-term PEM. Continuation of PEM beyond PD can be in consideration for selective patients with NS-NSCLC, as observed in patients treated with EGFR-TKI.

Background:
Nanoparticle albumin-bound (nab) paclitaxel is a biologically interactive nanoparticle, combining albumin with paclitaxel and has a better toxicity profile compared to solvent-based paclitaxel. Recently some studies are reported which show the efficacy of nab-paclitaxel as first line chemotherapy for non-small cell lung cancer (NSCLC), but rarely reported until today to elucidate the efficacy of nab-paclitaxel with carboplatin (CBDCA) as second or later phase chemotherapy for NSCLC. We here evaluate the efficiency and feasibility of nab-paclitaxel plus CBDCA as second or later phase chemotherapy in patients with recurrent or advanced NSCLC in this study.

Methods:
Twenty-five patients with recurrence after radical surgery for NSCLC and unresectable stage IIIB/IV NSCLC who had received previous chemotherapies were treated with nab-paclitaxel 70mg/m[2] intravenously on day1, 8, and 15 with CBDCA area under the concentration-time curve of 4 (AUC4) intravenously on day1, every 28 days. Progression-free (PFS) and overall survival (OS) rates were calculated by means of Kaplan-Meier analysis and statistical significance between the groups was analyzed by using log-rank tests. Disease control rates and toxicity were also evaluated. Disease response in all of the patients was monitored after two cycles of chemotherapy.

Results:
Of 25 patients who participated in this study, 9 were recurrent and 16 were advanced case. 13 were adenocarcinoma, 11 were squamous cell carcinoma and 1 was large cell carcinoma. 13 were performed as second line chemotherapy, 6 were as third line and 6 were forth or later line. EGFR mutation status was positive in 5 patients (20.0%) and they all received EGFR-TKI in their serial chemotherapy. One achieved complete response (CR), 7 reached a stage of partial responses (PR), 10 maintained stable disease (SD) and 7 suffered progressive diseases (PD). The overall response rate (ORR) was 32.0% and disease control rate (DCR) was 72.0%. The median PFS was 4.8 months and median OS was 29.0 months. Common treatment related adverse events were myelosuppression, baldness, peripheral neuropathy and gastrointestinal symptoms, most of which were grade 1 to 2. Grade 3-4 neutropenia was present in 6 patients (24.0%), thrombocytopenia and anemia in 2 patients (8.0%), respectively. No patients experienced grade 3-4 neuropathy. The need of a dose reduction was 26.9% because of toxicity, but there were no adverse effects of grade 5.

Conclusion:
Nab-paclitaxel plus CBDCA as second or later phase chemotherapy offers a small but significant survival benefits for the patients with recurrent and advanced NSCLC, and its adverse effects are tolerable. Further studies including prospective studies of this regimen are required.

Background:
Standard first-line therapy in stage IV NSCLC patients remains a platinum-based regimen. Currently, there are limited FDA approved agents for second line therapy following progressive disease. The purpose of this study was to evaluate the response to retreatment with platinum-based regimens upon progression in a group of platinum-sensitive patients.

Methods:
Patients with stage IV NSCLC previously treated with a platinum-based first-line regimen were retrospectively reviewed. We examined the outcomes of 52 patients retreated with a platinum-based regimen upon progression between February 2002 and March 2015. Patients were evaluated for response rate, progression free survival, overall survival and platinum reactions.

Results:
Of the 52 patients reviewed, 31 were women (59.6%) and 21 were men (40.4%). Median age was 62.6 (range 42-89) and adenocarcinoma was the most prevalent histology (86.5%). The response rate for retreatment was 21.15%. A notable 57.69% of patients had stable disease. The median PFS for the first line platinum regimen was 9.2 months (CI 95%; 6.28-12.13) and for the retreatment was 4.8 months (CI 95%; 3.17-6.42). The median OS from diagnosis was 23.31 months (CI 95%; 11.76-34.85). A platinum reaction was noted in 9 of the patients (17.3%) though none were fatal.

Conclusion:
Patients with prolonged PFS with frontline chemotherapy appear to benefit from retreatment with a platinum-based regimen. This cohort demonstrated by a PFS of 4.8 months upon retreatment. Patients with prolonged progression free survivals with frontline chemotherapy may be reasonable candidates to consider for retreatment with a platinum-based regimen.

Background:
Despite the available positive results of targeted therapy (TT) in clinical oncology, more and more actual is a problem of preliminary screening of patients with solid tumors to whom TT will bring success. TDR is an integrated indicator of redox balance in biological cells which reflects dynamics of activity of a set of the thiol-containing cellular enzymes. It is known that the TDR level in a blood of cancer patients has a direct correlation with TDR in cancer cells. It assumes possibility of use change of TDR in a blood under the influence of drugs for indirect research of influence on biochemical processes in tumor cells. The possibility of prognosis of clinical efficacy and choice of effective targeting agents by means of TDR-test in blood in vitro in patients with advanced NSCLC was the purpose of the study.

Methods:
Between 09/11 and 10/14 we enrolled 52 treated patients (M/F - 44/8) with advanced NSCLC (stage IIIB/IV - 44/8); adenocarcinoma -21, squamous-cell carcinoma - 27, large-cell carcinoma - 4. The median number of prior chemotherapy regimens was 3 (range 1-6), median performance status - 1 (range 0 -3). Prior before TT course, patient’s blood was tested in vitro with targeting agents: erlotinib, gefitinib, cetuximab, trastuzumab, bevacizumab; the respons was evaluated on the dynamics of TDR during 24- our incubation. All the patients received two 4-week courses of treatment: the standard TT (control group, n=25) or such targeting agent susceptibility to which was confirmed by the TDR-test (study group, n=27). Clinical respons was evaluated by RECIST.

Results:
After the end of treatment, the analysis of in vitro TDR reactions on the targeted agents tested showed direct correlation with the clinical results. According to the TDR-test, a portion of effective drugs was 50% - 100% in 92% of the patients, whose treatment resulted in regression or stabilization of disease. At the same time, in 94% of the patients, whose treatment resulted in progression of disease, a portion of effective agents was only 0 - 49%. Among the two groups of patients, objective clinical effects were observed in 7(26%) pts [(PR - 7(26%) pts, 95% CI: 11,6 - 55,2%), SD - 16(59%) pts, PD - 4(15%) pts)] in the study group versus 2(8)% pts [(PR - 2(8)% pts, 95% CI: 3,3 - 16,2%); SD - 8(32%) pts, PD - 15(60%) pts.)] in the control group; grade 3 and 4 toxicity was experienced by 1(4,0%) pt and 2(8%) pts, respectively, - in the control group, and by 1(3,7%) pt and 0, respectively, - in the study group. Sensitivity of the method used to choice efficacious targeting agent amounted to 91,8%, specificity (selectivity) was 94,5% in forecasting the cases resistant to targeting agent.

Conclusion:
The determination of individual sensitivity to targeted agents in patient’s blood in vitro by means of TDR- test is an effective method both for forecasting clinical efficacy of the treatment and for individual choice of TT in patients with advanced NSCLC. These findings need futher validation in additional clinical studies.

Background:
Continuation maintenance therapy with pemetrexed has been proved to be well tolerated ,offers an overall survival benefit and reduced risk of disease progression in Phase III Paramount trial. Based on same it is approved as a category 1 recommendation for patients with nonsquamous advanced lung cancer, who do not progress after pemetrexed plus platinum induction regimen. However there is lack of data from Indian subcontinent. Here we report the data from a tertiary care cancer centre in North India

Methods:
- In all 280 patients were registered as advanced non squamous lung cancer(stage IV) between JAN 14 to DEC 14. Subsequently 96 patients received pemetrexed plus platinum based initial chemotherapy. 46 patients with no disease progression and ECOG PS 0 or 1 received maintenance pemetrexed (500 mg/m[2 on] day 1 of 21 day cycles). Statistical tests were applied to calculate progression free survival. Toxicity profile was evaluated

Results:
The mean number of maintenance cycles was 9.5. Pemetrexed maintenance therapy resulted in progression free survival (PFS) of 5.4 months. PFS on pemetrexed was consistent for all patient subgroups, including induction response: complete/partial responders (n-24 ) and stable disease (n-22 ). 3 patients developed grade 3 or 4 toxicity as to cause a delay in cycles.2 patients also developed renal dysfunction during maintenance therapy. 7 patients continue to receive pemetrexed maintenance till date.

Conclusion:
Pemetrexed continuation maintenance therapy is well-tolerated and offers benefits consistent with Paramount trial, demonstrating that it is an efficacious treatment strategy for Indian patients with advanced nonsquamous NSCLC and good performance status who do not progress during pemetrexed-platinum induction therapy

Background:
KRAS mutations are among the most commonly encountered mutations in lung adenocarcinoma. Although differential outcomes from cytotoxic agents according to histology have been shown in lung adenocarcinoma, the prognostic and predictive impact of KRAS mutational status is controversial. Recently, a study identified greater dependency on folate metabolism pathways in KRAS mutant (mt) compared to KRAS wildtype (wt) NSCLC (Moran et al, Mol Cancer Ther 2014, 6:1611-24). We sought to evaluate the clinical outcomes of patients with lung adenocarcinoma to first-line cytotoxic chemotherapy according to KRAS mutational status.

Methods:
This IRB-approved retrospective study involved patients from Roswell Park Cancer Institute (RPCI) diagnosed with inoperable stage III or IV lung adenocarcinoma from January 1, 2012 to December 31, 2013. Patients with documented KRAS mutational status who received chemotherapy were eligible. Patients with EGFR mutation or ALK translocation were excluded. The objective response (OR) to chemotherapy was assessed using RECIST version 1.1 criteria. The primary end points were Progression Free survival (PFS) and Overall Survival (OS). Secondary endpoint was the time to achieve OR. OS was estimated by the Kaplan-Meier method and compared using the Log-rank method. The association between study endpoints and variables of interest (age, gender, stage, ECOG performance status [PS], KRAS mutation status) were conducted with univariate and multiple Cox models. SAS version 9.4 (SAS Institute, Cary, NC) were used for statistical analyses. All tests were two-sided and performed at a nominal significance level of 0.05.

Results:
A total of 123 patients were eligible for this analysis. In our study, 53 (42%) patients carried KRAS mutations. Majority of patients had stage IV cancer at presentation (74%). There was no difference in distribution of KRAS mutation status by the stage of disease at presentation. The most common first-line chemotherapy regimen was pemetrexed-based platinum combination (85%). When pemetrexed-based regimen was utilized as first-line therapy, univariate analysis showed correlation between KRAS status, gender, stage and PS with OS, favoring KRAS wt, female, stage III and PS 0, respectively. After controlling for other related covariates, only gender, stage and PS remain independently associated with better OS. Patients with KRAS wt had a longer median OS compared to KRAS mt patients (414 vs 249 days, p=0.027). PFS and time to OR were similarly better in KRAS wt group although these were not statistically significant. There was no imbalance in terms of second-line therapy between KRAS mt vs wt patients. There was no difference in study endpoints according to KRAS mutation status observed in patients who received taxane-based chemotherapy as first line treatment. There was also no difference in survival outcomes according to first-line treatment regimen used when patients were stratified according to KRAS mutation status.

Conclusion:
KRAS mutation status is not correlated with treatment outcomes in patients with advanced lung adenocarcinoma receiving first-line cytotoxic chemotherapy.

Background:
The current standard of care for patients with Stage IIIB/IV NSCLC with no activating Epidermal Growth Factor Receptor (EGFR) mutations recommends platinum (carboplatin or cisplatin) doublet chemotherapy in patients who are performance status 0-2. Although a number of options are available, evidence from Phase 3 Randomised Controlled Trials have previously shown no differences in survival outcomes in non-pemetrexed based regimens. We set out to prospectively audit toxicity and efficacy of four commonly offered platinum-based doublets in the West of Scotland with a view to making comparative conclusions from our data.

Methods:
Patients undergoing first line palliative chemotherapy with a platinum doublet in two lung cancer clinics in the West of Scotland (Glasgow and Lanarkshire) between July 2014 and April 2015 were included. Baseline demographics were obtained and entered into a common database. On each attendance for chemotherapy pre-assessment, toxicity data was recorded using CTC version 4.0 and prospectively entered into the database. Requirements for admission to hospital and the need for blood and platelet transfusions were also recorded.

Results:
To date 54 patients have been included. The median number of chemotherapy cycles was 2.7(150). 55% (30) of patients were male and 45% (24) female, with the majority sub-type being adenocarcinomas. The most commonly prescribed agent with platinum was pemetrexed (52%) followed by gemcitabine (24%) and vinorelbine (22%). The use of paclitaxel was lower than anticipated (2%). Toxicity data is available for all 54 patients (see table 1). Survival outcomes will be reported subsequently along with ongoing collated data on toxicity in additional patients in this prospective audit. Table 1. Figure 1



Conclusion:
First line treatment of advanced NSCLC with platinum doublets in the West of Scotland is generally well tolerated. Toxicities exceeding Grade 2 were uncommon with any of the 4 platinum doublets. However, hospital admission was more likely in those receiving pemetrexed or vinorelbine doublets. The need for blood transfusion was more common in doublets containing pemetrexed or gemcitabine.

Background:
Squamous cell carcinoma is the second most common histologic subtype of non-small-cell lung cancer (NSCLC). Platinum-based doublet chemotherapy regimens remain the basis of front-line systemic treatment. Most studies in NSCLC included all histologic subtypes. Here we present a pooled analysis of gemcitabine in combination with cisplatin or carboplatin, specifically focusing on patients with squamous NSCLC, from three studies for which individual patient data are available. The objective of this analysis was to evaluate the efficacy of first-line gemcitabine plus platinum (GP) compared with other regimens plus platinum (OP).

Methods:
This analysis included squamous NSCLC patients from three randomized, open-label, phase III studies of gemcitabine: 1) gemcitabine plus cisplatin versus etoposide plus cisplatin (n=61), 2) gemcitabine plus carboplatin versus paclitaxel plus carboplatin (n=128), and 3) gemcitabine plus cisplatin versus pemetrexed plus cisplatin (n=473). Patients were grouped into the GP subgroup (n=324) or the OP subgroup (n=338). Efficacy measures included overall response rate (ORR), overall survival (OS), and time to disease progression (TTP). Stratified (by study) Cox proportional hazard regression models were used to analyze OS and TTP by random assignment factors to identify potential prognostic factors and explore their predictive value.

Results:
Baseline characteristics were similar between the GP and OP groups. Median OS was 9.72 months for GP versus 9.33 months for OP (HR=0.898, p=0.223) (Figure 1). There was a significant difference in median TTP (5.52 months for GP versus 4.73 months for OP; HR=0.792, p=0.008) (Figure 2). ORR was 31.5% for GP, and 27.2% for OP (p=0.229). Cox regression model identified three prognostic factors for OS: Eastern Cooperative Oncology Group performance status, prior radiotherapy, and body mass index. Figure 1. Kaplan–Meier estimates of overall survival Figure 1 Figure 2. Kaplan–Meier estimates of time to disease progressionFigure 2





Conclusion:
This pooled analysis further confirmed the efficacy of gemcitabine plus platinum as first-line treatment of squamous NSCLC.

Background:
Targeted therapies have shown clinical benefit in the treatment of solid tumors. The route, frequency, and duration of administration of these agents as well as toxicity profiles differ significantly from traditional cytotoxic chemotherapy. Many studies of targeted therapies report significant numbers of grade 1 or 2 toxicities, which are often regarded as clinically insignificant. We sought to explore whether anticipation of low-grade toxicities and dosing convenience would affect lung cancer patient willingness to undergo therapy.

Methods:
101 lung cancer patients were surveyed at the Vanderbilt Ingram Cancer Center regarding willingness to comply with treatment based on anticipated efficacy, dosing convenience, and toxicity profiles. All toxicities described were CTCAE V.4.0 grade 1 and 2. Willingness to comply with treatment depending upon toxicity, anticipated benefit, and dosing convenience were compared.

Results:
A substantial number of patients professed unwillingness to undergo treatment due to anticipation of chronic grade 1 and 2 toxicities (Table 1). Gastrointestinal (anorexia, nausea, vomiting, diarrhea, or dysgeusia) and constitutional toxicity (fatigue) had a stronger negative impact on patient willingness to undergo therapy than dermatologic toxicity (rash, hand-foot syndrome, or acne). Willingness to tolerate toxicities correlated with expected benefit in life expectancy and chance of cure. Lengthy travel distance for treatment also negatively impacted willingness to undergo treatment.

Table 1: Percentage of lung cancer patients who stated that they would be unwilling to receive treatment by toxicity type and grade.

Adverse Effect	Unwilling to Receive Treatment
Grade 1 Dermatologic Toxicity	5.2%
Grade 1 Gastrointestinal Toxicity	9.5%
Grade 1 Constitutional Toxicity	6.8%
Grade 2 Dermatologic Toxicity	8.7%
Grade 2 Gastrointestinal Toxicity	18.1%
Grade 2 Constitutional Toxicity	19.4%

Conclusion:
Anticipation of chronic low grade toxicities and dosing inconvenience has a negative impact on patient willingness to be treated, which may affect patient adherence and outcomes from therapy. Long-term tolerability should be considered when developing and using novel agents in lung cancer patients.

Background:
Integration of mobile devices/health-related apps into medical practice is transforming healthcare. For clinicians treating NSCLC, the addition of a new app, NSCLC @Point of Care, and its patient companion app, are practice-based tools designed to provide content at the time it is actually needed and the ability to sync with patient data, potentially enabling better decisions, outcomes and care. This survey assesses how this mobile dashboard is used in the NSCLC setting, its effect as a learning tool, and how it can improve patient outcomes.

Methods:
To assess how clinicians utilize the NSCLC @Point of Care dashboard and patient companion app, Projects In Knowledge, the CME provider, sent an online survey to its proprietary database of over 53,000 clinicians caring for NSCLC patients. Respondents reported: demographic information, use of EMR technology, frequency and reasons for accessing the NSCLC @Point of Care app, interest in tracking patient-reported data, and use of patient-reported data in institutional EMR reports.

Results:
Overall findings show a large number of responding clinicians use EMR technology, access the NSCLC @Point of Care App daily for relevant disease/treatment-specific information, and want to track patient-reported data. The survey demonstrates many clinicians are in agreement that the clinician app, NSCLC @Point of Care, and its companion app will not only provide important disease- and treatment-specific information that they need and can access at point of care, but also improve communication of critical and accurate patient data in real-time to ensure optimal interventions and patient outcomes, incorporate patient-reported data from the companion app into EMRs and believe this maneuver can streamline time efficiencies in practice.

Conclusion:
Management of NSCLC, a leading cause of cancer-related mortality, is evolving so rapidly that it is difficult for clinicians to keep current and integrate new improved treatment strategies into practice. Many clinicians surveyed believe the NSCLC @Point of Care dashboard provides a desirable approach for busy clinicians to access information needed to support practice change and improve patient outcomes through point of care accessibility.

Background:
‘Care for Outcome’ is a Value Based Health Care project of Santeon (a cooperation of six leading, top clinical hospitals spread across the Netherlands) in which outcome measures for lung cancer are being measured and reported on a yearly base. In this observational study we report differences in outcome of the 6 participating hospitals.

Methods:
In this retrospective study, data of all lung cancer patients from the Santeon hospitals who were diagnosed between 1-1-2008 and 31-12-2012 was analysed. Primary endpoint in this analysis is mortality. Logistic regression analysis was performed to identify correlating factors for outcome.

Results:
Data of 5922 lung cancer patients was collected. Of these, 3584 (61%) patients had stage IIIB or IV disease. Tumour stage, performance status, age, co morbidity and treatment with or without chemotherapy correlated significantly with survival. Of these factors, treatment with or without chemotherapy had the highest correlation The percentage of patients receiving chemotherapy was significantly different between hospitals, ranging from 36% to 59% (mean 47,6%). The median survival of patients treated with or without chemotherapy (excluding those who died within 45 days and therefore passing the ‘immortal time bias’ effect) was 124 (95%CI 116-132) and 295 (95%CI 281-309) days (p<0.001) respectively. The difference persisted after correction for tumour stage, performance state, age and co morbidity.

Conclusion:
There is a strong variation between hospitals in the percentage of patients with stage IIIB / IV lung cancer receiving chemotherapy. Our data indicate that chemotherapy is an independent prognostic factor for survival. Santeon’s ‘Care for Outcome’ team for lung cancer: Onze Lieve Vrouwe Gasthuis, Amsterdam: A.A.J. Smit, MD PhD, St Lucas Andreas Hospital, Amsterdam: H.J. Smit, MD PhD, Catharina Hospital, Eindhoven: D.W. Dumoulin, MD; B.E.E.M. van den Borne, MD PhD, Medisch Spectrum Twente, Enschede: A.J. Polman MD, Martini Hospital, Groningen: J.W.G. van Putten, MD PhD, Antonius Hospital, Nieuwegein: G.J.M. Herder MD PhD; F.M.N.H. Schramel MD PhD; W.F. van den Bosch PhD, Canisius Hospital, Nijmegen: A. Termeer MD

Background:
An increasing amount of clinical data is available to biomedical researchers, but specifically designed databases and informatics infrastructures are needed to handle this data effectively. Multiple research groups should be able to pool and share this data in an efficient manner. The Chicago Thoracic Oncology Database Consortium (CTODC) was created to standardize data collection and facilitate the pooling and sharing of data at institutions throughout Chicago and across the world.

Methods:
The Salgia Laboratory has implemented the Thoracic Oncology Program Database Project (TOPDP) Microsoft Access, the TORP Velos, and the TORP REDCap databases for translational research efforts. Standard operating procedures (SOPs) were created that document the construction and proper utilization of these databases. These SOPs have been made available freely to other institutions that have implemented their own databases patterned on these SOPs. In order to evaluate the effectiveness of this consortium, we have performed an investigation examining patients receiving erlotinib at three institutions belonging to the CTODC: The University of Chicago Medical Center, Ingalls Health System, and NorthShore University Health System.

Results:
A cohort of 373 lung cancer patients who are taking erlotinib was identified by querying data from all three institutions of the consortium. The patients’ demographic and clinical data were compiled. In addition, the EGFR statuses of patients were analyzed, showing that out of the 70 patients that were tested, 55 had mutations while 15 did not have any mutations. The overall survival and duration of treatment were calculated from the data that was provided. It was shown that patients with an EGFR mutation had longer duration of erlotinib treatment and longer overall survival compared to patients who received erlotinib and were EGFR wild type.

Conclusion:
The investigation described herein demonstrates the successful data collection from multiple institutions in the context of a collaborative effort. However, the investigation identified many challenges in this type of collaboration, such as difficulty of transferring data between institutions and potential duplication of patient data. Overall, these issues do not lessen the findings of the investigation or the effectiveness of the CTODC. With greater cooperation and communication between institutions of the consortium, these issues can be readily resolved. The data presented here can be utilized as the basis for further collaborative efforts and/or development of a larger, more streamlined collection of databases within the consortium.

Background:
SQUIRE, a randomized, phase III study (n=1,093), demonstrated that the addition of the EGFR monoclonal antibody necitumumab (N) to gemcitabine-cisplatin (GC) improved overall survival in patients with stage IV squamous NSCLC. Rash is an established class side-effect associated with EGFR-targeting agents. Previous studies have suggested a positive association between rash and clinical outcomes with EGFR-targeted therapy.

Methods:
Pre-emptive treatment for rash was not allowed per protocol until completion of the first cycle of study therapy. For the purpose of this analysis, patients randomized to the N+GC arm were categorized and grouped according to whether or not they experienced rash during the first two cycles of study therapy. Patients who died or were lost to follow-up before completing two cycles of study therapy were not included in this analysis. Overall survival (OS) and progression-free survival (PFS) were measured from the date of randomization, with parameters estimated using the Kaplan-Meier method. Hazard ratios and 95% CIs between subgroups were estimated from stratified Cox proportional hazards models, with comparisons between arms using a stratified log-rank test.

Results:
505 patients were evaluable in the N+GC arm at the end of cycle 2 of which 69% experienced rash during cycle 1 and/or cycle 2. Patients experiencing rash in the N+GC arm had improved OS (HR=0.738, p=0.0001) and PFS (HR=0.808, p=0.0066) compared with patients in the GC arm. Patients experiencing rash in the N+GC arm had improved OS (HR=0.656, p=0.0001) compared with patients in the N+GC arm who did not experience rash. The difference in PFS between patients in the N+GC arm experiencing rash versus those not experiencing rash was not statistically significant. Median PFS and OS for patients experiencing rash in the N+GC arm was 6.2 mo and 13.6 mo respectively, as compared to 5.6 and 10.2 mo for patients in the N+GC arm without rash and 5.6 and 10.6 mo for patients in the GC arm.

	Patients alive and under follow-up after Cycle 2
	N+GC with rash N=350	N+GC no rash N=155	GC N=508
Overall Survival, mo (CI)	13.6 mo (11.6, 15.2)	10.2 (8.7, 11.6)	10.6 (9.5, 11.9)
HR* (95% CI)		0.656 (0.529, 0.813)	0.738 (0.631, 0.864)
Stratified log-rank p value*		0.0001	0.0001
PFS, mo (CI)	6.2 mo (5.7, 6.9)	5.6 (5.0, 5.7)	5.6 (5.3, 5.6)
HR* (95% CI)		0.867 (0.693, 1.084)	0.808 (0.692, 0.942)
Stratified log-rank p value*		0.2127	0.0066

*In comparison to the N+GC group with rash

Conclusion:
Rash occurring during the first two cycles of treatment with necitumumab (N+GC) is associated with improved OS in patients with advanced squamous NSCLC.

Background:
Erlotinib is epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor which showed efficacy and tolerability in patients with advanced non-small cell lung cancer (NSCLC), especially in patients which harbor activating mutations in EGFR. However, erlotinib also showed efficafy in patient with unknown or wild type EGFR mutation status. The iam of the study was to determine safety and efficacy of erlotinib in patients with advanced (stage IIIB and IV) squamous NSCLC.

Methods:
patients with advanced squamous NSCLC who had failed prior chemotherapy were treated with oral erlotinib 150 mg daily until disease progression or unaccaptable toxicity. Data was analyzed retrospectively.

Results:
a total of 122 patients (107 men and 15 women, mean age 62±8 years) with advanced squamous NSCLC were enrolled in the study from 2006 to 2012 in 14 centers throughout Croatia. More than 50% of patients were active smokers at time of enrollment. Most of the patients had performance status ECOG 1 and 2 (91%). Vast majority of patients were treated with erlotinib in third line setting. After cycle 2, 10% of patients had partial response (PR), and 45% of patients had stable diseases. In total, 55% of patients had disease control after cycle 2. Progression free survival (PFS) was 3.7 months in overall population. Statistically significant differences in PFS were recorded according to response to treatment; patients with PR after two cycles had PFS of 6.2 months comparing to patients with progressive disease (PFS 2.0 months, p<0.001). Patients with better ECOG status (ECOG 1 and 2) had trend to improved PFS (3.8 vs 1.9 months) compared to ECOG 2 and patients with rash after cycle 2 also showed trend to improved PFS (4.1 vs 2.4 months) compared to no rash. There were no grade 3 and 4 toxicities noticed during the study. Overall survival in our study was meaningfully prolonged.

Conclusion:
erlotinib as a single agent showed efficacy in treatment of patients with squamous cell lung cancer without significant toxicities. The best predictive factor of response to treatment was response to erlotinib after 2 months of treatment.

Background:
To report the efficacy and safety results from a study of necitumumab (N), manufactured under process D, modified from Process C, used in the pivotal SQUIRE study, in combination with gemcitabine (G) plus cisplatin (C) as first-line treatment in patients with advanced squamous non-small cell lung cancer (Sq-NSCLC). (NCT01788566)

Methods:
This was an open-label, single-arm, multicenter, phase II study in patients with advanced Sq-NSCLC. Patients were enrolled who were aged ≥18 years and had measurable, pathologically confirmed stage IV Sq-NSCLC without prior chemotherapy. Patients had ECOG-PS 0-1, adequate organ function, and life expectancy of ≥12 weeks. Patients received N (800 mg iv, Days 1 and 8) plus GC (G=1250 mg/m² iv, Days 1 and 8; C=75 mg/m² iv, Day 1) each 3-week cycle for up to 6 cycles. Patients with at least stable disease (SD) could continue to receive N alone until progressive disease (PD) or other discontinuation criteria. Primary endpoint was objective response rate (ORR) based on RECIST1.1. Secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), change in tumor size (CTS; % improvement in lesions), and safety.

Results:
Patients (N=61), median age 65 years, heavy metastatic disease burden; approximately 70% of the patients had metastases to ≥ 2 organ systems. Efficacy results, including an ORR of 48.1% are shown in the Table. Survival and PFS findings were similar to those reported in the SQUIRE study in the GC+N arm (SQUIRE results: median OS of 11.5 months, 1-year survival rate of 47.7%, and median PFS of 5.7 months). Median duration of treatment was 12 weeks (4 cycles) for G and C and 16 weeks (5 cycles) for N; the median relative dose intensity was 85% for G and 93% for C and N. Twenty-eight (46%) patients continued on single-agent N (median: 4 cycles). Skin reactions (n=49; 80.3%) and hypomagnesemia (n=21; 34.4%) were the most commonly reported adverse events of special interest (AESIs, all grades). AESI ≥ Grade 3 were skin reactions (n=8; 13.1%), thromboembolic events (n=7; 11.5%), hypomagnesemia (n=6; 9.8%), and hypersensitivity/ IRR (n=3; 4.9%). There were 27 deaths (20 due to PD and 7 due to AEs [5 had no causal relationship to study drug]) at the time of data cut-off.

Table. Efficacy Results

	N=61
ORR*† (CR+PR), n (%) [95% CI]	26/54 (48.1)† [34.34–62.16]
CR	0
PR, n (%)	26/54 (48.1)†
SD	18 (29.5)
PD	9 (14.8)
Not evaluable	1 (1.6)
Not assessable	7 (11.5)
DCR CR+PR+SD, n (%) [95% CI]	44 (81.5)† [68.57–90.75]
Median OS, months (95% CI)	11.7 [7.59–NA]
1-year survival rate, % (95% CI)	47.6% [30.20–63.08]
Median PFS, months (95% CI)	5.6 [3.68–6.87]
Median CTS, (%)	42.1
*Assessed by investigators
†Patients who had a post-baseline radiological assessment, n=54

Conclusion:
The efficacy results and the safety profile, with N manufactured under process D, are consistent with what is expected for this combination as first-line therapy of patients with metastatic Sq-NSCLC.

Background:
Bevacizumab is a monoclonal antibody which selectively binds to human vascular endothelia growth factor（VEGF）.The combination of bevacizumab with chemotherapy has been one of the choices for advanced non-squamous non-small cell lung cancer（NSNSCLC） patients.In this study we evaluate the efficacy,safety and imaging findings of bevacizumab plus chemotheray in patients with advanced NSNSCLC.In addition, the mutation status of EGFR gene and KRAS gene were detected.

Methods:
Patients adimitted in the hospital were treated with bevacizumab (15mg/kg or 7.5mg/kg, d1) plus chemotherapy(paclitaxel 175mg/m2, d1, carboplatin AUC=5 or 6, d1) with 3 weeks in one cycle,up to 6 cycles,followed with maintenance therapy of bevacizumab(15mg/kg or 7.5 mg/kg, d1) till disease progression. Efficacy, safety, tumoral cavitation, therapeutic outcome of malignant pleural effusion and EGFR, KRAS mutation status were analysed.

Results:
Figure 1 Fig. Imaging changes of pleural effusion before and after treatment. A: Baseline CT of the chest showed plenty of pleural effusion on left side;B: Follow-up CT scan after 4 cycles of therapy demonstrated the pleural effusion had disappeared. 26 Patients were collected.They were all treated with bevacizumab plus chemotherapy.17 patients received maintenance therapy.The median cycle number of chemotherapy was 6, and that of bevacizumab was 8.Partial response(PR), stable disease(SD) and progressive disease(PD) rates were 53.8%, 42.3% and 3.8%，respectively. The median progression free survival(PFS) and overall survival(OS) were11.0 and 25.8 months respectively. Out of 26 patients, 15.4% developed cavitation after treatment.2 years and 3 years survivle rates of cavitation group were lightly higher than those of non-cavitation group(75.0% vs 44.4%, P=0.293, 25.0% vs 12.5%, P=0.509, respectively). Of the 13 patients with malignant pleural effusion, disease control rate of malignant pleural effusion was 100%: complete response(CR) rate was 38.5% and SD rate was 61.5%. EGFR gene ststus were detected in 11 patients. 36.4% showed sensitive mutation. The PR rate of EGFR mutation positive group was higher than that of mutation negitive group (75% vs 28.6%, P=0.262),but not statistically. KRAS mutation has not been found in all the 10 patients whose samsples were capable of being detected. Common adverse effects included myelosuppression, digestive symptoms,epistaxis, ect. Special adverse effects were also observed such as hemoptysis,hypertension,proteinuria etc. Most adverse effects were mild and controllable.



Conclusion:
Bevacizumab with chemotherapy is a promising and safe treatment for patients with NSNSCLC. It was also effective in controlling malignant pleural effusion. Tumoral cavitation were found, but the clinical significance was indeterminate. The relationship of EGFR gene status and efficacy of bevacizumab-based chemotheray is subject to further research.

Background:
Lung cancer is the first cancer in term of incidence and mortality for men in Algeria and a majority of the patients are stage IIIB or IV at the diagnostic. Bevacizumab + chemotherapy as first line followed by continuation maintenance with bevacizumab showed in many phase III randomized trial, an increase of PFS and overall survival. The purpose of this study is the evaluation of efficacy and toxicity of patient after continuation maintenance with bevacizumab in stage IIIB and IV for no squamous lung cancer in single institution.

Methods:
A retrospective study including all patients seen between September 2013 and April 2015, at department of medical oncology in Algiers. • Patients should have advanced or metastatic non squamous (adenocarcinoma and carcinoma with large cell) lung cancer, and received 4 cycles of induction chemotherapy with platine + pemetrexed + bevacizumab. • All patients with response or stable disease received bevacizumab as maintenance therapy, evaluation by CT scan was done every three cycles.

Results:
Twenty (3 F and 17 M) patients were enrolled, and all are evaluable for response and toxicity. Median age was 61.5 years (range m 31 years – M 74 years). Histology was adenocarcinoma in 19 patients and carcinoma with large cell in 1 patient. Sixteen (16) patients had IV stage and four (4) patients had IIIB stage disease. Response rate (1 CR, 4 PR) was seen in 5 patients (25 %), Stable Disease (SD) was achieved in 5 patients (25 %) and Progressive Disease (PD) in 10 patients (50 %). Among the 20 patients who achieved 4 cycles of induction bitherapy + bevacizumab, 10 patients (50 %) underwent for maintenance therapy. All the ten patients received the first three cycle of maintenance with bevacizumab and well tolerated without toxicity. At this time, two patients achieved one year maintenance with stabilization of disease. One of them developed hypertension and is under treatment.

Conclusion:
Bevacizumab was well tolerated in first line treatment and as maintenance, for patients with advanced or metastatic non-squamous lung cancer.

Background:
Tyrozine kinase inhibitors (TKI) targeting epidermal growth factor receptor (EGFR) represent a novel effective tools in management of advanced-stage non-small cell lung cancer (NSCLC). We aimed to evaluate the incidence and predictive role of EGFR gene amplification in patients with advanced-stage NSCLC treated with EGFR-TKIs.

Methods:
The study included 290 patients with advanced-stage (IIIB or IV) NSCLC. Multiplex ligation-dependent probe amplification (MLPA) and Polymerase chain reaction (PCR) were used for detection of EGFR mutations and EGFR gene amplification, respectively.

Results:
EGFR amplification was detected in 26 (9.0%) patients. EGFR amplification was found more frequent in patients harboring EGFR mutation (p < 0.001). No significant corelation between EGFR gene amplification and survival was observed.

Conclusion:
The presence of EGFR gene amplification is associated with EGFR gene mutations. EGFR gene amplification is not a feasible predictive biomarker for the treatment with EGFR-TKIs in patients with advanced-stage NSCLC. This study is supported by Ministry of Health, Czech Republic - conceptual development of research organization Faculty Hospital in Pilsen - FNPl, 00669806 and by the project CZ.1.05/2.1.00/03.0076 from European Regional Development Fund.

Background:
Following first-line chemotherapy, maintenance therapy regimens have shown modest yet statistically significant benefits in progression free survival (PFS). To date, there have been no completed, prospective randomized trials examining the role of locally aggressive therapy in limited metastastic, advanced stage non-small cell lung cancer (NSCLC). We hypothesized that stereotactic body radiotherapy (SBRT) prior to maintenance chemotherapy would further improve PFS. This trial also serves to provide prospective survival data for a population with limited metastatic NSCLC.

Methods:
This is a two-arm randomized phase II trial. Eligible patients have stable disease or partial response with limited metastatic disease (defined by six or fewer sites amenable to SBRT) after treatment with up to 6 cycles of first line platinum doublet chemotherapy. Patients are then randomized to investigator’s choice maintenance chemotherapy alone or SBRT to all amenable sites followed by maintenance chemotherapy. The primary endpoint of the study is PFS, with 36 patients required to demonstrate an increase from 4 months in the control arm to 10 months in the experimental arm, with 80% statistical power and a 2-sided significance level of 0.10.

Results:
Since May 2014, 11 patients have been enrolled (5 to SBRT + maintenance arm; 6 to maintenance arm). The median number of first-line chemotherapy cycles was four, with the most common regimen carboplatin/paclitaxel followed by carboplatin/pemetrexed. The median number of maintenance chemotherapy cycles was six, the most common agent being pemetrexed followed by bevacizumab. The median number of sites treated with SBRT were two, with the lung the most common anatomic location followed by the adrenal gland. Five patients have progressed to date, three in the maintenance chemotherapy arm and two in the SBRT + maintenance chemotherapy arm. Progression in the maintenance alone arm occurred in original sites of disease in two of three patients. There have been no in-field failures in the SBRT arm. There has been one death due to disease progression in the maintenance chemotherapy arm. No patients have suffered a grade 3 or higher adverse event related to protocol therapy.

Conclusion:
This study demonstrates the feasibility of enrolling patients with limited metastatic lung cancer to a randomized trial of local therapy following first-line chemotherapy. To date, all patients have tolerated the administration of SBRT to multiple sites in between first-line and maintenance chemotherapy without any grade 3 or higher adverse events. Continued follow-up will be necessary to determine the efficacy of the experimental arm.

Background:
In general, bevacizumab is well-tolerated treatment in patients with advanced, metastatic non-squamous NSCLC. Despite this, permanent discontinuations of bevacizumab occur also before progressive disease (PD), both in clinical trials and in clinical practice. Purpose of this study was to find out the reasons for permanent discontinuation of bevacizumab before PD in patients treated in two centers in the Slovak republic.

Methods:
In this retrospective study, approved by the Ethics Committee of the Specialized Hospital of St Zoerardus Zobor, the institutional databases were searched for patients with advanced NSCLC treated with bevacizumab between 2007 and 2013.

Results:
Altogether 161 patients were included into the analysis. Patients' characteristics: M/W: 99/62, age: median 61 years (32 - 83), histologically /cytologically confirmed NSCLC: adenocarcinoma/large cell/adenosquamous: 158/2/1. Number of cycles with bevacizumab (induction and maintenance): median 8 (1 - 52), PFS: median 7 months (1 - 42). Bevacizumab was permanently discontinued before PD in 28 of 161 patients (17,4%), in 18 of 161 (11,2%) due to undesirable effects - Table 1. Table 1: Reasons for permanent discontinuation of bevacizumab in non-progressing NSCLC

Undesirable effects	N	Other reasons	N
Cavitation	3	Lost to FU	2
Pneumothoraces	3	Molecular testing, start of TKI	2
Cerebrovascular event	2	Patients' preference	2
Gastrointestinal perforation	2	Car accident, death	1
Hypertensive crisis	2	Planned surgery	1
Pneumonia	2	Traumatic fractures	1
Proteinuria	2	Other	1
Thrombotic event	2
All	18	All	10

Conclusion:
Permanent discontinuation of bevacizumab in non-progressing NSCLC was seen in this study in the similar rate as in the larger trials (Wozniak AJ et al. Clin Oncol [Coll Radiol]. 2015, 27:187-96.) However, some differences are in the type of undesirable effects, which are in part also chemotherapy related.

Background:
KRAS mutations are the most common mutations in non-small cell lung cancer (NSCLC). Theoretically those patients are resistant to tyrosine kinase inhibitors, but studies are contradictory. The aim of this study was to compare second-line chemotherapy with docetaxel and erlotinib in patients with NSCLC, EGFR wild-type, depending on their KRAS status.

Methods:
We included 47 patients diagnosed with NSCLC, EGFR wild type, followed in a Lung Cancer Unit and treated with docetaxel or erlotinib as second-line chemotherapy. KRAS mutations in exon 12 and 13 were screened. Patients were divided in two arms: docetaxel arm and erlotinib arm. Time to progression to each second-line chemotherapy and overall survival after second-line chemotherapy was compared between patients with KRAS mutations and KRAS wild-type. In patients with KRAS mutations, time to progression and overall survival after second-line chemotherapy was compared between docetaxel and erlotinib.

Results:
87% were male, mean age 65±11 years, 77% smokers or ex-smokers, 81% non-squamous tumors, 70% stage IV at diagnosis. Analyzing all patients, there was no statistical difference regarding the time to progression and overall survival between patients with or without KRAS. 14 patients were in docetaxel arm and 33 patients in erlotinib arm. There were no statistical differences between arms regarding gender, smoking status, performance status and stage at diagnosis. Patients in docetaxel group were younger (60±9 years vs. 67±11 years, p=0.027). In docetaxel arm, 3 patients had KRAS mutations. We found no statistical differences between patients with or without mutations regarding time to progression and overall survival after docetaxel. In erlotinib arm, 7 patients had KRAS mutations. We found no statistical differences between patients with or without mutations regarding time to progression and overall survival after erlotinib. In patients with KRAS mutations, time to progression tends to be slightly higher in erlotinib arm (2 vs. 1 month, p=0.088) and overall survival after second-line chemotherapy seems to be similar.

Conclusion:
Unlike what is reported in some studies, we found no differences concerning KRAS status with respect to overall survival and time to progression. Moreover, it seems that there are no differences between docetaxel and erlotinib in second-line treatment. This questions the non-use of erlotinib in second-line treatment of KRAS mutated NSCLC patients.

Background:
Following the gefitinib (IRESSA[®]) NDA voluntary withdrawal, which previously had allowed for limited commercial distribution of IRESSA, gefitinib became available under the IRESSA Clinical Access Program (ICAP) in June 2011. The ICAP continued to provide drug access to patients who were benefiting or had benefited from treatment with gefitinib through restricted distribution (2005-2011) or through a clinical trial that was IRB approved prior to June 2005. ICAP participants constitute a unique subset of cancer patients in whom long-term use of gefitinib can be studied. Consequently, this is the first study to describe long-term safety and tolerability data for an EGFR TKI in cancer patients outside of the clinical trial setting.

Methods:
This study utilizes 2 data sources: (1) retrospective patient medical chart review of demographics, including safety and tolerability of prolonged treatment with gefitinib as part of the ICAP; and (2) retrospective review of serious adverse event (SAE) reports in the AstraZeneca safety database, as all ICAP investigators are responsible, per protocol, for reporting all SAEs observed for ICAP participants.

Results:
A total of 188 patients were enrolled in the ICAP from 134 sites across the US; 94 patients (50.0%) remain on active treatment. This study aims to include as many sites and patients as feasible. Currently, 46 sites representing 77 patients have agreed to participate; site enrollment and data collection are ongoing. As of July 16, 2015, chart abstractions of 16 patients were completed. These patients have a median age of 68.0 years, are predominantly female (75.0%), non-Hispanic white (87.5%), with a confirmed NSCLC diagnosis (93.8%). More patients received gefitinib in second line (43.8%) followed by first line (37.5%) and third line (18.8%). Median gefitinib duration prior to ICAP initiation was 11.3 years (range 9.1-13.9 years), with median gefitinib duration as part of the ICAP being an additional 3.5 years (range: 0.3-3.8 years). During the ICAP, 93.8% of patients (95% CI: 87.9-99.6) did not experience any dose reductions, interruptions, or discontinuation due to gefitinib-related adverse events. The AstraZeneca Safety Database showed 123 SAEs reported from 54 ICAP patients as of February 26, 2015. The majority of SAEs were consistent with underlying disease conditions and were considered unrelated to gefitinib therapy by investigators. 5.6% of patients (3/54) had potentially causally related SAEs as determined by investigators: one patient had procedure-related bronchitis, lung infection, and exacerbation of preexisting COPD with a fatal outcome; one patient experienced interstitial lung disease, pulmonary alveolar hemorrhage, and acute respiratory and renal failure (patient recovered with sequelae); and one patient developed dermatitis acneiform and pruritus. Of the remaining 51 patients, 20 had fatal outcomes (39.2%). The majority of fatalities (12) had insufficient information to assess cause of death and may have had other alternative causes, including underlying or concurrent diseases (6) and possible disease progression (2).

Conclusion:
: Characterization of long-term gefitinib use among this subset of NSCLC patients indicates acceptable long-term tolerability and indicates that some patients have long-term (>10 year) benefit. Clinical and genetic features associated with long-term benefit need further study.

Background:
MicroRNA expression is commonly suppressed in cancer, contributing to tumor cell biology. Recently we demonstrated that multiple members of the miR-15/16 family are downregulated and have tumor suppressor functions in malignant pleural mesothelioma (MPM), an asbestos-related cancer for which few treatments are available. These results are similar to previous findings in non-small cell lung cancer (NSCLC). As multiple microRNAs from the same family are downregulated in MPM, we investigated whether a single synthetic mimic based on the consensus sequence of the entire family could restore activity of the entire family.

Methods:
Novel microRNA mimics based on the consensus sequence of the miR-15/107 group were designed (con15/107.1 to 4). The effects on growth, migration, target regulation, drug sensitivity and angiogenesis of the con15/107 mimics were compared with native miR-15 and miR-16 mimics using standard assays in MPM and lung cancer cell lines in vitro. The regulation of specific target genes was assessed by RT-qPCR, Western blot and luciferase reporter assays. Global gene regulation was assessed by proteomics. Activity of con15/107 mimics was investigated in vivo in xenograft models in nude mice.

Results:
The consensus mimics inhibited growth and migration of MPM and lung cancer cell lines in vitro, and effects were greater than with native miR-15 or miR-16 mimics. Growth inhibition was associated with an induction of apoptosis, and downregulation of predicted targets of the mimics. Target gene interactions were confirmed with 3’UTR reporter constructs, and proteomics identified a number of candidate genes involved in consensus mimic-induced growth inhibition. Consensus mimics also sensitized multiple MPM and lung cancer cell lines to chemotherapy agents, and inhibited angiogenic activity in endothelial cells. In a xenograft model, the consensus mimic con15/107.2, packaged in bacterially-derived, EGFR antibody-targeted, EDV[TM]nanocells, inhibited MPM tumor growth in vivo.

Conclusion:
The novel con15/107 mimics based on the consensus sequence of the miR-15/107 group have greater activity than native miR-15 or miR-16 mimics in vitro and are active in vivo. Increased activity correlates to greater target gene downregulation. These preclinical studies support a Phase I clinical trial has been initiated for patients with MPM or NSCLC failing standard therapy. This represents the first trial of microRNA replacement as a therapy for thoracic cancer.

Background:
There is molecular heterogeneity of lung cancers, especially non-small cell lung cancer (NSCLC). Even though pathways such as EGFR and ALK are understood much more, we are beginning to understand the role of MET receptor tyrosine kinase (RTK). The initial trial of EGFR with MET inhibitor was no better than single agent, we strongly believe that it is a subset of MET abnormalities that lead to the pathogenesis of lung cancer. In order to better define this, we are studying the MET function in invasion of NSCLC. We are utilizing the novel ECIS method to study biological behavior.

Methods:
Immunofluorescence of Met/pMet staining was performed with the following antibodies: c-MET (NovusBio) and p-METet (Tyr1230,1234,1235, Invitrogen). Immunoblot analyses of MET/pMET and related signal transduction molecules were performed on H1993 (MET amplified cell line) and A549 (KRAS mutated cell line, with activated MET) cell lysates. ECIS instrument (Applied Biophysics Inc) was used for motility assay and proliferation assay. Confluent cell monolayer was electrically abrased at 6V for 30 seconds. Impedance and resistance of the cell layer were immediately recorded for a period of up to 20 hours. For proliferation assay cells were seeded in 8W10E plates without or with inhibitors. Impedance and resistance were measured for 48 hours at 15 kHz. MET inhibitors were also utilized in the study.

Results:
In our study we investigated the inhibition potential of MET inhibitors. Staining with MET antibody resulted in nuclear and perinuclear staining of both of the cell lines. HGF treatment (100 nM, 20 min) increased nuclear staining. p-MET also increased in the presence of HGF and had plasma membrane, perinuclear and nuclear pattern. 48 hours pre-incubation with MET inhibitors reduced cellular MET staining and abolished MET phosphorylation. Moreover immunoblotting assay demonstrated significant reduction of MET phosphorylation in untreated and HGF treated cells. We measured biological activity of the cells in the presence of inhibitors. MET inhibitors significantly reduced growth rate compared with untreated cells as assessed by electrical resistance measurement. Next we did ECIS based wound-healing assay for a quantitative determination of MET inhibitors on migration potential of NSCLC cells. Voltage pulse led to drastic decrease of cell resistance. MET inhibitors delayed for 35% return to resistance value of the resting cells.

Conclusion:
MET inhibitors reduced NSCLC cell motility, migration and invasion. Novel MET inhibitors can be used for therapeutic intervention against NSCLC. The nuclear localization of MET is a novle function and needs to be explored further. ECIS also is a novel technique to study the biology of epithelial cancers.

Background:
More effective treatment strategies are required for pts with brain metastasis (BM) from non-small cell lung cancer although whole-brain radiotherapy (WBRT) remains the standard treatment. Erlotinib, an effective TKI in EGFR mutant NSCLC, has shown evidence of intracranial accumulation, and has been proven with well tolerability and favorable objective response rate (71%) when concurrent with WBRT. One phase II study (n=80) reported no advantage in median neurological PFS or OS for concurrent erlotinib (100mg/d) and WBRT (20 Gy/5f) in pts with predominantly EGFR wild-type NSCLC compared to WBRT alone, while another single arm phase II study (n=40) found that pre-treatment with erlotinib (150mg/d for 1 wk) followed by concurrently with WBRT (35 Gy/12f) could extend median OS to 11.8 months in all population and 19.1 months in EGFR mut pts. The optimal administration schedule for erlotinib concurrent with WBRT for BM NSCLC is controversial, which should be confirmed in a randomized controlled trial in a more larger population. This phase III trial is to investigate the efficacy and safety of erlotinib pre-treatment followed by combination of erlotinib and WBRT in comparison to WBRT alone in multiple BM NSCLC pts.

Methods:
This was an open-labeled, randomized, multicenter phase III clinical trial. Pts, aged≥18 and KPS≥70, with at least two BMs of NSCLC from 7 medical centers were recruited began in August 2013. Pts with previous use of EGFR-TKI need to withdraw≥4 weeks if assigned to the experimental arm. ARMs for detection of EGFR mutation in tumor tissue is mandatory. The major exclusion criteria included previous brain radiotherapy, or any uncontrolled or symptomatic major medical illnesses or neurologic/psychiatric illnesses. The enrolled pts would be randomly assigned to either erlotinib (150mg/day) concurrent WBRT (2.0Gy/day, 5 days/week, total dose 40Gy) or WBRT alone group with a 1:1 allocation (Fig.1). Only pts with EGFR sensitive mutation will continue to use erlotinib until disease progression or intolerable adverse events. The primary endpoint is the time to neurologic progression (TTP), defined as evidence of progression of brain metastasis (The total of longest diameter more than 20% enhanced area in MRI) or of emergency of new intracranial metastases. The secondary endpoints include, OS, ORR and QoL and subgroup analyses. Till February 12, 2015, 125 of planned 224 pts have been enrolled. This study is registered in clnicaltrials.gov (NCT01887795). Figure 1



Results:
not applicable

Conclusion:
not applicable

Background:
Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. PS binding to PS receptors on myeloid derived suppressor cells (MDSC) and M2 macrophages leads to production of anti-inflammatory cytokines such as TGF-β and IL-10. Bavituximab, a first-in-class PS-targeting monoclonal antibody, counters these effects, resulting in production of pro-inflammatory cytokines such as TNF-α and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte (CTL) immunity. Docetaxel has also been shown to suppress MDSCs while increasing tumor antigens and T-cell mediated cytotoxicity, thereby enhancing bavituximab’s immunomodulatory effects. In a prior double-blind Phase II trial in 2nd line non-squamous non-small cell lung cancer, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control.

Methods:
SUNRISE is a Phase III, double-blind trial where patients with previously treated Stage IIIb/IV non-squamous, non-small cell lung cancer are randomized in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab or placebo, followed by maintenance with weekly bavituximab or placebo until progression or toxicity. Patients will be stratified by region (North America, Europe, or Rest of World), disease stage (IIIb or IV), and previous maintenance/targeted therapy (yes or no). This trial was initiated in December 2013 and accrual of 582 patients across 160+ sites in 14 countries is planned over 24 months. The primary endpoint is OS and two interim analyses are planned. Secondary endpoints include progression-free survival (PFS), overall response rate (ORR) and safety. Radiographic tumor response is centrally assessed every two cycles during combination therapy and every nine weeks during maintenance. Exploratory analysis will include the assessment of changes in circulating immune cells and cytokines to better understand the immunotherapeutic mechanism.

Results:
Trial in progress

Conclusion:
Trial in progress

Background:
Activating EGFR mutations including the L858R mutation and exon 19 deletions (del19) are key drivers of non-small cell lung cancer (NSCLC) in 10%–15% of patients of European and 30%–35% of Asian descent.[1] Acquired resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib can be driven by additional EGFR mutations, with exon 20 T790M accounting for 50%–60% of cases.[2] Rociletinib (CO-1686) was designed to inhibit T790M as well as L858R and del19 while sparing wild-type EGFR and has demonstrated response rates up to 67% in patients with T790M mutations who had progressed on first or later line EGFR inhibitor therapy. Rociletinib continues to be well tolerated by patients in ongoing studies.[3] Given that T790M mutated subclones commonly emerge during treatment with existing EGFR inhibitors, early targeting of T790M along with initial activating mutations is a rational approach to delay progression.

Methods:
TIGER-1 (NCT02186301) is a randomized, open label study of rociletinib vs erlotinib in patients with mutant EGFR NSCLC. Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced treatment-naive NSCLC (no prior therapy in the metastatic setting and no CNS disease), with documentation of ≥1 activating EGFR mutation (excluding exon 20 insertions) and biopsy within 60 days will be enrolled in this 2-part study. All patients will be randomized 1:1 to rociletinib (500 mg twice daily) or erlotinib (150 mg once daily) and treated until death, qualifying adverse events or disease progression. Patients will be stratified by sensitizing EGFR mutation (T790M, del19, L858R, or other) and territory (Asian vs non-Asian geography). The same patient eligibility criteria will be used for the Phase 2 and Phase 3 portions of TIGER-1. The phase 2 portion is currently enrolling and will transition to the Phase 3 portion upon enrollment of the 201[st] patient. The maturing Phase 2 dataset will contribute to decision-making rules for the Phase 3 interim analyses. The Phase 3 portion will incorporate larger cohorts; the final sample sizes will be determined by interim analyses where the chances of success will be estimated at pre-planned enrollment milestones. The primary endpoint is PFS; secondary efficacy endpoints include objective response rate, duration of response, disease control rate and overall survival. Safety will be assessed via standard adverse event reporting. PFS and OS will be summarized with Kaplan-Meier plots. The stratified log-rank and hazard ratio will compare PFS distributions for rociletinib- vs erlotinib-treated patients. Enrollment is ongoing. 1. Herbst R et al. N Engl J Med. 2008 2. Yu H et al. Clin Cancer Res. 2013 3. Sequist LV J Clin Oncol. 2014

Results:
Not applicable

Conclusion:
Not applicable

Background:
Nivolumab, an anti-PD-1 inhibitor, has demonstrated anti-tumor activity in several solid tumors and is approved for unresectable/metastatic melanoma and disease progression following ipilimumab, and if BRAF V600 mutation positive, a BRAF inhibitor; and for metastatic squamous NSCLC in patients with progression on/after platinum-based chemotherapy. Combining a taxane, which can act as a cytotoxic and an immunomodulator, with an immune checkpoint inhibitor has demonstrated improved outcomes over chemotherapy alone in NSCLC. First-line nivolumab and solvent-based paclitaxel plus C (sb-P/C) resulted in a 43% overall response rate and a median progression-free survival of 31 weeks in an interim analyses from a phase I trial in patients with advanced NSCLC (Antonia et al. Presented at ASCO 2014 [Abstract 8113]). nab-Paclitaxel (nab-P) based therapy has demonstrated improved efficacy over standard treatment in pancreatic and breast cancers, and nab-P plus carboplatin (nab-P/C) significantly improved the primary endpoint (ORR) vs sb-P/C in a phase III trial of patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-2062) and does not requires immunosuppressive premedication. This phase I, open-label, 6-arm, multicenter trial, will evaluate safety of nivolumab with nab-P in 3 cancer types: advanced NSCLC (+ C), advanced pancreatic cancer (± gemcitabine), and metastatic breast cancer; 2 arms in each disease. The study design for the NSCLC portion is described below.

Methods:
Eligibility criteria include histologically/cytologically confirmed stage IIIB/IV NSCLC, no prior chemotherapy for metastatic disease, prior adjuvant chemotherapy allowed providing completion >12 months before study entry, ECOG PS 0-1, adequate organ function, and preexisting peripheral neuropathy grade <2. NSCLC patients will be treated in 2 arms: 4 cycles of nab-P 100 mg/m[2] on days 1, 8, and 15 plus C AUC 6 on day 1 of a 21 day cycle with nivolumab 5 mg/kg on day 15 starting at cycle 1 or the same nab-P/C regimen with nivolumab 5 mg/kg on day 15 starting at cycle 3. In both arms, nivolumab monotherapy will begin at cycle 5. Part 1 will assess the dose-limiting toxicities (DLTs) of the nivolumab dose with nab-P/C (≈ 6 patients/arm). If deemed safe, the treatment arms may be expanded using the recommended part 2 dose with an additional ≈ 14 patients/arm (total of 20 nivolumab-treated patients/arm) to further assess safety and tolerability as well as anti-tumor activity. Patients will be allowed to continue nivolumab treatment beyond RECIST 1.1 disease progression (physician discretion). ClinicalTrials.gov number NCT02309177. Figure 1 .



Results:
Not applicable

Conclusion:
Not applicable

Background:
Platinum-doublet chemotherapy with or without maintenance therapy is the standard-of-care first-line therapy for patients with NSCLC that do not harbor EGFR sensitizing mutations or ALK translocations. Most patients experience disease progression despite treatment with chemotherapy, with median overall survival <12 months. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1, has demonstrated a manageable safety profile and robust antitumor activity as first-line therapy in patients with advanced NSCLC enrolled in the phase 1b KEYNOTE-001 study. Improved efficacy was observed in patients whose tumors strongly expressed PD-L1 (ie, showed membranous staining in ≥50% of tumor cells). The international, open-label, phase 3 KEYNOTE-024 trial (ClinicalTrials.gov identifier NCT02142738) is designed to assess the efficacy and safety of pembrolizumab with those of standard-of-care platinum-doublet chemotherapy in patients with treatment-naive metastatic NSCLC and PD-L1 expression in ≥50% of tumor cells.

Methods:
Patients aged ≥18 years with previously untreated advanced NSCLC without EGFR sensitizing mutations or ALK translocations, membranous PD-L1 expression in ≥50% of tumor cells, Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, no active autoimmune disease, or history of interstitial lung disease are eligible. PD-L1 expression is determined by immunohistochemistry in newly collected tumor samples at a central laboratory. Patients are randomly assigned in a 1:1 ratio to receive a 200-mg fixed dose of intravenous pembrolizumab every 3 weeks (Q3W) or investigator’s choice of up to 6 cycles of gemcitabine 1250 mg/m[2] plus cisplatin 75 mg/m[2], gemcitabine 1250 mg/m[2] plus carboplatin AUC 5 or 6, pemetrexed 500 mg/m[2] plus carboplatin AUC 5 or 6, pemetrexed 500 mg/m[2] plus cisplatin 75 mg/m[2], or paclitaxel 200 mg/m[2] plus carboplatin AUC 5 or 6; patients with nonsquamous histology may receive pemetrexed 500 mg/m[2] Q3W maintenance therapy. Randomization is stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and region (East Asia vs non-East Asia). Pembrolizumab will be given for up to 35 cycles or until disease progression, intolerable toxicity, or patient withdrawal. Eligible patients may remain on pembrolizumab therapy after initial radiographic disease progression. Patients who complete 35 cycles of pembrolizumab or who stop treatment after achieving complete response may be eligible for 1 year of pembrolizumab retreatment. Crossover to pembrolizumab is permitted for patients who progress on chemotherapy. Tumor imaging is performed every 9 weeks; response is assessed per RECIST v1.1 by independent central review and by modified RECIST by investigator review. Adverse events will be collected throughout the study and for 30 days (90 days for serious adverse events) thereafter; all toxicities will be graded according to NCI CTCAE v4.0. The primary end point is progression-free survival per RECIST 1.1 by central review; secondary end points are overall response rate per RECIST 1.1, overall survival, and safety. Enrollment is ongoing and will continue until approximately 300 patients are assigned to treatment.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Platinum doublet chemotherapy with or without bevacizumab is the standard first-line therapy for patients with advanced NSCLC without EGFR sensitizing mutations or ALK rearrangement. Pembrolizumab (MK-3475), a humanized monoclonal antibody against PD-1 designed to block the interaction of PD-1 with its ligands PD-L1 and PD-L2, has shown efficacy and a manageable toxicity profile in patients with NSCLC treated at doses ranging from 2 mg/kg every 3 weeks to 10 mg/kg every 2 weeks. In 45 patients with treatment-naive advanced NSCLC treated in KEYNOTE-001, single-agent pembrolizumab has demonstrated a response rate of 26%.

Methods:
KEYNOTE-021 (ClinicalTrials.gov, NCT02039674) is an international, open-label, multi-arm, phase 1/2 trial of pembrolizumab for advanced NSCLC. After establishing the safety and tolerability of pembrolizumab plus carboplatin and pemetrexed in phase 1, a randomized phase 2 cohort comparing the efficacy of pembrolizumab plus carboplatin and pemetrexed with that of carboplatin and pemetrexed has been initiated. Key eligibility criteria for this cohort are previously untreated stage IIIB/IV nonsquamous NSCLC, no sensitizing EGFR mutation or ALK rearrangement, and ECOG PS 0-1. Patients will be randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W plus carboplatin and pemetrexed at standard doses or carboplatin and pemetrexed alone. Randomization will be stratified by PD-L1 expression determined by immunohistochemistry at a central laboratory (positive [membranous expression in ≥1% of tumor cells] vs negative). Pembrolizumab will be given for 24 months or until progression, intolerable toxicity, or investigator decision. Pembrolizumab may be continued beyond radiographic progression in eligible patients. Carboplatin and pemetrexed will be given for 4 cycles followed by maintenance pemetrexed, alone or with pembrolizumab. Patients allocated to the chemotherapy-alone arm who experience progression may cross over to the pembrolizumab arm of the study. AEs will be monitored throughout treatment and for 30 days thereafter. Response will be assessed every 6 weeks for the first 18 weeks, then every 9 weeks in year 1 and every 12 weeks in year 2. Survival follow-up will occur every 3 months after discontinuation of study treatment. Primary end point is progression-free survival (RECIST v1.1, central review); secondary end points include overall survival, objective response rate, and correlation of PD-L1 expression with antitumor activity. This cohort is currently enrolling patients.

Results:
Not applicable.

Conclusion:
Not applicable.

Background:
Abemaciclib (LY2835219) is a potent, selective small molecule inhibitor of CDK4/6, which has been shown to inhibit cell cycle progression by preventing the phosphorylation and functional inactivation of the Rb tumor-suppressor protein. Cell cycle dysfunction due to abnormalities in the CDK4/6 pathway occurs in NSCLC. KRAS mutant xenografts predict for greater sensitivity to CDK4/6 inhibitors. In a phase 1 study with abemaciclib (Goldman ASCO 2014), 16 patients with KRAS mutant tumors (N=29) had a response of stable disease (SD) or better (disease control rate [DCR]=55.2%), and 9 patients with KRAS wild-type tumors (N=24) had a response of SD or better (DCR=37.5%).

Methods:
JUNIPER (NCT02152631) is a randomized, phase 3 study of abemaciclib (200 mg orally q12hrs) + best supportive care (BSC) versus erlotinib (150 mg orally q24hrs) + BSC in patients with stage IV NSCLC whose tumors have detectable KRAS mutations and who have progressed after platinum-based chemotherapy and one other prior therapy or who are not eligible for further chemotherapy. About 550 patients will be randomized to abemaciclib or erlotinib 3:2 ratio using following factors: number of prior chemotherapy regimens (1 vs. 2), ECOG PS (0 vs. 1), gender (male vs. female) and KRAS mutation (G12C vs. others). This design has 80% power to detect overall survival (OS) hazard ratio (HR) of 0.75 (type I error 0.045) and progression-free survival (PFS) HR of 0.67 (type I error 0.005). Erlotinib was chosen as the control arm, as it is the only agent indicated for both 2nd and 3rd line therapy in advanced NSCLC. Treatment will continue until disease progression or unacceptable toxicity occurs, with assessments every 28 days, followed by short-term and long-term follow-up. Primary objectives are to compare OS and PFS of the treatment arms. Enrollment began December 2014. If the primary objectives are achieved, this study will provide results on an alternative treatment option, abemaciclib + BSC, for patients with NSCLC whose tumors have detectable KRAS mutations, currently a patient population with few treatment options.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Patritumab (P) is a fully human monoclonal antibody directed against human epidermal growth factor receptor 3 (HER3) that blocks activation by the ligand, heregulin (HRG), and induces receptor internalization. A Phase 2 study (NCT01211483) demonstrated that addition of P to erlotinib (E) increased progression-free survival (PFS) for the subgroup of advanced non–small cell lung cancer (NSCLC) patients with high HRG mRNA expression (HRG-high); a generally similar safety profile was seen with P+E compared with E monotherapy. To confirm these results, P+E vs. E is being investigated in a 2-part Phase 3 study designed to further evaluate the predictiveness of the HRG biomarker in patients with advanced NSCLC (https://clinicaltrials.gov/ct2/show/NCT02134015).

Methods:
HER3-Lung is randomized, placebo-controlled, double-blind, 2-part (A and B), Phase 3 study. Part A will enroll subjects with any HRG expression (limited to approximately one-third of subjects with HRG-low expression) to confirm efficacy of P+E vs. E in HRG-high disease and to possibly refine the cut-off level of HRG expression. The primary endpoint of Part A is PFS and secondary endpoints are objective response rate, overall survival, and safety. Part B will enroll subjects with HRG-high disease, defined as having a cut-off based upon the results of Part A and previous Phase 2 results. Part B is designed to independently provide pivotal confirmation of the efficacy and safety of P+E vs. E in the biomarker-defined population (n=600). The primary endpoint of Part B is overall survival. For both Part A and Part B, subjects must be aged ≥20 years with advanced NSCLC previously treated with 1 or 2 systemic therapies, and if adenocarcinoma histology, wild-type for EGFR and ALK. Tissue assessable for HRG expression must be available from archival or recently collected tumor sample. For Part A, subjects will be stratified by histology subtype, Eastern Cooperative Oncology Group performance status (0, 1) and best response to the most recent systemic therapy. Within each stratum, patients will be randomized 1:1 to P (18 mg/kg intravenous loading dose, then 9 mg/kg maintenance dose every 3 weeks) + E (150 mg/day orally) or placebo + E. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal of consent.

Results:
Recruitment commenced in April 2014, and enrollment of Part A is ongoing. Investigational sites are located in Europe, United States and Canada.

Conclusion:
This study employs an innovative design to confirm efficacy in HRG-selected subjects while evaluating the expression cut-off before pivotal confirmation of efficacy and safety in the HRG-high subpopulation of EGFR wild-type NSCLC.

Background:
M is a human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to programmed cell death-1 and CD-80 with high affinity and selectivity, and T is a selective human IgG2 mAb inhibitor of cytotoxic T-lymphocyte antigen-4 (CTLA-4). Both PD-L1 and CTLA-4 are regulators, or checkpoints, of T-cell activation. PD-L1 expression may be associated with greater clinical benefit of anti-PD-1/PD-L1 agents. Thus, the subset of patients with PD-L1-negative tumors represent a cohort with limited therapeutic options, and may benefit from the combination of M+T. Preclinical data, including mouse models of transplantable solid tumors, suggest that targeting both pathways may have synergistic antitumor activity. Emerging pharmacokinetics, pharmacodynamics, safety and efficacy data from a phase Ib study of M+T in advanced NSCLC (NCT02000947) has determined the appropriate dose for this combination.

Methods:
This randomized, open label, multi-center, phase III study (NCT02352948) is designed to evaluate the efficacy and safety of M (10mg/kg once every 2 weeks [Q2W] for up to 12 months) vs SoC (gemcitabine 1000 mg/m[2] iv Days 1, 8, and 15, vinorelbine 30 mg/m[2] iv on Days 1, 8, 15 and 22 or erlotinib 150 mg once daily, on a 4-weekly schedule until PD at the investigator’s discretion) in NSCLC patients with PD-L1-positive tumors (based on archival tumor sample or recent biopsy) (Sub-study A), and the combination of M+T (M 20mg/kg + T 1mg/kg Q4W for 12 weeks then M alone 10mg/kg Q2W for 34 weeks) vs M or T (10mg/kg Q4W for 24 weeks then Q12W for 24 weeks) vs SoC in NSCLC patients with PD-L1-negative tumors (Sub-study B). PD-L1-positive is defined as ≥25% of tumor cells with membrane staining based on central assessment. Approximately 300 patients will be randomized 1:1 in Sub-study A and approximately 600 patients in a 3:2:2:1 ratio (M+T or SoC or M or T) in Sub-study B. Retreatment with immune-therapy is allowed within the setting of PD. For both sub-studies, an interim analysis for OS (and also PFS for Sub-study B) will be performed. Eligible patients include patients (PS of 0-1) with locally advanced or metastatic NSCLC, who have received at least 2 prior treatment regimens including 1 platinum-based chemotherapy. Patients with brain metastases or spinal cord compression are excluded unless asymptomatic, treated and stable off steroids. Patients with known EGFR activating mutations or ALK rearrangements are not eligible, nor patients previously exposed to any anti-PD-1 or anti-PD-L1 antibody. The primary objective is to assess PFS (per RECIST 1.1 as assessed by the Blinded Independent Central Review) and OS of M (PD-L1-positive) and M+T (PD-L1-negative), compared with SoC, in sub-study A and B, respectively. Secondary objectives include proportion of patients alive at 12 months, objective response rate, duration of response, PFS at 6 and 12 months, safety, tolerability, pharmacokinetics, immunogenicity and health-related QoL. Tumor assessments are performed every 8 weeks (first 48 weeks) then every 12 weeks. A confirmatory scan is required following the initial demonstration of PD. Recruitment in the study is ongoing since January 2015.

Results:
Not applicable

Conclusion:
Not applicable

Background:
The role of third and further line therapies in advanced NSCLC is contentious both for patients harboring EGFR mutations and ALK translocations and for patients without activating mutations. Recent studies have demonstrated that activation of the EGFR pathway induces PD-L1 expression, thereby facilitating evasion of the host’s anti-tumor immune response as a potential mechanism of targeted therapy resistance. This evidence suggests a promising and inadequately explored role of immunotherapy in this particular setting of patients in whom only targeted agents were considered of unique interest. For the ~85% of patients with non-squamous NSCLC without ALK/EGFR aberrations, single agent chemotherapy represents the only option with its associated poor results and chemotherapy-related toxicities. Many cancers co-opt the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway to evade immune-mediated tumor rejection. Encouraging clinical activity against several tumor types has been seen for anti-PD-L1/PD-1 monoclonal antibodies (mAbs), including the proven benefit of nivolumab in advanced refractory squamous NSCLC. MEDI4736 is a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD-80 with high affinity and selectivity. Evidence of clinical activity for MEDI4736 in NSCLC has been observed in a Phase 1 study (Study 1108, NCT01693562), with initial data indicating that PD-L1 expression is associated with a higher objective response rate (ORR). A clinical development program of MEDI4736 in NSCLC is underway. Here we describe the ATLANTIC study (NCT02087423).

Methods:
In this Phase 2, open-label, international, multicenter, non-comparative study, the efficacy and safety of MEDI4736 (10 mg/kg IV every 2 weeks for up to 12 months) is being assessed in patients with PD-L1[+] locally advanced or metastatic NSCLC (Stage IIIb–IV). The present study design includes three patient cohorts: 1) Cohort 1 (n=≥94): patients with EGFR mutations or ALK alterations; 2) Cohort 2 (n=≥94): patients with wild-type EGFR and ALK; 3) Cohort 3 (n=≥94): patients with wild-type EGFR/ALK and ≥90% of tumor cells PD-L1[+]. Cohorts 1 and 2 include patients whose tumor tissue samples have ≥25% of tumor cells with membrane staining for PD-L1. The PD-L1 status was tested according to the VENTANA proprietary assay. At the time the study was conceived, patients were initially included regardless of PD-L1 status. However, based on the observation that PD-L1 expression may enrich response to MEDI4736 (Study 1108), the trial was amended accordingly to include PD-L1[+] tumors only. Eligible patients must have an ECOG Performance Status of 0 or 1, and have received ≥2 prior systemic treatment regimens, including one platinum-based chemotherapy and a tyrosine kinase inhibitor if EGFR or ALK positive. The primary outcome measure is ORR (RECIST v1.1), based on independent central review. Secondary outcome measures will further assess efficacy (including disease control rate, duration of response, progression-free survival and overall survival), safety (CTCAE v4.03), tolerability, pharmacokinetics, and immunogenicity of MEDI4736. Patients will be recruited at ~100–150 sites across North America, Asia, and Europe.

Results:
Not applicable

Conclusion:
Not applicable

Background:
While EGFR-TKI therapy is initially effective for patients with EGFR-mutant NSCLC, eventual resistance to EFGR-TKI therapy is expected. For patients with non‑T790M resistance to EGFR-TKIs, the optimal treatment is unclear. Sensitizing mutations in EGFR are often heterozygous with co-expression of both wild type (WT) and mutant EGFR. Tumor hypoxia upregulates WT EGFR signaling through several HIF-dependent mechanisms. Clinical studies indicate that EGFR-mutant NSCLC with WT EGFR present is associated with a poorer response to EGFR-TKIs. NSCLC is known to be a hypoxic tumor; thus, hypoxia-induced activation of WT EGFR signaling may be a mechanism of EGFR-TKI resistance. TH-4000 is a clinical-stage hypoxia-activated prodrug that releases an irreversible pan-ErbB TKI targeting WT EGFR, mutant EGFR and HER2. Hypoxic tumor targeting using TH-4000 may allow a greater therapeutic index with greater intratumoral TKI levels and less dose-limiting systemic toxicity seen with current EGFR-TKIs. In xenograft models of EGFR-mutant NSCLC that co‑express WT EGFR, TH-4000 reverses resistance to current EGFR-TKIs, and is effective as a single‑agent. A Phase 1 study was conducted in patients with advanced solid tumors; the maximum tolerated dose (MTD) of TH-4000 administered as a 1-hour weekly intravenous (IV) infusion was established at 150 mg/m[2]. The most common treatment-related adverse events were dose-dependent and included rash, QT prolongation, nausea, infusion reaction, vomiting, diarrhea and fatigue.

Methods:
A multicenter Phase 2 trial was initiated to evaluate the safety and activity of TH-4000 as a single‑agent in patients with EGFR‑mutant, T790M-negative Stage IV NSCLC progressing on an EGFR TKI. Hypoxia PET imaging with [18F]-HX4 and molecular analyses of tumor tissue and plasma are incorporated in the study design to identify potential predictors of response to treatment. The primary endpoint is response rate. Secondary endpoints include progression-free survival, duration of response, overall survival, pharmacokinetics and safety, as well as evaluation of imaging, serum, and tissue biomarkers that may be associated with tumor response. Up to 37 patients will be enrolled with recurrent EGFR-mutant Stage IV NSCLC which has progressed while on treatment with EGFR-TKI, absence of EGFR T790M mutation, measureable disease according to RECIST 1.1, and ECOG performance status 0-1. Eligible patients must also have adequate pre-therapy tumor tissue available to enable tumor biomarker assessment. TH-4000 (150 mg/m[2]) is administered weekly by IV infusion over 60 minutes. The study design incorporates a Simon two-stage design (alpha = 0.10; beta = 0.10). Recruitment is ongoing.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Ceritinib is a novel, highly selective, orally active and potent tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), and has demonstrated clinical efficacy in ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC) (ASCEND-1; NCT01283516). Nivolumab is a fully human, immunoglobulin G4 programmed cell death protein-1 (PD-1) immune checkpoint inhibitor antibody that selectively prevents interaction with PD-1 ligands (PD-L1 and PD-L2), thereby promoting antitumor T-cell function, and is approved by the United States Food and Drug Administration for treatment of squamous NSCLC patients with progression following platinum doublet (Checkmate-017; NCT01642004). Nivolumab in combination with chemotherapy, other immune modulators and molecular targeted therapy has shown promising preliminary results in Stage IIIB/IV NSCLC patients (CheckMate-012; NCT01454102). The demonstrated efficacy of ceritinib in ALK+ NSCLC, and nivolumab in Stage IIIB/IV NSCLC, provides a rationale to study ceritinib in combination with nivolumab in patients with ALK+ NSCLC.

Methods:
In this prospective, open-label, multicenter phase 1B study (CLDK378A2120C; NCT02393625), the primary objectives are to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) and to evaluate the preliminary efficacy, based on overall response rate of ceritinib in combination with a fixed dose of nivolumab in adult stage IIIB/IV ALK+ NSCLC patients. Secondary objectives include evaluating duration of response, disease control rate, time to response, progression-free survival, overall intracranial response rate for patients with baseline measurable brain metastases, overall survival, and safety profile. In dose escalation phase, patients may have had ≥ 1 prior ALK inhibitors (except ceritinib) or prior chemotherapy regimens. In expansion phase, there will be 2 arms: 1) ALK-inhibitor pre-treated patients with 0 or 1 prior chemotherapies; 2) ALK-inhibitor naïve patients with 0 or 1 prior chemotherapies. Other key inclusion criteria are: presence of ≥ 1 measurable lesion as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, and a World Health Organization performance status 0-1. Patients with asymptomatic, untreated brain metastases at baseline are allowed. Dose-escalation phase will consist of successive cohorts of patients (3 to 6) receiving increasing doses of ceritinib (starting dose: 450 mg/d with a low-fat meal; 28-day cycles) plus nivolumab (3 mg/kg Q2W) and will enroll a minimum of 12 patients. In expansion phase, approximately 60 patients will be allocated to arms 1 and 2 (30 in each arm) and treated with ceritinib at MTD/RDE plus nivolumab (3 mg/kg Q2W). Material required for central assessment of ALK rearrangement must be either archival tissue or, preferably, a fresh biopsy. Apart from ALK rearrangement, potential predictive markers of PD-L1 and PD-L2 expression and/or additional immunological biomarkers will also be assessed. Patients may continue treatment until unacceptable toxicity, disease progression, discontinuation at the discretion of the investigator, or consent withdrawal. MTD and/or RDE estimation will be based on the probability of dose-limiting toxicities using an adaptive Bayesian logistic regression model guided by the escalation with overdose control principle and an overall assessment of safety and tolerability data. Tumor responses will be assessed per RECIST v1.1 by investigator assessment.

Results:
Not available

Conclusion:
Not available

Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) that has demonstrated efficacy against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X, a Phase I/II dose-ranging trial, has provided evidence that rociletinib is associated with durable response and is well tolerated in patients with NSCLC and positive T790M status following progression on a TKI.[1 ]Efficacy has also been noted for patients with T790M negative status in TIGER-X.[2] TIGER-3 is designed to investigate single agent rociletinib vs chemotherapy in patients who have failed EGFR therapy and platinum-based doublet chemotherapy, which is a setting of acquired resistance and high unmet need for targeted therapeutic options. TIGER-3 will evaluate patients with T790M positive and negative status based on tumor biopsies and plasma, and biomarkers of response and/or resistance.

Methods:
Patients with histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC, with radiological progression on the most recent therapy will be enrolled in this phase 3, randomized, open-label study (NCT02322281). Patients must have documented evidence of a tumor with ≥1 EGFR activating mutations excluding exon 20 insertion, and prior treatment with an EGFR TKI and platinum-containing doublet chemotherapy. Patients will be randomized 1:1 to receive rociletinib twice daily (500 mg) or single agent cytotoxic chemotherapy (investigator choice specified before randomization) until disease progression according to RECIST 1.1. Patients will be stratified by presence or absence of brain metastases, ECOG performance status (0 vs 1), and race (Asian vs non-Asian). The primary endpoint is progression-free survival (PFS). Secondary endpoints include safety, objective response rates, duration of response, disease control rate, and overall survival. Kaplan-Meier methodology will assess time to event variables. The stratified log-rank and the hazard ratio will be used for comparing PFS distributions. Serial assessment of safety will be carried out based on standard adverse event reporting. Planned enrolment is 600 patients; enrolment has been open since March 2015. Sequist LV J Clin Oncol. 2014 Soria J-C EORTC-NCI-AACR 2014

Results:
Not applicable

Conclusion:
Not applicable

Background:
Autophagy is the catabolic degradation of cellular constituents that can promote cancer cell survival by maintaining cellular energy levels during periods of stress, including exposure to radiation or chemotherapy. The antimalarial, chloroquine (CQ), has received attention as an inhibitor of autophagy. The lysosomotropic properties of CQ are probably responsible for many of its biological effects. Manipulation of autophagy is a potentially exciting area for the development of new cancer treatments. Recently, accumulating evidence suggest that CQ can effectively sensitize cancer cells to the cell-killing effects of ionizing radiation and chemotherapeutic agents, thus suggesting its use as a sensitizer for conventional therapies. Hypothesis: CQ may sensitize chemotherapy-resistant tumor cells by inhibiting autophagy and enhance tumor response and survival of patients with solid tumors. Patients with non small cell lung cancer (NSCLC) squamous cell carcinoma subtype will be enrolled and followed for possible improved outcome with the addition of choloroquine to platinum doublet especially agents as Bevacuzimab can not be added to their standard doublet therapy. Patients with other advanced solid tumors will be eligible as long as carboplatin and Gemcitabine are considered an acceptable therapeutic option.

Methods:

Dose Level	Patients(N)	CQ mg/dl D-7-D21	Carboplatin AUC D1	Gemcitabine mg/m2 D1 &D8
1	3-6	50	5	1,000
2	3-6	100	5	1,000
3	3-6	150	5	1,000
4	3-6	200	5	1,000
Expansion cohort	10-12	MTD	5	1,000

Primary Objectives: The aim of this phase I study is to determine the adverse events (AE) and maximum tolerated dose (MTD) associated with adding chloroquine (CQ) to carboplatin and gemcitabine (CG) in patients with previously treated advanced solid tumors. Secondary Objectives: To estimate overall response rate (ORR), progression-free survival (PFS), and overall survival (OS); to determine the pharmacokinetics of CQ in combination with CG, and its effect on tumor burden by measurement of circulating tumor cells (CTCs). Methods: A single institution phase I dose-escalation study. Patients with advanced solid malignancies with no available standard of care treatment options, and ECOG performance status 0-2 are eligible. Sequential cohorts of 3-6 patients will be treated with escalating daily doses of oral CQ in addition to carboplatin and gemcitabine (Table 1). The study is ongoing and patient accrual is in the first cohort.

Results:
Not applicable

Conclusion:
Not applicable

Background:
Surgical treatment is the most efficient therapy for early non-small lung cancer (NSCLC). However, after radical surgery many patients relapse or progress to systemic disease, even in stage I NSCLC. The objective of this study was to examine the recurrence predictors, especially focused on location of recurrence (local or distant), in patients who underwent potentially curative resection for stage 1NSCLC.

Methods:
The study included 371 consecutive patients who underwent lobectomy with radical mediastinum lymph node dissection from 1998 to 2011 without any preoperative therapy. For analysis of recurrence, 342 patients were enrolled after excluding patients with non-cancer related death or loss of their follow-up within 3 years of resection. Disease recurrence at the surgical margin, ipsilateral pleural dissemination, ipsilateral hilum, and/or mediastinum was considered as local recurrence. The median follow-up was 62 months. There were 205 males and 137 females with a median age of 69 years. Two hundred and forty-four patients had adenocarcinoma, 86 had squamous cell carcinoma, and 12 had other types. On pathologic staging 194 patients were in stage IA and 148 in stage IB. Lymph/vascular invasion were detected in 123, moderate/poor degree of tumor differentiation in 210, and 129 were non-smokers. The patients were divided into two groups: recurrence (n = 70) and non-recurrence (n = 272) within 3 years.

Results:
The 1, 3, and 5-year overall survival was 97%, 85% and 74%, respectively. Postoperative recurrence within 1, 2 and 3 years was observed in 26 (7.1%), 58 (16.6%) and 70 (20.4%) patients, respectively. Recurrence in local tissue only within 1, 2 and 3 years was observed in 4 (15%), 14 (24%) and 17 (24%) cases, respectively. Age, sex, smoking history, pathologic stage (IB), lymphatic/vascular invasion, and the degree of tumor differentiation were also significantly different between recurrence and non-recurrence group. Regarding tumor markers, the serum concentrations of SLX, CEA and CYFRA21-1 in the recurrence group were significantly higher than those in the non-recurrence group (p = 0.003, 0.030, and 0.006, respectively). By multivariate analysis, independent predictors of recurrence within 3 years were age more than 75 years (HR 2.51; 1.27–4.96), lymph/vascular invasion (HR 1.95; 1.06–3.63), stage IB (vs IA; HR 2.17; 1.14–4.18) and SLX (HR 1.04; 1.01-1.08). Although the rate of distant recurrence within 3 years was higher in stage IB (p = 0.032), there was no significant difference in age, sex, smoking history, lymphatic/vascular invasion, degree of tumor differentiation, CEA and CYFRA between distant and local recurrence group. The serum tumor marker SLX was also significantly higher in the distant metastasis group than in the local recurrence group (mean 29.8 and 21.4U/ml, respectively; p = 0.007)

Conclusion:
Early recurrence predictors after complete resection in patients with pathological stage 1 NSCLC were age (over 75 years), lymph/vascular invasion, stage 1B and high serum concentration of SLX. Furthermore, SLX is potentially useful to predict distant metastasis. Adjuvant chemotherapy might be considered in patients who are positive for these predictive factors.

Background:
Interstitial lung diseases (ILDs) are at increased risk of developing lung cancer. The purpose of this study is to evaluate the survival and predictors of survival after surgical resection in patients with non-small cell lung cancer (NSCLC) and ILDs.

Methods:
We retrospectively analyzed data from 55 patients with NSCLC with a clinical diagnosis of ILD who underwent pulmonary resection between 1994 and 2010 at our institution. Kaplan-Meier analysis and Cox proportional hazards regression analysis were used.

Results:
Male patients (94.5%) and smokers (98.2%) were in majority. The overall 5-year survival was 15.4%. The 5-year survivals were 9.1% and 31.6% for patients with a predicted percent vital capacity of 80% or less and a predicted percent vital capacity greater than 80%, respectively (log-rank test, P = .036). The 5-year survival of patients in which NSCLC was developed in the ILD positive background was 15.4%. On the other hand, the 5-year survival of patients in which NSCLC was developed in the ILD negative background was 47.5% (P = .033). Surgical procedures had an association with survival (P = .051), the 5-year survival were 0% and 31.3% in the wedge resection and segmentectomy / lobectomy groups, respectively. Multivariable analysis revealed that lower predicted percent vital capacity, ILD-associated cancer genesis, and non-anatomical pulmonary resection were independent poor prognostic factor for survival. Carbon monoxide diffusing capacity and Krebs von den Lungen-6 (KL-6) were not included in the analysis because of missing data more than 5%.

Conclusion:
Anatomical resection is recommended for patients with NSCLC and ILD with predicted percent vital capacity greater than 80%. ILD-associated cancer genesis is noble predictor for patients with a clinical diagnosis of ILD who underwent pulmonary resection for NSCLC.

Background:
Accurate non-small cell lung cancer (NSCLC) clinical staging (CS) guides treatment options and prognosis. In addition, clinical and quality improvement registries incorporate CS and pathological staging (PS) for patients undergoing pulmonary resection. In residency education programs, CS and PS for NSCLC patients are essential educational components of thoracic surgical care. To determine the accuracy of CS by our house staff, we prospectively collected CS of patients who were treated by lobectomy (traditionally entered by our house staff) and compared those results to CS and PS in our cancer registry for accuracy and concordance.

Methods:
We conducted a retrospective analysis of prospectively collected clinical data between January 2005 and December 2014. Only patients with NSCLC who underwent anatomic pulmonary resection were included. We compared accuracy and Kappa score of preoperative CS entered by our house staff with the CS and PS obtained by our institutional cancer registry.

Results:
A total of 915 patients underwent pulmonary resection operation for known or suspected lung cancer. 582 patients underwent lobectomy, segmentectomy, or sleeve resection for non-small cell lung cancer. The mean age at time of surgery was 65 years (95%CI: 64, 66), and 316 (56%) were women. Histology included adenocarcinoma, 292 (50%); squamous, 181, (31%); carcinoid, 40, (7%); large cell, 36, (6%); and others, NOS 30 (5%). CS by house staff compared to registry CS had 49% agreement and (expected agreement at random was 27% given 7 possible staging choices; Kappa score of interrater reliability of the 7 possible staging levels was 0.31). Agreement was significantly better than random (p<0.001) but Kappa score was relatively low. CS by house staff was compared to final PS had 52% agreement of an expected 28% and a Kappa score of 0.34. Final pathological stage by the author [MJA] or pathologist compared to cancer registry final pathology had 87% agreement and Kappa 0.83. House staff clinical nodal staging accuracy compared to pathological nodal staging had a higher absolute agreement (73%) than tumor staging (67%); however, due to fewer levels of nodal disease, higher agreement was expected in nodal staging. Adjusted level of agreement measured by Kappa score was lower in nodal staging, (0.14) compared to moderate agreement in tumor staging, Kappa 0.48. Registry CS absolute agreement for lymph nodes (66%) and tumor (63%) compared to PS was slightly lower than that of house staff (73% nodal and 67% tumor staging). This was largely due to the greater number of unstaged cancers (n=105) found in the registry.

Conclusion:
The cancer registry generally under stages the patient's CS compared to the PS. In addition, CS by trainees was only accurate in 52% of patients. The clinical nodal status had the lowest agreement (42%) after adjusting for the number of choices available by both our house staff and the cancer registry. Additional attention in trainee education, especially in the area of clinical nodal staging is necessary for improving CS and subsequent clinical decision making for our patients with NSCLC.

Background:
It is difficult to estimate lymphatic vessel invasion (LVI) and blood vessel invasion (BVI) by Hematoxylin-Eosin (HE) staining for lung cancer specimens. The aim of this study was to compare HE with D2-40 and Victoria blue staining for detection of LVI and BVI, respectively, and to assess the relationship between these measurements and recurrence in patients with pathological stage I non-small cell lung cancer (NSCLC).

Methods:
We retrospectively analyzed 251 patients who underwent complete resection for pathological stage I NSCLC from 1997 to 2008. This study included 152 males and 99 females with a median age of 69 years (range, 20–93 years). Using criteria detailed in the seventh edition of the TNM classification for lung cancer, 129 cases were pathological stage IA and 122 cases were IB. Histologically, 175 adenocarcinomas, 67 squamous cell carcinomas, and 9 other subtypes of carcinomas were found. There were 81 well-differentiated carcinomas and 170 moderate or poorly differentiated carcinomas. The median follow-up across the cohort was 70.2 months and the 5-year survival rate was 72.2%. The paraffin-embedded sections were stained with HE, D2-40, and Victoria blue. Specimens with each staining were reevaluated and classified into three grades according to numbers of vessel invasion in one section: Ly0/V0, no invasion; Ly1/V1, one or two invasions; and Ly2/V2, more than three invasions.

Results:
Assessment of vessel invasion by HE revealed the following distribution of LVI grades: Ly0=125 (49.8%); Ly1=104 (41.4%); Ly2=22 (8.8%), and BVI grades: V0=224 (89.2%); V1=24 (9.6%); and V2=3 (1.2%). In contrast, segregation of patients according to reassessment of LVI and BVI by D2-40 and Victoria blue, respectively, resulted in the following distributions: Ly0=177 (70.5%); Ly1=53 (21.1%); Ly2=21 (8.4%); V0=186 (74.1%); V1=53 (21.1%); and V2=12 (4.8%). After reassessment using D2-40 and Victoria blue, 50% (11 of 22) of Ly2 cases by HE changed to Ly0, and 22.7% (5 of 22) of Ly2 cases by HE changed to Ly1, 66% (2 of 3) of V2 cases by HE changed to V0 and V1, respectively. According to accurate assessment of vessel invasion using D2-40 and Victoria blue, there was no significant difference in disease-free survival between patients who were negative and positive for LVI or BVI (p=0.1062 and 0.1849, respectively); however, when patients were divided according to the intensity of LVI/BVI (Ly0&1/V0&1 vs. Ly2/V2), there was a significant difference in disease-free survival (p=0.0281 and p<0.0001, respectively). A recurrence of lung cancer was discovered in 50 patients (19.9%) within 3 years. On multivariate analysis, the independent recurrence factors were pleural invasion (HR 2.64; 1.40–4.86) and V2 based on Victoria blue (HR 8.54; 3.46–19.1).

Conclusion:
Our study suggests that accurate reassessment of LVI and BVI using D2-40 and Victoria blue staining, used to assess not only presence but also intensity, is important to predict the postoperative recurrence in patients with pathological stage I NSCLC. If the predictive factors of pleural invasion and V2 based on Victoria blue staining were recognized, adjuvant chemotherapy might be considered for these patients.

Background:
Recent studies indicate that postoperative complications after various types of cancer surgery are associated with poor cancer-specific survival. Postoperative complications induce severe inflammatory reaction during the perioperative period. Emerging evidence suggests that systemic inflammation can accelerate the adhesion of circulating tumor cells to the vascular endothelium of distant organs, which is the first step of extravasation in hematogenous metastasis. The objective of this study was to investigate the impact of postoperative cardiopulmonary complications on cancer recurrence after lung cancer surgery.

Methods:
From a prospective database of 675 consecutive patients who underwent a lung cancer surgery between April 2007 and March 2012, we retrospectively analyzed medical charts of all patients with curative surgery. The primary endpoint was the incidence of cancer recurrence after surgery between the patients with and without postoperative cardiopulmonary complications. Perioperative white blood cell counts and C-reactive protein levels were also compared.

Results:
Postoperative cardiovascular or respiratory complications were identified in 98 (15%) or 30 (4%) patients, respectively. There were no significant differences in the incidence of cancer recurrence between the patients with postoperative cardiovascular complications and without cardiopulmonary complications (23% vs. 19%; p = 0.26). In contrast, there was significantly higher incidence of cancer recurrence in those with postoperative respiratory complications than those without cardiopulmonary complications (42% vs. 19%; p < 0.05). Multiple regression analysis adjusted age, sex, and pathological staging showed the similar tendency, however there was no significant difference. There were significantly higher levels of white blood cell counts and C-reactive protein levels in the acute phase after surgery in those with postoperative respiratory complications than those without. Figure 1



Conclusion:
Not cardiovascular but respiratory complications following lung cancer surgery might have the negative predictor in the incidence of cancer recurrence. Severe inflammation induced by postoperative complications might be associated with high incidence of cancer recurrence.

Background:
Visceral pleural invasion (VPI) had been demonstrated as an aggressive sign in solid-density non-small-cell lung cancers. However, its incidence and clinical relevance in ground glass nodules (GGNs) has not been clarified. The present study aims to investigate the clinical, radiological and pathological features of GGNs in patients with VPI.

Methods:
All consecutive surgically treated patients with solitary GGNs between 2008 and 2013 were retrospectively reviewed. Inclusion criteria were defined as: lesions < 3 cm and pleura abutting on computed tomography scan; pathologically confirmed non-small cell lung cancers. Patients with and without VPI were compared for clinical, radiological and pathologic parameters and survival.

Results:
A total of 121 patients were enrolled and 38 had pathologically proven VPI. The median patient age was 61 years old (range, 30-81 years old) and 45 (37.2%) patients were male. The mean follow-up duration was 30 months. The incidence of VPI was 43.9% (25/57) if the tumor diameter was > 2.0 cm and 20.3% (13/64) in < 2.0 cm (p=0.005). It was 20.9% (9/43) in pure GGNs and 37.2% (29/78) in part-solid GGNs (p=0.065). In cases with pleura indentation the incidence was 37.5% (24/64). In lepidic predominant, acinar predominant, papillary predominant and mucinous variant adenocarcinomas, the VPI rate was 44.7%, 84.60%, 52.9% and 100%, respectively (p=0.07). There were five lymph node involvement cases and three death cases due to distant metastasis. There was no statistical difference in 3-year overall survival between patients with VPI and without, nor between pure (all alive) and part-solid GGNs (p=0.956).

Conclusion:
VPI was more commonly seen in large (> 2 cm) GGNs and those with pleural indentations. Histologically it was more frequently seen when acinar was also predominant. Although commonly taken as an aggressive sign predictive of poor prognosis, the presence of VPI in GGNs may be associated with less prognostic significance. Therefore, upgrading of the TNM stage on the basis of VPI for such patients needs further verification.

Background:
The International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society pathological classification of lung cancer allows for a more comprehensive understanding of the prognostic factors associated with subtypes of lung adenocarcinoma. Micropapillary and solid (MIP/SOL) subtypes have been associated with higher recurrence rates. Some have therefore suggested that sublobar resection (SLR) should be considered a compromise procedure in patients with MIP or SOL tumors. We conducted this study to examine the effect of the resection type [lobectomy (LO) or SLR] on oncological outcomes of patients with MIP/SOL.

Methods:
A retrospective review of a prospective database (2000-2014) was performed to identify patients with clinical stage IA adenocarcinoma, excluding pure ground glass opacities. Propensity score matching (age, gender, FEV1%, and clinical tumor size) was done to obtain balanced cohorts of patients undergoing LO and SLR. The presence of MIP and/or SOL components (≥5%) was assessed by a single pathologist to avoid inter-observer bias. The SLR group of patients had more comorbidities. Therefore, deaths from causes other than lung cancer were censored and freedom from recurrence was used to assess oncological outcomes. Survival analysis was done using the Kaplan Meier method. Multivariable analysis (MVA) was done using Cox regression.

Results:
This study included 300 patients (150 LO vs. 150 SLR, including 77 segmentectomy and 73 wedge resection). Patients undergoing SLR had higher Charlson comorbidity index (P=0.002) and lower DLco% (P=0.01). Patients undergoing LO were more likely to have nodal assessment (99% vs. 85%,P<0.001). Otherwise, no differences in the clinicopathological characteristics were found between the two groups. The presence of ≥5% MIP and/or SOL components was found in 135 patients; LO (58), SLR (77). The 3-year probability of freedom from recurrence in the whole cohort was: MIP (77%), synchronous MIP/SOL (76%), and SOL (61%), compared to 86% freedom from recurrence for other pathological subtypes (median follow-up 41 months). The probability of freedom from recurrence in patients with MIP/SOL subtypes showed a trend favoring the LO group (P=0.092). However, when we excluded patients with SLR with resection margin <1 cm (n=64), there was no difference between LO (80%-72%) and SLR (81%-75%) at 3 and 5 years respectively (P=0.812)(Fig.1). Also, the type of resection (LO/SLR) was not associated with higher recurrence rates in the MVA of the whole cohort. Figure 1



Conclusion:
SLR can be safely performed in clinical stage-IA lung adenocarcinoma, regardless of the histological subtype, provided that a resection margin >1 cm is obtained.

Background:
Multiple lung cancers (MLCs) are determined using the Martini-Melamed clinical criteria, and comprehensive pathologic assessment. The underlying biology for why MLCs develop is not known. Herein, we evaluate clinicopathologic data for patients with MLCs, and report clonality between MLC lesions using diagnostic molecular testing.

Methods:
After IRB approval, we conducted a retrospective review of all patients who underwent an R0 resection for stage IA-IIIA LC from 2008-2013 in our institution. Patients with carcinoid tumors, adenocarcinoma-in-situ, multiple ground-glass opacities, intrapulmonary metastases, and cancers not originating from the lung, were excluded. MLCs were defined using Martini-Melamed criteria, and comprehensive pathologic assessment. Clinico-pathologic data was collected for patients with MLCs, including available diagnostic molecular data from sizing assays, Sanger sequencing and mass spectrometry genotyping (Sequenom).

Results:
2352 pts were identified: one LC (n=2238), recurrent LC (n=348), MLC (n=113). In patients with MLCs, adenocarcinoma histology (n=97) was associated with improved OS (p=0.049) compared to squamous histology (n=13, other n=3). Paired diagnostic molecular pathology was available in 51 patients with adequate tissue from MLCs. MLC pairs stratified by mutation type are depicted in Table 1. In 49 patients, both MLCs were adenocarcinomas (20= extended panel: sizing assays/Sanger sequencing/Sequenom, 29=limited panel: EGFR/KRAS sizing assay/Sanger sequencing): 51% (n=25/49) had concordant molecular results, suggesting a common tumor clone, and 49% (n=24/49) had discordant results. In 1 patient, one MLC was an adenocarcinoma and the other was a squamous carcinoma, and had discordant molecular results by limited panel testing. In 1 patient, both MLCs were squamous carcinomas, and had concordant molecular results by limited panel testing. In patients where MLCs both had a KRAS mutation (n=11), 3 pairs had the same mutation (KRAS G12C, KRAS G12D, KRAS G12F), and 8 had different mutations. Table 1: Multiple Lung Cancer: Molecular DataFigure 1



Conclusion:
Martini-Melamed criteria and comprehensive pathologic assessment, are currently used to diagnose MLCs. Assuming separate MLC lesions harbor distinct molecularly defined clones, paired molecular testing using limited panels is not sufficient to diagnose MLCs. Concordant molecular profiles do not necessarily define whether a lesion is an MLC or a metastatic lesion. Paired prospective testing of suspected MLC lesions including broader molecular tests such as DNA, RNA, protein expression and immune correlates, may advance our understanding of the biology of these tumors.

Background:
The prognostic roles of the dominate tumor and tumor combination pattern in synchronous multiple primary adenocarcinoma (SMPADCs) remain unclear.

Methods:
The predominant histologic pattern of each tumor among SMPADCs was determined according to the new IASLC/ATS/ERS classification system. For recurrence analysis, each tumor was further divided into low, intermediate and high grade prognostic group. The dominate tumor (DT) was representative of the highest prognostic grade in each SMPADCs.

Results:
From 2004 to 2012, there were 108 consecutive nodal-negative patients who underwent surgery for SMPADCs in a tertiary referral center. The median follow-up time was 52.4 months. During follow-up, 38 (35.2%) patients developed recurrence. The pattern of recurrence included local recurrence only in 8 patients (21.1%), distal metastasis only in 11 (28.9%), and both local recurrence and distal metastasis in 19 (50.0%). In multivariate analysis, the percentage of recurrence was significantly higher in older age (p=0.002; odds ratio 6.324) and DT presented with radiologic solid-appearance (vs. pure- , Mixed-GGNs, p=0.032; odds ratio 7.041). In addition, there was no tumor recurrence identified in 17 DTs presented with radiologic pure GGN and 6 DTs in low grade prognostic group. The 5-year overall and disease-free survival of SMPADCs determined by DT in low, intermittent and high grade were 100%, 84.6%, 32.5% (p<0.001) and 100%, 73.9%, 23.3%, respectively (p<0.001). Compared to low/intermediate grade, DT in high grade had significantly worse overall survival (p=0.007; hazard ratio 4.313) and disease-free survival (p=0.045; hazard ratio 2.360) in multivariate analysis. For further combination pattern analysis, high grade DT combined with high grade 2[nd] dominate tumor had significantly worse disease-free survival than that combined with intermediate and low grade 2[nd] dominate tumors.

Conclusion:

Risks analysis of disease-free survival
Variables	HR	p value	HR	p value
Age	3.212	0.001	2.228	0.026
Gender	1.552	0.182	--	--
Smoking Hx	1.443	0.270	--	--
Preop CEA	1.640	0.217	--	--
Tumor size	2.108	0.024	0.967	0.927
Radiologic appearance	10.814	0.001	3.911	0.086
Pleural invasion	2.069	0.050	0.930	0.869
TNM stage	3.405	0.021	1.334	0.669
Histologic differentiation	4.170	<0.001	1.840	0.118
Angiolymphatic invasion	4.089	<0.001	1.773	0.175
Subtyping predominate	5.399	<0.001	2.360	0.045
Tumor distribution	0.523	0.146	--	--
Same lobe	1.269	0.481	--	--
Adjuvant chemotherapy	1.855	0.072	1.391	0.360
Similar CHS	1.251	0.521	--	--

DT analyzed with prognostic grouping of the IASLC/ATS/RES histological classification was an independent risk factor regarding to overall and disease-free survivals in complete resected nodal-negative SMPADCs. Figure 1

Background:
Clinical guideline recommends that spirometry and/or lung perfusion scan be performed for patients undergoing pneumonectomy. Unlike in patients with lung cancer, the affected lungs to be resected have been destroyed due to inflammatory changes in patients with infectious lung diseases. This study was aimed to assess whether there is any difference in predicted postoperative pulmonary function between patients with lung cancer and patients with infectious lung disease.

Methods:
The study was done on 55 patients undergoing pneumonectomy from January 2005 to February 2015, including 22 patients with lung cancer (three right, 19 left) and 33 patients with infectious lung disease (13 right, 20 left). Infectious diseases included 10 pulmonary aspergillosis, 15 multidrug-resistant tuberculosis (MDR-TB), and 8 non-tuberculosis mycobacterial (NTM) infections. In all cases, predicted postoperative pulmonary function was evaluated by spirometry and quantitative lung perfusion scan before operation. We analyzed the differences in patient characteristics and pulmonary function between the two groups, such as percentage of forced expiratory volume in one second (%FEV1), percentage of postoperative FEV1.0 (%ppoFEV1), and estimated postoperative epoFEV1/m2 (epoFEV1/m[2]).

Results:
The mean %FEV1 in spirometry was significantly higher in patients with lung cancer than in patients with infectious lung disease (79.5% vs 67.0%; p=0.01). The rate of perfusion to the operative lung was significantly higher in patients with lung cancer than in patients with infectious lung disease (35.8% vs. 19.3%; p<0.01). Consequently, the mean %ppoFEV1 was not significantly different between the two groups (51.8% vs 50.6%; p=0.72). Body surface area of lung cancer patients was larger than that of infectious lung disease patients (1.65m[2] vs 1.50m[2]; p<0.01). The mean calculated epoFEV1/m[2] after pneumonectomy in patients with lung cancer and in patients with infectious lung disease were 869ml/m[2] and 993ml/m[2] (p=0.05), respectively.

Conclusion:
Preoperative %FEV1 in patients with lung cancer was higher than that in patients with infectious lung disease. However, %ppoFEV1.0 and epoFEV1/m[2] after pneumonectomy were not different between the two groups. These differences were caused by destructive feature of infectious lung diseases.

Background:
Chronic obstructive pulmonary disease (COPD) has been reported to be associated with the development of lung cancer and poor prognosis after curative surgery for early-stage non-small cell lung cancer (NSCLC). The Global Initiative for Chronic Obstructive Lung Disease defines COPD as a fixed post-bronchodilator ratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Age-dependent cut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population have been proposed as an alternative. In patients with obstruction according to the LLN cut-off point but not according to the fixed cut-off point, the prognosis after curative surgery for NSCLC is not known.

Methods:
We enrolled 556 patients with FEV1/FVC ≥0.7 who underwent curative surgical resection for pathological stage I or II NSCLC in our institute between January 2002 and December 2012. The post-surgical prognosis was compared between patients with obstruction (obstructed patients) and without obstruction (non-obstructed patients) according to the LLN cut-off point, using a Cox regression hazards model.

Results:
Of the 556 patients, 42 (7.6%) met the criteria of the LLN cut-off point. The 5-year recurrence-free rate was significantly lower in the obstructed patients (54.4%) than in the non-obstructed patients (77.1%), in univariate analysis (p < 0.01). The 5-year overall survival rate was also significantly lower in the obstructed patients (64.0%) than in the non-obstructed patients (91.1%), in univariate analysis (p < 0.01). Multivariate analysis showed that the obstructed patients had a poor recurrence-free (p = 0.05) and overall survival (p < 0.01) probability.

Conclusion:
Even if COPD is not diagnosed according to the fixed cut-off point, those who meet the criteria of the LLN cut-off point have a poor prognosis after curative surgery for NSCLC.

Background:
Size criteria have been used as a gold standard for a long time in cancer staging of all kinds of solid tumors. However, real tumor mass is usually neither spherical, nor symmetrical in shape. Therefore, single dimension length of tumor does not stand for the tumor volume exactly. We conducted the feasibility test of volume criteria for T staging.

Methods:
From April 1998 to April 2015, 425 lung tumor masses were resected. Among them, 187 masses of completely resected (R0) pT1a,1b,2a,2bN0M0 were enrolled for study. Their survival data were used for comparing log-rank statistics between size-based T(s) stage and volume-based T(v) stage. Tumor volumes were calculated from two-to-three dimension lengths of tumor from biopsy specimen.

Results:
Overall log-rank statistics was p=0.4377 and there was no detectable numerical order for trend among pT1a~pT2b in size-based T(s) stage. However, overall log-rank was p=0.1153 and log-rank for trend was p=0.0241 in volume-based T(v) stage. Cut-off values for volume T stage were selected as V1 (less than 2cc), V2 (more than 2cc and less than 4cc), V3 (more than 4cc and less than 9cc) and V4 (more than 9cc) from log-rank statistics.

Conclusion:
Volume-based T(v) stage shows better discrimination power comparing size-based T(s) stage in T1-2N0 NSCLCa.

Background:
Ground-glass opacity (GGO) nodules at peripheral parenchyma of the lung noted at thin –section computed tomography (CT) scan have shown to have a histopathologic relationship with atypical adenomatous hyperplasia (AAH) and adenocarcinoma (AIS) which is newly classified by International Association for the study of Lung Cancer (IASLC). We hypothesize that those early lung cancers in peripheral parenchyma such as AIS, do not need surgical resection may be curred by interventional approach such as Photodynamic therapy (PDT). For peripheral type early lung cancer, it is unable to observe using bronchoscopy nor to treat by PDT. Therefore, we have developed a new minimally invasive laser device using a 1.0 mm in diameter composite-type optical fiberscope (COF), which could transmit laser energy and images for observation in parallel, consisting a laser Doppler blood-flow meter. The use of COF technology was previously used in the field of atomic energy. It enables the acquisition of an image while simultaneously performing laser treatment such as PDT, measuring the blood-flow, estimating the irradiational distance.

Methods:
In this study, we aimed to develop a new endoscopical treatment for peripheral parenchymal cancer by NPe6-PDT and a COF. We administered NPe6, 10mg/kg to pigs and we observed the peripheral parenchyma through the bronchus using COF. One h after the administration of NPe6, we irradiated 664 nm-laser (120 mW, 100J) for normal lesion of the peripheral lung using COF. Seven days after PDT, we extracted lungs and examined pathologically.

Results:
We were able to introduce the 1.0 mm COF into pig peripheral parenchyma of the lungs and observed feasibly and clearly, and then we performed NPe6-PDT safely. We measured the blood-flow at the irradiated area by COF during PDT, and we observed gradually disappearance of the blood-flow. The mean diameter of necrosis in normal peripheral lung caused by NPe6-PDT was 16 mm.

Conclusion:
The 1.0 mm COF was a very useful device of NPe6-PDT for peripheral parenchyma of the lung. In the future, for non-invasive adenocarcinoma such as AIS, NPe6-PDT using COF will become one option of standard treatment and play a important role for the treatment of syncronous or metachronous multiple primary lung cancer lesions.

Background:
Currently, postoperative acute exacerbation (AE) of idiopathic interstitial pneumonia (IIP) accounts for the most common cause of death after pulmonary resection for lung cancer. Preoperative risk assessment and prevention of postoperative AE is essential for the operative performance improvement.

Methods:
From 2000 through 2013, a total of 1730 patients underwent pulmonary resections for primary lung cancer. One hundred and two patients (5.9%) were diagnosed the lung cancer combined with IIP based on the postoperative pathological findings. Postoperative AE was defined as acute exacerbation within 30 days after the operation.

Results:
Postoperative AE was observed in 9 patients (8.8%), of which 6 patients (66.7%) died of respiratory failure. Although three patients had improved and discharged, two patients of which finally died with re-exacerbation. All of the postoperative AE patients were men having all cases smoking history, and many of them were advanced stage. The AE patients were significantly worse than non-AE patients in following clinicopathological factors. Preoperative serum LDH（248±52IU/l vs 206±45）、CRP（1.6±1.8mg/dl vs 0.9±1.8）、PaO2（78.1±7.8mmHg vs 84.9±10.5） and ％VC（78.9±14.3% vs 94.4±15.1）. Moreover, for the postoperative AE patients, the changes of these factors and X-ray or CT findings before operation were analyzed. An exacerbation before operation observed for serum LDH in five patients, CRP in three patients, and increased lung opacity on imaging findings observed in four patients.

Conclusion:
To see the exacerbation of laboratory values (LDH, CRP) and imaging findings (increasing lung opacity) during preoperative time, there is a possibility of selecting high-risk patients of postoperative AE.

Background:
Lung cancer recurrence following treatment with radical intent remains a significant problem for thoracic oncology specialists. Identifying novel predictors of recurrence may inform future management strategies including indications for adjuvant chemotherapy and the intensity of surveillance programs. This study used survival analysis, as a surrogate marker of disease recurrence, to assess if pathological variables in resected NSCLC could predict survival.

Methods:
We retrospectively reviewed all pathological reports for patients undergoing surgical resection for NSCLC at the University Hospital South Manchester from 01/01/2011 to 31/12/2013. The following variables were analysed in univariate and multivariate (cox regression) analysis: extra-capsular nodal disease, lymphovascular invasion, pleural invasion (PL0-3), residual disease (R0 vs R1), grade of differentiation, pT-stage and pN-stage. Survival was provided by national death registry data.

Results:
Extra-capsular nodal disease (p=<0.001, Figure 1), Lymphovascular invasion (p=<0.001), pleural invasion (PL3, p=<0.001), residual disease (R1, p=<0.001), pT-stage (pT4, pT3, pT2b, p=<0.001) and pN-stage (pN2, p<0.001) were all associated with significantly lower survival on univariate analysis. A multivariate cox regrerssion model was run with all significant univariate variables. The least significant variable was removed and this was repeated until only those significant at the 0.05 level remained (Table 1). Figure 1 Table 1

Variables	Hazard ratio (95% CI)	p-value
Extracapsular spread	Yes vs no	1.47 (1.00, 2.17)	0.049
Pleural invasion	PL1 vs PL0	1.37 (0.97, 1.93)	0.002
PL2 vs PL0	1.08 (0.63, 1.85)
PL3 vs PL0	2.42 (1.53, 3.83)
T stage	1b vs 1a	1.04 (0.61, 1.79)	0.006
2a vs 1a	1.30 (0.81, 2.08)
2b vs 1a	1.63 (0.95, 2.81)
3 vs 1a	2.17 (1.28, 3.66)
4 vs 1a	2.99 (1.46, 6.11)
N stage	N1 vs N0	1.30 (0.91, 1.87)	0.005
N2 vs N0	1.80 (1.26, 2.58)

Conclusion:
Pathological T-stage and N-stage are well established predictors of prognosis and inform decisions around adjuvant chemotherapy. Extra-capsular nodal disease and pleural invasion (PL3) are additional independent predictors of survival. The presence of these pathological findings in resected NSCLC may help in the decision making around adjuvant therapy, the appropriate intensity of surveillance programs and the design or stratification of adjuvant therapy trials.

Background:
Pulmonary thromboembolism (PTE) is a well-recognized potentially fatal complication after thoracic surgery. In Japan, PTE had been relatively uncommon. However, it has recently been increasing probably due to changes in lifestyle. Therefore the first guideline for the prevention of venous thromboembolism (VTE) were published in February 2004 in Japan. In this guideline, the patients with history of VTE are classified as highest risk group for PTE. Recently, it has been reported that the presence of normal D-dimer levels can exclude acute-phase deep vein thrombosis (DVT). Therefore, in our institution, DVT had been intensively screened by measuring preoperative D-dimer. The objective of this study was to investigate prevalence of preoperative DVT in Japanese patients scheduled for thoracic surgery.

Methods:
A total of 276 patients who underwent thoracic surgery from June 2013 through July 2014 in our institution were reviewed. The patients who were deemed high-risk for DVT (those with elevated preoperative D-dimer (≧1.0μg/ml), with past history of thrombosis, or with varicose veins in their lower extremities) were defined as preoperative screening positive. They were examined with venous ultrasonography of lower extremities. Those with DVT underwent contrast-enhanced computed tomographic scan (CT) for PTE.

Results:
Of all patients, only 1 failed to undergo preoperative measurement of D-dimer because of emergency surgery. Among the remaining 275 patients, a total of 113 patients ( 95 with elevated D-dimer, 15 with varicose veins in their lower extremities, one with swelling in his extremities, one with paralyzed inferior limbs, and one with previously diagnosed PTE ) were examined with venous ultrasonography of lower extremities. Of them, 34 patients (12.6%) were diagnosed DVT (Figure 1) Proximal and distal DVT were diagnosed in ten patients ( three with isolated DVT, three with multiple DVT, and four with a wide range of huge clots ) and 24 patients ( 15 with isolated DVT and nine with multiple DVT ) , respectively. Of them, none was diagnosed preoperative PTE. For a peri-operative management, all the patients received unfractionated heparin. In addition, of four patients with a wide range of huge clots, three had prophylactic inferior vena cava filter placed. Of 34 patients, one was diagnosed asymptomatic exacerbation of DVT by ultrasonography one week after surgery, but none developed symptomatic PTE. Figure 1



Conclusion:
This study showed an DVT prevalence of 12.6% in patients undergoing thoracic surgery in Japan. However, none developed symptomatic PTE in the peri-operative period.

Background:
Although lobectomy is considered the standard surgical approach for clinical T1aN0M0 non-small cell lung cancer (NSCLC), several recent studies have shown segmentectomy could be a substitute for lobectomy for early stage NSCLC. However, the differences of perioperative complications between lobectomy and segmentectomy have not yet been fully evaluated. The aim of this study is to investigate the postoperative complications which occurred after lobectomy or segmentectomy using propensity-matched analysis.

Methods:
Between February 2006 and February 2013, 100 patients underwent lobectomy and 111 patients underwent segmentectomy for clinical T1aN0M0 NSCLC. A retrospective comparison with each group was performed in perioperative mortality, morbidity, operative time, blood loss, length of hospital stay, chest tube duration and clinical parameters including age, gender, preoperative forced expiratory volume in 1 second percentage predicted (preop FEV1%), and Charlson Comorbidity Index (CCI). Data was analyzed for all patients and their propensity score matched pairs.

Results:
The rate of postoperative complications in the segmentectomy group (n = 21, 19%) was significantly higher than that in the lobectomy group (n = 7, 7%) (p < 0.01). The majority of complications were prolonged air leak. There was no significant difference in postoperative length of hopital stay and chest tube duration.The average operative time of 263 ± 64 minutes and estimated blood loss of 133 ± 125 ml for segmentectomy were significantly more than those of lobectomy (201 ± 61 minutes and 88 ± 101ml, respectively). In propensity score matched analysis (61 patients each), the average operative time of 270 ± 70 minutes for segmentectomy was longer than that of lobectomy (202 ± 67 minutes). Postoperative complications were more frequent in the segmentectomy group than those in lobectomy group (19.6% and 6.5%, p = 0.03).

Conclusion:
Although segmentectomy could offer preservation of pulmonary function, significantly more postoperative complications occurred in the segmentectomy group compared with lobectomy group. The majority of complications were prolonged air leaks in all patients and propensity matched pairs. The operation time was also longer in the segmentectomy group. Surgeons should bear in mind that complications can happen more frequently after segmentectomy than after lobectomy for cT1aN0M0 NSCLC.

Background:
If we can maintain a satisfactory technical level, safeness and prognosis equal to conventional surgery, a less invasive procedure will bring more benefits to patients. We have performed thoracoscopic anatomical lobectomy and segmentectomy for primary lung cancer for twenty years. At first we used and slid 10mm-diameter scope and forceps through three or four ports. Later we changed to 5mm-diameter scope and forceps, and presently we start performing the needlescopic surgery（1 port+3 punctures method）using a 3mm-diameter scope and forceps, which we have used since September 2012. Now we would like to explain this operative procedure and effectiveness.

Methods:
【Patients】One hundred and eleven patients underwent the needlescopic anatomical lobectomy and segmentectomy of the lung between September 2012 to March 2015. 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 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 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 remove specimens and set the chest tube within the main port incision at the end of surgery.

Results:
We performed 15 segmentectomies and 96 lobectomies of the lung using this method for the lung cancer. We dissected mediastinal nodes in all cases. We had one case that was converted to the conventional method, and one case that was converted to the open method. However we elongated the incision of one puncture from 3 mm to 10 mm in four cases in order to insert endostaplers for dissecting pulmonary veins and arteries. Mean operation time was 220±63 minutes. It was not significantly different from that of the conventional method. Mean blood loss volume was 16.6±22.3 ml. It was significantly less than that of the conventional method. Post-operative peak titers of CK and CRP 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:
This one plus three method is less invasive than a conventional procedure. We were able to successfully perform the needlescopic lobectomy and segmentectomy for lung cancer as well as conventional thoracoscopic surgery. This method would be the optimal and optional method if and when we appropriately select cases.

Background:
Assessing the presence of cancer cells in resected margins following partial or segmental resection of malignant lung tumors is an important step when planning complete resection. When the tumor is deemed proximal to the resection margin, the policy at our hospital is to swiftly conduct touch cytology on the staple line of the resected tissue sample and, when positive, to perform additional resection. In the present study, we evaluated whether or not this strategy is appropriate.

Methods:
From among 161 patients who had a partial or segmental lung resection at our hospital between April 2009 and December 2013, forty-two patients who underwent touch cytology of resection margins were evaluated. Variables investigated were cytodiagnostic findings, tumor size and distance from margin, and subsequent occurrence of local relapse.

Results:
Resection of lung metastasis was performed on 16 of the 42 patients, intentional limited resection for primary lung carcinoma was performed in 13 patients, and conservative limited resection was performed on 13 patients due to issues with their respiratory function and systemic condition. Two patients tested positive on cytodiagnosis of the resected margin; hence, the surgical procedure was modified from partial to segmental resection and from lung lobe and partial resection to resection of both lobes, respectively. Moreover, both of these patients underwent conservative procedures, and both tumors were adenocarcinoma. Mean tumor size (mm) in the metastasis group, intentional limited resection group and conservative limited resection group was 14 mm, 15 mm and 24 mm respectively, and distance to resection margin was 9.3 mm, 11.2 mm and 8.6 mm respectively. None of the 42 patients, including the 2 patients who tested positive, exhibited subsequent local relapse.

Conclusion:
Both the patients who tested positive on cytodiagnosis belonged to the conservative limited resection group and tended to have a larger tumor size than patients in the other groups. Inadequate distance from the resected margin with respect to tumor size increases the risk of a positive result at the resected margin. Of the 42 patients in the present study who underwent touch cytology of resected margins, none experienced subsequent local relapse, which implies the appropriateness of our evaluation method.

Background:
Surgical resection is the best curative option in patients with appropriately staged lung cancer. Physiological assessment is vital in selecting patients for surgical resection with particular attention to risk of mortality and morbidity with the planned surgery. This is most crucial in patients deemed high-risk. Physiological parameters employed include spirometry (FEV1%), diffusion (DLCO%), Shuttle walks, Cardiopulmonary Exercise Testing (VO2Max absolute value and %) as well as post-operative predicted values for all of these tests using segment counting to discriminate depending on the planned surgery. However, three major international guidelines exist which advocate different approaches to assessing this patient group (BTS, ERS, ACCP). We aim to assess how these guidelines compare to one another and our local practice in informing decision-making.

Methods:
Patients with operable thoracic malignancy who were candidates for surgery and had CPET were eligible for inclusion. We retrospectively analysed all patients who underwent CPET at the University Hospital of South Manchester, a tertiary Thoracic Oncology Centre, between 01/01/2013 and 31/12/2013. Physiology reports, clinical correspondence and survival databases were analysed.

Results:
96 patients fulfilled the inclusion criteria. 3 were excluded due to no available pulmonary function data. A further 17 were excluded as they were denied surgery for non-physiology reasons (patient declined surgery, metastatic disease discovered before, small cell histology, adequate resection margin impossible, severe comorbidities). The remaining 74 patients were included in the final analysis. 62/74(84%) underwent surgery (12 pneumonectomy, 3 bilobectomy, 33 lobectomy, 4 segmentectomy, 6 wedge resection, 4 futile thoracotomy due to finding unexpected advanced disease) The overall breakdown of risk classification of patients using the 3 guidelines was as follows. BTS: low-risk 27/74 (36%), medium-risk 31/74 (42%), high-risk 16/74 (22%). ACCP: low-risk 19/74 (26%), medium-risk 52/74 (70%), high-risk 3/74 (4%). ERS: low-risk 47/74 (63%), medium-risk 16/74 (22%), high-risk 11/74 (15%). Of the patients BTS guidelines classed high-risk, we operated on 8/16 (1 pneumonectomy, 3 lobectomy, 1 segmentectomy, 2 wedge resection, 1 futile thoracotomy) with 100% survival at 90 days. We did not operate on any of the 3 patients classed high-risk by ACCP guidelines. Of the patients ERS guidelines classed high-risk, we operated on 5/11 (1 pneumonectomy, 1 bilobectomy, 2 lobectomy, 1 segmentectomy) with 100% survival at 90 days. Of those classed high-risk by ACCP 2/3 would be high-risk by BTS guidelines and of those classed high risk by BTS 2/16 would be high-risk by ACCP guidelines. Of those classed high-risk by ERS 8/11 would be high-risk by BTS guidelines and of those classed high-risk by BTS 2/16 would be high-risk by ERS guidelines.

Conclusion:
From our results a lack of concordance between the three guidelines in classification of high-risk is evident. Also, with the exception of the ACCP guidelines, our local practice has shown that patients deemed high-risk for surgery were operated on (upto and including pneumonectomy) with no cases of 90-day mortality. With this in mind an appraisal of current guidelines is indicated as well as a more consistent approach worldwide to ensure that no potentially fit patients are excluded from surgical resection of lung cancer.

Background:
Recently, fluorescence imaging using indocyanine green (ICG) has been applied to cancer, not only to visualize the sentinel lymph node, but also to identify mass during surgery. We hypothesized that this fluorescence imaging will also be useful to identify and locate pulmonary nodules during surgery. We try to detect pulmonary nodules and measure fluorescence intensity by using reasonable dosage of ICG.

Methods:
We enrolled 11 patients who were diagnosed with a pulmonary nodule. ICG is administered intravenously at a dose of 1 mg/kg prior to operation. Surgical specimens were investigated using a near-infrared light camera system (SPY Elite) at 20 hours after injection. And we examined the histologic characteristics of the specimens.

Results:
Figure 1 ICG-fluorescent imaging was observed 10 out of the 11 patient. 1 squamous cell carcinoma was not detected fluorescent. 2 false – positive nodules (necrotic inflammation) were identified among the 10 fluorescent specimens. Fluorescence signal of nodules (Signal to Background Ratio (SBR)) was 4.3 ± 2.5. There was no significant difference depending on histology, size and tumor grade. However, Fluorescence signal of 2 false – positive nodules was 9.5 ± 0.7 was higher than nodules.



Conclusion:
This study demonstrated that fluorescence imaging using a low dosage of ICG can be useful to identify and locate pulmonary nodules during surgery. However, our results (2 false positive) also show limitation of present fluorescence image guide surgery which used only ICG for passive cancer targeting. Base on this result, we thought that for ideal fluorescence guided surgery, we will need a further study about active targeting by using biomarker as well as passive targeting. We hope that this data will give us some clue to develop fluorescence guided surgery technique in lung cancer surgery.

Background:
Sleeve lobectomy is a parenchyma-sparing technique suitable for treating central tumors, avoiding pneumonectomy. The aim of this study was to assess perioperative and long-term survival outcomes in patients treated by sleeve lobectomy.

Methods:
Data were analysed from a prospectively collected database. All consecutive cases of sleeve lobectomy/bilobectomy (1985 - 2013) were included. Cox-Regression was used to analyse survival outcomes. There were 300 patients available for analysis. Sleeve lobectomy was performed in 272 patients (RUL:153; RML:5; RLL:1; LUL:83; LLL:30), sleeve bilobectomy in 28 (RUM:17; RLM:11). In most patients a sleeve of the bronchus (n=219) or a reversed sleeve of the bronchus (n=19) was performed. Arterial (n=35) or combined arterial and bronchial sleeve (n=27) resections were less common. The most common operative indication was non-small cell lung cancer (254 cases, 85%), less commonly for carcinoid (n=27), small cell lung cancer (n=6) , pulmonary metastasis (n=9) and 4 others.

Results:
Patients were predominantly male (85%) with a mean age of 62.7 years (range 20.1-84.6). Postoperative course was uneventful (Dindo-grade 0/1) in 60%; with minor complications (Dindo-grade 2/3a) in 30% and major complications (Dindo-grade 3b/4) in 7.3%. In hospital mortality (Dindo-grade 5) was 2.7%. Overall median survival was 68 months, with a 5- and 10-year survival of 52.3% and 35.8%. A Cox-Regression model showed five independent prognosticators for survival: asymptomatic at presentation, age, pT, pN and neoadjuvant treatment (see table). Although neoadjuvant treatment showed to be a negative prognosticator for survival, complete responders (n=8 or 14.5% of neoadjuvant treated patients) showed a mean survival of 132 months and a 5-year survival of 80%. Figure 1



Conclusion:
Sleeve lobectomy can be safely performed as treatment for centrally-located lung tumours. A single-institution experience over 3 decades demonstrates acceptable morbidity and mortality rates. Overall survival seems to be mainly determined by oncologic variables (TNM-staging factors).

Background:
Accurate pre-operative staging of the mediastinum in lung cancer is essential to determine the type of treatment. The commonly used investigations are CT scan, PET scan, EBUS-TBNA (Endobronchial ultrasound-guided transbronchial needle aspiration) and mediastinoscopy, and often these tests complement each other to increase the accuracy of staging. With advances in technology and increased experience, EBUS has the potential to replace mediastinoscopy to stage the mediastinum. Surgical mediastinal dissection, though commonly performed, has not been convincingly proven to have a therapeutic value. We postulate that if the mediastinum can be staged accurately with EBUS-TBNA (a low morbid procedure) then a surgical staging of the mediastinum (mediastinoscopy and / or dissection) can be avoided and therefore, avoid the morbidity associated with these procedures. We have studied the use of selective EBUS-TBNA which is sampling abnormal nodes on imaging (CT, PET scan) and compared it with the mediastinal dissection done surgically.

Methods:
This is a retrospective study of patients who underwent surgery (lobectomy/pneumonectomy + mediastinal lymphnode dissection) for early stage lung cancer (stage I/II).Patients who had negative N2 lymph nodes on EBUS-TBNA evaluation were included in the study. All patients had CT and PET scans which assisted the EBUS study. The results of EBUS-TBNA were compared with that of the surgical mediastinal lymph node dissection.

Results:
A total of 86 patients were included in the study. EBUS-TBNA correctly staged the mediastinum in 78 patients (90.7%, negative predictive value (NPV) = 0.90). Eight patients had false negative (FN) evaluation by EBUS-TBNA. On review, two of these patients had a sampling error. Three patients had incomplete evaluation of the mediastinum. All these 3 patients had left lung cancer whose level 5 lymph nodes could not be sampled, and surgical sampling displayed these nodes to be involved with extracapsular spread. There were three other patients with FN results, and they had mediastinal nodes biopsied by EBUS which with surgical removal showed metastasis. Two of these patients had metastatic deposits < 3mm in size. We feel that diligent and systematic EBUS would have avoided the FN result in most of the above patients except for sampling of level 5 nodes which may not be technically accessible by EBUS. The NPV for right lung cancers, especially right upper lobe (NPV=0.96) was higher as compared to left sided cancers.

Conclusion:
This study shows that selective EBUS-TBNA mediastinal staging in early lung cancer is feasible, has an acceptable NPV and provides evidence to facilitate studies on systematic EBUS. This study draws attention thorough the identified 8 FNs to the real and potentially avoidable limitations of selective EBUS mediastinal lymphnode sampling. The accuracy of systematic EBUS evaluation should be superior to a selective study and can therefore potentially avoid a surgical staging of the mediastinum and its associated complications.

Background:
Conditional survival (CS) is an estimate of survival probability for patients who have already survived at least 1 year after diagnosis or treatment. This study was intended to find some useful informations in postoperative follow-up plan by CS analyses of resected non-small lung cancer patients.

Methods:
We retrospectively analyzed data on the clinicopathological features and survival outcomes of 925 patients with non-small cell lung cancer who had undergone complete resection at Nagoya University Hospital between 2005 and 2012. CS is the probability of surviving additional time (y) after already surviving time (x), and can be calculated from the following formula: CS(y|x) = S(x+y)/S(x), where S(t) is the overall survival at time (t). In this study, two methods of CS analyses were performed. Briefly, CS(5|x), which meant 5-year conditional survival (5Y-CS(x)), and CS(5-x|x), which was the probability of surviving when five years has passed from surgery (CS5(x)), were calculated in the various setting or subgroups.

Results:
The cohort consisted of 624 males and 301 females, ranging in age 26 to 89. The 5-year overall survival rate of all patients was 76%. 5Y-CS(1,2,3,4) was 74, 76, 77, 80%, respecively, showing gradually improvement. This meant that the given treatment for NSCLC including surgery contributed the survival of the patients to some degree. However, the 5Y-CS did not approach 100%, which indicated a certain number of patients coninued to die during the follow-up period. The CS5(1, 2, 3, 4) in all patients were 79%, 84%, 90% and 96%, respectively, which meant the 90% of patients who were alive at 3 years after surgery would survive for next 2 years. The patients with younger female (≤ 70 years), no or light smoker, adenocarcinoma histology, pathologocal stage I and normal serum carcinoembryonal antigen level showed the CS5(3) higher than 90%. Both CS5(3) and 5Y-CS(3) of the patients with all the six favorable factors reached 98%.

Conclusion:
Postoperative follow-up visit after 3 years from surgery might be minimum for the patients with younger female, no or light smoker, adenocarcinoma histology, pathological stage I, and normal serum carcinoembryonic antigen level.

Background:
General thoracic surgery involving carinal and/or tracheal reconstruction is technically demanding. The aim of this study is to discuss the feasibility of complete video assisted thoracoscopic surgery (VATS) in the surgical treatment of disease involving the carina and/or trachea.

Methods:
Between May 2012 and April 2015, seven cases of malignant or benign disease involving carina and/or trachea were treated via complete VATS resection and reconstruction of carina and trachea in our hospital. Among the seven patients (median age, 47 years; range, 43-60 years), two patients suffered from a malignant tracheal tumor, one from a main bronchial malignant tumor invading the carina, two from right upper lobe malignant tumor invading the carina, and two from benign bronchial stenosis due to endobronchial tuberculosis. A prospective analysis of clinical characteristics, operative data, and postoperative events was performed. Figure 1



Results:
There were five different types of VATS airway reconstruction in our group, including left main bronchus resection and carinal reconstruction, right main bronchus resection and carinal reconstruction, right upper lobectomy and carinal reconstruction, right upper lobectomy and half carinal reconstruction, and tracheal resection and reconstruction. Median data of surgical outcome are as follows: operative time-200 minutes (range, 50-300 minutes); time of airway reconstruction-50 minutes (range, 19-130 minutes); blood loss-100 mL (range, 30-1000 mL). One patient suffered from endobronchial tuberculosis; during the thoracic procedure we observed complete pleural adhesions which led to large volume of blood loss during pleuropneumonolysis. No conversions to thoracotomy were performed. There was no 30-day mortality. Median data of perioperative outcomes are as follows: postoperative hospital stay-12 days (range, 7-15 days); ICU stay -1 day (range, 0-6 days) and duration of thoracic drainage- 2 days (range, 1-5 days). No patient required postoperative mechanical ventilation. One patient had to be assisted with bronchoscopy as a result of insufficient sputum excretion. Median duration of follow-up was 6 months (range, 0-37 months). Minor anastomotic stenosis(less than 1/4 diameter) was found in two patients during follow-up, but no complaints of significant impact on activity were noted.

Conclusion:
Complete VATS for carina and trachea resection and reconstruction is a technically challenging, but feasible procedure for both benign and malignant disease and should be restricted to skilled VATS surgeons.

Background:
Pneumonectomy has traditionally been the treatment of choice for central lung tumors for which the alternative is sleeve lobectomy. The aim of this study was to compare early and long-term results after sleeve lobectomy and pneumonectomy in focusing on T3 central non-small cell lung cancer (NSCLC).

Methods:
Patients who underwent sleeve lobectomy (n = 58) or pneumonectomy (n = 42) were retrospectively analyzed. For bias reduction, these 100 patients had been selected according to the following criteria: (1) tumor located in the main bronchus less than 2 cm distal to the carina, (2) there was no N2 disease, (3) no induction therapy was applied, (4) a complete resection was achieved.

Results:
Sleeve lobectomy and pneumonectomy patients have had comparable mean ages, gender distribution, mean forced expiratory volume in 1 second, stage and tumor grade. Postoperative mortality (3.4% vs 4.8%, p = 1.0) and morbidity (41% vs 38%, p = 0.74) were similar between the two groups. Recurrences occurred in 48% of patients after sleeve lobectomy and in 31% of those after pneumonectomy (p = 0.08). The 5-year survival after sleeve lobectomy (64.8%) and pneumonectomy (61.4%) was not significantly different (p = 0.20). Multivariable survival analysis showed that there were no independent prognostic factors.

Conclusion:
Sleeve lobectomy does not compromise survival for NSCLC with T3 central disease compared with pneumonectomy. It is an adequate oncologic resection and should be treated as the first line intervention whenever complete resection can be achieved.

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 for thoracoscopic segmentectomy.

Methods:
Thirteen patients underwent video-assisted thoracoscopic surgery for removal of 14 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 segmentectomy under fluoroscopic and thoracoscopic guidance.

Results:
The marking procedure took 10 to 50 minutes from insertion to removal of the bronchoscope. There were no complications from the marking, and all 14 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 segmentectomy. The pathologic diagnosis was primary adenocarcinoma in 7 patients, a primary adenosquamous carcinoma in 1 patient, pulmonary metastases in 3 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.

Background:
Sarcomatoid carcinoma of the lung is not very common. It consists of poorly differentiated non-small cell carcinomas with sarcoma or sarcoma-like differentiation component. The World Health Organization lists five subtypes representing an overall continuum of epithelial and mesenchymal differentiation: pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma. The diagnosis is pathological and requires a good sampling of the tumor. The purpose of this study was to assess the surgical management of primary sarcomatoid carcinomas of the lung which could benefit from surgery with curative intent.

Methods:
We retrospectively reviewed the 38 cases of primary sarcomatoid carcinoma, which were managed between 2000 and 2012, in the thoracic surgery department of our Hospital. All the included patients had surgical resection.

Results:
There were 33 males and 5 females with a mean age of 59.7 years (42-81). The main symptoms were respiratory. Imaging features showed a pulmonary mass invading pleura or the thoracic wall in 14 cases. The diagnosis was confirmed in all cases on histological examination of the resected tumor. According to the pathological results there were 23 pleomorphic carcinomas, 7 giant cell carcinomas, 1 spindle cell carcinoma, 5 carcinosarcomas and 2 blastomas. Associated treatments were split as follows: neoadjuvant (four cases) or adjuvant (six cases) chemotherapy, and radiotherapy (ten cases). Lobectomy (26 cases) or bilobectomy (2 cases) was performed in 28 patients and pneumonectomy in 9 patients. Chest wall enlargement with costal resection was associated in 5 cases. One patient had a conservative resection (segmentectomy) because of a history of contralateral adenocarcinoma for which he had a lobectomy (2 years earlier). The tumors were classified as: T1 in 2 cases, T2 in 16, T3 in 16 and T4 in 4. The different stages were: Ia (n=2), Ib (n=8), IIa (n=1), IIb (n=13), IIIa (n=8), IIIb (n=2) and IV (n=4). The margins of the resected parenchyma showed tumoral involvement in 1 case. The median survival of our patients was 9 months. Two patients died in the early postoperative course.

Conclusion:
Sarcomatoid carcinomas are rare, aggressive tumors which require early diagnosis and management. Surgery whenever performed can be beneficial for these tumors which are of bad prognosis compared to other NSCLC.

Background:
More than 65% of patients diagnosed with non-small cell lung cancer (NSCLC) are above the age of 65 years. Half of this cohort are ≥75 years who are at higher risk following surgical resection, which is the mainstay of treatment for early-stage NSCLC. The purpose of this study is to determine the factors influencing the outcomes in patients ≥75 years who underwent lobectomy for stage I NSCLC: postoperative complications, short-term (30- and 90-day mortality) and long-term (overall survival (OS) and cancer-specific survival (CSS)). In addition to the routinely used clinical factors, we investigated the utility of lung age, the tool commonly used for smoking cessation.

Methods:
Patients with pathological stage I NSCLC who underwent lobectomy between 2000 and 2011, age ≥75 years at surgery with no induction therapy, and no previous lung resection were included in the study (n =435). We investigated the influence of smoking history, preoperative history of cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD), Carlson comorbidity index (CCI), serum creatinine level, lung age (calculated by height and forced expiratory volume in one second), percent predicted diffusing capacity of the lung for carbon monoxide (%DLCO), and p-stage. Outcomes studied were postoperative in-hospital complication (CTCAE grade ≥3), 30- and 90-day mortality, OS, and CSS. Complications and mortality were analyzed by chi-square tests for univariate analysis. OS and CSS were analyzed by Kaplan-Meier methods with log-rank tests for univariate analysis, and Cox proportional analysis for multivariate analysis.

Results:
Median chronological age was 79 years, whereas median lung age was 89 years (female gender n = 334, positive smoking history n = 391, p-stage IA/IB were 282/153). In univariate analysis, low %DLCO and CVD history were significantly associated with postoperative complications (p = 0.032 and 0.018, respectively), and only high serum creatinine level was significantly associated with 30- and 90-day mortality (p = 0.02 and 0.027, respectively). P-stage, lung age, %DLCO, and COPD history were significantly associated with poor OS (p <0.001, p <0.001, p = 0.009 and 0.008, respectively). P-stage, lung age, and COPD history were significantly associated with poor CSS (p =0.003, 0.004, and 0.046, respectively). In multivariate analysis, both p-stage and lung age were independently associated with poor OS (p <0.001 and <0.001, respectively) and poor CSS (p = 0.006 and 0.01, respectively).

Conclusion:
In elderly patients with stage I NSCLC undergoing lobectomy, p-stage and lung age were independent risk predictor for long-term prognosis (OS and CSS); serum creatinine level was associated with short-term mortality; and %DLCO and CVD history were associated with postoperative complications. Our observations from this large cohort are useful for treatment decision making in elderly patients with stage I NSCLC.

Background:
Lymph node dissection plays important role in oncologic surgery. The removal of the whole regional lymphatic system together with primary tumor is one of the fundamental rules in oncological surgery. But, the role of surgical treatment in non-small-cell lung cancer　(NSCLC) with clinically manifested mediastinal lymph node metastasis is controversial. Bilateral paratracheal lymphnodes for left side tumors are considered inaccessible through a standard thoracotomy. It is difficult to perform complete dissection of superior mediastinal lymph nodes through the left thoracotomy in the left lung cancer. We had devised Systemic extended bilateral superior mediastinal dissection and lung resection through a median sternotomy (ND3 operation, Hata’s method), and reported that ND3 operation can allow for complete dissection of all stations of mediastinal lymph nodes. The aim of this study was to evaluate the surgical outcomes and long term survival in patients of survival of the patient with non-small lung cancer (NSCLC) who underwent our ND3 operation.

Methods:
We retrospectively studied 289 patients ( 202 male and 87 female, mean ages 59.7 years (range, 38-75)) , underwent ND3 operation due to Left NSCLC, from January 1988 till December 2014. The patients with NSCLC of left side primary who are estimated to be able to conventional radical operation and aged 75 years old or less becomes the adaptation of our ND3 operation. Postoperative survival rates calculated with Kaplan-Meier method. Clinicopathological data were compared according to the p stage.

Results:
Overall 5-year survival rate in the 289 patients of left lung primary was 64.6%. Operative mortality in 289 patients was 3.0%,1.2% from January 200１ till December 2014. Lymph node metastasis to the mediastinum was confirmed in 98 (33.9%) patients (pN2 was 50 patients,pN3α was 29 patients, pN3β was 2 patients, pN3γ was 17 patients). According to pathological stages, five-year survival rate was was 88.7% in stage IA, 75.3% in stage IB, 60.6% in stage IIA, 71.4% in stageIIB, 47.5% in stageIIIA, 39.6% in stageIIIB. Five-year survival rate was 48% in pN2 cases, and 48.8% in pN3α cases.　Compere with previouse our reports, this result is more safety and better prognosis.

Conclusion:
Our result suggest that ND3 operation　would provide better prognosis in the patients with pN2 and pN3α Lt.NSCLC. And better local tumor control by ND3 operation than conventional lung cancer operation does not increase mortality.Lung cancer surgery should be denied due to clinical N status because patient with N2,N3 disease NSCLC can be operated for curative intent by our ND3 with acceptable surgical risk and long term survival.

Background:
Anatomic resections of the lung are firmly considered the gold standard treatment for early stage Non Small Cell Lung Cancer (NSCLC). The role of non-anatomic surgery is still not clear and it is generally used for very selected patients, who cannot undergo an anatomical resection of lung parenchyma for functional reasons. The aim of this study is to analyze whether surgical approach (VATS or open) might have an influence on the long term outcome of NSCLC patients treated by wedge resection.

Methods:
From December 2006 till 2010, 1695 patients underwent surgery for primary NSCLC at our Institution. Among them, 97 patients received a wedge resection either by open or thoracoscopic apprach due to coexisting morbidities or low pulmonary function; 54 were selected for our study. We excluded from our analysis all patients with a previous lung cancer, with suspected (on the basis of CT or PET CT images) or confirmed N2 disease, nodules greater than 5 cm or with involvement of the chest wall or mediastinal structures. Follow-up was carried out at December 2013.

Results:
Out of the 54 wedge resections, 30 were performed through a thoracothomy, while 24 cases by means of a VATS procedures. There were no statistically significant difference among clinical features of the two groups. Mean tumor diameter were 2,1 cm in the open group (OG) and 1,7 cm in the VATS group (VG); mean distance from visceral pleura was significantly higher in the OG (2,1 cm vs 0,8 cm; p=0,02) and so were the stapler edge (2,4 cm vs 1,2 cm; p<0,03). Mean follow-up was 42 months. In the open surgery group 2 patients (6,7%) had a local recurrence and in 10 patients (33,3%) we noticed systemic metasthasis. In the VATS group we had 4 cases (16,7%) of local recurrences and 7 (29,2%) of distant metasthasis. Local recurrence rate was significantly different between the two groups (p=0,048), while no significant correlation was found regarding the distant methastasis rate. Three patients died during the follow up period (two in the group treated with thoracotomy, 1 with VATS).

Conclusion:
Although different deepness of nodule between the two groups may represent a bias, we noticed a significant lower recurrence rate when surgery was performed by thoracotomy. Tumors larger than 1,5 cm are more likely to develop a recurrence, regardless to the kind of surgical approach. Wedge resection may be considered a feasible procedure for highly selected patients affected by NSCLC: open approach may be related to a better long term outcome in patients with small and deep nodules.

Background:
The aim of this multicenter study (the Setouchi Lung Cancer Group Study 0701) was to determine the feasible administration schedule of S-1, an oral fluoropyrimidine, for adjuvant chemotherapy in patients with completely-resected pathological stage IA (tumor diameter, 2 to 3 cm) non-small-cell lung cancer (NSCLC).

Methods:
Patients were randomly assigned to receive an adjuvant chemotherapy of either 4-week oral administration of S-1 (80 mg/m2/day) followed by 2-week rest (group A), or 2-week oral administration of S-1 (80 mg/m2/day) followed by one week rest (Group B). The duration of adjuvant chemotherapy was one year in both arms. The primary endpoint was feasibility.

Results:
Figure 1 Eighty patients were enrolled, of whom 76 were received S-1 treatment. The treatment completion rates were 49.4% [95% confidential interval (CI), 32.8 to 65.9%] in group A and 52.1 % (95%CI, 35.5 to 68.6%) in group B (P = 0.4). The relative dose intensities were 40.4% (95%CI, 20.3 to 60.5%) in group A and 53.5% (95%CI, 37.7 to 69.3%) in group B (P = 0.4). There were no treatment-related deaths. Patients with grade 3/4 toxicities were significantly more frequent in group A (40.5%) than group B (15.4%, P = 0.02). The 2-year relapse-free survival rates were 97.5% in group A and 92.5% in group B, and the 2-year overall survival rates were 100% in both groups.



Conclusion:
Two-week oral administration of S-1 followed by one week rest for one year may be more feasible for adjuvant chemotherapy in patients with completely-resected stage IA (T diameter, 2 to 3 cm) NSCLC.

Background:
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death around the world. Currently, adjuvant platinum-based chemotherapy is recommended as the standard treatment for patients with completely resected stage IB-IIIA NSCLC. Pemetrexed, a multitargeted antifolate agent, has been shown to have definite activity in non-squamous NSCLC and has proven to be efficacious in the first-line metastatic NSCLC. Hence, the aim of this study was to evaluate the efficacy and toxicity of pemetrexed/ platinum in patients with completely resected lung adenocarcinoma and identify prognostic factors in this setting.

Methods:
A retrospective study was performed in patients with completely resected stage IB-IIIA lung adenocarcinoma who received pemetrexed and a platinum as adjuvant therapy. Generally, pemetrexed 500mg/m2 d1 and cisplatin 30mg/ m2 day1-3 were administrated every 21-28 days for 4 cycles. Study endpoints included overall survival (OS), progression-free survival (PFS) and treated-related toxicities. Immunohistochemical (IHC) was used to examine the protein expression of p53, thymidylate synthase (TS), dihydrofolate reductase (DHFR), Lipocalin 2 and nm23-H1 in surgical resection specimens of 23 patients. The associations between protein expression level and clinical outcome were evaluated using cox proportional hazards model.

Results:
Between Feb. 2012 and Jan.2014, 49 patients were treated with pemetrexed-based chemotherapy. Median age 57(range35-79, years), males 47%; stage IB 41%, II 18%, IIIA 41%; ever smokers 35%; lobectomy 92%, wedge resection 8%. The completion of 4-cycle chemotherapy was 67.3%. Grade 3+ hematologic and gastrointestinal toxicities were observed in 5 (10%) patients and 4 (8%) patients, respectively. The median PFS was 39.63 months (95%CI 26.55-52.71 months), and the median OS was unreachable. 1-, 2- and 3-year survival rates were 95.9%, 93.6%, 83.2%, respectively. 1-, 2- and 3-year PFS rates were 93.9%, 75.3% and 56.8%, respectively. Of 23 patients measured by IHC, 19 expressed TS, 9 expressed p53, 10 expressed DHFR, and none expressed Lipocalin 2 or nm23-H1. No significant correlations of these protein expression and clinical outcome were observed.

Conclusion:
The regimen of pemetrexed/platinum showed lower incidence rates of toxicities and promising treatment outcomes in patients with completely resected stage IB-IIIA lung adenocarcinoma. However,no prognostic biomarker was identified in our study, which may be related to the small sample size.

Background:
Intensity Modulated Radiotherapy (IMRT) facilitates superior dose conformity, due to sculpting of the high dose volume and reduction of dose to normal tissues. However, the use of IMRT for lung cancer in the U.K. remains low, as a result of the paucity of clinical data and concerns about the impact of the low dose bath on toxicity. Our institution has treated 738 lung cancer patients with IMRT since 2008. Here we report the results of 227 patients, focusing on toxicity. Survival will be reported at a later date.

Methods:
A retrospective review of the first 227 patients receiving 6MV inversely planned (6-8 field) step and shoot IMRT for lung cancer from 2008-2013 was carried out. A database was interrogated to correlate planning parameters with toxicity. Toxicity was collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

Results:
227 patients with a median age of 66 (36-87) were included. Patients received a dose of 50-68 Gy in 20-33 fractions. One hundred and sixty (70%) had non-small cell lung cancer, 47 (21%) small cell lung cancer, 8 (4%) mixed histology and 12 (5%) no histology. At presentation, 6 (3%), 27 (12%), 184 (81%) and 9 patients (4%) had stage I, II, III and IV disease respectively. Treatment modalities were split evenly between concurrent (37%), sequential (31%) chemo-radiotherapy and radiotherapy alone (32%). Median PTV volume was 502.7 cc (67.3-1297.2). Median lung V20, V10 and V5 were 27.7% (6.8-35.3), 50.4% (9.8-83.1) and 64.3% (12.9-98.9). Mean dose to the oesophagus was 23.8 Gy (3.1-51.0); oesophageal V55 and V35 were 2.9% (0-70.8) and 36.8% (0-79.8). Heart V30 and V5 were 23.6% (0-60.6) and 57.6% (0-100) respectively. Despite 104 patients (46%) with V5 values > 65%, acute G3 pneumonitis was observed in only 7 (3.1%) patients. Acute G3 oesophagitis was observed in 31 (13.7%) patients. Late toxicity was not available in all patients. 6/154 (4%) developed late G3 pneumonitis, 8/154 (5.3%) had late G3 dyspnoea and late G2 cough was reported in 12/154 (8.1%). Grades 1, 2 and 3 pulmonary fibrosis occurred in 68/178 (30%), 13/178 (6%) and 1/178 (0.4%) patients respectively. Oesophageal stricture was evident in 7/173 (3%) and 4 patients developed an oesophageal fistula. There was no significant correlation between lung V5 and acute or late lung toxicity, using >65% as a cut off. Similar results were found with lung V10. There was also no relationship between mean oesophageal dose/V35/V55 and fistula or oesophageal stricture.

Conclusion:
From our experience, IMRT to the thorax is well tolerated, with minimal grade 3 toxicity. Contrary to reports, we did not observe a correlation between lung V5 and acute/late lung toxicity. However the heterogeneous population, retrospective nature of this study and small number of grade 3+ events limit the scope for multivariate analysis of toxicity. The data needs to be confirmed with a larger number of patients and integrated within predictive models of radiation-induced toxicity using patient reported outcome tools to facilitate collection of prospective toxicity data in the routine clinical setting. Data will be updated prior to the meeting.

Background:
To describe radiographic evidence of radiation pneumonitis (rRP) and fibrosis (rRF) and determine what dosimetric parameters correlate with rRP and rRF after stereotactic ablative radiation therapy (SABR) to the lung.

Methods:
98 follow up CT scans from 32 patients treated by SABR were retrospectively reviewed for CT appearance of rRP and rRF determined by the Ikezoe (≤ 6 months) and Koenig (≥ 7 months) systems. The correlation of dosimetric parameters such as planning target volume (PTV) and the volume of lung receiving dose of radiation (V2.5, V5, V7, V10, V15, V20, V25, and V30) to rRP, rRF, and fibrotic volume (V~fibrosis~) were analyzed using Spearman’s rho.

Results:
The median follow up was 10 months (range 2 – 24 months). There was a 55% incidence of rRP and 59% incidence of rRF. The low dose parameters of V~2.5, ~V~5, ~V~7~, and V~10 ~(the volume of lung receiving more than 2.5, 5, 7, and 10 Gy of radiation, respectively) were correlated to the development of rRP (p < 0.05). There was only V~10 ~correlated statistic significantly to the incidence of rRF, with V~5~, V~7,~ and V~10~ trended towards significance. The median V~fibrosis~ was 119 cm[3] with a range of 49 – 829 cm[3]. The medians of the PTV and ITV were 52.6 cm[3] and 12.6 cm[3]~, ~respectively. The absolute fibrotic volume was correlated with the planning target volume (PTV), V~7 ~and V~10 ~(p < 0.05).

Conclusion:
The development of rRP and rRF was associated with the volume of lung that received lower dose of radiation. The absolute fibrotic volume from SABR was correlated with PTV and the volume of lung receiving lower dose of radiation. This finding needs to be validated with more patients’ data and longer follow up.

Background:
Stereotactic ablative radiotherapy (SAR) is a standard therapy for early stage, medically inoperable non-small cell lung cancer (NSCLC) and select metastatic tumors. Strategies combining SAR and immune checkpoint inhibitors are of great interest in potentially augmenting anti-tumor immune response, and prospective trials evaluating SAR/immunotherapy combinations are underway. However, the systemic immune response profile following SAR is poorly defined. Better understanding of the systemic immune response following SAR should allow optimization of SAR/immunotherapy protocols. We performed pre and 1 week post-SAR immune profiling on patients undergoing lung SAR, focusing on central memory T-cells which have been implicated as important mediators of systemic anti-tumor immune responses.

Methods:
Patients are actively accruing to an IRB approved protocol examining systemic immunophenotype changes following SAR for early stage (T1-2N0) NSCLC or metastatic lesions to the lung. Patients underwent collection of 30 cc blood by venipuncture immediately prior to and at 1 week post-SAR to a median dose of 50 Gy (range: 50-54 Gy) over 5 fractions (range: 3-5 fractions). Immunophenotyping of peripheral blood mononuclear cells (pbmc’s) was performed using flow cytometric analysis. Central Memory T-cells were defined as CD62L+ and CD45RA- subsets of CD4+ or CD8+ T-cells. Changes pre-treatment to post-treatment were compared across the cohort using a paired T-test.

Results:
To date eleven NSCLC patients have accrued, and evaluable pre- and post-SAR specimens are available for six, all with early stage NSCLC (T1=4, T2=2, synchronous primaries =1). At one week post-SAR increases in systemic central memory CD4+ T-cells were observed in 4/6 patients and increases in systemic central memory CD8+ T-cells were observed in 3/6 patients with substantial (up to 10-fold) increases observed in some patients. Across the cohort the percent of circulating memory CD4+ T-cells increased from 1.9% pre-SAR to 3.1% post-SAR (p=0.06, Figure 1) and the percent of circulating memory CD8+ T-cells increased from 0.3% pre-SAR to 0.5% post-SAR (p=0.34, Figure 1).

Conclusion:
Our preliminary data in a limited patient cohort suggest lung SAR may induce systemic upregulation of circulating central memory T-cells which may be important mediators of the anti-tumor immune response. As more patients accrue, additional post-treatment time points are evaluated, and further analyses including cytokine/chemokine signatures are performed, we aim to better define systemic immunophenotype changes induced by lung SAR, assess how these changes relate to treatment toxicity and efficacy, and whether they can predict which patients will most likely benefit from the addition of immunotherapy to SAR. Figure 1

Background:
Pleural effusion is regarded as a frequent late toxicity after thoracic radiotherapy (TRT). However, recent literature is lacking on this toxicity. This study aimed to examine the patient and dosimetric risk factors associated with radiation induced pleural effusion (RIPE) in lung cancer patients treated with TRT.

Methods:
Lung cancer patients treated with TRT having follow-up imaging, CT or PET/CT, were eligible. Pleural effusion of increased volume after TRT without evidence of tumor progression was considered to be RIPE. Parameters of lung dose-volume histogram including percent volumes irradiated with 5 to 55 Gy (V5-V55) and mean lung dose (MLD) were analyzed. Optimal dosimetric thresholds for RIPE were calculated by receiver operating characteristic (ROC) analysis. Associating clinical and treatment-related risk factors for RIPE were detected by univariate and multivariate analyses with SPSS 18.0. Data were considered statistically significant at value of p < 0.05.

Results:
Of 806 consecutive patients who received TRT at two institutions, 205 had post-treatment imaging available and were included in this study. The median (range) age was 63 (34-85) years; Male, Caucasian race, current smokers, stage III and squamous cell cancer accounted for 73.2%, 81.0%, 50.7%, 66.8% and 27.8%, respectively. The median follow-up duration was 14.6 (range, 0.7-80.8) months. Of 51 patients (24.9%) who developed RIPE, 40 had symptomatic RIPE including chest pain (47.1%), cough (23.5%) and short of breath or dyspnea (35.3%). The median (range) RIPE interval from end of TRT was 3.7 (0.6-18.0) months. The RIPE rates of the two institutions were 20.2% and 32.1% with a borderline significance (p = 0.053). Caucasian race (HR = 2.930, 95% CI: 1.197-7.172, p = 0.019) and histology of squamous cell lung cancer (HR = 0.645, 95% CI: 0.425-0.980, p = 0.04) were significantly associated with the low risk of RIPE, while age (p = 0.378), gender (p = 0.071), stage (p = 0.148), radiation dose (p = 0.782) and concurrent chemotherapy (p = 0.173) were not. The whole lung V5, V10, V15, V20, V25, V30, V35, V40, V45, V50 and MLD were significantly higher in patients with RIPE than in those without RIPE (p = 0.007, 0.022, 0.044, 0.048, 0.034, 0.016, 0.010, 0.026, 0.040 and 0.014), and only V5 was the significant predictive factor for both RIPE and symptomatic RIPE (p = 0.007 and 0.021) with the largest areas under ROC curve (AUC = 0.779). Using a cutpoint of 41.5% for V5, the sensitivity and specificity were 100% and 61.5%, respectively.

Conclusion:
Radiation induced pleural effusion is notable. Caucasian race and squamous cell tumor histology may be associated with lower risk of RIPE. The whole lung V5 seems to be a significant risk factor for symptomatic RIPE.

Background:
Scarce information is available concerning the natural history of untreated patients with early-stage Non-Small Cell Lung Cancer (NSCLC). No randomized studies have been conducted comparing Stereotactic Body Radiation Therapy (SBRT) with no treatment for patients with early-stage NSCLC. Previously, it has been suggested that SBRT increases overall survival for patients with NSCLC T1-2N0M0. In this study a national group of untreated patients with early-stage NSCLC was identified in order to compare the effect of SBRT with the natural history in a retrospective setting.

Methods:
From 2007 to 2013, 136 patients diagnosed NSCLC T1-2N0M0 with a tumor diameter up to 5 cm were treated with SBRT at Odense University Hospital. The thoracic RT consisted of 45-66 Gy/3 F delivered in 9 days. For the same period, a national group of 121 untreated patients with early-stage NSCLC was extracted from the Danish Lung Cancer Registry. Of these, 85 patients survived more than one month after the diagnosis was established and might have been candiates to SBRT. Twenty-four patients with unrecorded tumor diameter were excluded from the present analysis thus, 61 patients remained in the untreated group. Pathoanatomical diagnosis was known for all patients. Kaplan-Meier and Cox proportional hazard analyses were used for uni- and multivariable survival analyses, respectively. Overall survival (OS) was calculated from the date of diagnosis.

Results:
The mean age was 72 vs. 78 years in the SBRT and untreated group, respectively. Statistically significant (p<0.05) inter-group differences in patient characteristics were observed for pathological type and FEV1 (%predicted). No difference in gender, tumor size, ECOG performance status, or pack years was observed. The potential median follow-up time was 38 months in the SBRT group vs. 57 months among untreated. A log rank test showed a significant difference of overall survival (OS) between groups e.g. resulting in an OS at 5-year of 44% vs. 10% respectively and a median OS of 47.8 vs. 12.2 months for SBRT and untreated group, respectively (p < 0.01). Multivariate analysis indicated that age, tumor size, pack years, gender, adenocarcinoma and FEV1 (%predicted) had no significant influence on survival, while SBRT and ECOG performance status had (Table 1). Figure 1



Conclusion:
In this study SBRT was associated with significantly longer OS compared to no treatment, suggesting that SBRT is a convenient treatment that increases survival for patients with early-stage NSCLC.

Background:
Lobectomy is regarded as the standard of care for early stage non-small-cell lung cancer (NSCLC), but stereotactic radiotherapy (SBRT) is an option for patients who are not candidates for surgery. Although the curative intention treatments, a significant proportion of patients with NSCLC will develop recurrent disease. For patients previously treated with SBRT little is known of retreatment with SBRT in the recurrent setting.

Methods:
All patients with lung cancer treated at our center with SBRT have been registered prospectively. We identified the patients who had salvage SBRT after prior pulmonary surgery or SBRT. Overall survival was calculated from the day of salvage SBRT.

Results:
Between November 2008 and February 2015, 198 patients were treated with SBRT. We identified 24 patients that had received SBRT as salvage treatment for their first recurrence in the lung. Surgery was the initial treatment for 13 of the patients (OP-group) and SBRT was the initial treatment for the remaining 11 patients (RT-group). By the end of follow up, 5 patients in the OP-group had died and 3 in the RT-group. In the OP-group all the salvage SBRT was given as 66 Gy in 3 fractions. In the SB-group, 5 was treated with 56 Gy in 8 fractions, 1 with 45 Gy in 3 fraction and 1 with 45 Gy in 10 fractions when given salvage SBRT.

	Primary surgery	Primary SBRT	All
Number of patients	13	11	24
Age mean (range)	75 (62-88)	69 (53-87)	72 (53-88)
Histology Plano/Adeno/NOS	3/8/2	4/5/2	7/13/4
Time in months from primary treatment to salvage SBRT median (range)	65 (4-236)	17 (5-44)	21 (4-236)
Survival time from SBRT 1 year (%) 2 year (%)	85 62	89 61	87 60
Median follow-up months (range)	27.6 (14.3-62.8)	15.9 (1.4-32.9)	21 (1.4-62.9)
Lung function FEV1, median (range	1.4 (0.6-2.7)	1.4 (0.4-2.8)	1.4 (0.4-2.8)
ECOG Performance Status 0 1 2 3	4 5 3 1	1 2 7 1	5 7 10 2

Conclusion:
Although the time from primary treatment to salvage SBRT was longer if surgery was the primary treatment than if the primary treatment was SBRT, the overall survival was equal for the two groups.

Background:
The aim of this study was to determine the survival rate of patients with non-small cell lung cancer (NSCLC) who were preoperatively diagnosed with positive N2 lymph node and compare survival with chemo- or chemoradiotherapy treated patients to surgically operated patients, with or without preoperative chemoradiation therapy.

Methods:
Study included two patient groups. Operative patient group consisted of 74 clinical Stage IIIA patients with cN2 lymph node involment, from a 1105 patient cohort, who were operated between January 2000 and December 2014. Definitive chemoradiation group consisted of 49 Stage IIIA NSCLC patients that were treated between September 2008 and October 2014. Institutional tumour board was used to evaluate operative treatment. Routine positron emission tomography (PET) was established in 2006 at our institution.

Results:
37 had preoperative mediastinoscopy, 66 PET-CT and 24 received both. In the operative patient group, adjuvant chemotherapy was administered 25 and chemoradiation to 7 patients. No differences were observed between patient groups in age or Charlson Co-morbidity Index. A total of 47 operated patients were downstaged to pathological N0 or N1 disease and pathological N2 disease was observed in 27 patients, of 11 patients had multi-level N2 involvement. Median survival for pN0/1 was 47 months, pN2 15 months and definitive chemoradiation 19 months. Survival for pathological N-stage is presented in Figure 1, and for preoperative therapy in Figure 2. Figure 1Figure 2





Conclusion:
Operative treatment for clinically suspected N2 disease is feasible option if patients are downstaged to pathological N0 or N1 with means of chemoradiation therapy or pre- or intraoperative frozen sections. Surgery for pathological N2 disease has no survival advantage over definitive chemoradiation and should be discouraged.

Background:
Lung cancer with mediastinal lymph node involvement (N2) is a heterogeneous entity. The Robinson-classification subdivided these N2-patients in four groups (IIIA~1~-IIIA~4~). Objective of this analysis was to investigate the result of strict treatment strategies for N2-patients determined by the interdisciplinary tumorboard.

Methods:
Retrospective study and survival analysis of 118 consecutive patients with stage IIIA-N2 lung cancer classified according to the Robinson-classification and treated within a multimodality treatment regime between January 2009 and June 2014. All patients were evaluated and discussed in an interdisciplinary lung tumorboard and a therapy recommendation was made based on the Interdisciplinary Guideline of the German Respiratory Society and German Cancer Society.

Results:
Robinson subgroups were: IIIA~1~ (n= 28; mean age 60.4 years), IIIA~3~ (n= 70; mean age 63 years) and IIIA~4~ (n= 20; mean age 64.4 years). We have no stage IIIA~2~, because we did not perform an intraoperative frozen section of mediastinal lymph nodes. Surgical resection with systematic lymph node dissection was performed in all patients with stage IIIA~1~ (n= 28). After induction chemotherapy or chemo-/radiotherapy, 47% of patients in IIIA~3~ (n= 33) and 10% of patients in IIIA~4~ (n= 2) could be operated with curative intention. Complete tumor resection (R0) was achieved in 93% (n= 26) in stage IIIA~1~, in 94% (n= 31) in stage IIIA~3~ and in 100% (n= 2) in stage IIIA~4~. Operative mortality within 30 days was 3.17%. Overall median survival was 29.8 months. The 3- and 5-year survivals were 44.9% and 28.5%, respectively, in all patients with stage IIIA-N2 disease. There were no significant differences (p= 0.477) in survival regarding the Robinson subgroups. Patients who underwent surgical tumor resection had a significant better median survival (43.6 vs. 22.8 months; p= 0.013) compared to patients treated conservatively. In addition, patients in stage IIIA~3~ who were considered for surgery after induction therapy had a significant better median survival according to non-surgically treated patients (45.4 vs. 22.8 months; p= 0.014) and they had the good overall survival of IIIA~1~ patients (3- and 5-year survival rates of 59.4% and 40.8%). Deviation of the interdisciplinary recommended therapy (n= 15) lead to a significant reduced median survival (12.9 vs. 31.9 months; p= 0.011) compared to implementation of the suggested treatment approach (n= 100).

Conclusion:
Stage IIIA-N2-patients should be classified according to the Robinson-classification and discussed in the tumorboard. The treatment recommendation should be respected, because enforcement of the interdisciplinary recommended therapy significantly impacts survival. Surgical resection did lead to significant better survival rates. All stage IIIA~3~ and IIIA~4~ patients should be reevaluated for surgery depending on their response to induction therapy.

Background:
The detection of small-sized (≤ 2 cm) non-small cell lung cancer (NSCLC) has increased with the development of high-resolution computed tomography. The reported 5-year survival rate of T1a (≤ 2 cm) N0M0 patients is more than 80%, and that of p-T (≤ 2 cm) N2M0 patients has also steadily improved.

Methods:
Between January 1991 and December 2011, a total of 917 patients with small-sized NSCLC underwent curative pulmonary resection with systematic lymph node dissection by open thoracotomy or video-assisted thoracic surgery at our hospital. We retrospectively evaluated their postoperative clinical outcomes and survival rates. Survival was analyzed using the Kaplan-Meier method and log-rank test.

Results:
There were 57 (6.2%) patients with mediastinal lymph node metastasis (pN2 disease). The distributions of the histological types were adenocarcinoma 41 cases, squamous cell carcinoma 11, large cell carcinoma 4, and carcinoid 1. The procedures included lobectomy in 48 cases, segmentectomy in 6, and pneumonectomy in 3. The respectively status of lymph node metastasis was single station in 36 cases and multiple station in 21. Skip lymph node metastasis (no hilum lymph node metastasis) was observed in 13 cases. In 44 cases, there was both hilum lymph node and mediastinal lymph node metastases. There were 34 cases (59.6%) that were upstaged from preoperative clinical diagnosis (cN0 or N1). The median overall survival period and 5 year survival of the 57 patients with pN2 was 43.5 months and 41%. The recurrence rate was 70% (40/57) and the median disease-free interval was 41.3 months. Of the 18 patients without recurrence, 14 (77.8%) had single station mediastinal metastasis. The 5-year overall survival rates with multiple station or single station mediastinal metastases were 34.5% and 48.9%, respectively (NS). The 5-year overall survival rates with multiple (hilum and mediastinal) station lymph node metastases and only mediastinal station lymph node metastasis were 37.7% and 64.8%, respectively.

Conclusion:
This study showed that 6.2% of small-sized NSCLC had N2 disease. Moreover, 59.6% of small-sized NSCLC was upstaged from clinical diagnosis to pathological diagnosis. Single station mediastinal metastases showed a longer overall survival rate (64.8%) than multiple station mediastinal lymph node metastases. Therefore, we recommend systematic lymph node dissection for local treatment as well as accurate diagnosis. As multiple mediastinal node metastases showed an unfavorable prognosis, surgery combined with systematic treatment is recommended.

Background:
Non-small cell lung cancer (NSCLC) involving mediastinal lymph nodes without an identifiable primary tumor is a rare presentation. While definitive surgery or radiotherapy with or without concurrent chemotherapy is typically recommended, little is known about the treatment outcomes. As such, we reviewed our institutional experience to determine if subsequent development of lung tumors is common and whether prognosis is comparable to stage III NSCLC in general.

Methods:
This study was an IRB-approved retrospective review of an institutional NSCLC database. Twenty-six patients with biopsy-proven NSCLC involving mediastinal lymph nodes with no identifiable lung primary lesion and no evidence of distant metastases treated with curative intent between 1995-2013 were identified. PET-CT staging was performed in 25 of 26 patients. All followup was calculated from date of diagnosis.

Results:
The median followup was 44 months. The median age at diagnosis was 60 years (range 51-81) among the 18 males (69%) and 8 females (31%). N2 and N3 disease were each present in 13 (50%) patients, respectively. Histologies included adenocarcinoma in 12 (46%), squamous cell carcinoma in 10 (38%), NSCLC not otherwise specified in 3 (12%), and large cell lung carcinoma in 1 (4%). Eleven patients underwent EGFR mutation analysis, with no sensitizing mutations identified. All patients had a smoking history (median 35 pack-years). Four (15%) patients underwent complete surgical resection, of whom 3 underwent induction chemotherapy and 1 was treated with surgery alone. One of the four patients underwent post-operative radiation therapy to 54 Gy. Twenty-two (85%) patients were treated with definitive radiation therapy including sequential chemotherapy and radiation in 8 (mean RT dose = 70 Gy), concurrent chemoradiation in 10 (mean RT dose = 60 Gy), neoadjuvant chemotherapy followed by concurrent chemoradiation in 3 (mean RT dose = 66 Gy), and radiation alone in 1 (treated to 60 Gy). The median overall survival was 78.1 months with actuarial 2- and 5-year survival rates of 78% and 67%, respectively. Five patients developed intrathoracic failure at a median of 19.8 months. One patient had an isolated lung failure at 13.6 years, but this likely represents a secondary primary and not tumor recurrence. Two patients had isolated mediastinal lymph node failures at 18.1 and 19.8 months and 2 patients initially had a mediastinal lymph node recurrence at 0.2 and 3.4 years, but subsequently failed in the lung at 8.5 and 3.6 years respectively. The actuarial 2- and 5-year intrathoracic control rates were 85.7% and 78.6%. Nine patients developed metastatic disease at a median of 16.5 months. The 2- and 5-year actuarial freedom from distant metastases was 70.9% and 59.1%. Among patients receiving definitive radiation, there was no difference between those receiving concurrent chemotherapy and those who did not.

Conclusion:
To our knowledge, this is the largest reported series of occult primary NSCLC involving mediastinal nodes. Definitive local therapy, including radiotherapy and surgery, was associated with very favorable locoregional control and survival, particularly compared with expected outcomes for stage III NSCLC.

Background:
Bilobectomy for treatment of lung cancer is considered a high-risk procedure as it is associated with increased postoperative complication rate and the negative impact on survival. We analyzed the safety and the oncologic results of this procedure.

Methods:
We retrospectively reviewed a prospectively collected database to retrieve patients who underwent bilobectomy for lung cancer between 1991 and 2015. Age, gender, neoadjuvant treatment, bilobectomy type and indication, complications, pathology, stage, and survival were analyzed using Cox regression in univariate and multivariate analysis. Kaplan–Meier survival curves were obtained and compared by log–rank.

Results:
From our 4144 resected lung cancer cases, bilobectomy was performed on 106(2.5%) patients (55 men; mean age, 65.5 years). There were 51 upper-middle and 55 middle-lower bilobectomies (adenocarcinoma,67 (63.3%); squamous cell carcinoma,35(33%); carcinoid tumor,4(3.8%)). Indications were tumor invasion of the bronchus intermedius in 58 (54.7%), vascular invasion in 26 (24.5%), and tumor crossing the fissure in 22 (20.8%) patients. Induction therapy was performed in 24 patients (24.5%). Thirty-day mortality was 1.89% (n = 2). Overall major morbidity occurred in 13 patients ( 12.3%) among them 9 patients(69.2%) had pulmonary complications . Overall 3 and 5-year survivals were 64.5% and 56.2% respectively. Disease free 3 and 5-year survivals were 47.4% and 43.8% respectively. Significant decrease in 5 year survival was observed among smoker (p=0.046), higher tumor grades (Grade3 versus 1or2 (p=<0.005)), higher stages (stage I, 66.6%; stage II, 51.5%; stage III, 31.2%; p = 0.012)(see Figure) and the nodal(N) disease s (N0, 58.2%; N1and 2, 38.1%; p = 0.054) adversely influenced survival. Multivariate analysis demonstrated that a higher tumor grade (p = 0.005), a larger tumor (p=0.019), advanced N status (p=0.085) and smoking (p=0.056) adversely affecting prognosis. Figure 1



Conclusion:
Bilobectomy is associated with a low mortality and an acceptable morbidity. Survival relates to disease stage and N factor. Optimal prognosis is obtained in patients with early stage, low grade tumors and nonsmoker.

Background:
Lung cancer is the leading cause of both morbidity and mortality related to cancer worldwide. The most controversial academic strategies for the treatment of lung cancer is ⅢA-N2 non-small cell lung cancer.This study was a retrospective analysis of the clinical features of stage ⅢA-N2 patients, in order to find the factors that affecting long-term survival in the postoperative patients of stage ⅢA-N2 NSCLC.

Methods:
One thousand two houndred and ningtyLung cancer patients from a prospectively maintained database, treated by a single surgeon group between January 2000 and Jun 2013, at Beijing Cancer Hospital, Peking University, were reviewed.121 patients of stage ⅢA-N2 NSCLCs were analyzed, comparing gender, age, smoking index, perioperative chemotherapy, surgical approach, histological type, intravascular cancer emboli, pT stage and N2 lymph node status with long-term survival.

Results:
The postoperative pathological findings in this group showed that 79 patients(65.3%) were single-station N2, 42 patients (34.7%, 30 patients had 2 stations N2, 8 patients had 3 stations N2, 4 patients had 4 stations N2) were multi-stations N2; 42 patients’ (34.7%) N2 status were ⅢA1/A2, and 79 patients (65.3%) N2 status were ⅢA3/A4; 54 patients (44.6%) had subcarinal lymph node metastasis. The overall 1,3,5-year survival rates of 121 patients was 91.7%, 62.2%, 43.6%, respectively, and the median survival time was 50.3 months. Univariate analysis showed that the 1,3,5-year survival rates between single-station N2 and multi-station N2 metastasis was 94.9% vs. 85.5%, 70.3% vs. 46.7%, 58.3% vs. 25.5% respectively, with a significant difference (p= 0.001); the 1,3,5-year survival rates between ⅢA1/A2 and ⅢA3/A4 was 97.6% vs. 88.5%, 78.3% vs. 53.5%, 52.7% vs. 38.4% respectively, with a significant difference (p=0.020); subcarinal lymph node metastasis was not a prognostic factor, the 1,3,5-year survival rates between metastesis and no metastasis was 92.6% vs. 91.0%, 56.0% vs. 68.4%, 37.4 vs. 49.5% respectively, with no significant difference (p=0.276). Gender, age, smoking index, perioperative chemotherapy, T stage, histological type, intravascular cancer emboli and other factors are not prognostic factors in this group. COX regression analysis showed that only single station N2 metastasis（HR=0.326，95%CI：0.186～0.572）and IIIA1/A2（HR=0.494，95%CI：0.259～0.941）were the independence factors.

Conclusion:
1. After a rigorous selection of stage ⅢA-N2 NSCLC, patients obtain good prognosis by surgery combined with multidisciplinary treatment. 2. Single-station N2 metastasis had a better survial comparing to multi-station N2 metastasis. 3. The dicovery of pathology of N2 metastasis in intraoperative or postoperative pathological findings (ⅢA1/A2) had a better survival comparing to pretreatment fingdings(ⅢA3/A4). 4. Subcarinal lymph node metastasis was not ⅢA-N2 indicator of poor prognosis in NSCLC. 5. Gender, age, surgical approach, histological type, pT staging does not affect the stage ⅢA-N2 NSCLC prognosis.

Background:
The aims of this study were to assess the prognosis of microscopic residual (R1) disease at different resection margins and to evaluate the prognostic impact of adjuvant therapy for R1 disease at different sites.

Methods:
We retrospectively reviewed the clinical records of 1,667 patients who underwent lung resection at the Aichi Cancer Center from 1998 to 2007. Twenty-eight patients (1.7%) were found to have R1 disease, and they were divided into three groups according to the site of residual disease. The “bronchus group” included 9 patients: 5 with cancer cells at the bronchial stump, 3 with carcinoma in situ change at the bronchial stump, and 1 with a clump of tumor cells in the parabronchial tissues (1 patient). The “lymph node group” included 5 patients with residual cancer cells in the lymph node. The “chest wall and lung tissue group” included 14 patients with cancer cells present at the following locations: the margin of chest wall invasion (9 patients), vertebral bodies (2 patients), the pericardium (1 patient) and lung tissue (2 patients). Actuarial survival curves were estimated by the Kaplan-Meier method. Statistical comparisons between survival distributions were performed using the log-rank test. A multivariate analysis was performed using the Cox proportional hazards model for overall survival analysis. A probability value of less than 0.05 was considered to be statistically significant.

Results:
This study included 24 men and 4 women with an age range of 49 to 80 years (median, 64 years). Six (21%), 18 (64%), and 4 (15%) patients had undergone pneumonectomy, lobectomy, and the other procedures, respectively. One (4%), 5 (18%), 19 (68%), and 3 (10%) patients had stage I, II, III, and IV disease, respectively. All 28 patients had non-small cell lung carcinoma. Eleven (39%), 12 (43%), and 5 (18%) patients had adenocarcinoma, squamous carcinoma, and other forms of carcinoma, respectively. The 5-year survival rate and median survival period were 30.3% and 37 months, respectively. The median recurrence-free survival time was 14.8 months. Regarding recurrence patterns, 11 (39%) patients did not experience recurrence, 4 (14%) developed only local recurrence, 5 (18%) developed only distant metastasis, 7 (25%) developed both local recurrence and distant metastasis, and 1 was lost to follow up. Sixteen patients received adjuvant therapy: 11 received radiotherapy, 3 received chemotherapy, and 2 received chemo-radiotherapy. Six patients (66%) in the bronchus group received radiotherapy. Six of the 11 patients with no recurrence were in the bronchus group. The univariate survival analysis identified the following factors that significantly influenced the 5-year overall survival rate: R1 anatomical sites (other sites vs the bronchus, p=0.0467, HR 2.775) and adjuvant therapy (no adjuvant therapy vs adjuvant therapy, p=0.0084, HR 3.509). The multivariate survival analysis identified only one factor that influenced survival: adjuvant therapy (adjuvant therapy vs no adjuvant therapy, p=0.0056, HR7.284).

Conclusion:
Patients with R1 disease generally had a poor prognosis, but this study suggested that adjuvant therapy improves the prognosis of these patients. In terms of sites of R1 disease, the bronchus group had a better prognosis than the other groups.

Background:
Concurrent chemo and radiotherapy (CT- RT) is standard of care for inoperable stage IIIA/B non-small cell lung cancer (NSCLC). Optimal regimen and schedule of concurrent CT- RT remain undefined. This phase II trial evaluated carboplatin –gemcitabine + concurrent RT followed by consolidation carboplatin – gemcitabine

Methods:
Treatment schedule during CT-RT phase: weekly carboplatin (AUC 2) + gemcitabine (200mg/m2) for 6 weeks + concurrent RT (60 Gy). CT consolidation phase: carboplatin (AUC 3) gemcitabine (2500 mg/m2) every two weeks for 3 cycles. Primary endpoint was security and secondary response rate, time to progression (TTP) and overall survival (OS)

Results:
24 patients were enrolled: Sex 18 male, 6 female. Histology: 12 adenocarcinoma, 8 squamous, 4 undifferentiated large cell carcinoma. Stage: IIIB: 20, IIIA: 4. ECOG 0-1: 23, ECOG 2: 1. All the patients completed concurrent CT-RT and 22 consolidation CT. Toxicity: CT- RT phase: No grade 4 toxicity was observed. Grade 3: Neutropenia 0, anemia 4.1%, thrombocytopenia 12.5%, esophagitis 16.6%. CT consolidation phase: Grade 3-4 toxicity: Neutropenia 16.6%, Anemia 21%, Thrombocytopenia 16.6% of the patients. 3 patients required red blood cell transfusion and 1 patient died for febrile neutropenia grade 4 during consolidation. Efficacy: Response Rate: 75% (Partial: 50% Complete: 22%), Stable disease 21% Progression 4%. Median TTP: 11 months (95% CI 7-17) and median OS: 18 months (95% CI 16.2- 20.5)

Conclusion:
Concurrent carboplatin – gemcitabine with thoracic RT is feasible with a favorable profile showing less hematologic toxicity and esophagitis than other CT-RT regimens. CT consolidation showed severe hematological toxicity. This regimen is active and could be a good option to combine with concurrent RT.

Background:
One of the major challenges to delivering coordinated oncologic care is multimodality management. While it has been hypothesized that providing all treatment in a single institution (“integrated”) may improve access and outcomes, it is unclear whether outcomes are affected by receiving treatment at more than one facility (“nonintegrated”). Our aim was to determine whether integration of concurrent chemoradiation therapy (CCRT) at a single center impacts outcomes for patients with locally advanced non-small cell lung cancer (NSCLC).

Methods:
Using the National Cancer Data Base, we identified adult patients with stage III NSCLC diagnosed in 2010-2011. We included non-surgical patients who underwent CCRT with thoracic radiotherapy to 59.4-74.0 Gy delivered at the reporting facility. Demographic, clinicopathologic, and healthcare system characteristics were compared among patients receiving integrated vs. nonintegrated therapy using hierarchical mixed-effects logistic regression analysis with clustering by reporting facility and bootstrapping. Overall survival was compared using Kaplan-Meier analysis, the log-rank test, and Cox proportional hazards regression analysis. Time from diagnosis to radiotherapy initiation was compared using the Wilcoxon rank-sum test given a non-normal distribution.

Results:
A total of 2,794 patients were included, among whom 1,695 (61%) received integrated therapy and 1,099 (39%) received nonintegrated therapy. Patients receiving integrated therapy were significantly more likely to have a Charlson-Deyo comorbidity score ≥1 (OR 1.67, 95% CI 1.24-2.24, p=0.001) and receive treatment at an academic center (OR 3.26, 95% CI 2.13-5.15, p<0.001) compared to those receiving nonintegrated therapy. In both unadjusted and adjusted analyses, there was no difference in overall survival among patients receiving integrated vs. nonintegrated therapy (HR 0.95, 95% CI 0.85-1.06, p=0.33). Time to radiotherapy initiation was also not significantly different among patients receiving integrated vs. nonintegrated therapy (median 35 vs. 36 days, p=0.06). Figure 1



Conclusion:
Our results demonstrate that administering CCRT at more than one facility may not adversely affect survival outcomes for patients with stage III NSCLC, suggesting that this approach may be reasonable based on individual patient preference and specialist availability. Further research is needed to determine the impact of integrated CCRT on tumor control and complication rates.

Background:
The role of addition radiotherapy for resected stage IIIA (N2) non-small cell lung cancer (NSCLC) in the setting of standard adjuvant chemotherapy remains controversial.

Methods:
A comprehensive search of PubMed, Embase, Medline database (last search updated in March 2015) for relevant studies comparing patients with stage IIIA (N2) NSCLC undergoing resection after treatment with adjuvant chemotherapy alone (POCT) or adjuvant chemoradiotherapy (POCRT) was conducted. Hazard ratios (HR) were extracted from these studies to give pooled estimates of the effect of POCRT on overall survival (OS) and disease free survival (DFS).

Results:
A total of six studies including two randomized controlled trials (RCTs) and four retrospective studies were enrolled in this meta-analysis. There were 6 studies that met criteria for analysis, including 2 RCTs and 4 retrospective reviews. The meta-analysis enrolling all studies (5172 cases) demonstrated an OS benefit to POCRT versus POCT (HR 0.87, 95% confidence interval [CI] 0.79 to 0.96, p = 0.006). DFS was investigated in four studies including 2 RCTs and 2 retrospective reviews. Unfortunately, there was no significant difference in DFS of two groups for the combined HR for PFS was 0.86 (95% CI: 0.70-1.06; p = 0.158). The sub-group analysis performed on two RCTs (n = 172 patients) demonstrated no benefit from adding radiation in neither OS (HR 0.72, 95% CI 0.49 to 1.06, p = 0.094) nor DFS (HR 1.45, 95% CI 1.00 to 2.09, p = 0.047).

Conclusion:
Compared with POCT, POCRT had a benefit for OS but not DFS in the patients with IIIA-pN2 NSCLC. Considering the relatively small sample size of most studies and only included two RCTs, caution should be taken when adopting the conclusions. Future RCT to investigate the role of POCRT after surgical resection of stage IIIA (N2) NSCLC is warranted.