Virtual Library

Background
Significance of blood immune cell circuit for start of phase transition (PT) “norm---early lung cancer” (LC) was investigated.

Methods
In trial (1987-2012) consecutive cases after radical surgery (R0, bi/lobectomies=48, N2-lymphadenectomies=48; squamous=21, adenocarcinoma=25, large cell=2; G1=16, G2=21, G3=11), monitored 48 early LC patients (LCP) (age=59±6.5 years, m=40, f=8; T1AN0M0=48, tumor size=1.7±0.3 cm, 5-year survival=100%) and 120 healthy donors (m=69, f=51) were reviewed. Variables selected for study were input levels of immunity blood parameters. The percentage, absolute count and total population number (per human organism) of T, B, CD4, CD8, CD16, CD1, CDw26, monocytes, CD4+2H, CD8+VV, leukocytes, lymphocytes, monocytes, eosinophils, stick and segmented neutrophils were estimated. The laboratory blood studies also included input levels of NST (tests of oxygen dependent metabolism of neutrophils spontaneous and stimulated by Staphylococcus aureus or by Streptococcus pyogenes), index of stimulation of leukocytes by Staphylococcus aureus or Streptococcus pyogenes, index of thymus function, phagocytic number, phagocyte index, index of complete phagocytosis. Differences between groups were evaluated using discriminant analysis, clustering, structural equation modeling, Monte Carlo, bootstrap simulation and neural networks computing.

Results
It was revealed that start of PT “norm---early lung cancer” significantly depended on T-, B-, CD16-, CD8- cell circuit, neutrophils, monocyte circuit (P=0.000-0.027). Neural networks computing, genetic algorithm selection and bootstrap simulation revealed relationships of PT “norm---early lung cancer” and neutrophils (rank=1), CD16 (rank=2), monocytes (3), lymphocytes (4), CD4 (5), CD8 (6), B-cells (7), T-cells (8), eosinophils (9). Correct detection of start of PT “norm---early lung cancer” was 100% by neural networks computing (error=0.000; urea under ROC curve=1.0).

Conclusion
Start of phase transition “norm---early lung cancer” significantly depended on blood immune cell circuit.

Background
We hypothesized that modern postoperative radiotherapy (PORT) could decrease local recurrence (LR) and improve overall survival (OS) in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC).

Methods
To investigate the effect of modern PORT on LR and OS, we identified published phase III trials for PORT and stratified them according to use or non-use of linear accelerators. We modelled the potential benefit of modern PORT in stage IIIA-N2 NSCLC treated with induction chemotherapy and resection.

Results
Of the PORT phase III studies, eleven trials (2387 patients) were included for OS analysis and eight (1677 patients) for LR. PORT decreased LR, whether given with cobalt, cobalt and linear accelerators, or with linear accelerators only. An increase in OS was only seen when PORT was given with linear accelerators, along with the most significant effect on LR (relative risk for LR and OS 0.31 (p=0.01) and 0.76 (p=0.02) for PORT vs. controls, respectively). Four trials (357 patients) were suitable to assess LR rates after surgery and/or induction chemotherapy in stage III NSCLC. LR as first relapse was 30 % (105/357) after 5 years. In the modelling part, PORT with linear accelerators was estimated to reduce LR rates to 10 % as first relapse and to increase the absolute 5-year OS by 13 %.

Conclusion
This modelling study generates the hypothesis that modern PORT may increase both LR and OS in stage IIIA-N2 NSCLC even in patients being treated with induction chemotherapy and surgery.

Background
Whether IFRT could replace ENI or not has been a controversial topic for years because of rare data from large sample sizes, prospective, randomized studies were available. This study is to evaluate the locoregional failure and its impact on survival by prospectively comparing involved field radiotherapy (IFRT) with elective nodal irradiation (ENI) for locally advanced non-small cell lung cancer with concurrent chemoradiotherapy.

Methods
Patients were randomized into IFRT or ENI arm，treated with 2 cycles of carboplatin combined with paclitaxel. Those without distant metastasis continued to receive chemoradiotherapy. The target volumes for IFRT included primary tumor, ipsilateral hilum and positive mediastinal lymph nodes, while that for ENI included the primary lesion, ipsilateral hilum, bilateral mediastinal lymph node drainage areas and bilateral supraclavicular fossa. The radiation dose was prescribed as high as possible if the restrictions could be met: percent volume of bilateral lung receiving ≥ 20Gy (V20) was ≤35% and the maximum dose to spinal cord was ≤50Gy.

Results
99 consecutive patients were assigned (45 IFRT vs. 54 ENI), with more patients in IFRT iiradiated with ＞60Gy than those in ENI (48.9% vs. 25.9%, P=0.018). the local failure rates were 34.1% and 30.0%（P=0.673）, Of which the isolated ENF was 0.0% and 2.0%, respectively (P=0.363). The median survival time was 27.8 months (95% CI, 18.0-37.5 months) and 16.7 months (95% CI, 15.0-18.4 months); the 1-, 2- and 3-year local tumor progression-free survival rates were 78.1%、72.6%、62.9% and 85.5%、61.2%、56.1% （P=0.895）, respectively; the 1-, 2- and 3-year overall survival rates were 80.0%、53.3%、36.6% and 70.4%、34.9%、30.3% （P=0.08）, respectively.

Conclusion
Preliminary results indicated that IFRT did not increase locoregional failure related to ENF. With IFRT, higher radiation dose could be administered compared with ENI and it is expected to improve survival. Further investigation is warranted.

Background
Stereotactic body radiotherapy (SBRT) is an effective treatment for early stage inoperable non-small cell lung cancer (NSCLC), with loco-regional control of 80-90%. However, the median overall survival of these patients is limited. We evaluate the impact of co-morbidities on patient survival and whether a subset of patients who may not benefit from SBRT can be identified.

Methods
Patients treated on a prospective protocol at a single cancer center with SBRT for T1-T2N0 NSCLC from Oct 2004-May 2012 were evaluated. The most common doses delivered were 48Gy/4fr and 54Gy/3fr. The presence of significant medical co-morbidities including cardiac disease, COPD, cerebro-vascular disease, diabetes, previous pneumonectomy and oxygen dependence were recorded at baseline. Patient, tumor, and treatment data as well as outcomes were prospectively collected. Log rank tests were performed for survival analysis and chi squared tests used to analyze deaths within 1 year from radiotherapy treatment (D<1y). Cancer specific deaths (CSD) were defined as any death following a recurrence of the previously treated NSCLC.

Results
There were 279 patients identified, 134 female (48%) and 145 male (52%). The median age was 76 years (range 48-93). The performance status was ECOG 0 in 87 patients (31%), ECOG 1 in 127 patients (46%), ECOG 2 in 53 patients (19%) and ECOG 3 in 9 patients (3%). There were 212 (76%) with T1 tumors, the remainder (24%) T2 tumors. The median follow up was 1.3 years. At last follow up, 111 patients (40%) had died, including 42 (15%) patients with D<1y. Of all deaths, 25 (22.5%) were CSD, the remainder from other causes. There were 222 patients (80%) identified as having a significant co-morbidity, collectively these conditions did not influence deaths from any cause (DAC) or CSD. The presence of cardiac disease (N=67) led to an increased risk of DAC (HR 4.1, p = 0.04) but not CSD (HR 1.2, p=0.28). These results were more pronounced for D<1y, patients with cardiac disease having increased D<1y, (HR 7.34, p=0.007), but not CSD<1y, (HR 2.9, p=0.09). Other co-morbidities were not correlated of survival. ECOG status was correlated with both DAC (HR 15.1, p=0.005) and CSD (HR 9.3, p=0.05).

Conclusion
The presence of respiratory and vascular co-morbidities should not necessarily preclude a patient from receiving SBRT. ECOG status and prognosis from a cardiac point of view may be associated with poorer overall survival at 1 year and should be considered when assessing a patient’s suitability for SBRT.

Background
There has been recent interest in dose escalation in LA-NSCLC, with the aim to improve both loco-regional control and overall survival. Attempts to dose escalate CT-defined volumes for radiotherapy (RT) for LA-NSCLC have been limited due to organ at risk (OAR) toxicity. We investigated the potential for adaptive dose-escalation to PET-defined volumes, using 4DPET/CT scans acquired prior to and during a course of radical chemo/RT (CRT).

Methods
This single institution study prospectively enrolled patients with NSCLC receiving CRT to a dose ≥60Gy, delivered in daily 2Gy treatments. 4DPET/CT scans were acquired prior to (week 0) and at weeks 2 and 4 during RT. RT was delivered using the intensity modulated RT (IMRT) plan developed from the week 0 scans. Three alternative dose escalated IMRT plans were developed offline based on the week 0, 2 and 4 scans. The PET avid primary (PET-T) and nodal disease (PET-N) volumes were auto-contoured using the 50%SUV~max~ metric. PET-T and PET-N were dose escalated to as high as possible while respecting OAR constraints and ensuring coverage of the clinical plan PTV. The D95% and D~max~ of the PET-T and PET-N were calculated and compared between week 0-2-4.

Results
Thirty-two patients were recruited, with 27 completing all scans. Sixteen patients were stage IIIA (60%), 9 were IIIB (33%) and 2 were IIA (7%). Eight patients (30%) had been prescribed a clinical dose of 60 Gy, 17 (63%) had 66 Gy, 1 patient 70Gy and 1 patient 74Gy. 25 patients (93%) were boosted successfully above the clinical plan doses at week 0; this reduced to 23 (85%) at week 2 and 20 (74%) at week 4. For all weeks combined, the D95 for PET-T was higher than that delivered to clinical PTV by a median of 16.2 Gy (4.2-37.4Gy). The D95 for PET-N exceeded that delivered to clinical PTV by 13.4Gy (6.8-29.7Gy). The median D95% to the PET-T at week 0, 2 and 4 were 74.4 Gy, 75.3Gy and 74.1Gy respectively. The median D~max~ to PET-T at week 0, 2 and 4 were 85.9Gy, 83.8Gy and 81.2Gy. The median D95% to PET-N at week 0, 2 and 4 was 74.3Gy, 71.0Gy and 69.5Gy. The median D~max~ to PET-N at week 0, 2 and 4 were 82.7Gy, 82.5Gy and 78.9Gy.

Conclusion
Using 4DPET/CT derived volumes, it is feasible to dose escalate a majority of patients, either at the onset or during RT. Though the PET-T was able to be escalated to higher doses than PET-N, nodal disease can still be boosted to significant doses. More patients were able to be dose escalated at the onset of RT; however mid-RT dose escalation allows the additional potential for adaptation.

Background
To investigate the efficacy of single dose 8-Gy palliative chest re-irradiation (PCRI) in metastatic non-small cell lung cancer (M-NSCLC) patients with painful recurrences in previously irradiated thoracic region.

Methods
Clinical data of 63 M-NSCLC patients, who received single dose 8-Gy PCRT due to painful thoracic recurrences from February 2007 to June 2010 were retrospectively analyzed. All patients had previously received upfront definitive 60-66 Gy concurrent chemoradiotherapy (C-CRT), and 52 of them had also received salvage chemotherapy. Primary endpoint was change in visual analogue score (VAS), and secondary endpoints were time to lowest VAS record and duration of pain control.

Results
Treatment was well tolerated with only 3 (4.8%) grade III radiation-induced pneumonitis. For all patients median, 1-, 2-year survival were 9.2 months, 28.4%, and 12.3%. Median pre-PCRI and minimum achievable post-PCRI VAS values were 6.7 (range: 5-8) and 3.4 (range: 0-8), and the decline in VAS values was statistically significant (p<0.001). Objective response defined as reduction of at least 2 points in VAS value was achieved in 54 (85.7%) patients. Median time to lowest VAS and duration of pain control were; 27 (95% CI: 21 - 33) days and 7.1 (95% CI: 6.3 - 7.9) months, respectively.

Conclusion
Single dose 8-Gy PCRI is safe and highly efficient in palliating moderate to severe pain in locoregionally recurrent M-NSCLC patients, who have previously received upfront definitive C-CRT

Background
Aim of this study was to compare surgical resection and radiosurgical treatment modalities directed to brain metastasis (BM) in terms of survival outcomes in newly diagnosed non-small cell lung cancer (NSCLC) patients with synchronous single brain metastasis (SSBM).

Methods
Medical records of medically fit NSCLC patients with SSBM treated at our department were retrospectively evaluated. A total of 64 patients were staged with PET-CT besides conventional staging tools. TRT to a total dose of 66 Gy in 2 Gy fx was delivered with 2 cycles of concomitant cisplatin –based chemotherapy (CT) following surgery+30 Gy whole-brain RT (WBRT) (n:33) or 30 Gy WBRT+stereotactic radiosurgery (SRS) (n:31) for their BM.

Results
Pretreatment patient characteristics were given in Table. Whole study population could complete planned treatment to their BM and thoracic primaries. At median 20.7 months (7.1-58.7) of follow-up, Median overall (OS), neurological progression-free (NPFS), locoregional progression-free (LRPFS) and progression-free survival (PFS) were 23.4, 22.8, 14.9, ve 9.4 months, respectively. There was no statistically significant survival difference between two groups (p>0.05 for each survival parameter) (Figure 1). On univariate analyses, patients with ECOG performance status of 0-1 (p<0.001), younger than median 50 years (p=0.031) and with no weight loss (p=0.001) revealed superior OS. On multivariate analyses performed with these factor, all factors except age retained their independent prognostic value (p<0.05 for each parameter). Table 1. Pretreatment patient characteristics Figure 1Figure 2

Conclusion
Results of this study has shown that, in line with the literature, surgical or radiosurgical treatment modalities directed to SSBM in NSCLC patients could not demonstrate any superiority over each other. Therefore, management of BM should be tailored according to the facilities available, and patient or disease-specific conditions. Moreover, although larger prospective data are needed, survival outcome in such patients similar to locally advanced patients indicates the potentially curative role of definitive CRT.

Background
There are no randomized trials comparing CT versus FDG-PET/CT based radiotherapy planning for lung cancer or any other disease site.Based on phase II studies, a convincing body of data has emerged within the last 10 years incorporating the use of FDG-PET scans for radiotherapy planning in lung cancer.Published data comparing changes in volume measured with FDG-PET/CT to CT alone indicates that the magnitude of treatment volume changes with incorporation of PET in radiotherapy planning for lung cancer varies from 27% - 100%. However, volumetric data only provides information on changes in size and does not account for potential changes in position and shape of the target, thereby affecting variability of the GTV in NSCLC. In this study we describe influence of FDG-PET/CT or CT alone for the primary and mediastinal nodal disease in radiation planning for stage III NSCLC in relation to changes in volume, position and overlap of the GTV. We also report the interobserver variability between radiation oncologists for FDG-PET/CT and CT alone-derived GTV. In addition to volumetric measurements, we have used a vector displacement method for three-dimensional (3D) positional analysis. We have further evaluated the overlap of the primary and nodal GTV with Dice Similarity Coefficient (DSC) method

Methods
Patients (n=29) underwent Three Dimensional Conformal Radiotherapy (3DCRT) planning by three different radiation oncologists. Simultaneous co-registered CT and FDG-PET/CT were obtained in the same treatment planning position. Gross Tumor Volume (GTV) for lung tumor and mediastinal lymphadenopathy was contoured and compared for changes in volume and position. Interobserver variability was determined using three-dimensional analysis with vector displacement and the Dice Similarity Coefficient (DSC). Concordance for the number of lymph nodes contoured was performed.

Results
Mean GTV for lung tumor with FDG-PET/CT and CT alone was 62.0 cm[3] and 74.64 cm[3], respectively (p=0.0005), resulting in a 17% reduction by FDG-PET/CT. Mean GTV for mediastinal lymphadenopathy was 15.72 cm[3] and 19.02 cm[3] (p=0.084), equalling a 17% reduction GTV for FDG-PET/CT. Mean vector displacement of lung tumor was 2.0 mm with FDG-PET/CT versus 7.1 mm with CT alone (p = 0.0016), equating to a 3.6 fold reduction in interobserver variability of position. Mean vector displacement of the mediastinal lymphadenopathy was 1.53 mm with FDG-PET versus 10.2 mm for CT alone (p= 0.0005), resulting in a 6.7 fold reduction in interobserver variability. Median Dice Similarity Coefficient (DSC) for the primary GTV contours was 0.87 for FDG-PET/CT and 0.74 for CT alone. For the nodal GTV DSC were 0.79 and 0.59, respectively. Physician agreement on the number of lymph nodes contoured was 15/29 on CT and 27/29 patients for FDG-PET/CT. Only two of the three physicians agreed on the number of lymph nodes contoured for CT alone in 12/29 versus only 2/29 patients for FDG-PET/CT (p=0.0018).

Conclusion
FDG-PET/CT significantly reduces mean lung tumor and mediastinal nodal GTV, is more precise for size and position in defining target volumes, and reduces interobserver variability. There was greater agreement for the number of lymph nodes contoured on FDG-PET/CT compared to CT alone.

Background
To evaluate the clinical outcomes following SABR to early-stage NSCLC and pulmonary metastases (Mets) from NSCLC, including potential predictive factors and a focus on chest wall (CW) toxicities.

Methods
From our prospective lung SBRT database, we identified 240 NSCLC lung tumors in 209 patients treated with SABR between 2008 and 2011. 228 were primary NSCLC and 12 were NSCLC Mets. The institutional policy was to deliver 48-52 Gy in 4 fractions (fx) for peripheral tumors and 50 Gy in 5 fx for central tumors. Local control (LC) was defined as the absence of recurrence within or ≤1 cm beyond the planning target volume (PTV). Lobar LC was defined as absence of recurrence within the same lobe. All tumors were categorized as adjacent to the CW (PTV touching the CW) or not, to determine if this localisation can predict for rib fracture. Age, comorbidities, lobe of the target lesion, stage, tumor size, maximal tumor standardized uptake value (SUV), total dose and various dose-volume histogram metrics were also evaluated for their predictive significance.

Results
The median follow-up was 20.8 and 18.1 months (range, 0.2–52.1 and 15.3–46.2) for primary NSCLC and Mets, respectively. 168/240 tumors (70%) were biopsy-proven NSCLC. Of the 228 primary NSCLC, the majority were stage I (192/228; T1a=136, T1b=21, T2a=35). Among all primary tumors, the 2-year LC was 94.8%. LC did not differ between biopsy-proven or presumed tumor, and did not differ between primary NSCLC and NSCLC Mets. For the whole cohort, only the presence of a respiratory comorbidity predicted for better local control (p=0.021) on multivariate analysis. In stage I NSCLC, the 2-year LC, lobar LC, regional control, distant control (DC) and overall survival (OS) were 95.5%, 91.3%, 89.3%, 74.7% and 77.9%, respectively. The 2-year OS rates for non-stage I primary NSCLC and Mets from lung were 69.2% and 48.6%, respectively. The 2-year DC rates in all primary NSCLC and NSCLC Mets were 73.6% and 20.8%, respectively. Among primary NSCLC, upper lobe tumors predicted for a better DC compared to lower lobe tumors (p=0.009). Of the 240 lung tumors, 132 (55%) were adjacent to the CW and had a significant greater risk of rib fracture. The 2-year risk of fracture was 29.6% versus 8.1%, for tumors adjacent and not adjacent to the CW, respectively (p<0.001). The median time to fracture was 15.9 months. 51% of rib fractures were symptomatic. There was a suggestion that a higher conformity index (ratio of the 95% isodose volume to the PTV) predicted for a higher risk of rib fracture (p=0.067).

Conclusion
The excellent LC rate post-SABR seems similar in primary NSCLC and in NSCLC Mets, and having a respiratory comorbidity predicted favourably for LC. Patients with lower lobe tumors had higher risk of distant relapse. Patients with tumors adjacent to the CW are at significantly greater risk of rib fracture post-SABR and should be well informed prior to treatment.

Background
In February 2012 a specific GPA scale for assessing the prognosis of BM in NSCLC was published (JCO, 2012; 30(4): 419-426). Retrospective series have showed longer survival for patients with cerebral metastases and EGFR sensitizing mutations (m) compared with those without them.

Methods
Charts from EGFRm NSCLC p with BM were reviewed. We classified p with the lung-GPA prognosis scale at the time of diagnosis of BM and compared the expected GPA overall survival (GPA-OS) with the Observed OS (OS) for each group.

Results
24p were diagnosed from January 2007 to December 2012. 15 p were treated with whole-brain radiotherapy (WBRT), total dose 30Gy (2p GPA 0-1; 10p GPA 1.5-2; 3p GPA 2.5-3), 1 p with stereotactic radiosurgery (SRS), mean dose 18Gy (GPA 3.5-4), 1p with SRS and WBRT (GPA 2.5-3) and 2p with surgery (S) and WBRT (1p GPA 2.5-3; 1p GPA 3.5-4). 5p receive no treatment (3p GPA 0-1; 2p GPA 1.5-2). Outcomes were [Expected median (m) GPA-OS vs Observed m OS]:

GPA	Expected m GPA-OS(months)	Observed m OS (months)	Number of p
0-1	3.4	<1	5
1.5-2	4.7	6	12
2.5-3	8.8	34	5
3.5-4	14.8	Not reached (100% OS at 40 months)	2

Two p did not receive any EGFR tyrosine kinase inhibitor (TKI). 5p were receiving an EGFR TKI when they were diagnosed with BM and 12p were treated with EGFR TKI after the diagnosis of BM. Sixteen p have died. Further details of p characteristics and treatment received will be presented at the meeting.

Conclusion
Observed m OS of p with EGFR m-NSCLC and brain mets was much longer than expected by GPA-OS. The GPA subsets might predict prognosis in patients with mutated tumors as well.

Background
Lung cancer remains a challenging site to treat in radiotherapy. For tumour delineation CT combined with FDG PET is the current gold standard for delineating lung cancer volumes. MRI has been utilized in a limited number of cases such as superior sulcus tumours. However its use has been limited due to reduced MRI signal as a result of low proton density in lung, inhomogeneity of the magnetic field in lung and cardiac and respiratory motion. As technology improves, the utility of MRI in imaging lung cancer has become plausible. The aim of this literature review was to identify evidence to support the use of MRI in lung cancer imaging for radiotherapy.

Methods
Pubmed and Google Scholar were used to identify literature on MRI in Lung cancer using the keywords Lung Cancer, MRI, MR, thoracic imaging and radiotherapy. Articles were limited to human and phantom subjects. A total of 22 articles were identified between 1995 and 2013 and reviewed to assess the potential of MRI for lung radiotherapy imaging.

Results
Eighteen studies were performed on 1.5T and two on 3T magnets with magnet strength not specified in two studies. Gradient echo sequence and TrueFISP were most common sequences utilised. Thirteen articles examined tumour motion and nine concentrated on tumour volume analysis. One study illustrated minimal geometric distortion and inter-cycle reproducibility of tumour volume on free breathing MRI sequence. The possibility of defining tumour internal target volume for radiotherapy treatment was demonstrated in three studies Two further studies demonstrating variability of lung tumour motion based on location and variability of motion between tumour and non-tumour bearing lung. There was conflicting evidence on pulmonary node detection based on results from two studies. Four comparative studies with FDG PET and functional MRI sequences demonstrated diffusion weighted image (DWI) had higher specificity for lesion detection in the presence of inflammation. Correlation was seen between SUV and DWI value. Two studies demonstrated the potential for radiotherapy planning based on biological function by avoiding functional lung tissue.

Conclusion
This literature review indicates that improvement in MRI technology has overcome some of the initial limitations of utilising MRI for lung cancer imaging. MRI can not only provide the morphological information required for identifying lung cancer based on anatomical sequences but also functional information to identify both tumour activity and surrounding healthy or pathological structures. There is potential for MRI to be utilised in the clinical setting for defining tumour volumes for radiotherapy planning and in evaluating tumour response during and after treatment. However further research is required to determine protocols with defined standard sequences specific for lung cancer imaging.

Background
Multiple primary lung cancers (MPLC) are not an uncommon clinical presentation, with an incidence in the surgical literature of 1-8%. ESMO guidelines state that synchronously detected lesions should be treated as multiple primary tumors, and a curative approach for both lesions has been associated with improved survival in the surgical series. However, many patients with MLCP are elderly and have multiple co-morbidities, which can render them unfit to undergo surgery for both lesions. We analyzed clinical outcomes in such patients who were treated with SABR.

Methods
SABR was performed in 62 patients diagnosed with MPLC at the VUmc from 2003 – 2012. Staging included a mandatory FDG-PET scan, and all patients were discussed in a multi-disciplinary tumor board. A pathological diagnosis was available for both lesions in 3%, and for one lesion in 48%. Invasive nodal staging was performed in 13% of patients. SABR was used as a single modality for both lesions (n=56), or in combination with surgery for the second lesion (n=6). SABR was delivered to a total dose of 54-60 Gray (Gy) in 3-8 fractions, depending on tumor size and location. Clinical outcome, including survival, patterns of relapse and toxicity (CTC v4.0) was evaluated. A sub-analysis was performed for ipsilateral and bilateral lung lesions.

Results
Median overall survival was 31 months, with an actuarial survival of 56% at 2 years. Overall lesion local control rate was 84% at 2 years. Local control correlated significantly with number of fractions (p=0.013) and lesion location (p=0.004) on univariable Cox regression analysis. Lesion control at 2 years for bilateral lesions was 92% versus 74% for ipsilateral lesions (p=0.009). Regional failures at two years were observed in 13% (n=6) of all patients, and in 0% versus 31% in patients with respectively bilateral and ipsilateral lesions. Of the patients who developed a subsequent regional recurrence, only one had undergone EUS/EBUS prior to treatment, and others did not as pre-treatment FDG-PET-scans showed no nodal uptake. Distant failures were observed in 27% of all patients, at two years. No grade ≥3 early toxicity was observed. Late grade 3 toxicity was reported in 3 patients (5%), consisting of pneumonitis (n=1), rib fracture (n=1) and chest wall pain (n=1). No grades 4-5 late toxicity was reported.

Conclusion
Curative treatment of MPLC using SABR, either alone or combined with surgery, can lead to long-term survival with limited toxicity. The disappointing local control rates observed after SABR for ipsilateral double lesions merits further investigation. The higher rate of nodal recurrences in patients presenting with multiple ipsilateral lesions suggests that systematic nodal staging may be appropriate in such cases.

Background
As part of a feasibility study for a Hadron Therapy Centre in Belgium, an economic evaluation was performed to assess the potential cost-effectiveness of proton radiotherapy (PT) delivered concurrently with chemotherapy for locally-advanced non-small cell lung cancer (LA-NSCLC), compared to concurrent chemoradiotherapy employing photon therapy, either 3D-conformal (3D-CRT) or intensity-modulated (IMRT) radiotherapy.

Methods
A Markov decision-analytic model was developed using Microsoft Excel 2007 software. The model was defined for a time horizon of 10 years, allowing patients to transition between 5 health states (treatment, controlled disease, loco-regional progression, distant progression and death) using transition cycles of 3 months. Transition probabilities were derived from photon and proton literature on LA-NSCLC and from nationally available data. Results were to be expressed in cost per (quality adjusted) life years (LY and QALY). The occurrence of grade 3 toxicity or higher in terms of radiation pneumonitis, radiation esophagitis/dysphagia and pulmonary radiation fibrosis was accounted for in the calculation of QALYs. Treatment costs of the standard 3D-CRT and IMRT treatments were obtained from an Activity-Based Costing (ABC) exercise in Belgian radiotherapy centers (KCE report 198). Similarly, the cost of PT was calculated using ABC in different technical (proton-only vs. combined proton and carbon-ion center) and financing (private vs. public) scenarios. Toxicity and follow-up costs were based on literature evidence but adapted to the Belgian context.

Results
The base case analysis used the scenario of a publicly financed combined center. The survival curves generated by the model demonstrated it accurately predicts survival of published literature and of the Belgian Cancer Registry. Compared to 3D-CRT res. IMRT, PT generates 0.837 res. 0.664 extra LYs and 0.549 res. 0.452 extra QALYs. When combined with the higher cost (18,875€ res. 14,257€), this translates into an incremental cost-effectiveness ratio (ICER) of 22,543€/LY for PT compared to 3D-CRT and of 21,489€/LY compared to IMRT. Expressed in cost per QALY, the ICERs amount to 34,396€/QALY and 31,541€/QALY respectively. Assessing the effect of different technical scenarios and/or financing methods, the ICER ranges between 21,489€ to 53,685€/LY and 31,541€ to 78,873€/QALY, with the highest figures found for a combined center with private financing. One-way sensitivity analyses reveal that the results are most sensitive to the effect of proton therapy on disease control, loco-regionally as well as at distance, and to the quality of life pre-progression.

Conclusion
Based on a public financing scenario for a combined center, PT delivered concurrently with chemotherapy is found borderline cost-effective in the Belgian health care context, compared to the best available photon radiotherapy alternatives. These results are however highly sensitive to the cost of PT (hence the financing scenario) and the expected clinical advantage of PT, both in terms of improved survival and decreased long-term toxicity impacting on quality of life. Apart from clinical appropriateness and budgetary possibilities, such results support decision-making on the feasibility and desirability of introducing hadron therapy in Belgium.

Background
Concomitant chemo-radiotherapy (CRT) has been shown to be superior to single modality radiotherapy (RT) and to neoadjuvant chemotherapy (NeoCT) followed by RT. In this retrospective study we report the influence of age on survival in two groups of patients with locally advanced radiotherapy treated from 1995 to June 2012: 1) NoCRT-group: RT +/- NeoCT without CRT and 2) CRT-group: NeoCT followed by CRT.

Methods
Data for 446 patients that completed 3-D conformal RT or IMRT in planned doses of 60-66 Gy at 2 Gy/F without elective nodal irradiation was obtained. CRT was used for 114 patients with the regimens: weekly Docetaxel (N=43), Carboplatin-Vinorelbine (N=70) and Cisplatin-Vinorelbine (N=1). The NoCRT group consisted of 332 patients

Results
Figure 1 The median and 5 year survival was 17.2 months and 15% for NoCRT, and 21.4 months and 29% for CRT (p<0.02). The data was analyzed in the age groups ≤65 and >65 years. For NoCRT, no differences in survival was found (17.2 vs. 17.1 months), but in the CRT group significant longer survival was found in the younger age group, 29.2 vs. 20.0 months in the older group (p=0.03). CRT was the only significant factor among patients ≤65, while CRT was an insignificant factor among patients >65. The patients treated with CRT had significantly lower frequency of local relapse (33%) compared with patients treated without (46%, p = 0.016), while the rate of distant metastases was unaffected by the use of CRT. Patients ≤65 years had a low complication death rate (1-2%) independent of CRT, while the complication death rate among patients >65 years was 6-8%, also independent of CRT.

Conclusion
Patients ≤65 years had a very positive effect of CRT while CRT did not influence survival in older patients. The reason for this is unknown

Background
In this study we evaluated the feasibility and outcome of stereotactic body radiotherapy (SBRT) for lung tumors treated with helical tomotherapy.

Methods
Between December 2007 and January 2013, 26 Patients with a total of 49 lung tumors were treated with helical tomotherapy at a median 75 Gy of 10 fractions over 2 weeks. Thirteen lung lesions of primary lung tumors (group 1) and 36 of recurrent or metastatic lung tumors (group 2) were analyzed. Three patients received re-SBRT due to local recurrence after first SBRT were included. (Total 29 cases were analyzed). Radiation pneumonitis was graded according to the Common Terminology Criteria for Adverse Events V 4.0.

Results
The patients’ age was median 72 years (range, 47-82). Median follow up was 16 months (range, 2-57 months). Total 13 cases (45%) showed progressive disease after SBRT, and one of them was distant metastasis. Of 12 thoracic recurrences, in-field recurrences were noted in 5 patients and out-field recurrences in 7 patients. In group 1 (13 cases), there were 3 recurrences with 1 in-field thoracic recurrence, 1 out-field thoracic recurrence and 1 distant metastasis. Grade≥2 radiation pneumonitis was noted in 8 patients (30%). One patient died due to radiation pneumonitis at 2 months follow up after second SBRT.

Conclusion
The preliminary findings of our study suggest SBRT with helical tomotherapy is feasible for lung tumor treatment. But further studies with more patients and longer follow-up duration are required.

Background
Radiotherapy (RT) is commonly used for palliation of symptoms in patients with lung cancer. However, the time before onset of relief may be several weeks. It is therefore of interest to study how many patients who die within few weeks after the initiation RT since these patients are not likely to benefit from the treatment.

Methods
This is a retrospective review of the overall survival rate of 293 patients with lung cancer who received palliative RT in 2010 at our institution. If patients had received more than one course of RT, only data from the last course was included in the study.

Results
The planned fractionation (F) schedules were 8Gy/1F(N=34), 10Gy/1F(N=34), 20Gy/4-5F(N=16), 20Gy/10F(N=2), 25Gy/5F(N=44), and 30Gy/10F(N=167). The median survival was 11.9 weeks. The two-week mortality rate 10.2% and the four-week mortality rate was 22.2%.

	N	2 week mortality	4 week mortality	Median survival
8-10 Gy/1F	64	15 (23%)	26 (41%)	5.6 w
20-25Gy/4-5F	60	8 (13%)	20 (33%)	6.0 w
20-30Gy/10F	169	7 (4%)	19 (11%)	21.7 w
Total	293	30 (10%)	65 (22%)	11.9 w

Among the patients planned for 4-5F, only one patients (2%) did not receive the planned number of fractions, while 13 patients (8%) of the patients planned for 10F did not receive the planned number of fractions. In a logistic regression analysis using 2-week mortality as endpoint, only planned number of fractions <10F and bone metastases as indication of RT were significant factors for poor survival, while gender, CNS metastases, age, performance status and histology were not. The results are strikingly similar to Gupta et al. Radiother. Oncol. 2012;103 suppl.1(PO-0744).

Conclusion
Although 10% of the patients receiving palliative RT die within 2 weeks from the start of RT, the results indicate that prolonged treatment regimens were reserved for patients with longer life expectation. Nearly 1 of 4 of patients receiving 1F died within two weeks after start of RT indicating that the RT was futile in these patients.The radiation oncologists seem to expect a palliative effect of RT for bone metastases even in patients with short life expectations.

Background
Radiotherapy treatments of locally advanced NSCLC patients are associated with poor local control and low overall survival rates. Local recurrence often occurs within the initial primary tumour. Therefore, higher doses to locally advanced NSCLC tumours with conventional fractionation are required in order to increase the local control. However, current tumour dose levels are limited by the toxicity levels of the surrounding normal tissue, e.g. healthy lung tissue and mediastinal region. This study presents the concept of clinically applicable inhomogeneous dose plans that distribute higher doses in the tumour without compromising the expected lung toxicity, not only for isolated lung tumours, but also for patients with involved lymph nodes.

Methods
Twenty consecutive NSCLC patients previously treated with conventional radiotherapy treatment with a prescribed dose of 66Gy/33F were included in this planning study. The patients were staged T1b-T4 N0-N3 with a median tumour size of 56.7 cm[3] (range 3.2-399.2 cm[3]). Highly modulated IMRT plans were used for treatment with standard dose coverage of 95%-107% of the prescribed dose. For each patient, a new dose-escalated treatment plan was created with the same mean lung dose as obtained in the standard plan using an inhomogeneous dose distribution with minimum dose coverage of ≥95% of the prescribed dose. The maximum tumour dose was only limited by conservative tolerance levels of the surrounding healthy tissue: maximum doses of 45 to spinal canal, 66 Gy to oesophagus, and 74 Gy to less than 1 cm[3] within the mediastinal region. Two different tumour control probability (TCP) models were used to evaluate the homogeneous and inhomogeneous treatment plans. Furthermore, in order to estimate the reliability of the calculated doses in comparison to actual delivered doses, the treatment plans were re-calculated in 4D by accounting for uncertainties arisen from respiration, delineation, setup, and baseline shift.

Results
Dose escalation was possible for all patients. TCP values increased approximately 15 and 10 percentage points based on calculations related to the GTV and CTV, respectively, from an initial level of 18%. This increase in expected local control was obtained without increasing the mean lung dose. However, small increases in maximum doses to the mediastinum were observed: 2.5 Gy for aorta, 4.4 Gy for the connective tissue, 1.6 Gy for the heart, and 2.6 Gy for trachea and bronchi. The increase in TCP predictions from 4D calculations differed only slightly from the corresponding 3D calculation.

Conclusion
Increased target doses and TCP values using dose-escalated inhomogeneous dose distributions could be achieved for all patients, regardless of lymph node involvement, tumour stage, location, and size. These new treatment plans have the potential to increase the local tumour control with 10-15 percentage points without increasing the mean lung dose, which is often regarded as a measure for the expected lung toxicity. The conservative dose constraints used for the organs at risk ensures clinical applicable treatment plans that can be implemented today. Based on these promising results, a national randomised phase III study is under development.

Background
The aim of this study is to determine the interobserver variability between thoracic surgeons and radiation oncologists in defining and delineating target volume for postoperative radiotherapy for patients with non small cell lung cancer (NSCLC). These patients were offered postoperative RT due to microscopic non-radical operation.

Methods
Between 2002 and 2010, 48 NSCLC patients were offered postoperative radiotherapy at Department of Oncology, Odense University Hospital due to microscopic non-radical operation. Two thoracic surgeons (S1 and S2) and two clinical oncologists (O1 and O2) were retrospectively asked to delineate clinical target volume (CTV) on the 3D CT scanning used for radiotherapy planning in each patient. Instruction were given to include the non-radical site on basis of surgical-, pathological-, and radiological reports. The delineation was done independently by each physician. There are no local guidelines for delineation postoperative volume after non radical microscopic operation. The spatial volume discrepancy between the different physicians was the end-point.

Results
The mean volumes were very different between the physicians: S1 20.5 (SD 17.4) cm[3], S2 21.5 (28.1) cm[3], O1 14.4 (20.5) cm[3], and O2 32.9 (SD 35.6) cm[3]. A large spatial volume discrepancy between the different physicians was observed as well. Mean discrepancies were O1-O2 18.5 (SD 25.3) cm[3 ](p<0.0001), O1-S1 6.1 (SD 21.4) cm[3] (p=0.06), S1-S2 1.3 (SD 22.9) cm[3] (p=0.7). Mean Soerensen-Dice index O1-O2 0.27 (SD 0.19), O1-S1 0.27 (SD 0.16), S1-S2 0.29 (SD 0.18). There was a reasonable overlap in 25 patients (52%) between all 4 physicians. In another 9 cases (19%) 3 physicians had a reasonable overlap and one “outlier”. Figure 1 illustrates one case with reasonable overlap, and another case with one “outlier”.

Conclusion
Figure 1 Several conclusions can be drawn from this study. At first it is very challenging to define postoperative volume, when there is no gross tumor volume as is the case when RT it is due to microscopic non-radical operation. Secondly, it is important to have guidelines in order to define the approximate size of the CTV, this in context of the large difference in the size of the volume between the oncologists. Thirdly, surgeon and oncologist should delineate the postoperative target volume in collaboration to ensure the correct conclusion is drawn on the basis of operation and pathological reports, in order to hit the right target and reduce irradiated volume.

Background
Patient (pt) safety is of utmost concern to radiation oncologists. Pemetrexed (Pem) is an effective and well-tolerated treatment for advanced nonsquamous NSCLC. The safety of palliative radiation (XRT) during Pem treatment was studied in this subset of pts in the PARAMOUNT trial.

Methods
In PARAMOUNT, a randomized, double-blind study, 939 pts received 4 cycles of induction Pem (500 mg/m[2]) + cisplatin (Cis) (75 mg/m[2]) on day 1 every 21 days. Patients without progressive disease (PD) and with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1 (n=539) were then randomized (2:1) to maintenance Pem (500 mg/m[2], day 1) + best supportive care (BSC) (Arm A) or placebo + BSC (Arm B) until PD. Best supportive care (BSC) was defined as treatment without a specific antineoplastic regimen and included palliative XRT to extrathoracic structures. Safety was assessed via the incidence of adverse events (AEs) by maximum grade (Gr; CTCAE, v3).

Results
The 55 pts who received palliative XRT to extrathoracic structures during treatment had stage IV nonsquamous NSCLC. The majority of pts were male (58%), with an ECOG PS of 1 (75%). Patients’ median age was 61 yrs (range, 32-74) yrs, with 13% of pts ≥70 yrs. The most common location irradiated was bone (43/55 pts). Non-bone locations were: lymph node (3), mediastinum (2), chest (2), and adrenal gland, intraocular, lung, brain, and abdomen (1 each). Forty-five pts received XRT during Pem+Cis induction, 3 of whom also received XRT during maintenance. Seven pts (Arm A) and 6 pts (Arm B) received palliative XRT during maintenance. Total XRT doses ranged from 8-66 Gy. The time interval between day 1 of last chemotherapy cycle and the start of palliative XRT ranged from 0-28 days. Of 55 pts, 12 (22%) had ≥1 AE(s) during XRT considered possibly related to Pem and/or XRT (Table 1). All pts except 1 experienced the AE during induction. The most common AE was Gr 2 anemia. Three pts had Gr 3/4 anemia. Five pts had nonhematologic toxicities. One pt in Arm B, who received a total dose of 20 Gy in the hip during maintenance treatment, had pneumonitis. No AEs were reported for pts who received palliative XRT during Pem maintenance treatment.

Table 1: AEs during palliative XRT or within 2 weeks after the end of the last fraction in both phases of the PARAMOUNT trial.
Pts receiving palliative XRT (N=55)
Patients with AEs during induction and/or maintenance (n=12, 22%)
Toxicity	Gr 1, n (%)	Gr 2, n (%)	Gr 3-4, n (%)
Hematologic
Hemoglobin	1 (1.8)	4 (7.3)	3 (5.5)
Leukocytes	0	2 (3.6)	1 (1.8)
Platelets	0	1 (1.8)	0
Nonhematologic
Rash/dermatitis	1 (1.8)	1 (1.8)	0
Rash/desquamation	1 (1.8)	1 (1.8)	0
Pneumonitis	0	0	1 (1.8)*
*Pneumonitis was the only event reported for a pt during the maintenance phase. The pt was assigned to placebo.

Conclusion
Conclusions: In PARAMOUNT, palliative XRT is well tolerated and can be safely administered at low and high doses during Pem+Cis chemotherapy or Pem monotherapy to pts with advanced nonsquamous NSCLC.

Background
Traditionally, the same radiotherapy dose is prescribed to the primary tumor (PT) and involved lymph nodes (LN) for locally advanced NSCLC patients, independent of volume and metabolic activity of each lesion. On the other hand, the PT and lesions with a high [18]F-FDG uptake are often believed to have a higher recurrence rate. The purpose of this study was therefore to find prognostic parameters for the lesion control probability in locally advanced NSCLC.

Methods
A total of 279 patients treated between 2007 and 2011 with 24×2.75Gy IMRT and concurrent daily low dose cisplatin were included in this retrospective analysis. Patients had a staging FDG-PET scan within 6 weeks prior the start of treatment. For follow-up, CT thorax was performed 4-6 weeks after treatment and at 3-monthly intervals chest x-ray or CT scans were made up to 2 years after CCRT. Medical records of the patients were retrospectively reviewed. The PT and/or LN progression were classified based on follow-up records and scans by two physicians. The volume of each separate lesion on the planning CT and their SUVmax from the pre-RT staging PET scan were then tested as prognostic factors for disease progression using Cox proportional hazard model with patient as random effect. Data were analyzed using R, package “coxme”.

Results
A total of 291 PTs (8 patients had no PT, 252 had 1 PT, 18 had 2 PTs, 1 had 3 PTs) and 627 LNs (59 patients without LN, 57 had 1 LN, 57 had 2 LNs and 106 had >=3 LNs involved) were analyzed. The majority (92%) of the patients had TNM stage III and 86% patients had ≥N2. At a median follow-up of 30 months (95%CI 27-35) and median OS of 25 months (95% CI 21-29), 47 PTs had progression and 14 LNs had progression, 38% patients had systemic relapse. The log(Vol), SUVmax and lesion type (TP vs. LN) were each significant (p<0.001) as prognostic factor for progression in the univariate cox regression. In the multivariate analysis, log(Vol) remains as a significant predictor (p<0.001) with a trend toward significance for lesion type (p=0.07) (Figure 1). Figure 1

Conclusion
Our regimen of 66 Gy in 24fx results in excellent local-regional control in locally advanced NSCLC patients. The PT yields a significantly higher risk of progression than LNs. A larger lesion volume and higher SUVmax were associated with an increased risk of progression.

Background
Introduction: The treatment of locally advanced lung cancer with radiation therapy has traditionally utilised multiple beam conformal plans. On occasions, the curative intent is compromised due to excessive normal tissue dose, especially to healthy lung tissue. This necessitates a reduction in total delivered dose to a more palliative regimen. With the advent of Volumetric Modulated Arc Therapy (VMAT) at Nepean Cancer Care Centre (NCCC), the question arises of whether VMAT plans can be utilised in these circumstances in order to deliver curative tumour dose, whilst still delivering acceptable normal tissue doses. This study shows a planning comparison of the VMAT and traditional 3D Conformal Radiotherapy (3DCRT) planning techniques. Hypothesis: It is expected that VMAT plans will produce equivalent target volume coverage, whilst resulting in lower toxicities to surrounding healthy tissue, when compared to 3DCRT plans.

Methods
Method: This study was conducted retrospectively on three patients who had previously been treated with 3DCRT for stage IIIA or IIIB Non-Small Cell Lung Cancer at NCCC, and had undesirably high healthy lung doses when prescribed 60Gray (Gy) in 30 fractions. The original treatment volumes (planning target volume (PTV), clinical target volume/gross tumour volume) and total prescribed dose for each planning method was left unchanged for this study. The original 3DCRT plans utilised, on average, 4 static beams with 8mm field margins. Angles, wedges, weighting and energy were selected as a best fit to treat the target volume and avoid spinal cord irradiation and healthy lung tissue. Each VMAT replan comprised of one 352° arc, with 89 control points, delivered over a maximum of 90 seconds, with all radiotherapy dose delivered through this dynamic arc. This study compared the two planning methods based on PTV coverage, Conformity Index (CI), V20 (volume of normal lung receiving 20Gy) <30% and V30 (volume of normal lung receiving 30Gy) <20% of the combined healthy lung volume and mean lung dose.

Results
Results: Improved coverage of the PTV by 60Gy is achieved with VMAT, with an average of 92.5%, whilst 3DCRT plans achieved an average of 77.7% 60Gy PTV coverage. VMAT combined lung doses were reduced when compared to 3DCRT, with an average V20 of 29.9% for VMAT plans compared to 34.1% for conformal plans, and V30 of 18.4% for VMAT plans, compared to 27% for 3DCRT plans. Combined mean lung dose was also lower for VMAT plans, with an average reduction of 2Gy, with average mean lung dose of 18.01Gy for VMAT plans compared to 20.09Gy for 3DCRT plans. The CI of the D95% was improved in all three cases, with an average 100% CI of 1.01 for VMAT plans, and an average CI of 1.2 for 3DCRT plans.

Conclusion
Conclusion: VMAT is a viable planning method to achieve radical treatment intent to 60Gy in 30 fractions, adequate PTV coverage by D95% and improved healthy lung doses for patients with stage IIIA and IIIB NSCLC.

Background
Curative radiotherapy for non-small cell lung cancer (NSCLC) is usually delivered over a time period of 5-7 weeks. Tumour regression has been observed over the course of curative radiotherapy. Currently, the entire radiotherapy treatment is delivered based on the original tumour volume. An evolving approach is adaptive radiotherapy planning whereby the radiotherapy plan is modified during a course of treatment to account for tumour and patient changes. This has the potential to reduce the size of radiotherapy fields, allowing dose escalation and normal tissue sparing.

Methods
A cohort of 20 consecutive NSCLC patients receiving a curative course of radiotherapy and who had weekly kV cone beam computer tomography (CBCT) images was identified. The gross tumour volume (GTV) and anatomical reference points were delineated on all CBCT scans. Volume and positional changes were recorded and analyzed.

Results
Six patients with non-small cell lung cancer who received curative radiotherapy were assessed so far. Five patients had sufficient image quality for contouring. There was a mean percent decrease of 24.8% by fraction 16 and 37.2% by fraction 26. Average tumour migration was 0.4cm. Progressive anatomical changes were more prominent where there was tumour associated with atelectasis. Updated results for the whole cohort will be presented.

Conclusion
Tumour regression was observed in all patients and a proportion showed significant reduction. Adaptive planning was a feasible option in selected patients.

Background
Intensity-modulated radiation therapy (IMRT) is not covered by national health insurance in Korea until yet. This study is to retrospectively evaluate the clinical outcomes following IMRT in the patients with inoperable non-small cell lung cancer (NSCLC).

Methods
From May 2010 to November 2012, 43 patients with newly diagnosed, pathologically confirmed NSCLC, who seemed to be at excessive risk of pulmonary toxicity if treated with conventional radiation therapy (RT) techniques based on their disease extent and pulmonary function status, received IMRT. The median age was 58 (35~80) years. Clinical stages were IIIA in 7 (16.3%) and IIIB in 36 (83.7%) patients, where 26 patients (65.1%) had supraclavicular nodal metastases. Thirty-six (83.7%) received concurrent chemotherapy during IMRT. The most common chemotherapy regimen was weekly docetaxel plus cisplatin (N=18), followed by weekly paclitaxel plus cisplatin (N=11). Simulation with 4-dimensional CT was done in 27 patients (62.8%). RT was delivered with 6-MV photon beams using step-and-shoot IMRT method. The median RT dose was 66 Gy in 33 fractions. The median clinical target volume was 357.5 (89.3~881.2) cm[3], and elective irradiation to the uninvolved lymphatics was not added. Normal tissue constraints were as follow: maximum spinal cord dose was <46 Gy; relative lung volumes receiving 20 Gy/5 Gy were <35%/65%; and mean lung dose was <20 Gy. Early toxicities including treatment-related pneumonitis (TRP) and esophagitis were graded using the CTCAE version 4.0. In-field locoregional control (LRC), progression-free survival (PFS), and overall survival (OS) were estimated by the Kaplan-Meier method.

Results
At median follow-up of 11.6 (2.3~39.6) months, 30 patients (69.8%) experienced disease progression: distant metastases in 23 patients (53.5%); and locoregional relapse in 13 patients (30.2%) (Figure). Among 13 patients who experienced locoregional relapse, ten patients (23.3%) had in-field or marginal failure, while three (7.0%) had recurrence at initially uninvolved lymphatic regions. Grade 3 TRP and esophagitis occurred in one (2.3%) and ten (23.3%) patients. The one-year LRC, PFS, and OS rates were 75.0%, 33.7%, and 81.7%, respectively. Figure 1

Conclusion
The early experience of IMRT for the patients with advanced NSCLC, who are poor candidates for conventional RT techniques, seems favorable with respect to locoregional control and toxicity. Further studies will be directed to address the issues on the elective lymphatic irradiation extent, radiation dose escalation, long-term clinical outcomes, and comparison with conventional RT techniques. Authors hope to develop optimal clinical indications of IMRT that can be reimbursed by the national insurance system in Korea.

Background
Applying Intensity-Modulated Radiotherapy (IMRT) techniques to patients with stage III NSCLC allows treating large tumour volumes and bulky mediastinal lymph nodes while respecting the usual normal tissue constraints to the lungs and organs at risks. IMRT techniques lead to irradiating a large lung volume with low doses (lung bath). The volume of lung receiving doses of 5 Gy or more (V5) may estimate the toxicity related to low dose irradiation. In the current study, an analysis was performed to test whether the introduction of IMRT was associated with increased incidence of severe radiation pneumonitis (RP) compared to three-dimensional conformal radiotherapy (3D-CRT) and whether introducing a new dose constraints to the V5 (V5 = 60%) would reduce the incidence and/or severity of radiation pneumonitis.

Methods
The control group included 105 patients with pathologically confirmed inoperable stage III NSCLC receiving radical radiotherapy (60-66Gy in 2Gy/fraction) between 2007 and 2009, at our department using 3D-CRT. The Study group included ninety consecutive matching patients receiving the same radical dose of radiotherapy using IMRT in the period January 2011 to June 2012. The first 35 patients (group I) were treated with standard dose constrains on MLD (maximum 20 Gy) and V20 (Maximum 40%). In group II including 55 patients, a new dose constraint to V5 was introduced (maximum 60%). All patients were seen weekly under radiotherapy, 6 weeks after, and then with 3 months intervals. Radiation Pneumonitis was graded using CTC 3.3. The clinical and dosimetric parameters related to RP were analysed using SPSS.

Results
IMRT was delivered using 4 to 8 beam arrangements. The incidence of grade 3 or more RP in the control group reciving 3D conformal radiotherapy was 16.3% (2% lethal). This was increased to 33% (14% lethal) in group I. Introducing a new dose constrain for the volume receiving low dose (V5) reduced the incidence of severe radiation pneumonitis to less than 10% (0% lethal) in group II. Neither the Mean Lung Dose nor the volume receiving 20 Gy (V20) values were significantly different in the 3 groups.

Conclusion
Irradiating large lung volumes with low radiation doses of 5 Gy or more is associated with higher incidence of severe pneumonitis that is potentially lethal despite respecting the V20 and MLD constraints. Using IMRT in patients with large tumours especially if receiving concurrent chemotherapy should be performed with caution. The cut level of V5 of 60% was applied in our department and was found feasible.

Background
Respiratory induced tumour motion is one of several challenges encountered when delivering radical radiotherapy to lung cancer patients. In recent years, four-dimensional computed tomography (4DCT) has improved our ability to accurately define lung tumour motion during breathing. Using 4DCT images, our study aims to compare the magnitude of lung tumour motion due to respiration, amongst different anatomical lobes and pulmonary zones. This may help guide personalised radiotherapy margins for patients with lung cancer.

Methods
This is a retrospective study of 100 consecutive patients from the Peter MacCallum Cancer Centre treated with curative intent radiotherapy for lung cancer. All 4DCT scans accessible from patients scanned between December 2009 and May 2013 were included. Images were analysed using the MIM v5.6 software. Tumour volumes were delineated by a single observer and propagated to include all 10 phases of the respiratory cycle. Movements were tracked in the superior-inferior (SI), anterior-posterior (AP) and medio-lateral (ML) directions by changes in the gross tumour volume centroid coordinates. Tumour motion characteristics were correlated with anatomical lobe, pulmonary zone, tumour volume, histopathology, spirometry and T-stage. Tumours with chest wall or mediastinal invasion were excluded. Statistical analyses were performed using Prism v6.0.

Results
Preliminary data from 82 patients showed the greatest mean movement in the SI direction among lower lobe tumours compared to those located in the upper lobes [Left lower, 8.0mm, n = 13, vs. Left upper, 1.3mm, n = 24] [Right lower, 6.4mm, n = 19, vs Right upper, 1.9mm, n = 28], p < 0.01. In all lobes, mean movements were similar in the AP [1.6mm, Right lower; 2.1mm, Right middle; 1.8mm, Right upper; 2.3mm, Left lower; 1.6mm, Left upper] and lateral directions [0.9mm, Right lower; 2.4mm, Right middle; 1.2mm, Right upper; 1.5mm, Left lower; 1.2mm, Left upper]. 35 patients were staged as T1, 30 as T2 and 14 as T3. Mean lung tumour motion decreased with increasing T stage in the SI direction [3.9mm, T1; 3.7mm, T2; 3.5mm, T3], however this was not statistically significant. Assessment of the association between tumour motion and spirometry findings is ongoing. Figure 1

Conclusion
The degree of lung tumour motion varies widely according to its position within the lung. The largest differences in tumour motion was between the upper and lower lobes in the SI direction. Analysis of all 100 patient datasets is ongoing.

Background
To analyze the effects of hypofractionated-simultaneous integrated boost-intensity modulated radiation therapy (Hypo-SIB-IMRT) on medically inoperable patients with stage I non–small-cell lung cancer (NSCLC).

Methods
65 qualified patients from December 2003 to November 2012 at three centers in China were included, with a median follow-up time of 39 months. Hypo-SIB-IMRT was delivered in 15 fractions with iGTV 75Gy, CTV 60Gy, and PTV 45Gy in 3 weeks. The slow computer tomography (CT) scan, conventional planning CT scan with active breath control (ABC), [18]fluorodeoxyglucose-position emission tomography ([18]FDG-PET) scan, or four dimensional CT scan (4D CT) were employed to do simulation. During the treatment, electrical port imaging device (EPID) or cone beam CT (CBCT) were performed 2-3 times per week to verify the reproducibility of the targets. All IMRT plans were optimized with Pinnacle or Eclipse systems using heterogeneity correction.

Results
The 1-, 3- and 5-year overall survivals (OS) were 100%, 87% and 58%, respectively with a median survival of 66.5 months. The 1-, 3- and 5-year progression free survivals (PFS) were 98%, 83% and 74%, while cancer-specific survivals (CSS) were 100%, 92% and 73%, respectively. The distant metastasis-free survivals (DMFS) were 98%, 85% and 76%, meanwhile local control (LC) were 100%, 93%, and 91%, respectively. There were no significant differences in OS, PFS, CSS, DMFS and LC compared with stage (I~A~ vs. I~B~) or gross tumor volume (GTV＞20 cm[3] vs.≤20 cm[3]). However, patients with T~1~ tumors (stage I~A~) were inclined to better survivals than those with T~2a~ (stage I~B~) ones, and local relapses were more frequent for larger GTVs. 18.5% (12/65) had grade 1or 2 radiation pneumonitis (RP), and only 1.5% (1/65) grade 1 esophagitis. Of 12 patients with RP, 10.8% (7/65) developed grade 1 radiation pulmonary fibrosis (RPF).

Conclusion
Due to the favorable long-term OS, PFS, CSS, DMFS, LC in addition to the minimal toxicities for medically inoperable stage I NSCLC patients, Hypo-SIB-IMRT presented in this prospective study may be an option to stereotactic body radiotherapy.

Background
With the high radiation dose used in stereotactic ablative body radiotherapy (SABR), it is vital to accurately delineate radiosensitive normal tissues in the planning process such that the dose distributions can be optimised to avoid these regions. This can become a time consuming process. It is also well understood that there is variation in how these volumes are delineated and this has influence on the plan and follow-up data. This work aims to determine if the use of automatic atlas segmentation can help to quickly and accurately delineate CT volumes for SABR planning - saving time, reducing complexity and improving the uniformity of process between patients.

Methods
From a retrospective sample of 5 patients delineated by an oncologist, each patient’s CT scan and contours was used as an atlas for a deformable image registration to map volumes to the other patients. A range of quantitative metrics (based on both overlap and distance) were used to evaluate the agreement between the expert contours and the atlas contours for each.

Results
The Dice similarity co-efficient showed overlap varied depending on the structure – lungs and heart performed well with a mean of 90% (range 71 – 99%) while the airway structures (trachea, oesophagus, proximal bronchi) performed poorer, with a mean of 52% (range 17 – 99%). This indicates while some structures are well suited to atlas segmentation, some are not. The mean Hausdorff distance, indicated that contours requiring editing after applying the atlas, had mean Hausdorff distances on the order of 1 mm. Typically, atlases that did not perform acceptably had a mean Hausdorff distance > 3 mm indicating it was better to start again with manual delineation. From the sample of 5 atlases, none performed significantly better than the others across all cases.

Conclusion
The use of atlases could potentially encourage consistency in delineation and could reduce the laborious task of delineation for lung SBRT treatment planning, however editing of contours is still required. Larger structures performed well, however they could also be easily delineated with threshold-based automatic segmentation. Further investigation to develop a bank of representative atlases may improve performance.

Background
Few studies are dedicated to elderly patients with unresectable stage IIIA/B. We used a Standardized Geriatric Assessment (SGA) to select fit elderly patients and assess if this population can benefit from standard of care, namely concurrent CRT.

Methods
The aim of this multicentric phase II opened-study was to assess CRT in patients older 70 years with locally advanced NSCLC, evaluated as “fit” according to SGA.CRT associated oral vinorelbine (30 mg/m²/week) and IV cisplatinum (30 mg/m²/week) during 6 weeks concurrently with radiotherapy (66 Gy, 33 fractions, 6,5 weeks). Main inclusion criterias were : PS ≤ 1, weight loss < 10%, creatinine clearance ³ 50 ml/mn abreviated, VEMS ³ 40%, PaO2 ³ 60 mm Hg, KCO ³ 60% and patient classified as fit according to SGA. The principal end-point was early treatment tolerance (number of patients with adverse event grade ³ 3 (except nausea and vomiting) or grade 4 for hematologic toxicity and asthenia. Secondary end-points were RECIST response 4 weeks after treatment, quality of life, tolerance, progression-free survival and overall survival. Using a Simon's optimal plan in 2 steps, the total number of patients to be included was 59 with an intermediate analysis after 19 patients. Toxicities and serious adverse events were monitored by an independent peer committee.

Results
Interim analysis was done after 23 inclusions in 19 evaluable patients: males 84% , mean age 74.6 (70 to 83) years, 3 patients didn’t end the treatment (1 disease progression, 1 cons-indication for radiotherapy, 1 patient choice). Four patients had adverse event ≥ 3 (except nausea and vomiting) or grade 4 hematologic toxicity and asthenia. Treatment efficacy was: 1 RC, 10 RP, 5 SD, 1 PD. Two patients were not evaluable (1 early death, 1 patient’s refusal to further treatment). The independent peer committee judged that toxicities were acceptable and consistent with what was expected. Study is ongoing with 44 enroled patients currently.

Conclusion
The interim analysis of a phase II study of CRT in fit elderly patients with no resecable locally advanced NSCLC assessed by SGA showed an acceptable toxicity. Results will be upgraded for the congress.

Background
Mediastinal lymph node involvement (MLNI) is the strongest prognostic factor of resected locally advanced non-small cell lung cancers (LA-NSCLC). The 7[th] edition of the TNM is based in purely topographic criteria: N2 is applied for ipsilateral MLNI and N3 for contralateral and unresectable MLNI. Different authors have proposed many other prognostic classifications of MLNI

Methods
We retrospectively reviewed 45 resected LA-NSCLC previously treated with inductive chemo or chemoradiation in our center between October-2004 to June-2012. Three patients died due to early surgical complication were not analyzed. Systematic mediastinal dissection was performed in all of them. The prognostic impact of pN2 was statistically compared to number of resected nodes; number of affected areas; number of metastatic nodes; and ratio of metastatic/resected nodes

Results
Our series included 37 men and 5 women with a mean age of 64.64 years-old. There were diagnosed eight non-specified NSCLC, two adenocarcinomas, and 32 squamous carcinomas. Cis- and carboplatin-based chemotherapy was administered in 35 and seven patients, respectively. Concurrent radiation was administered in 21. pN2 MLNI clearly worsened both disease free (DSF) and overall survival (OS) of the patients (p= 0.006; and p= 0.018, respectively). Proportion of patients with pN2 MLNI was lower when radiation was applied (p= 0.033) and did not significantly vary according to chemotherapeutic regimen or histology. The number of resected nodes did not impact on survival (DFS p= 0.261, and OS p= 0.277), but OS was better in patients with a lower rate of pathologically detected nodes (p= 0.046). The number of metastatic nodes according to the Tokio score did not impact on survival. The Regina Elena and the Mount Sinai ratios of metastatic nodes according to the number of resected nodes neither impacted

Conclusion
The presence of pN2 MLNI according to the 7[th] edition of the TNM classification is the strongest mediastinal prognostic factor in our series of resected LA-NSCLC previously treated with inductive chemo or chemoradiation. No other tested classification of MLNI could predict significant differences in survival. The prognostic significance of the lower detection rate of resected nodes after inductive treatment should be explored. Figure 1. DFS and OS Kaplan-Meier curves according to MLNI. Figure 1

Background
Combined cytotoxic chemotherapy and radiation therapy is established as the standard treatment for patients with medically inoperable or technically unresectable stage III NSCLC. Multiple randomized studies and meta-analyses demonstrate that CChRT results in improved survival compared with sequential chemo-radiotherapy or radiotherapy alone. The aim of our study was to evaluate the effectiveness and toxicities of CChRT with bi-weekly Docetaxel (D) and Cisplatin (C) and thoracic radiotherapy, after one cycle D-C induction chemotherapy.

Methods
Between May 2009 and November 2012, 53 chemo-naive p with histologically confirmed inoperable locally advanced NSCLC, stage IIIAN2/IIIB (no pleural T4), PS 0-1 and adequate lung function (FEV1 > 1.1, V20 < 25%) were included: one cycle of D 75 mg/m2 on day 1 and C 40 mg/m2 days 1-2 followed at 21 days by CChRT with bi-weekly D 40 mg/m2 and C 40 mg/m2 for four courses, during conformal thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 17,8 months.

Results
The p characteristics were: mean age 59,4 years (34-75); male/female 47/6; ECOG PS 0/1 in 17/36 p; squamous/adeno/large cell carcinoma: 53%/34%/13%; stage IIIAN2 15 p (28.3%) and stage IIIB 38 p (71.7%). All p were evaluable for response and toxicity. RR: 6 CR, 37 PR (RR 81.8%; 95% CI:71-92), 4 SD (7.6%) and 6 PD (11.3%). The median PFS was 14 months (95% CI:11-17) and median OS was 21 months (95% CI:9-32). The PFS at 1/2 years were 55%/32% and the OS at 1/3 years were 82%/50%. A total of 53 cycles of D-C induction chemotherapy were given; main toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia 1.8/15; anemia 11.3/0; nausea/vomiting 26.4/1.8; diarrhea 22.6/3.7; fatigue 35.8/0; there were three episodes of hospitalization: febrile neutropenia 2 p and g3 diarrhea 1p. Main toxicities per p in CChRT (D-C doses: 203, 3.8 per p; mean doses RT: 64,6 Gys) were g1-2/3 (%): neutropenia 28.3/5.6; anemia 62.2/0; esophagitis 50.9/3.7 and pneumonitis 32/0; nausea/vomiting 20.7/0; fatigue 37.7/3.7; there were four episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis, 2 p.

Conclusion
CChRT with bi-weekly Docetaxel and Cisplatin and thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with acceptable long-term survival.

Background
Inoperable stage III NSCLC is increasingly diagnosed in poor-risk patients for whom there is not yet a standard treatment. We conducted a randomized two-stage phase II study to assess whether sequential or concurrent chemoradiation was feasible, tolerable and showed efficacy.

Methods
Patients with inoperable stage IIIA and B NSCLC and at least one of the following conditions: age ≤ 75 years, ECOG PS=2, weight loss > 5%, creatinine clearance < 60 ml/min, a comorbid condition precluding the patient from being treated in a protocol for fit patients,were randomized to receive either carboplatin AUC 2.5 and vinorelbine 15 mg /m[2] both on days 1,8,22, and 29, and thoracic radiotherapy (TRT) total dose 60 Gy starting day 1 (CT arm) or, carboplatin AUC 5, days 1 and 22 and vinorelbine 25 mg/m[2] days 1, 8, 22, and 29, followed by TRT 60 Gy starting day 43 to 50 (ST arm). The primary end-point was response rate.

Results
From June 2001 to June 2006, 70 patients from 8 centers were included : 47 in CT arm and 23 in ST arm. Forty-eight of these patients were randomized during the first stage of the trial. By September 2004, due to a decrease in treatment compliance and an increase in early deaths in the ST arm, accrual was continued in the second stage of the trial only in the CT arm. Patient characteristics: median age 74 (49-84), Male 96%, Stage IIIB 65%; ECOG =2, 28%; Weight loss >5%, 29%; Creatinine clearence <60, 26%; Comorbidity, 70%. More than one poor risk inclusion criteria: 59 %. Fifty-eight patients completed treatment 93 % in CT arm, and 73% in ST arm. There were 2 CR and 25 PR (RR 60%) in CT arm, and 10 PR (RR 45.5%) in ST arm. Grade 3- 4 hematological toxicity was absent in CT arm and was 14% (neutropenia) in ST arm. Grade 3 and 4 non-hematological toxicities experienced by more than 5% of patients were asthenia (7%) and dyspnea (9%) in CT arm and anorexia (9%), asthenia(14%), and dyspnea (14%) in ST arm. Only one patient developed grade 3 esophagitis (CT arm) There were five deaths during treatment: two in CT arm and three in ST arm. Median PFS and overall survival rate were 6.7 (95% CI:4.9-8.5) and 16.8 months (95% CI 9.5-24), and 7.9 (95% CI:3.9-16.2) and 5.6 months (95% CI:2.7-8.9 ), for the CT arm and ST arm, respectively.

Conclusion
In poor-risk patients with inoperable stage III NSCLC, concurrent chemoradiotherapy outperformed sequential chemotherapy and radiotherapy, and was feasible, very well tolerated, and provided efficacy. The survival outcome with concurrent chemoradiotherapy was notably longer than anticipated.

Background
Concurrent chemoradiotherapy is the standard treatment for locally advanced non-small-cell lung cancer (LA-NSCLC). However, its cure rate remains unsatisfied, and further improvement in the treatment outcome is strongly warranted. S-1 (S), an oral fluoropyrimidine, is a new active agent possessing a radio-sensitizing effect. Additionally, combining S and cisplatin (P) offered an active and safe regimen for metastatic non-small-cell lung cancer. The objective of this study was to assess the efficacy and safety of S plus P with concurrent thoracic radiotherapy (TRT) for LA-NSCLC.

Methods
Patients with stage IIIA/IIIB, aged ≤75 years and PS 0-1, and without any prior chemotherapy were eligible for this study. Patients were treated with P (40 mg/m² on day 1, 8, 29 and 36) and S (40 mg/m²/dose b.i.d. on days 1-14 and 29-42) and TRT (60 Gy/30 fr over 6 weeks starting on day 1). Primary endpoint was respsonse rate, and required sample size was 48 patients.

Results
Between 2006 and 2009, 48 patients were enrolled (37 men; median age, 66 years; PS 0/1, 36/14; IIIA/IIIB, 23/25; sq/non-sq, 22/26). Partial response was observed in 37 patients (77%; 95% confidence interval: 63-88%). At a median follow-up of 54 months for the surviving patients, median progression-free survival and median survival time were 9.3 months and 31.3 months, respectively. No difference in efficacy (response and survivals) was observed stratified by histology (sq vs. non-sq). Toxicities were generally mild, including G3/4 neutropenia (44%), G3/4 thrombocytopenia (13%), G3 febrile neutropenia (8%) and G3 pneumonitis (4%). No one developed Gr3/4 esophagitis. No toxic deaths have occurred.

Conclusion
This chemoradiotherapy regimen yielded a favorable overall survival data. Also, it was well-tolerated in patients with LA-NSCLC as compared with concurrent docetaxel plus P with TRT therapy especially in term of TRT-related toxicities.

Background
Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small cell lung cancer (NSCLC). S-1 has been shown to be significant efficacious for treating advanced NSCLC. Our previous phase II study reported short-term outcomes of cisplatin (CDDP)/S-1 chemoradiotherapy. Because CDDP/S-1 chemoradiotherapy is considered to have advantages over others in overall survival (OS) and toxicity, we analyzed its long-term outcomes by following up patients included in the phase II study.

Methods
Forty-eight patients (aged <75 years) with unresectable stage III NSCLC were evaluated. They were treated with CDDP (60 mg/m[2] on day 1) intravenously and oral S-1 (40 mg/m[2] twice daily on days 1–14); this regimen was repeated every 4 weeks for four cycles. A 60-Gy thoracic radiation dose was delivered in 30 fractions beginning on day 2.

Results
After a median follow-up of 6.3 years (range, 5.7–7.4 years), the median OS was 2.8 years [95% confidence interval (CI); 1.04–4.63 years], and the 3- and 5-year OS rates were 49.7% (95% CI: 35.6%–63.8%) and 33.0% (95% CI: 20.0%–46.6%), respectively. Out of the several variables evaluated as predictors of OS, including gender, age, stage, histology, and performance status (PS), only PS proved to be a statistically significant predictor in both univariate and multivariate analyses.

Conclusion
CDDP/S-1 concurrent thoracic radiotherapy is clinically feasible and highly efficacious. Despite our relatively small sample size, the benefits of this regimen revealed in this study warrant further research.

Background
Concurrent chemoradiotherapy (CCRT) has become the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). The comparative merits of two widely used regimens: carboplatin/paclitaxel (PC) and cisplatin/etoposide (PE), each given with concurrent radiotherapy, remain largely undefined.

Methods
Records for consecutive patients with stage III NSCLC treated with PC or PE and ≥60Gy chest radiotherapy between 2000-2011 were reviewed for outcomes and toxicity. Survival was estimated using the Kaplan-Meier method and Cox modeling with the Wald test. Comparison across groups was done using the student t and chi-squared tests.

Results
75 (PC: 44, PE: 31) patients were analyzed. PC patients were older (median 71 vs 63 years; p=0.0006). Other characteristics were comparable between groups. With PE, there was significantly increased grade ≥3 neutropenia (39% vs 14%, p=0.024) and thrombocytopenia (10% vs 0%, p=0.039). Radiation pneumonitis was more common with PC (66% vs 38%, p=0.033). Five treatment related deaths occurred (PC: 3 vs PE: 2, p=1.000). With a median follow up of 51.6 months, there were no significant differences in relapse free survival (median PC 12.0 vs PE 11.5 months, p=0.700) or overall survival (median PC 20.7 vs PE 13.7 months; p=0.989). In multivariate analyses, no factors predicted for improved survival for either regimen. Table 1: Non-hematological and hematological adverse events, by grade (CTCAE 4.0)

Adverse events	PC (n = 44)	PE (n = 31)
	n (%)	n	P~χ2~
Esophagitis 1 2 3 4	3 (7) 19 (43) 10 (23) 5 (11)	5 (16) 7 (23) 10 (32) 1 (3)	0.151
Pneumonitis 1 2 3 4 5	21 (48) 6 (14) 0 (0) 1 (2) 1 (2)	4 (13) 6 (19) 1 (3) 1 (3) 0 (0)	0.033
Neuropathy 1 2	1 (2) 1 (2)	0 (0) 0 (0)	0.485
Nephropathy 1 2 3	3 (7) 0 (0) 0 (0)	4 (13) 0 (0) 1 (3)	0.314
Nausea/vomiting 1 2 3	7 (16) 8 (18) 0 (0)	7 (23) 2 (6) 1 (3)	0.291
Chest infection 1 2 3 4 5	1 (2) 1 (2) 11 (25) 1 (2) 1 (2)	0 (0) 3 (10) 5 (16) 2 (6) 1 (3)	0.534
Neutropenia 1 2 3 4	4 (9) 5 (11) 6 (14) 0 (0)	2 (6) 0 (0) 8 (26) 4 (13)	0.024
Febrile neutropenia 3 4	5 (11) 0 (0)	5 (16) 1 (3)	0.394
Anemia 1 2 3 4	12 (27) 5 (11) 1 (2) 0 (0)	10 (32) 9 (29) 0 (0) 1 (3)	0.117
Thrombocytopenia 1 2 3	1 (2) 3 (7) 0 (0)	4(13) 1 (3) 3 (10)	0.039
Treatment-related deaths	3 (7)	2 (6)	1.000

Conclusion
PC was more likely to be used in elderly patients. Despite this, PC resulted in significantly less hematological toxicity but achieved similar survival outcomes as PE. PC is an acceptable CCRT regimen, especially in older patients with multiple comorbidities.

Background
cCTRT is the current standard treatment for good Performance Status (PS) unresectable locally advanced NSCLC. A phase III study demonstrated that Docetaxel consolidation does not improve overall survival (OS) after cCTRT (Hanna. JCO 2008). The role of consolidation chemotherapy after cCTRT is still investigational and our study was set up to evaluate the role of pemetrexed in this setting. A less toxic consolidation chemotherapy may enable a higher proportion of patients to comply to planned treatment which may improve outcome.

Methods
This was a single-institution prospective phase II study. Treatment comprised cisplatin (50 mg/m[2] days 1, 8, 29, 36), etoposide (50 mg/m[2] days 1-5 and 29-33) and concurrent thoracic radiotherapy starting on day 1 chemotherapy (66 Gy in 33 daily fractions; 3D conformal radiotherapy or IMRT) followed by consolidation pemetrexed (500 mg/m[2] on days 71, 92 and 133). The primary endpoint was 1 year OS. Secondary endpoints were progression-free survival (PFS), 2 yr OS, acute/late toxicity (CTCAE v3.0), compliance to treatment.

Results
35 patients were recruited between March 2008 and October 2010. Median age was 61 years (range 42-76). M:F ratio was 23(66%):12(34%). ECOG PS was 0:1 11(31%):24(69%). Histology: squamous 21(60%), adenocarcinoma 8(23%), undifferentiated 4(11%), other 2(6%). Stage: IIB 1(3%), IIIA 19(54%), IIIB 15(43%). All 35(100%) had PETCT staging. All 35 patients received concurrent chemotherapy (dose reduction in 3 patients) and 32 (91%) received the planned 66Gy (range 56-66 Gy). The number of patients who completed pemetrexed were: cycle 1=25 (71%), cycle 2=22 (63%), cycle 3=16 (46%). Radiation parameters: Gross Tumour Volume (GTV) was median 60.2 cm[3] (range 11.4-274.4 cm[3]), V~20Gy ~median 30.4% (range 10.5-35.3%), During the concurrent phase, grade 3/4 toxicity was noted for: neutropenia 17(49%) anaemia 1(3%), thrombocytopenia 1(3%), infection 8(23%), fatigue 6(17%), nausea±vomiting 4(11%), mucositis 3(9%), anorexia 3(9%). During the pemetrexed consolidation phase, the only grade 3/4 toxicities were: infection 5(20%), anaemia 3(12%), neutropenia 2(8%) and fatigue 2(8%). Acute radiotherapy toxicity (<3months): oesophagitis grade 3/4 10(29%) and late toxicity (>3months): pneumonitis grade 3/4 2(7%), oesophageal stricture 2 (7%), pulmonary fibrosis 1(3%). Median follow up was 25months. Median OS was 34months, with 1yr OS 77% (95% CI 60-88%), and 2yr OS 61% (95% CI 37-72%). Median PFS was 22months, with 1yr PFS 62% (95% CI 43-76%) and 2yr 49% (95% CI 31-65%). Of the 14 deaths, causes were, 1 suicide during radiotherapy, 2 treatment-related deaths (1 grade 5 pneumonitis and 1 grade 5 haemoptysis) and 13 due to lung cancer.

Conclusion
In an unselected locally advanced NSCLC population, staged with PETCT a median survival of 34 months can be achieved. The study reinforces the challenge of delivering consolidation chemotherapy and suggests that improved staging contributes to improved outcomes. Although there was failure to deliver all planned cycles of consolidation pemetrexed after cCTRT in 54% of patients, these are encouraging results that warrant further investigation.

Background
Purpose of this study was to evaluate the association between change in hemoglobin (Hb) levels during treatment and disease control and survival in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with concurrent chemoradiotherapy (CRT).

Methods
Medical records of 368 LA-NSCLC patients, who had been treated with definitive CRT at our department between dates January 2007 and December 2011, and whose pretreatment Hb levels were ≥12.0 g/L, and who had at least 3 Hb measurements during CRT, were retrospectively evaluated. All patients received 60-66 Gy thoracic 3-dimentional conformal radiotherapy concurrently with 1-3 cycle cisplatin/carboplatin-vinorelbine/taxane (q21) doublet chemotherapy. For all analyses, patients were divided into groups according to their nadir Hb level, percent Hb change, development of anemia (Hgb<12) and nadir Hb cut-off defined from ROC analysis. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and locoreginal PFS (LRPFS).

Results
At a median follow-up of 24.7 months (range 19.7-27.5), Median OS, PFS and LRPFS for whole group were 23.8 (%95 CI=22.8-24.8), 11.7 (%95 CI=11.0-12.5) and 15.3 months (%95 CI=14.7-15.9), respectively. During CRT course, 138(37.5%) patients developed anemia, and median OS, PFS, and LRPFS were significantly worse in these patients [(27.3 vs. 18.3; p<0.001), (12.7 vs. 9.2; p<0.001), and (16.4 vs. 11.2 months; p<0.001)]. While there was no statistically significant survival difference according to median nadir Hb level and % Hb change, patients with Hb levels above the cut-off point defined from ROC curves (12.4 g/L) revealed better OS (27.7 vs. 20.4; p<0.001), PFS (12.8 vs. 10.2; p<0.001) and LRPFS (16.4 vs. 13.8 months; p<0.001). On multivariate analyses, only these two factors found to be independent prognostic factors (p<0.001 for Hb > vs. < 120 g/L, p<0.03 for Hb> vs.

Conclusion
Results of this study has shown that 37.5% NSCLC patients with normal pretreatment Hb levels had developed anemia during the course of CRT, which was found to be a worse prognostic factor independent from other co-existing factors in terms of locoregional tumor control and survival outcome.

Background
Cancer Care Ontario’s (CCO) Program in Evidence-based Care has been developing lung cancer practice guidelines since 1997. Based on randomized clinical trials and published meta-analyses, a modest but clinically significant benefit for the use of concurrent chemo-radiotherapy treatment (CCRT) in selected inoperable stage III NSCLC (good performance status, limited weight loss), was recommended in a guideline published in 2005 and revised in 2006.

Methods
In 2008, CCO began to measure concordance with guidelines and to publically report regional results through the Cancer System Quality Index (CSQI),a web-based public reporting tool released annually by the Cancer Quality Council of Ontario (CQCO), Guideline concordance is a measure within the Effective quality domain of CSQI and is used to track the consistency of cancer treatment services across Ontario. This measure links data within Cancer Care Ontario’s Activity Level Reporting Enterprise Data Warehouse and the Ontario Cancer Registry with information from the Canadian Institute for Health Information’s Discharge Abstract Data and National Ambulatory Care Reporting System.

Results
Of 1312 patients with unresected stage III disease diagnosed in 2010 and 1259 in 2011, only 30.3% and 31.8% respectively received CCRT defined as radiation and chemotherapy given within 180 days of diagnosis. An additional 33.9% received an alternative form of treatment in 2011: 83.6% of these patients were treated only with radiation, 66% of whom had palliative radiotherapy while 33.4% had radical (curative) radiotherapy. In 2010, a similar pattern of treatment was observed with 33.5% of cases receiving alternate treatment: 81.3% of whom received only radiation; 70% of these patients received palliative treatment while 27.5% received radical radiotherapy. In 2011, 34.2% received no treatment, a decrease of 2% from 2010. Variation in guideline concordant practice was evident between the 14 health service regions of the province (range from 23.3% to 44.5%) but only one was significantly greater than the Ontario rate (95% Confidence Interval (CI); effect size (d =0.56). Six of 14 regions had a decline in the concordance rate between 2010 and 2011. There was no difference in the rate of CCRT use by gender (28.4%) but there was a sharp decline in CCRT after age 65 (45% < 65 yr vs. 25% > 65 yr), (95% CI, 21.5-28.5; p=0001). Less CCRT was given to the lowest income quintile (Q)(22.9% vs. 29.9% for Q4, 95% CI 23.9-35.9; p=0.0001), to urban vs. rural populations (22.9% vs. 34.8%; 95% CI, 28.6-40.9; p=0.0001) and in those areas of the province with higher populations of immigrants (lowest tercile 28.4% vs. 18.6% for middle and 19.0% for the highest tercile, p=0.0001).

Conclusion
Concordance with the CCO guideline on CCRT in Stage III unresectable NSCLC is particularly low in older, lower income, urban and immigrant populations. The absence of weight loss and performance status data makes interpretation of this data difficult. Further study of the reasons for these variations in practice will be necessary to inform appropriate strategies to reduce these inequities.

Background
Trimodality therapy consisting of induction chemoradiotherapy (CRT) followed by surgery can be one of the treatment options for locally advanced non-small cell lung cancer (NSCLC). While recent randomized phase III trials failed to demonstrate a benefit from the addition of surgery in the entire population, the subset analysis of the intergroup trial 0139 indicates that trimodality therapy is beneficial for population who did not undergo pneumonectomy. This result strongly suggests that the status of disease may influence the prognosis even in same stage population. Thus, identifying prognostic factors and their inclusion in stratification are critical for the appropriate randomized study. In this study, we retrospectively examined the prognostic impact of tumor location in NSCLC patients with clinical (c-) N2 disease who underwent trimodality therapy in our institute.

Methods
Among patients who underwent induction CRT followed by surgery between 1999 and 2011 at our institution, a total of 76 NSCLC patients with c- N2/3 stage III were enrolled for this retrospective study. Induction CRT basically consisted of docetaxel and cisplatin with concurrent radiation at a dose of 40 - 60 Gray.

Results
A total of 76 patients consisted of 53 male and 23 female, 43 adenocarcinomas and 33 non-adenocarcinomas, and 44 c-Stage IIIA and 32 c-Stage IIIB. Primary tumors were located in right upper lobe for 33 patients, right middle lobe for 5, right lower lobe for 11, left upper lobe for 20, and left lower lobe for 7. For all population, lower lobe tumors showed significantly shorter overall survival (OS) and disease-free survival (DFS) times compared to non-lower lobe tumors (OS, p = 0.022; DFS, p = 0.0007). In a multivariate analysis, tumor location was independent prognostic factor for poor prognosis. Limited to pathologically proven N2/3 disease before induction CRT (n = 36), location of lower lobe tend to be poor prognosis compared to other location (OS, p = 0.068; DFS, p = 0.0075).

Conclusion
We showed that tumor arising from lower lobes is a poor prognostic factor in NSCLC patients with N2 disease treated with induction CRT. The status of tumor location should be considered in stratification in randomized trails that estimate the impact of the trimodality therapy.

Background
The potential prognostic value of survivin is variably reported in various stage of lung cancer. This study evaluated the correlation between tumor survivin expression before and after chemoradiation therapy (CRT) and prognosis in stage III non-small cell lung cancer (NSCLC) patients treated with platinum-based chemoradiation therapy followed by surgery

Methods
Medical records from 53 patients whose tissues were suitable for study were reviewed. Tissues were stained by immunohistochemistry and were estimated the degree of stain with scoring for survivin. Clinicopathologic parameters and survivin expression score were evaluated for a prognostic relationship with overall survival (OS) and time to recurrence (TTR).

Results
Pathologic complete response, residual nodal involvement and radiologic response after CRT were not related with OS or TTR. Tumor survivin expression on pre-treatment tissues was presented in 47 patients (88.7%). Pre-treatment survivin score was not related with TTR and OS (p = 0.249 and p = 0.601, respectively). There was no correlation between pre-treatment and post-treatment survivin score (p = 0.309). Downregulation of survivin and post-treatment survivin score (0 – 1) after chemoradiation showed significant improvement in OS (p = 0.04 and p = 0.033, respectively). Age, downregulation of survivin score, and post-treatment survivin score (0 – 1) were significant prognostic factors for survival by multivariate analysis.

Conclusion
Downregulation of survivin score and post-treatment low survivin score in stage III NSCLC treated with platinum-based chemoradiation therapy followed by surgery has a value of prognostic factor regardless pre-treatment survivin score. Further studies to evaluate the relation of survivin expression and platinum-based chemoradiation therapy are warranted in NSCLC.

Background
to analyse survival data, treatment results, toxicity and prognostic factors, the influence of PET-staging in the combination of daily low-dose cisplatin with high-dose radiotherapy in stage III NSCLC patients.

Methods
retrospective study between 2005 -2012 of PET staged patients with mainly stage III irresectable, locally advanced non small cell lung cancer. Concurent chemoradiation is given by using daily low-dose cisplatin (6mg/m2) combined with 24 fractions 2,75 Gy to a total dose of 66 Gy.

Results
mean follow-up 20 months, median follow-up 15 months (1, 7-88). Prognostic factors at multivariate analysis are for survival: PTV1 < 380 cc (p=0.018), ECOG scale (p=0.09). For local control: PTV1 < 380 cc (p=0.031). Our data show a linear relationship between the size of the PTV1 and survival. The median survival was 36 months and the 5-year survival rate is 33%. The incidence of distant free survival of 5 years is 27%. The local relapse free survival of 5 years is 51%.

Conclusion
results for survival and local control are good and show a 100% increase in 5 yr overall survival compared to our historical control series. In our data toxicity is low. In multivariate analysis a low PTV volume (<380 cc) is the only significantly favorable prognostic factor for local disease-free and overall survival. Possibilities to increase the biological radiation dose (EQD2= 74 Gy) and/or in combination with biological response modifiers should be studied in the near future. Figure 1. Overall survival for all patients Mean follow-up 20m, median follow-up 15 m (1,7-88) Figure 1 Figure 2. Overall survival stage III < 380cc and > 380cc Survival: 1=PTV1 < 380 cc, 2=PTV1>380 cc (p=0.018) Figure 2

Background
Concomitant chemoradiotherapy is the standard treatment of unresectable stage III non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial, particularly in lung squamous cell carcinoma. We have conducted a phase II clinical trial in a Chinese population to evaluate concomitant treatment using docetaxel/cisplatin chemotherapy and thoracic radiotherapy followed by docetaxel/cisplatin consolidation chemotherapy in unresectable stage III lung squamous cell carcinoma. The purpose of this study is to evaluate the feasibility and activity, and also assess its impact on progression-free survival (PFS).

Methods
A total of 32 patients were enrolled between January 2011 and January 2013. Patients received concomitant docetaxel 30mg/m[2] on day 1 and day 8, cisplatin 25mg/m[2] on day 1 to day 3 repeated every 3 weeks for 2 cycles and thoracic radiotherapy, followed by docetaxel/cisplatin for 2 cycles as consolidation therapy (docetaxel 60mg/m[2] on day 1, cisplatin 25mg/m[2] on day 1 to day 3 repeated every 3 weeks). Objective response rate according to the RECIST criteria was recorded and toxicity was evaluated using the NCI Common Toxicity Criteria. The Kaplan–Meier method was used to evaluate patient survival. Univariate analysis of patient characteristics and tumor responses was conducted using the Chi-square and Fisher’s exact test.

Results
Eight (25.0%) and 20 patients (62.5%) had a complete or partial response, respectively, while 3 patient’s disease remained stable and 1 patient had progression of the disease. The overall response rate (87.2%, 95% confidence interval (CI): 63–97%) exceeded the goal per study design. The median PFS was 11.0 months (95% CI: 5.6–16.4 months). This approach obtained likely better effects than history control group. Main toxicity (grade 3 or greater, %): neutropenia 10 (31.3%); thrombocytopenia 7 (21.9%); anaemia 8 (25.0%); nausea/vomiting 5 (15.6%); anorexia 7 (21.9%), dysphagia 4 (12.5%), radiation pneumonitis 3 (9.4%) and fatigue 4 (12.5%).

Conclusion
This data suggests that concomitant treatment with docetaxel/cisplatin and thoracic radiotherapy was well tolerated, with promising activity in a Chinese population with unresectable stage III lung squamous cell carcinoma. Although the data presented herewith appears promising, this study is relatively small, and more data from randomized trials are needed to further validate this regimen.

Background
To evaluate the role of postoperative radiotherapy (PORT) after curative resection and adjuvant chemotherapy for patients with pathological stage N2 non-small cell lung cancer (NSCLC).

Methods
We performed a retrospective review of 219 consecutive patients who underwent curative surgery followed by adjuvant chemotherapy between 2000 and 2011. Among 219 patients, 41 received PORT additionally. Propensity scores for PORT receipt were calculated for each patient and used for matching to patients without PORT. 118 patients in non-PORT group and 39 patients in PORT group were matched. Clinical and pathologic characteristics were well-balanced after matching. PORT was delivered using conventional technique (n=13) or three-dimensional conformal technique (n=26) with median dose of 54 Gy (range, 50-60). The median follow-up duration for matched patients was 47 months.

Results
During the follow-up, 58 patients (49.2%) experienced loco-regional failure in the non-PORT group and 12 patients (30.8%) in the PORT group. Distant metastasis occurred in 68 patients (57.6%) in non-PORT group and 22 patients (56.4%) in PORT group. PORT was associated with improved loco-regional control rate (LRC) (5yr LRC 67.0% vs. 48.4%, p = 0.047), but not disease-free survival (DFS) (5yr DFS 43.3% vs. 32.3%, p = 0.257). An exploratory subgroup analysis suggested a potential DFS benefit of PORT in patients with multiple stations of mediastinal lymph node metastasis (5yr DFS 42.8% vs. 16.6%, p = 0.023). Grade 3 radiation pneumonitis and esophagitis was seen in only one patient, respectively.

Conclusion
In pathological stage N2 NSCLC patients, more than half eventually developed distant metastasis despite adjuvant chemotherapy. PORT increased LRC in these propensity-matched patients, but did not DFS. However, patients with multiple stations of mediastinal lymph node metastasis appear to benefit from PORT.

Background
Bevacizumab and pemetrexed/cisplatin improves the response and survival in patients with advanced or metastatic non-small cell lung cancer (NSCLC); however, the role of these medications in the setting of induction therapy for NSCLC is not well defined. The purpose of this study was to evaluate the feasibility of induction combination therapy with cisplatin, pemetrexed and bevacizumab followed by surgery in patients with clinical stage II/IIIA nonsquamous NSCLC.

Methods
Patients with clinical stage II/IIIA nonsquamous NSCLC were enrolled. The induction chemotherapy consisted of three cycles of cisplatin (75 mg/m[2]), pemetrexed (500 mg/m[2]) and bevacizumab (15 mg/kg) on Day 1, administered every 21 days. At least six weeks after the last administration of bevacizumab, the patients underwent surgical resection. The primary endpoint was the complete resection rate after the completion of three cycles of induction chemotherapy. The sample size was set at 30. The feasibility of the treatment was considered to be confirmed if the complete resection rate was 80% (24/30) or more.

Results
A total of six institutions in Japan participated in this trial. The study was initiated in June 2010, and patient enrollment was completed in November 2012. Thirty-one patients were recruited, 30 of which were eligible. The median age was 64 years (range: 54-71), and the male/female ratio was 17/13. The PS0/PS1 ratio was 29/1, the adenocarcinoma/large cell carcinoma ratio was 30/0 and the clinical stage IIA/IIB/IIIA ratio was 5/3/22. Grade 3 toxicities included neutropenia (7%), nausea (7%), appetite loss (13%), hypertension (23%) and pulmonary embolism (3%). There were no grade 4 events, and 27 (90%) patients completed three cycles at the full dose of chemotherapy. All but one patient exhibited radiologic tumor reduction based on the RECIST criteria. The objective responses to chemotherapy was CR in 0% of the patients, PR in 37%, SD in 50% and PD in 10% (due to new lesions). The disease control rate (CR+PR+SD) was 87%. Five patients dropped out from the study before surgery due to the patient’s decision in one patient, adverse events in three and disease progression in one. The complete resection rate after the completion of three cycles of induction chemotherapy was 83% (25/80). Therefore, the results met our criterion for feasibility.

Conclusion
Induction chemotherapy using a combination of cisplatin, pemetrexed and bevacizumab in patients with resectable clinical stage II/IIIA nonsquamous NSCLC is therefore considered to be a feasible treatment modality. Figure 1

Background
To evaluate pemetrexed in combination with cisplatin in these patients, a randomized phase III study of concurrent cisplatin with pemtrexed or vinorelbine and late course accelerated hyperfractionated radiotherapy (LCAHRT) was performed.

Methods
Patients with unresectable stage III non–small cell lung cancer （NSCLC） were randomly assigned to two concurrent regimens. Arm1 included cisplatin at 25 mg/m2 on days 1-3, 22-24 and vinorelbine at 25 mg/m2 on days 1,8 and 22,29 with concurrent LCAHRT. Arm 2 used cisplatin at 25 mg/m2 on days 1-3, 22-24 and pemtrexed at 500 mg/m2 on days 1 and 22 with the same radiotherapy protocol. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall survival (OS ) and toxicities. Kaplan–Meier analyses were used to assess survival, and toxic effects were examined using the Pearson Chi-Square test. All statistical tests were two-sided.

Results
A total of 104 patients were enrolled with 100 ones analyzed for 3 in arm 1 and 1 in arm 2 were not finished treatment according to the protocol. The characteristics of study population between the two arms were well balanced. The median PFS were 15 and 23 months , respectively （p=0.014）, while median OS were 25 and 25.5 months for arms 1–2, respectively （p= 0.270）. In arms 1 and 2, the median OS of squamous cell carcinoma was 22.5m and 23m, while non-squamous cell carcinoma 27m and not reached, respectively (p=0.216). The median PFS of squamous cell carcinoma was 17m and 20m, while non-squamous cell carcinoma 15m and not reached, respectively (p=0.020). Compared with lower radiation doses, patients treated with more than or equal to 70 Gy had a better OS and PFS (p=0.002) for both arms. Concerning toxicities, for arms 1 and 2, grade 3-4 depression of white blood cell was 20/48 and 11/52 (p=0.027), grade 2-3 hemotoblatin 8/48 and 5/52 (p=0.047), grade 1-3 radiation induced pneumonitis 40/48 and 31/52 (p=0.032). The differences of other adverse events including esophagitis, nausea, vomiting, platelet were not statistical difference.

Conclusion
Comparing with NP, concurrent pem/DDP at full systemic doses and LCAHRT was well tolerated, with promising activity and milder side effects in a Chinese population with inoperable stage III NSCLC in spite of histology types.

Background
EGFR tyrosine kinase inhibitors (TKIs) showed great survival benefit in the selected patients with stage IV non-small cell lung cancer (NSCLC) harboring TKI-sensitive EGFR mutations. Assuming that if the cases were properly selected, EGFR-TKIs would be integrated into treatment paradigms of stage III NSCLC as more effective systemic therapy, we designed this study to evaluate the efficacy and toxicity of erlotinib and chemotherapy in the combined-modality treatment of unresectable stage III NSCLC patients according to EGFR mutation status.

Methods
Patients over 18 years with unresectable stage IIIA (N2) or stage IIIB NSCLC, ECOG performance status 0–1, and adequate organ function are eligible. The mutational analysis of EGFR (exon 18–21) is performed using direct sequencing in tissue sample. EGFR mutation-positive patients initially receive 3 cycles of erlotinib and then are treated by concurrent chemoradiotherapy (CRT) with either erlotinib (Arm A) or irinotecan-cisplatin (IP) (Arm B). After CRT, patients in Arm A receive consolidation therapy with 6 cycles of erlotinib while those in Arm B are observed until progression. EGFR mutation-negative or unknown patients are treated either with 3 cycles of IP followed by CRT with IP (Arm C) or vice versa (Arm D). Erlotinib is given at 150mg daily with 3-week cycle. IP is given with cisplatin 30mg/m[2] (day 1 and 8) and irinotecan 60mg/m[2] (day 1 and 8) during radiotherapy (total 60 Gy/ 2.4 Gy/fr) or with cisplatin 30mg/m[2] (day 1 and 8) and irinotecan 65mg/m[2] (day 1 and 8) during induction or consolidation therapy with 3-week cycle. The primary endpoint is response rate (RR), toxicity, and survival estimation. Erlotinib and irinotecan were provided by Roche Korea and Pfizer, Inc., respectively

Results
From February 2008 to February 2013, 62 patients were screened and 50 patients were randomized into Arm A (n= 6), Arm B (n= 4), Arm C (n= 19), and Arm D (n= 21). The EGFR mutation status was positive in 10 (20.0%) patients, negative in 23 (46.0%), and unknown in 17 (34%). The median age was 65 years. The proportion of never smoker and adenocarcinoma histology was 80% (event/ total No. = 8/10) and 90% (9/10) in the EGFR mutation-positive group, 13% (3/23) and 48% (11/23) in the EGFR mutation-negative group, and 6% (1/17) and 18% (3/17) in the EGFR mutation-unknown group. The median follow-up time was 34.7 months (range, 3.8−53.8 months). The completion rate of planned treatment was 66.7% (4/6), 100% (4/4), 78.9% (15/19), and 76.2% (16/21) from Arm A to Arm D. For induction therapy, the RR to elrotinib of the EGFR mutation-positive group was 70.0% (7/10). Moreover, the subgroup harboring TKI-sensitive EGFR mutations (exon 19 deletion and exon 21 L858R mutations) showed the RR to erlotinib of 87.5% (7/8). The RR to IP induction therapy was 41.7% (5/12) in the EGFR mutation-negative group, 0% (0/4) in the EGFR mutation-unknown group, and thus 31.1% (5/16) in the EGFR mutation-negative or unknown patients.

Conclusion
The combined-modality treatment by molecular diagnostics was feasible in stage III NSCLC and accrual is ongoing.

Background
The addition of treatment predicitive biomarkers and the sequencing of treatments should effect outcomes in terms of survival and cost. in NSCLC. Clinical trials are expensive in time and resources. Generally one biomarker and a treatment at a particular sequence is tested in a clinical trial. Estimating the cost benefit of combining biomarkers and sequencing of treatment in a computer model as a teaching tool and for the design of trials would be useful. The adaption of a STATA model into a Filemaker program suitable for use on a personal computer or tablet would provide greater use for this modelling.

Methods
A decision analysis model in STATA 9 has been adapted to run on Filemaker which can be run on an IPAD. Biomarkers used in the model are histology and Epidermal Growth Factor Receptor mutation status . The model uses reported response rates and disease free survival for platinum doublet, erlotinib, Pemetrexed and Vinorelbine. Two trials of two hundred patients are created half are treated with a platinum agent first followed by treatments selected using no additional biomarker information. The other half are treated using the best suitable treatment as informed by knowing the biomarker information where 75% of the patients have Adenocarcinoma and 15% are EGFR mutation positive. Costs for treatments and the use of biomarker are used to establish cost benefits.

Results
The modelling has 5.9 months improved survival for Adenocarcinomas for the use of biomarkers but no significant improvement for Squamous cell cancer. The added cost per life year saved for the arm which used histology and EGFR1 mutation testing to control the sequence of therapy from first to fourth line therapy was $37,401.

Conclusion
The model showed a meaningful educational and design of a trial outcome for managment of NSCLC. The result was specific for the parameters in the model but can be adapted quickly to investigate other hypothesis. The adaption to Filemaker a data tool suitable for tablets should allow clinicians, students and researches to access the modelling to simulate other senarios.

Background
The subgroup analyses in several phase III trials have suggested that overall survival after platinum-doublet chemotherapy in elderly patients with non-small cell lung cancer (NSCLC) can be similar to those in younger patients. The combination of carboplatin (CBDCA) with pemetrexed (PEM) is expected as a suitable treatment for carefully selected elderly patients with advanced non-squamous (non-Sq) NSCLC.

Methods
Patients with ≥75 years, PS of 0-1, chemotherapy-naïve advanced non-Sq NSCLC were enrolled in this study. They received escalated doses of CBDCA at AUC 4 (cohort 1) or AUC 5 (cohort 2) and PEM 500 mg/m[2] every 3 weeks for six cycles. Dose escalation was decided by dose-limiting toxicity (DLT) occurred in the first cycle of chemotherapy. Study protocol stipulated that additional number of patients, up to maximum of 20 patients, was enrolled to receive the recommended dose of study treatment. The primary objectives were to evaluate feasibility and determine the recommended dose of this combination.

Results
A total of 20 patients (6 patients in cohort 1, 14 patients in cohort 2) were enrolled in this study. Median age was 77 (range 75-83). No DLTs were observed in the patients with cohort 1 and the first 6 patients of cohort 2 during the first cycle of chemotherapy, thus the combination of PEM 500 mg/m[2] plus CBDCA at AUC 5 was determined as the recommended dose. Median number of cycles was 4 (range 1-6). The major toxicities were neutropenia, thrombocytopenia and anemia. During the entire period of study, 2 and 5 patients needed to have platelet transfusion and RBC transfusion, respectively. Liver dysfunction, fatigue and anorexia were also common, but these were generally manageable. Six partial responses and 9 stable diseases were observed, giving an overall response rate of 30% and a disease control rate of 75%. Median progression-free survival time was 4.8 months (95% CI, 4.1 – 5.4 months).

Conclusion
The combination of PEM 500 mg/m[2] plus CBDCA at AUC 5 was determined as the recommended dose. This combination therapy is generally tolerable, and may have encouraging antitumor activity in chemotherapy-naïve elderly patients with advanced non-Sq NSCLC.

Background
Pemetrexed, a multi-targeted antifolate, requires supplementation with folic acid and vitamin B~12~ prior to its first administration in order to reduce toxicity. The lead-in time for this vitamin supplementation is advised to be at least seven days on the drug package insert. Previous studies suggested that parenteral vitamin B~12~ pervades the major organs in 24 hours, while oral folic acid supplementation usually takes much longer than seven days to correct folic acid deficiency. We hypothesized that the lead-in time for vitamin supplementation can be shortened to 24 hours, enabling earlier administration of standard chemotherapy and potential avoidance of treatment alterations due to rapid disease progression before starting chemotherapy. Since only a few retrospective analyses related to early initiation of pemetrexed have been conducted, the first prospective study evaluating shortened vitamin supplementation for pemetrexed-based chemotherapy was planned.

Methods
A multicenter, single-arm phase 2 study was conducted. Patients with advanced non-squamous non-small cell lung cancer were enrolled. Major eligibility criteria were adequate organ function, performance status 0-1, no symptomatic brain metastasis, and no prior cytotoxic chemotherapy. Patients who had provided written informed consent were administered 1000 μg of vitamin B~12~ by intramuscular injection and started taking 350-500 μg of folic acid per day. Cisplatin (75 mg/m[2]) plus pemetrexed (500 mg/m[2]) therapy was commenced 24-48 hours after vitamin B~12~ injection and repeated for four cycles unless disease progression or unacceptable toxicity was observed. The primary endpoint was the proportion of patients experiencing neutropenia ≥grade 3. Thirty patients were to be accrued to detect the difference between the expected 30% of patients with neutropenia ≥grade 3 and the null hypothesis of 50%, using a two-stage design with 70% power and 5% alpha. Clinical trial registry number UMIN000006546.

Results
From November 2011 to March 2013, 31 patients were enrolled. Their median age was 66 years (range, 34-74 years), with 32% female. Most patients had adenocarcinoma (87%) and stage IV disease (90%). Performance status was 0 in 16 (52%) and 1 in 15 (48%) patients. Of the 30 patients who started chemotherapy within 48 hours from vitamin administration, 21 (70%) patients completed four cycles of cisplatin/pemetrexed therapy. Six (20%) patients discontinued chemotherapy due to disease progression, and the treatment of three (10%) patients was stopped due to adverse events. No treatment-related deaths or grade 4 toxicity occurred. Grade 3 neutropenia was observed in 7% (95%CI, 2-21%) of patients. Other grade 3 toxicities were anemia (two patients), decreased white blood cell count, diarrhea, thromboembolic event, hypertension, and myocardial infarction (one patient, respectively). The plasma homocysteine level before vitamin administration, a marker for vitamin B~12~ and/or folate deficiency, was elevated in four patients, but none of the patients experienced grade 3 toxicities. The response rate and the disease control rate of chemotherapy were 43% (95%CI, 27-61%) and 77% (95%CI, 59-88%), respectively.

Conclusion
This study met its primary endpoint. Absence of relationship between baseline homocysteine levels and toxicities of chemotherapy suggests the efficacy of short-term vitamin supplementation. A pragmatic study with a larger cohort that can detect uncommon toxicities is being conducted.

Background
1st line PEM+CIS induction chemotherapy (CT) followed by PEM maintenance and 1st line BEV-based CT followed by BEV maintenance offer clinical benefit (progression-free and overall survival; PFS and OS) in NS-NSCLC. This study explored efficacy and safety of 1st line induction PEM+CIS+BEV followed by maintenance PEM+BEV.

Methods
Patients with advanced NS-NSCLC and ECOG performance status (PS) 0-1 were planned to receive 4 cycles PEM 500 mg/m[2], CIS 75 mg/m[2], BEV 7.5 mg/kg, given every 3 weeks. In the absence of progressive disease (PD) and in the case of ECOG PS 0-1, patients could continue on PEM+BEV until PD or unacceptable toxicity. All patients received vitamin supplementation as per PEM label. Primary endpoint was PFS; secondary endpoints included OS, response rate and toxicity. PFS without Grade (G)4 toxicity was additionally assessed.

Results
109 patients were enrolled in 5 countries. Characteristics: median age 61 years, males/females 59/41%, ECOG PS 0/1 54/46%, stage IIIB/IV 9/91%, adenocarcinoma 91%. 72 patients (66%) received maintenance CT. Overall median (maximum) number of cycles were 8(34) for PEM+BEV and 4(4) for CIS. Median PFS was 6.9 months (90% CI 5.7, 8.3). Table 1 summarizes efficacy data; Table 2 presents G1-4 adverse event (AE) data, including AEs of special interest regarding BEV. 2 patients died from study-drug related toxicity (GI hemorrhage, pneumonia aspiration; during induction CT). Figure 1 Figure 2

Conclusion
In this study of PEM+CIS+BEV induction CT followed by PEM+BEV maintenance, median PFS was 6.9 months. The addition of BEV to PEM-CIS induction and PEM maintenance was associated with acceptable and expected toxicities. Main G3/4 toxicities included neutropenia and fatigue, hypertension was less common.

Background
Besides chemotherapy, E is another option in NSCLC pts especially in those with EGFR mutations. Elderly pts enrolled in trials are fit without cM, but in clinical practice most suffer from cM.

Methods
Medical records of 1221 pts diagnosed with NSCLC between 2008-2012 were screened. We examined pts ≥75 yrs for demographics, clinical data and Tx details.

Results
233/1221 NSCLC pts received E at any line. 53/233 (23%) were ≥75 yrs old. Male:female ratio was 34:19 and median age 79 yrs (range 75-88). NSCLC subtypes included 31 adenoca, 8 squamous cell, 9 NOS and 5 others. 50/53 pts had cM (≥2 in 46 pts, 1 in 4pt). Main cM were cardiovascular disease (n=41), COPD (n=14), other cancer (n=10) and diabetes (n=8). 8 pts were tested for EGFR mutations (5 -ve, 3 +ve). Performance Status was satisfactory (ECOG 0-1) in 8 pts and poor (2-3) in 45pts. 8pts were treated with E 100mg and 45 pts with E 150mg (12 pts needed dose reduction). Complete follow up data were found in 46pts. Mean duration of treatment was 79 days (range 9-662). 35/46 pts experienced side effects (s.e) [rash n=29, diarrhea n=17] which led to treatment discontinuation in 12pts. Pts with abnormal creatinine clearance (n=13) were more likely to stop treatment due to s.e (6/13 versus 6/33). 17/46 pts (37%) achieved disease control (5 PR, 12 SD) and a time to progression (TTP) of 157 days (range 106-662, 95% CI 132.79-270,74) while 22/46 pts had PD as best response (TTP 49d, range 19-88, CI 44,67-64,97). 7pts were not evaluable (stopped Tx due to s.e). All EGFR+ve pts had disease control (2PR, 1SD).

Conclusion
E is a valuable option in elderly NSCLC patients with co-morbidities, especially if they harbor EGFR mutations. Impaired renal function might be associated with propensity to side effects and earlyTx discontinuation.

Background
In Surgically Resected Non–Small Cell Lung Cancer,a previous study has shown ratio of maximum standardized uptake value to primary tumor size is a more important indicator of prognosis than SUVmax alone. The objective of this study was to assess the prognostic value of patients with advanced non-small cell lung cancer (NSCLC). We have investigated whether SUVmax to tumor size ratio is associated with response to first-line therapy and survival in advanced Non–Small Cell Lung Cancer.

Methods
A retrospective review of 186 consecutive patients who had a pretreatment 18F-FDG PET/CT done before receiving first-line therapy for advanced(III/IV) non-small cell lung cancer (NSCLC) was performed. Response was assessed by CT Response Evaluation Criteria in Solid Tumors (RECIST) at after every two cycles or emerge symptoms relate to disease progression . Overall survival(OS), progression-free survival (PFS), and post-progression survival(PPS) were Recorded. Primary tumor maximum standardized uptake value (SUVmax)、primary tumor size were all derived from the PET/CT data. Survival curves stratified by median SUVmax and SUVmax to tumor size ratio by the Kaplan-Meier method and statistical differences were assessed using the log-rank test. Multivariate proportional hazards (Cox) regression analyses were applied to test the SUVmax’s and SUVmax to tumor size ratio’s independency of other prognostic factors for the prediction of survival.A retrospective review of 186 consecutive patients who had a pretreatment 18F-FDG PET/CT done before receiving first-line therapy for advanced(III/IV) non-small cell lung cancer (NSCLC) was performed. Response was assessed by CT Response Evaluation Criteria in Solid Tumors (RECIST) at after every two cycles or emerge symptoms relate to disease progression . Overall survival(OS), progression-free survival (PFS), and post-progression survival(PPS) were Recorded. Primary tumor maximum standardized uptake value (SUVmax)、primary tumor size were all derived from the PET/CT data. Survival curves stratified by median SUVmax and SUVmax to tumor size ratio by the Kaplan-Meier method and statistical differences were assessed using the log-rank test. Multivariate proportional hazards (Cox) regression analyses were applied to test the SUVmax’s and SUVmax to tumor size ratio’s independency of other prognostic factors for the prediction of survival.

Results
Total 186 patients were enrolled into the current study. Median OS was 14.9 m (range, 3.1–64.0 m), PFS was 5.6 m (range, 0.8–41.1 mo), and PPS was 7.9m(range, 0–51.3 m). The statistical analysis data indicated that Low pretreatment SUV≤7.9(P=0.026), and SUVmax to tumor size ratio＜2.2(0.000) were associated with response to first-line therapy. Clinical response was independent prognostic factors for PFS (OR= 3.152, P=0.000), low stage(Ⅲ) was associated with PPS independently, with OR=1.700, P= 0.027,and for OS, low SUVmax to tumor size ratio(OR= 1.764, P=0.027), tumor diameter (OR= 1.743, P=0.013)and clinical response(OR= 1.678, P=0.002) were all independent prognostic factors.

Conclusion
The ratio of SUVmax to tumor size may be a more important indicator of prognosis than SUVmax alone in patients with NSCLC.

Background
Survival benefits of pemetrexed for advanced non-squamous non-small cell lung cancer (NSCLC) have been demonstrated in both switch- and continuation-maintenance settings after platinum-based induction. A phase III trial (PARAMOUNT) comparing pemetrexed maintenance with best supportive care after 4 cycles of induction pemetrexed plus cisplatin in non-squamous NSCLC patients demonstrated benefits both in progression-free-survival (PFS) and overall survival (OS) by pemetrexed continuation-maintenance. However, it remained undetermined whether pemetrexed could improve survival when it was continued to administer after carboplatin plus pemetrexed induction. We conducted a phase II study to evaluate the efficacy and safety of this regimen.

Methods
Thirty-four chemonaïve patients with stage IIIB/IV or postoperative recurrent non-squamous NSCLC received carboplatin (area under the concentration-time curve 6 mg/mL/min, day 1) plus pemetrexed (500 mg/m[2], day 1) every 3 weeks. Non-progressive patients after 4 cycles of induction received pemetrexed maintenance (500 mg/m[2], day 1) every 3 weeks until disease progression or unacceptable toxicity. The primary objective was to investigate 1-year survival rate. Secondary objectives were to investigate the safety, the objective response rate (ORR) during induction chemotherapy and PFS, defined as the time from enrollment to disease progression or death.

Results
From December 2009 to March 2011, a total of 34 patients were enrolled. The median follow-up time was 20.9 months (range, 2 to 32.3). At the time of the data collection, 19 patients were dead, 13 still alive, 2 lost follow-up. Twenty-five patients (73.5%) completed induction and 22 patients (64.7%) received maintenance therapy. The 1-year survival rate was 70.3% (95% CI, 53.0 to 83.2). The 2-year survival rate was 45.5% (95% CI, 28.7 to 63.5). The median PFS and OS were 5.2 months (95% CI, 4.1 to 8.2) and 23.0 months (95% CI, 15.5 to not available) from enrollment in all 34 patients, in addition 9.0 months (95% CI, 5.2 to 12.1) and 24.3 months (95% CI, 17.8 to not available) from the start of maintenance therapy in 22 patients who proceeded to maintenance therapy. The objective response rate and the disease control rate were 32.4% and 88.2%. The incidental rates of grade 3 or more severe adverse events were low except for one case of grade 5 pneumonitis. A multivariate analysis of 21 patients who received maintenance therapy with any tumor regression showed that the longer time to the best response achievement, positive epidermal growth factor receptor mutation status and better Karnofsky performance status contributed to achieve longer PFS.

Conclusion
Pemetrexed continuation-maintenance following pemetrexed plus carboplatin induction is a promising treatment for chemonaïve patients with advanced non-squamous NSCLC because of its good efficacy and less cumulative toxicities. This regimen could be substitutable for pemetrexed continuation-maintenance following cisplatin-based induction.

Background
Chemotherapy drugs have still the major disadvantage of non-specific cytotoxic effects. Although, new drugs targeting the genome of the tumor are already on the market, doublet chemotherapy regimens still remain the cornerstone of lung cancer treatment. Novel modalities of administration are under investigation such as; aerosol, intratumoral and intravascular.

Methods
In the present study five chemotherapy drugs; paclitaxel, docetaxel, gemcitabine, carboplatin and cisplatin were nebulized with three different jet nebulisers (Maxineb[®], Sunmist[®], Invacare[®]) and six different residual cups at different concentrations. The purpose of the study was to identify the ``ideal`` combination of nebulizer-residual cup design-drug-drug loading for a future concept of aerosol chemotherapy in lung cancer patients. The Mastersizer® 2000 was used to evaluate the aerosol droplet mass median aerodynamic diameter.

Results
The drug, nebulizer and residual cup design greatly influences the producing droplet size (p<0.005, in each case). However; the design of the residual cup is the most important factor affecting the produced droplet size (F=834.6, p<0,001). The drug loading plays a vital role in the production of the desired droplet size (F=10.42, p<0.001). The smallest droplet size was produced at 8ml loading (1.26μm), while it remained the same at 2, 4 and 6 mls of drug loading.

Conclusion
The ideal nebulizer would be Maxineb[®], with a large residual cup (10 ml maximum loading capacity) and 8 mls loading and the drug with efficient pulmonary deposition would be docetaxel.

Background
Platinum-based chemotherapy (PBC) yields clinical benefit in some but not all patients with advanced NSCLC. All patients eventually become resistant to treatment. We assessed degree and timing of onset of tumor regression (TR) and tumor growth (TG) as a surrogate indicator of sensitivity and resistance patterns.

Methods
In 130 NSCLC patients on PBC, we assessed percent change in tumor diameter (TG or maximum TR on treatment) compared to pre PBC, and also assessed incremental percent further TR or TG in serial scans compared to the most recent prior scan on treatment.

Results
Of the 130 patients, 32 (25%) had intrinsic resistance, with TG at 1[st] repeat scan after 2 cycles of PBC. Only 1 patient with initial TG had later TR on PBC. Among those with TR at 1[st] re-evaluation, pattern of onset of acquired resistance varied: 81 had a 2[nd] repeat scan after 4 cycles of PBC, of whom 20 (25%) had TG. Of 41 patients with earlier TR who then had a 3[rd] repeat scan <4 weeks post PBC cycle 6, 13 (32%) had TG compared to prior scans. In 76% of those with TR, the greatest TR compared to most recent prior scan was seen at the first re-evaluation, with TG or a lower percent TR on later scans. 26 patients had progressive further TR over each of >4 re-evaluation scans, of whom 11 had initial rapid TR at 1[st] re-evaluation, with subsequent more gradual further TR over later scans (a pattern that we designated as “Incremental TR pattern 1”). The other 15 patients with progressive TR over >4 re-evaluation scans had modest initial TR followed by greater TR on a later scan (a pattern that we designated as “Incremental TR pattern 2”). By Spearman coefficients, maximum percent TR from pre PBC (with TG coded as a negative value for TR) correlated with OS (r=0.46, p<0.0001), time to progression (TTP) (r=0.69, p<0.0001) and post-progression survival (PPS) (r=0.30, p=0.001). OS also correlated with TTP (r=0.63, p<0.0001), and PPS correlated with TTP (r=0.44, p<0.0001), and with OS (r=0.95, p<0.0001). Median OS was 11.0 months, and varied with TR pattern (p<0.0001): for patients with first TG at 1[st], 2[nd], 3[rd] and 4[th] repeat scans, median OS was 5.9, 10.8, 10.5 and 15.1 months, respectively. Median OS was 18.2 months in patients with “Incremental TR pattern 1”, and was 30.5 months in patients with “Incremental TR pattern 2”. Median OS with RECIST partial response (23% of patients), minor TR (52%), minor TG (13%) and RECIST progressive disease (13%) was 16.9, 12.4, 9.8 and 4.0 months, respectively (p<0.0001).

Conclusion
Intrinsic resistance was noted in 25% of patients. Degree of TR vs TG and patterns of intrinsic and acquired resistance correlated strongly with OS, TTP and PPS, with longest median OS in patients with “Incremental TR pattern 2”. Our observations require confirmation. While numerous biological factors correlate with resistance preclinically, it remains unclear which are most relevant clinically, and it is also unclear what factors may be responsible for the different patterns of clinical resistance observed.

Background
Lung cancer is the leading cause of cancer mortality in the Czech Republic. Approximately 80%are NSCLC and 65% of patients have advanced disease at the time of diagnosis. Most patients who receive first-line chemotherapy experience disease progression within 3 to 6 months of initiating therapy and the median survival time observed is 8 to 10 months. In this situation, there is a need to find effective therapeutic regimen with an administration as simple as possible and the most favorable toxicity profile. The purpose of this study was to evaluate the activity and feasibility of CBDCA together with full oral vinorelbin (NVBO).

Methods
Patients with advanced NSCLC received NVBO 80 mg/m² on D1 and D8 with CBDCA AUC5 on D1 every three weeks. In stage III, chemotherapy was followed by external radiotherapy. The outcomes include following: response, median overall survival (mOS) and median progression free survival (mPFS). Response was assessed by imaging techniques after 4-6 weeks of treatment and was confirmed one month later by chest X-ray and/or CT scanning. The difference in response relative to baseline characteristics was determined using Pearson Chi-square test. Differences in OS and PFS relative to baseline characteristics were evaluated for significance using Log-rank test.

Results
396 patients were treated: 311 men (78,5) and 50 women (21,5%), median age 65 years. ECOG performance status at inclusion was PS 0 in 51 (12,9% patients, PS 1 in 287 (72,7%) and PS 2 in 57 (14,4%) patients. Most patients had stage IIIB 116 (29,3%) and stage IV NSCLC 257 (64,9), only 32 (5,84%) were stage IIIA . Adenocarcinoma was confirmed in 90 patients (22,7%), squamous-cell carcinoma in 238 (60,1%), large-cell carcinoma 11 and other in 57 (17,2%). Complete response was confirmed in 2 (0,5%) patient, partial response in 136 (34,3%), stable disease in 104 (26,3%), 154 (38,9%) patients progressed. The regimen was well tolerated. Median cycles was 4, the dosage of NVBO was without changes in 268 (67,7%) patients, the dosage of NVBO was reduced in 28 (7,1%) and escalated in 77 (19,48%). In 23 (5,8%)of patients was the dosage of NVBO reduced after escalation. Major toxicities (Grade 3-4) were neutropenia in 29%, leucopenia in 20,8%, anemia in 3,3% and thrombocytopenia in 1,8% patients. Febrile neutropenia was observed in 6,1% patients. Gastrointestinal toxicity grade 3-4 was observed in 4,6% patients. The mPFS was 7,4 moths and mOS was 9,92 months by median follow-up 8,5 months. The differences between groups of pts according to PS (0+1 vs. 2) were statistically significant (p < 0,001) better for patiens with PS 0+1. The differences between groups of pts according histology were not statistically significant (p=0,3975).

Conclusion
In this group of 396 unselected patients with advanced NSCLC was the treatment with full NVBO and-CBDCA in first line more convenient and well tolerated with evidence of high antitumour activity. This combination was active in all groups patients according histology (mOS was 9,92 and mPFS was 7,4 months). Statistically significant better were the results in patients with PS 0+1.

Background
Pemetrexed in combination with cisplatin in the first-line treatment of advanced non-squamous NSCLC (non-smal-cell lung cancer) has been administered in the Czech Republic since 10/2010. The purpose of this study was to evaluate the activity and feasibility of pemetrexed in first-line treatment of NSCLC in combination with cisplatin.

Methods
Patients with advanced non-squamous NSCLC were treated with pemetrexed in first line and in combination with cisplatin between 10/2012 and 03/2013 in 12 institutions. Retrospective analyses were carried out to assess the effectiveness of treatment and applied regimens, and to evaluate the safety of targeted therapy. The outcomes include following: response, median overall survival (mOS) and median progression free survival (mPFS). Response was assessed by imaging techniques after 4-6 weeks of treatment and was confirmed one month later by chest X-ray and/or CT scanning. The difference in response relative to baseline characteristics was determined using Pearson Chi-square test. Differences in OS and PFS relative to baseline characteristics were evaluated for significance using Log-rank test.

Results
Out of 233 treated patients, 125 were men (53.6%) and 108 were women (46.4%). At the time of treatment initiation with pemetrexed, the following characteristics were recorded. The median age of patients was 61 years. 97 patients (41.6%) were smokers, 72 patients (30.9%) were former smokers, 64 patients (27.5%) were non-smokers. Performance status (PS) was 0 in 53 patients (22.7%), 1 in 172 patients (73.8%) and 2 in 8 patients (3.4%). Adenocarcinoma) was confirmed in 226 patients (97.0%), large-cell carcinoma was reported in 7 patients (3.0%). Most of the patients were diagnosed in stage IV (186 patients, 80.2%) and treatment of most patients was also initiated in stage IV (84.5%). As on the date of data analysis (18 March 2013), treatment was terminated in 185 patients (79.4%), and the median duration of treatment in these patients was 12.1 weeks. Adverse effects during treatment with pemetrexed were reported in 73 patients (31.3%). Complete response was achieved in 4 patients (1.7%), partial response in 58 patients (24.9%), stable disease in 79 patients (33.9%) and progressive disease in 38 patients (16.3%); treatment response was not evaluated in 54 patients (23.2%). Median overall survival (OS) starting from treatment initiation with pemetrexed was 11.6 months (95% CI: 7.0; 16.3). Median progression-free survival (PFS) starting from treatment initiation with pemetrexed was 4.2 months (95% CI: 3.4; 5.1).

Conclusion
In a group of 233 patients with advanced non-squamous NSCLC who were treated with pemetrexed in first line and in combination with cisplatin, the therapy was well tolerated: termination of treatment due to adverse events was reported only in 3.8% of patients. Median overall was 11.6 months, median progression-free survival was 4.2 months

Background
Currently, there are no standard cytotoxic treatments for non-small-cell lung cancer (NSCLC) patients beyond third-line or further line therapy. Previous studies of amrubicin in patients with previously untreated advanced NSCLC in succession demonstrated an overall response rate of 18.3-27.9%, and a median survival time of 8.2-9.8 months. Accordingly, amrubicin was equivalent to anticancer agents such as taxanes, gemcitabine, vinorelbine, and pemetrexed in terms of single-agent activity against NSCLC. The purpose of this study was to evaluate the efficacy of amrubicin monotherapy as a salvage treatment in heavily pretreated NSCLC patients.

Methods
The records of NSCLC patients who received amrubicin monotherapy as a third or later line of chemotherapy at a Kitasato University Hospital between January 2009 and December 2012 were retrospectively reviewed. Amrubicin was administered to patients by intravenous injection in a dose of 35 mg/m[2] or 40 mg/m[2] daily on 3 consecutive days, and cycles were repeated at 3-week intervals.

Results
There were 36 patients who met the inclusion criteria. Their median number of prior chemotherapy was 4 (range: 2 to 7), and the median number of cycles of chemotherapy per patient was 4 (range: 1 to 9). Grade 3 or 4 hematologic toxicities included neutropenia (61.1%), leukopenia (58.3%), thrombocytopenia (22.2%), and anemia (11.1%). Febrile neutropenia occurred in 8 patients (22.2%). Non-hematologic toxicities were mild. Treatment related death was not observed. The overall response rate, median progression-free survival time, and median survival time were 8.3%, 1.7 months, and 6.3 months, respectively. Progression-free survival time was the same, 1.7 months, in both the 35 mg/m[2] dose group and the 40 mg/m[2] dose group.Figure 1Figure 2

Conclusion
Amrubicin exhibits modest activity and acceptable toxicity when used as a third or later line of chemotherapy for advanced NSCLC.

Background
Erlotinib and docetaxel are approved in second line treatment of advanced NSCLC. Concomitant administration of a tyrosine kinase inhibitor (TKi) of EGFR with standard chemotherapy in first line did not improve survival compared to chemotherapy alone. Preliminary studies support a possible efficacy of sequential administration of EGFR TKi and chemotherapy. Objective: This open randomized phase II trial (Tarseq) was designed to assess the efficacy and tolerability of second-line sequential erlotinib plus docetaxel in advanced NSCLC.

Methods
Patients were randomized (1/1, stratified by center, disease status: recurrent or refractory (no response observed after 4 cycles of first-line chemotherapy))between sequential erlotinib 150 mg/d (day 2-16) + docetaxel (75 mg /m2 d1- 21) (arm A) versus docetaxel (75mg/m2 d1) alone (arm B) until disease progression or unacceptable toxicity. Primary endpoint was the rate of patients with progression-free survival at 15 weeks (PFS15) ; second endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and tolerability. Main eligibility criteria were advanced NSCLC, EGFR wild type or unknown, performance status 0 to 2, failure of first line cisplatin based chemotherapy; main exclusion criteria were more than 2 lines of treatment, previous anti-EGFR or docetaxel treatment. Statistical analysis was based on a Simon’s optimal two stage design . The primary endpoint is rejected if the number of efficacy is less 33 over 66 pts (25+ 41) at the end of the two stages.

Results
147 patients were randomized by 33 centers: median age: 60 ± 8 years, PS 0/1/2 (44/83/20 pts) ; male: 78%, EGFR status: wild type 66%, unknown: 34%; recurrent patients: 65% (arms A/B :66%/65%), nonsquamous: 86% (arms A/B : 84%/90%), smoking status: smokers 35%, formers 57,5%, never 7,5%. Baseline characteristics were balanced between 2 arms. In ITT, the primary objective was not meet with 18/66 pts without progression at 15 weeks in arm A, 17 /66 pts in arm B. In arm A and B, median PFS was 2,2 (CI95% 1,6-2,8) and 2,5 (CI 95% 1,7-2,8) months and median OS was 6,6 (CI 95% 4,3-10,3) and 8,4 (CI 95% 4,5-11,3) months respectively. Toxicity was acceptable in both arms with 60.2 % and 54% of G3/4 toxicity in arms A and B, respectively.

Conclusion
The sequential combination of erlotinib with docetaxel did not demonstrate any benefit in second-line treatment of EGFR wild type or unknown advanced NSCLC, despite acceptable toxicity. The Pharmacological hypothesis of synergism between erlotinib given sequentially and standard chemotherapy is not confirmed in the present study. Clinical trial information: NCT01350817 / Supported by an academic grant from Roche, Chugai, Sanofi Aventis,with the help of clinical research direction ( Limoges University Hospital)

Background
EGFR-TKIs’ mono-therapy is one of the standard 1[st] line therapy for NSCLC harboring EGFR gene mutations. Although platinum doublet ± bevacizumab recommended for 2nd line therapy after failing EGFR-TKIs in National Comprehensive Cancer Network guideline, there is little information of these setting. Therefore, we planned prospective phaseⅡ study to evaluate the efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel(PCB) for EGFR-TKIs resistant Non-Sq NSCLC.

Methods
In multicenter phase II trial, we recruited non-squamous NSCLC harboring EGFR gene mutation after failing EGFR-TKIs. Key eligibility criteria were as follows: Non-Sq NSCLC with EGFR mutation, failure of 1[st] line EGFR-TKIs, stageIIIB or IV or recurrence after surgery, measurable lesion, age 20 or over, ECOG Performance status (PS) 0 or 1, adequate organ function. Clinically significant hemoptysis, symptomatic brain metastasis, uncontrollable hypertension, interstitial pneumonia were excluded. Patients received carboplatin (AUC=6/5), paclitaxel (200mg/m2), bevacizumab (15mg/kg) intravenously on day1 every 3 weeks for three to six cycles, and bevacizumab was administered every 3 weeks until disease progression or intolerable toxic effects. Primary endpoint was response rate (RR) and secondary endpoints were progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety.

Results
A total of 31 patients were assigned between March 2010 and February 2013. One patient was excluded because of unfitted eligibility criteria. Therefore, we analyzed thirty patients’ data. Median age was 60 years (45~74), male/female : 11/19, PS 0/1 : 9/21, non-smoker/smoker : 18/12, EGFR mutation status exon19 del/exon21 L858R : 20/11, 1[st] line EGFR-TKIs gefitinib/erlotinib/other : 22/7/1. RR : 40% (95%CI:22%-58%), DCR : 83% (95%CI:70%-97%), PFS : 6.0 month (95%CI:4.8-12.2). Major severe adverse event (Grade 3,4) were one patient with dyspnea (G4), 6 with fever neutropenia (G3) and 3 patients with hyper tension (G3). There was no grade 5 adverse event.

Conclusion
In patients with Non-Sq NSCLC harboring EGFR gene mutation failed 1[st] line EGFR-TKIs, RR of 2[nd] line PCB therapy was lower than it was in 1[st ]line phase II study of PCB in Japan, but same RR of E4599 study. Safety was similar to previous reports. We considered PCB therapy is one of the treatment option in 2[nd]-line for patient with EGFR-TKIs resistant Non-Sq NSCLC.

Background
The platinum doublet is standard first-line therapy in advanced NSCLC. Over the past decade, well tolerated second-line therapies have been approved including erlotinib and pemetrexed. We hypothesize that the introduction of less toxic chemotherapy has increased treatment of advanced NSCLC resulting in improved survival.

Methods
The BC Cancer Agency provides cancer care to a population of 4.5 million. A retrospective review was conducted of all referred Stage IIIB/IV patients in four 1 yr time cohorts; C1 baseline (1998) and 6 months after the provincial approval of C2 docetaxel (2001), C3 erlotinib (2006) and C4 pemetrexed (2007).

Results
2, 623 patients were referred and 720 had systemic therapy. Characteristics: M/F 55%/45%, median age 67 (33-101), ECOG <=1/>=2/unknown 33%/56%/11%, never/former/current/unknown smoker 9%/35%/36%/20%, squam/nonsquam/NOS 18%/41%/41%. More patients received first line chemotherapy over time; 16%, 23%, 34%, 33% C1-4 respectively. In C1 to C4 uptake of second line (21%, 27%, 38%, 55%) and third line (10%, 10% 14%, 18%) increased. In C1 the most common first line doublet was cis/vino (70%) and in C4, cis/gem (45%). Second line doce was frequently used in C2 (51%) but usage decreased in C4 to 7% vs. erlo 50% and pem 26%. In the >=70 group (n=1118), 1[st] line usage increased from C1 9% to C4 19% and 2[nd]line in the C2 (doce) 4% to C4 (erlo+pem avail) 56%. The increased use of systemic therapy was associated with improved survival in all patients: C1 4.56 m vs C4 4.98 m (p=0.004) and treated patients; C1 9.48 m vs C4 12.07 m (p=0.014) and the >= 70 group; C1 9.7 m vs C4 12.5 m (p=0.07).

Conclusion
This population-based data set represents the trend of treatments over time in a large geographical area, including community and tertiary care cancer treatment sites. The introduction of less toxic systemic therapy for advanced NSCLC resulted in an increased proportion of patients treated with first-line chemotherapy and an even greater increase in 2nd/3rd line treatment. This trend was particularly evident in the elderly. Associated with this was a significant improvement in overall survival for all subsets.

Background
Gefitinib yields a longer progression-free survival (PFS) period than platinum-doublet chemotherapy as a first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) activating mutation, but most patients develop resistance against gefitinib after the initial response. We hypothesized that the insertion of platinum-doublet chemotherapy during the initial response could prevent the emergence of acquired resistance and prolong survival, compared with gefitinib monotherapy.

Methods
We performed a phase II study of the following first-line treatment for patients with advanced NSCLC with EGFR mutation. Gefitinib (250 mg) was administrated on days 1-56. After a two-week rest, three cycles of cisplatin (80 mg/m[2]) and docetaxel (60 mg/m[2]) were administered on days 71, 92, and 113. Gefitinib was re-started on day 134 and was continued until progression. The primary endpoint was the two-year PFS rate. The sample size was estimated at 33, and this treatment was considered worthy for further development if more than 11 of the 33 patients who started treatment had a 2-year PFS.

Results
Thirty-three Japanese patients were enrolled. Twenty-five patients could recieve the second gefitinib, 12 achieved a PFS period of over 2 years, and 7 continued to receive the protocol treatment without experiencing progression. The 1-, 2-, and 3-year estimated PFS rates were 67.0%, 40.2%, and 36.9%, respectively, and the median PFS time was 19.5 months. The 1-, 2-, and 3-year estimated survival rates were 90.6%, 71.9%, and 64.8%, respectively, and the median survival time had not been reached at the time of analysis. Treatment-related deaths and unexpected severe toxicities were not seen.

Conclusion
Our results indicated that first-line treatment consisting of gefitinib and inserted cisplatin plus docetaxel is promising in patients with advanced NSCLC with EGFR mutation. A phase III study of this treatment compared with gefitinib monotherapy is warranted.

Background
Conventionally, the role of chemotherapy in brain metastases (BM) from non-small cell lung cancer (NSCLC) remains limited. However, some cases in which brain metastases (BM) are responsive to Pemetrexed (PEM) have been recognized recently.

Methods
We conducted a retrospective analysis of 74 advanced NSCLC patients who had received PEM-containing regimens in our institution from January 2006 to May 2013.

Results
Twenty-seven patients had been diagnosed as having BM before starting chemotherapy of PEM-containing regimens. The patient characteristics were: male/female = 12/15; median age (range) = 63 (25-85) years; smoking status: ever/never = 13/14; performance status: 0/1/2 = 0/26/1; histology: adenocarcinoma/NSCLC-NOS = 26/1; EGFR mutation status: positive/negative/unknown = 12/12/3; prior EGFR-TKI therapy: yes/no = 13/14 ; response to prior EGFR-TKI: CR/PR/SD/PD = 1/8/3/1. Fourteen patients had received any local treatments for BM, consisting of 7 whole brain radiotherapy (WBRT), 6 stereotactic radiotherapy (SRT), 2 stereotactic radiosurgery (SRS) and 2 brain surgery. The PEM-containing regimens administered were; CDDP+PEM/CBDCA+PEM/PEM alone = 2/9/16. The lines of chemotherapy was; 1st/2nd/3rd/4th or later = 5/7/9/6. They received the chemotherapy for a median cycle of 3 cycles (range 1-15). The overall response rate (ORR) was 14.8% (4/27) in total and the cranial response rate regarding BM was 14.8%(4/27), consisting of 1 CR and 3 PR. Of 13 patients who received prior EGFR-TKI, the cranial response rate was 23.1% (3/13). Of 17 patients without any prior local treatments for BM or with disease progression of BM after the prior local treatment, the cranial response rate was 23.5% (4/17).

Conclusion
The PEM-containing regimens might be a promising therapy for asymptomatic BM in NSCLC including those who showed resistance to EGFR-TKI.

Background
The main purpose of chemotherapy in patients of non-small cell lung cancer (NSCLC) is similar in both physician and patients, prolonging survival time and improve quality of life. But, priority of the criteria for selection of regimen is different. To investigate types of systemic anticancer therapy in patients with NSCLC, to describe regimen-wise characteristics of patients’ clinical profile, and to examine factors influencing the selection of regimen.

Methods
This observational study was conducted at 19 study centers in Korea from June 2008 to July 2010. Patients above 18 years of age with histologically confirmed NSCLC stage IIIa, IIIb, or IV, who received systemic chemotherapy for lung cancer for the first time and were willing to provide written consent, were included in the study. Descriptive statistics were performed on the data collected.

Results
In total, 435 patients were included and evaluated in the study. Docetaxel (85.1%) was the most common drug prescribed followed by carboplatin (46.4%) and cisplatin (37.9%). Across regimens, no difference in the distribution of patients for tumor-node-metastasis stage, histology of the disease as well as previous chemotherapy and radiation therapy was observed. Of all the reasons for selecting chemotherapy, efficacy as measured by disease free survival/overall survival was reported as being “most important” in the highest proportion (28.1%, 122/435) of patients.

Conclusion
For the physicians, the first priority of regimen selecting chemotherapy was efficacy, different from patients’ perspective, adverse effects. We should evaluate this again in the era of new drugs with less side effects.

Background
In several clinical trials, first line combination chemotherapies with bevacizumab (Bev) have been reported to improve clinical outcomes in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC). Although Bev was approved for NSCLC in autumn of 2009 in Japan, there are not enough data regarding the efficacy and toxicity with Bev treatment in real-world clinical practice in Japan. We have evaluated the efficacy and safety of the combination chemotherapy with Bev in patients with non-sq NSCLC at four major hospitals in Shinjuku area, Tokyo, Japan.

Methods
From August 2010 to July 2012, 102 patients planned to treat with Bev was prospectively enrolled in this study with written informed consent. Eligible patients were histlogically or cytologically documented non-sq NSCLC with advanced stage (IIIB-IV) or recurrence, ECOG-PS 0-2, and adequate organ function for cytotoxic chemotherapy. Patients received Bev (15mg/kg, every 3 weeks) plus any chemotherapy (physician’s choice) followed by maintenance Bev. The primary endpoints were safety and efficacy (PFS). Patients were treated at four major hospitals (three university hospitals and one national center) participating in Shinjuku Thoracic Oncology Group (STOG).

Results
Patients characteristics: median age (range) 64 (36-85) years, male/female = 60/42, clinical staging: IIIB/IV/post-operation recurrence/others ＝ 8/77/15/1, ECOG-PS 0/1/2 = 66/34/2, adenocarcinoma/others = 98/4, non-smoker/smoker = 40/60, EGFR mutation (+)/(-)/unknown ＝ 43/56/3, 1[st ]line /2[nd] line />=3[rd] line ＝ 56/23/23, Bev combination regimen: CBDCA+PEM/ CDDP+PEM/ CBDCA+PTX/ others ＝ 40/22/18/22. At the time of April 2013, median Bev administration number (range) was 7 (1-29) in total; 7.5 (1-29) in 1[st] line, 8 (1-24) in 2[nd] line, 7 (1-21) in >= 3[rd] line. With evaluable 102 cases, response rate (RR) was 39.2%, disease control rate (DCR) was 90.2%, median PFS was 321 (95%CI: 195-410) days (10.6 months (M)). Median overall survival was not reached. RR, DCR, and PFS were 46.4%, 96.4%, 10.9M with 1[st] line, 39.1%, 87.0%, 9.1M with 2[nd] line, 21.7%, 78.3%, 9.3M with >= 3[rd] line. Hematological toxicities (>=G3): leucocytopenia 24%, neutropenia 40%, anemia 8%, thrombocytopenia 5%, febrile neutropenia 3%. Bev related adverse events (>=G3): Hypertension 28%, proteinuria 5%, thromboembolism 5%, hemosputum 1%. There was no treatment related death.

Conclusion
Combination chemotherapy with Bev was effective for the patients with non-sq NSCLC in real-world clinical practice in Japan, as similar or superior efficacy as clinical trials. Also, adverse events were well tolerated. The efficacy was good at 1[st] line and also at 2[nd] line and thereafter.

Background
This study was designed to determine the recommended dose of carboplatin-pemetrexed in elderly(≧70 years old), chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer. Also, we measured the blood level of pemetrexed in order to explore significant factors associated with toxicity or efficacy.

Methods
The patients were treated with carboplatin and pemetrexed every three weeks from 4 to 8 cycles. The dose of the anticancer drug escalated according to protocol.

Results
Grade 3 infection was observed as DLT at a dose of carboplatin AUC 5 and pemetrexed 500 mg/m[2], and we determined this phase as a recommended dose. Overall response rate was 15.3%, and the disease control rate was 76.9% in all cases. The median duration of progression-free survival was 3.9 months. The AUC of pemetrexed was associated with hematotoxicity, but not the efficacy. We observed that renal dysfunction induced high blood concentration of pemetrexed.

Conclusion
The combination of carboplatin AUC5 and 500mg/m[2] of pemetrexed is promising for elderly chemo-naïve patients with advanced non-squamous NSCLC, but dose reduction of pemetrexed may be required for patients with renal dysfunction in further study.

Background
For patients with postoperative recurrent non-small cell lung cancer (NSCLC) harbouring mutations of the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitor, such as gefitinib, is frequently used in clinical practice, in accordance with the treatment for patients with stage IV NSCLC. However, it is unclear whether there is a difference in effect of gefitinib between patients with postoperative recurrent NSCLC and patients with stage IV NSCLC, harbouring EGFR mutations.

Methods
We reviewed consecutive patients with postoperative recurrent or stage IV (at diagnosis) NSCLC harbouring EGFR mutations, who were treated with gefitinib at the Shizuoka Cancer Center between September 2002 and March 2012. The clinical data of the patients were obtained from their medical records, and retrospectively reviewed. The baseline patient characteristics, response to gefitinib, and survival were compared between patients with postoperative recurrent NSCLC (postoperative group) and patients with stage IV NSCLC at diagnosis (stage IV group). Patients were not included if they had received other EGFR tyrosine kinase inhibitors before administration of gefitinib.

Results
A total of 169 patients met the eligibility criteria for this study (postoperative group; 50, stage IV group; 119). The baseline characteristics (sex, age, histology, EGFR mutations status, prior cytotoxic chemotherapy) were well balanced between both groups, with the exception of performance status (PS). Patients in postoperative group had better PS than those in stage IV group (p = 0.044). At the start of treatment with gefitinib, bone and liver metastases were more common in stage IV group (p = 0.002 and p = 0.032), and pulmonary metastases were more common in postoperative group (p = 0.004). There was no significant difference in number of metastatic sites between two groups. The response rate of gefitinib in postoperative group was similar to that in stage IV group (58 vs 61%, p = 0.685). In contrast, progression free survival (PFS) (median PFS 16.7 vs 9.8 months, p < 0.001) and overall survival (OS) (median OS 63.3 vs 23.9 months, p < 0.001) were significantly longer in postoperative group than in stage IV group. Additionally, postoperative recurrent disease, PS (0-1) and single metastatic site were independent prognostic factors in the multivariate analysis of survival.

Conclusion
PFS and OS were superior in patients with postoperative recurrent NSCLC harbouring EGFR mutations treated by gefitinib than in those with stage IV disease. These results suggest, postoperative recurrent disease may be considered to be a stratification factor in clinical trial for NSCLC with EGFR mutations.

Background
In advanced non- small cell lung cancer (NSCLC), second-line chemotherapy (second-CT) after the progression of the first-line platinum-based chemotherapy (first-CT) is the standard of care. More recently, maintenance therapy after the first-CT has been reported to be beneficial. However, its impact on overall survival appears to be marginal or negligible, when most patients could receive timely active second-CT after progression. The purposes of this study are to investigate the proportion of those who actually received the second-CT, and to elucidate factors associated with its administration in advanced NSCLC patients.

Methods
From April 2010 to September 2011, patients with advanced NSCLC who received platinum-based first-CT at 30 institutions in Japan were enrolled in this prospective observational study. Baseline characteristics, regimens and responses to the first-CT, presence or absense of the second-CT administration, and if not administered, its reasons were recorded. This is an interim report describing patients with at least 6 months of follow up. This study was supported by the Public Health Research Center Foundation CSPOR and registered at UMIN#000006393.

Results
A total of 865 eligible patients with advanced NSCLC provided patient characteristics and details of the first-CT. Median age was 65 (range: 24-86), proportion of patients with adenocarcinoma/squamous/NOS/others were 70/20/8/2%, and with EGFR mutant/wild/unknown were 10/60/30%. Platinum compound used in the first-CT were: cisplatin in 38.3% of the cases, carboplatin in 57.9%, and nedaplatin in 2.8%. Of the patients with non-squamous histology, 24% received bevacizumab. At the time of cut off, 797 patients were assessable for response of the first-CT. Among them, 225 patients had either disease progression or inadequate data (NE) to the first-CT and 572 patients were evaluated CR/PR/SD; 194 (22%) received maintenance therapy, including bevacizumab. Of the 572 patients, 51 have no disease progression after the first-CT, and data are not yet available in another 13. Therefore, 508 patients were further analyzed for the administaration of the second-CT. Among those, 132 patients (26%) failed to receive the second-CT. The reasons for not receiving were as follows: declined PS, 79 (60%); patient refusal, 28 (21%); death of any cause, 6 (5%); loss of follow-up and others, 19 (14%). Explorative analysis of association between characterisics and administration of the second-CT revealed age (<65 vs ≥65, odds ratio [OR], 0.59; 95% CI, 0.39-0.90, p=0.01), PS (0 vs 1-4, OR 0.33, 95% CI 0.22-0.53, p<0.0001), and smoking status (never vs ever, OR 0.47, 95% CI 0.26-0.85, p=0.01) as possible factors.

Conclusion
Preliminary results of this large observational study in Japan suggested that around one-fourth of the patients missed an opportunity to receive appropriate the second-CT. Further investigation is needed to clarify optimal management of the patients after the first-CT, particularly on how to identify the patients that would be less likely to receive the second-CT after disease progression and thus would be more likely to receive benefit from maintenance therapy strategy.

Background
The addition of BV to cytotoxic agent(s) prolonged survival for non-Sq NSCLC patients (pts). However, there is no definitive evidence for the cytotoxic agent(s) plus BV is superior to the cytotoxic agent(s) alone for elderly non-Sq NSCLC. We conducted the feasibility study of PEM plus BV as the first-line treatment for elderly advanced or recurrent non-Sq NSCLC.

Methods
Major eligibility and exclusion criteria were followings; chemotherapy-naïve; unfit for bolus combination chemotherapy; stage III/IV or relapsed non-Sq NSCLC; age≥70; PS 0-1; no evidence of brain metastasis; no history of hemoptysis and irradiation for thorax. PEM (500mg/m[2]) and BV (15mg/kg) were administrated intravenously on day 1 every 3 weeks. The primary endpoint was toxicity and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the percentage of pts who completed more than 3 cycles.

Results
From November 2010 to April 2012, total 12 pts were enrolled. Patients characteristics were following; Male/Female=6/6; Median age (range) 78 (72-81); Histology was all adenocarcinoma; Activating EGFR mutation No/Yes/unknown=9/2/1; Stage IIIB/IV/Recurrence=2/8/2; ECOG PS 0/1=6/6; Smoking History Yes/No=6/6. Severe toxicities (Grade 3≥) were leukopenia (25%), neutropenia (25%), anemia (8%), thrombocytopenia (8%), febrile neutropenia (8%), anorexia (8%), hypertension (8%), fatigue (8%), nausea (8%), and perforation (colon) (8%). No dose-limiting toxicity and treatment-related death was occurred. Three patients achieved PR and the ORR was 25%. The median PFS and OS were 5.6 months (mo) (95% C.I. 1.1-7.9 mo) and 10.3 mo (95% C.I. 6.9-15.6 mo) in 11 evaluated pts, respectively. The 1-year survival rate was 49% (95% C.I. 12-79%). Seven of 12 pts (58%) received more than 3 cycles.

Conclusion
PEM plus BV as first-line treatment for elderly non-Sq NSCLC was well tolerable and promising.

Background
Cystatin C has often been used as a marker of renal function and rarely is influenced by muscle mass, whereas the Creatinine/cystatine C ratio (Cr/CysC) is influenced by muscle mass. However, it is unknown if the Cr/CysC ratio can be used as a predicitive marker for adverse side effects of chemotherapy. The aim of this study is to if the Cr/CysC ratio can be used as a predictive marker for adverse effects of chemotherapy.

Methods
We measured cystatin C levels in 25 patients with either non-small cell cancer (NSCLC) or small cell lung cancer (SCLC) as a marker of renal function at the initial commencement of chemotherapy and conducted a retrospective comparative study utilizing the Cr/CysC ratio and clinical data.

Results
Patient characteristics were as follows: median age = 67 years (age range 54-84 years; age 70 ≤ 10 out of 15 cases); male:female = 23:3; NSCLC:SCLC = 18:7; ECOG PS 0-1:2 = 22:3. Epidermal growth factor receptor (EGFR) genetic mutation was observed in one case, was not present in 13 cases, and the remaining 11 cases were unknown. Twenty two cases were in the first line therapy, and 3 cases were in the second line therapy. The ratio of platinum-based combination to single agent therapy was 20:5 cases. NSCLC patients with toxicity grades over 3 had hematological toxicity (n = 4, 22.2%) and non-hematological toxicity (n = 3, 16.7%). All SCLC patients with toxicity grades over 3 had hematological toxicity (n = 7, 100%) while non-hematological toxicity wasn’t present (n = 0, 0%). There were no significant differences between the Cr/CysC ratios in patients > 70 years. There was a highly significant difference in the Cr/CysC ratios in patients with NSCLC and patients with SCLC (0.92 vs 0.78, p < 0.05). There was significant difference between Cr/CysC ratios in patients with toxicity grade over 3 and under 2 (0.84 vs 0.70, p＜0.05), and this trend was also shown in the confined platinum-based combination therapy group (0.85 vs 0.69, p < 0.05).

Conclusion
The Cr/CysC ratio could prove useful as a predictive marker for adverse effects of chemotherapy in patients with NSCLC.

Background
Pemetrexed and docetaxel represent the reference treatments as second line chemotherapy for pts with aNSCLC after failure of a platinum-based treatment, with a response rate (RR) < 10%. However, non-squamous aNSCLC pts could have received pemetrexed into the first line setting and docetaxel may present a relevant side effects burden, in both 3-week and weekly schedules. wPCT is a well tolerated drug which proved to be active in aNSCLC. In the attempt to improve pts compliance we adopted wPCT in the daily practice.

Methods
From January, 2010, all pts with aNSCLC progressing after platinum-based chemotherapy and eligible for further chemotherapy received wPCT at 80 mg/sqm for 6 consecutive weeks, followed by a 2-week rest. In absence of clinical evidence of progressive disease at least two courses of wPCT were planned before instrumental re-staging. Responders pts continued the treatment up to a maximum of 4 courses.

Results
From January, 2010 to October 2012 a consecutive series of 43 pts was treated with wPCT. The median age was 62 yrs (range 32-74); all but two presented metastatic disease at the diagnosis. Thirty-three, 5, and 5 pts received wPCT as second, third and fourth line treatment, respectively. Five pts received only 1 wPCT course, 30 pts 2 courses, 3 pts 3 courses, and 5 pts 4 courses, for a total number of 94 administered courses. wPCT was well tolerated: only 2 pts experienced a grade 3 toxicity (1 pt liver and 1 pt diarrhea). No toxicity-related treatment interruptions were recorded. Nine pts (21%) achieved a partial response and 9 a stable disease. After a median follow-up of 9 mos, the median PFS and OS were 4 and 11 mos, respectively. The 1-y OS was 30.2%.

Conclusion
From our experience wPCT in daily clinical practice may represent a reasonable chemotherapeutic option for pre-treated aNSCLC pts, with a manageable toxicity profile, and may provide disease control rates comparable to those of docetaxel and pemetrexed.

Background
Erlotinib might benefit non-small cell lung cancer (NSCLC) patients with EGFR wild-type (WT) genotype based on the subgroup analysis of the BR21 trial and SATURN trial. However, the sensitivity of methods for detection of EGFR mutation can influence the evaluation of erlotinib efficacy. We conducted CJLSG0903 trial, a phase II study of erlotinib for previously treated EGFR WT NSCLC patients screened by peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp method. The efficacy and safety results of CJLSG0903 were previously reported at the ESMO meeting 2012. Here we present the final results of EGFR mutation reanalysis and KRAS mutation screening by S-ARMS method.

Methods
Stage IIIB or IV NSCLC patients were eligible. EGFR mutation status was screened by PNA-LNA PCR clamp method, which is known to be a highly sensitive. Primary endpoint was objective response rate (ORR). Oral erlotinib 150 mg was given daily until progression or unacceptable toxicity.

Results
From February 2010 and April 2012, 53 evaluable patients were enrolled. ORR was 11.3% (95% confidence interval: 4.3–23.0%). We performed preplanned reanalysis of EGFR mutation status and KRAS mutation by Scorpion ARMS (S-ARMS) methods if remaining samples from participants were available. Samples from 26 patients (49%) were available for EGFR mutation reanalysis. Only one patient who achieved partial response (PR) was EGFR mutation positive (exon 19 deletion). In 25 patients, EGFR WT genotype was reconfirmed by S-ARMS method. Two of them achieved PR. ORR was 8.0 % in patient with EGFR WT genotype confirmed by both PNA-LNA PCR clamp and S-ARMS methods. Samples from 42 patients (79%) were available for KRAS mutation screening. KRAS mutations were detected in 4 of 42 patients, and progressive disease (PD) was observed in all of KRAS mutation positive patients.

Conclusion
Erlotinib still shows activity in patients with EGFR WT genotype confirmed by two different highly sensitive methods. Activating KRAS mutation might be negative predictive factor for erlotinib efficacy in patients with EGFR WT genotype. (UMIN Clinical Trials Registry: UMIN000002692)

Background
The epidermal growth factor receptor (EGFR) gene mutation has been reported as an important predictive factor for EGFR-tyrosine kinase inhibitor (TKI) efficacy in NSCLC. In "The Lung Cancer Diagnosis and Treatment Guideline published by The Japan Lung Cancer Society 2012 edition", the EGFR gene mutation is strongly recommended to be analyzed in deciding the treatment policy of advanced non- squamous cell carcinoma. In addition, it is known that the EGFR gene mutation is frequently observed in adenocarcinoma (Ad), but very rare in squamous cell carcinoma (Sq). Efficacy of EGFR-TKI in EGFR gene mutation positive Sq has not examined enough.

Methods
We obtained tumor samples from 50 patients diagnosed as Sq (excluded Ad-Sq carcinoma) by two or more pathologist between January 2008 to March 2013. The EGFR gene mutation status was determined by PCR-Invader assay (BML Incorporation) and direct sequencing method.

Results
EGFR gene mutations were detected in 2 of 50 (4%) samples. Common characteristics of two patients were male, elderly, high level of CEA, and good PS. One patient was an on-smoker and the other was a heavy smoker. The type of the EGFR gene mutation was both exon 21 point mutation. Gefitinib was administered to two patients and PRs were observed. Their progression-free-suvival were 9 months and 20 months.

Conclusion
The frequency of the EGFR gene mutation in Sq was low. However, it was suggested that gene mutation positive Sq is responded to EGFR-TKI. It is necessary to analyze the EGFR gene mutation in Sq.

Background
Compared with younger patients, elderly NSCLC patients are often considered unfit for standard chemotherapy due to increased chemotherapy-related toxicity, more comorbidities, and the consequent deterioration in patient quality of life. Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has demonstrated survival benefits with good tolerability in previously treated NSCLC patients regardless of EGFR mutation status. Erlotinib has become a standard treatment for this indication. As it is well tolerated compared with cytotoxic agents, erlotinib is also expected to be a valid treatment option for previously treated elderly NSCLC patients. This analysis of the POLARSTAR surveillance study compared the efficacy and safety of erlotinib treatment for elderly versus non-elderly patients.

Methods
From December 2007 to October 2009 all recurrent/advanced NSCLC patients in Japan treated with erlotinib were enrolled onto the POLARSTAR surveillance study. Erlotinib efficacy and safety data were analyzed by age group: Group A <75 years; Group B 75–84 years; and Group C ≥85 years. Kaplan–Meier methods were used to estimate median progression-free survival (PFS). All adverse event reports were collected and graded using the NCI-CTCAE version 3.0 and coded using MedDRA version 14.1.

Results
Of 9,909 patients evaluated, 9,907 were eligible for safety assessment (Group A, n=7,848; Group B, n=1,911; Group C, n=148). Baseline characteristics (including histology, smoking status and performance status [PS]) were well-balanced between groups. Non-hematologic toxicities are shown (Table). Grade 1–4 hematologic toxicities (neutropenia/leukopenia/anemia/thrombocytopenia) were observed at <1.0% in each group. One patient had grade 5 anemia (Group A) and one patient had grade 5 thrombocytopenia (Group B). A total of 9,651 patients were eligible for efficacy assessment. The median PFS was 65 days for Group A (n=7,701), 74 days for Group B (n=1,815) and 72 days for Group C (n=135). In patients with clinical features associated with better EGFR TKI efficacy (adenocarcinoma/non-smoker/PS 0–2/second- or third-line setting/EGFR TKI naïve) the median PFS was 176 days (Group A, n=651), 213 days (Group B, n=180), and 341 days (Group C, n=14). Figure 1

Conclusion
Efficacy and tolerability of erlotinib treatment for elderly patients (≥75 years) with previously treated NSCLC was similar to that seen in younger patients. Erlotinib could be considered as standard therapy for elderly NSCLC patients in second- or later line treatment settings.

Background
Previous research demonstrated significant delays from the onset of lung cancer symptoms to diagnosis and commencement of treatment. This has potential to influence the outcome of treatment. However, the diagnosis of lung cancer is complicated by considerable overlap between lung cancer symptoms and those of other common respiratory illnesses such as COPD. We sought to evaluate the impact of education of community health professionals about lung cancer on perception of knowledge.

Methods
A web-based educational program was developed by expert panel, to disseminate information about lung cancer. Interactive small group workshops were organized within local communities targeting primary care physicians and primary care nurses involved in the initial evaluation of patients with suspected lung cancer. The web-based application covered lung cancer statistics, presenting symptoms, frequently asked questions, links to the new diagnostic assessment program, and key advances in treatment. Invitations were sent to all family physicians in the Hamilton and Haldimand regions of Ontario to attend a pilot session. Pre and post questionnaires were administered to assess the utility of the educational program. Follow up questionnaires were mailed out after six months to evaluate the value of the educational program.

Results
Education sessions were conducted in six family practice offices and one occupational health practice, involving 67 health professionals. There were 46 pre and 40 post intervention questionnaires completed (24 physicians, 10 nurses and 12 other). Responses were similar between city (n=20) and rural-based (n=26) health professionals. All respondents felt the educational session was beneficial to attend. Over 85% of respondents agreed the information was clear and easy to understand, of sufficient detail and relevant to practice. Most respondents (88%) felt they would use the web-based tool personally and 90% felt they would use it for patient education. Following the educational intervention, there was some improvement in respondents’ assessment of their knowledge about lung cancer: understanding and background knowledge about lung cancer (79% v 90%); common presenting symptoms of lung cancer (81% v 92%); understand steps needed to diagnose lung cancer (79% v 80%), standard approach to treatment of lung cancer (52% v 95%); recent advances in treatment of lung cancer (19% v 92%). Six month follow up questionnaires were sent to 45 individuals, with 31 replies. Only 4 respondents (13%) had used the web-based tool. The most commonly used section was on the treatment of lung cancer. The majority of respondents (52%) had not seen a lung cancer patient during this time period. Other reasons included for not using the program included: no need (7%), insufficient time (15%), and did not think about it (11%). Respondents’ assessment of their lung cancer knowledge was lower at six months (range 45%-80%).

Conclusion
have shown that it is feasible to implement a web-based lung cancer interventional program in family practice. This may improve short term knowledge about lung cancer, but this does not appear sustained at six months. One limitation to the utility of this program is the relative infrequency of lung cancer patients seen by individual family physicians.

Background
Oncologists use ECOG score to assess patients’ performance status (PS) and guide treatment decisions, but patients and doctors do not necessarily agree on their score. We compared ECOG scores assessed by NSCLC patients and their oncologists to determine if this has implications on treatment and survival prediction.

Methods
NSCLC patients who underwent chemotherapy in prospective inter-ethnic difference and nutrition studies at Concord Hospital were included. Patients self-assessed their ECOG score as part of the Patient-Generated Subjective Global Assessment questionnaire prior to chemotherapy. Kappa was used to assess agreement of ECOG score between patients and oncologists. Survival was calculated from date of chemotherapy, using Kaplan Meier method.

Results
79 patients (median age 63 years, 86% Stages IIIB/IV, median survival of 15.5 months) were included. ECOG scores differed in 34 (43%) cases (Table).The interrater reliability between patients and their oncologists was Kappa = 0.35 (p <0.001). Figure 1 If patient ECOG scores were used, 11 patients (14%) would be deemed unfit for chemotherapy (ECOG≥3) and 21 patients (27%) would be excluded from clinical trials (ECOG≥2). ECOG status (0 versus >0) irrespective of assessor was predictive of overall survival (18.7 vs. 12.1 months with p=0.023 and 17.4 vs. 11.1 months with p=0.017 for patient and oncologist-assessed ECOG respectively). In patients whose ECOG score was assessed to be 0 by their oncologist (n=39), a worse survival was associated with a poorer patient assessed PS (median survival 16.7 vs. 18.2 months for patient assessed ECOG >0 vs. ECOG=0 respectively; p=0.31).

Conclusion
Both physician and patient-assessed ECOG scores are predictive of overall survival. In this study, there was only fair agreement in ECOG assessed by NSCLC patients and their oncologists, with patient scores usually poorer. A number of patients would have excluded themselves from therapeutic interventions including clinical trials based on their ECOG PS rating. Patient-assessed ECOG scores of > 0 may be associated with worse survival despite their oncologist’s more optimistic scoring, a finding which may be incorporated to benefit clinical decision-making.

Background
BRCA1 serves as a differential modulator of chemosensitivity to docetaxel (doc) and cisplatin (cis). RAP80 targets the BRCA1-BARD1 E3 ligase at double-strand breaks. A Spanish Lung Cancer Group (SLCG) phase II customized chemotherapy trial (NCT00883480) indicated that RAP80 and BRCA1 jointly influenced outcome in NSCLC p treated with cis- or doc-based chemotherapy. Based on these findings, the SLCG initiated a randomized phase III trial (NCT00617656/GECP-BREC), and we have performed a parallel phase II trial comparing non-customized cis/doc with customized therapy in metastatic NSCLC p in China.

Methods
Since October 2010, 104 p have been randomized 1:3 to control and three experimental arms. p in the control arm receive cis/doc; p in the experimental arm receive treatment according to their BRCA1 and RAP80 levels: p with low RAP80, regardless of BRCA1 levels, cis/gemcitabine (gem); p with intermediate/high RAP80 and low/intermediate BRCA1, cis/doc; p with intermediate/high RAP80 and high BRCA1, doc alone. The primary endpoint is progression-free survival (PFS).

Results
PFS was 4.15 months (m) in the control and 3.59 m in the experimental arm (P=0.68). Overall survival (OS) was 10.82 m in the control and 11.74 m in the experimental arm (P=0.68). Response rate (RR) was 23.3% in the control and 32.4% in the experimental arm (P=0.48). In ancillary analyses of p with low, intermediate and high BRCA1 levels, PFS in the control arm was 2.66, 4.15 m and 7.5 m, respectively, while PFS in the experimental arm was 10.66 m, 3.45 m and 3.06 m, respectively. In the multivariate analysis including PS, treatment arm, BRCA1, RAP80, histology and smoking status, only ex-smokers were associated with an increased risk of progression (HR, 1.906; P=0.029).

Conclusion
Customized chemotherapy based on BRCA1/RAP80 expression does not improve PFS. The predictive value of BRCA1 alone seems to be stronger than that of BRCA1/RAP80 combined.

Background
Elderly patients with cancer are significantly under-represented in all clinical trials, including those for lung cancer. However, there is a general agreement that age alone cannot be the only parameter to be taken into consideration for decision making. We investigated feasibility and efficacy of palliative chemotherapy for elderly patients with lung cancer.

Methods
We reviewed medical record based on database of Jeju National University Hospital. Between January,2007, and December,2012, Elderly patients (aged 70 or more) with lung cancer who began to receive palliative chemotherapy were 28 persons. Progression-free survival(PFS) and overall survival(OS) in terms of Non-small cell lung cancer(NSCLC) and small cell lung cancer(SCLC) were investigated respectively.

Results
Median age of patients were 75 year-old (range, 70-82) and 20 patients were male. 20 patients were non-small cell lung cancer and eight patients were small cell lung cancer. In overall patients, median PFS of 1st line palliative chemotherapy and median OS were 5.0 months (95% confidence interval[CI], 4.43-9.86 months) and 18 months (95% CI, 14.99-26.80 months), respectively. In NSCLC patients, mPFS was 5.0months (95% CI, 3.77-11.23 months) and mOS was 21.5 months (95% CI, 16.63-31.21 months).In SCLC patients mPFS and mOS were 5.5 months (95% CI, 2.97-9.53 months) and 11.0 months (95% CI, 3.46-23.04 months), respectively. 19 patients with NSCLC received sequential second line chemotherapy after progresssion. median number of chemotherapy regimen they received after progression was 1 (range, 1-6, 95% CI, 0.90-2.40). There was no significant difference of survival between age group of 70-74, 75-79 and more than 80.

Conclusion
Palliative chemotherapy for elerly patients with lung cancer is feasible. Even patients aged more than 70 would expect similar survival benefit compared to younger patients.

Background
Amrubicin (AMR) is a potent topoisomerase II inhibitor, and promising agent for both small cell and non-small cell lung cancer. AMR is usually administered on days 1-3 of a 21-day course by intravenous infusion. However, it causes severe, occasionally fatal, toxicity of febrile neutropenia. Otherwise, previous trials revealed that a weekly schedule of chemotherapy had a higher dose intensity, less severe adverse effects and anti-tumor activity as effective as other treatments. We conducted a phase I study, and reported the safety and recommended dose in a weekly schedule (60 mg/m[2] weekly on 1st and 8th day with a rest on day 15).

Methods
Refractory or relapsed non-small cell lung cancer patients after 1 or 2 regimens, with older than 20 and with adequate main organ functions were eligible. AMR was administered at the dose of 60 mg/m2 weekly (on days 1 and 8 every 3weeks). Primary endpoint was objective response rate. Secondary endpoints were adverse events, progression-free survival, and disease control rate (CR, PR, and SD).

Results
Thirty-three patients were enrolled. Twelve were female, 21 were male, and their median age was 67 years (range, 38-80). Twenty-four were adeno- carcinoma, 7 were squamous cell carcinoma, and 2 were non-small cell carcinoma. One hundred twenty-nine courses were given (median: 3, range: 1-20). The objective response rate was 6.0%, and the disease control rate was 51.5%. Median follow-up time was 9.3 months, and median progression-free survival was 2.7 months. Common grade 3/4 adverse events were white blood cell decreased (63.6%), neutrophil count decreased (45.5%), anemia (15.2%), anorexia (15.2%), and fatigue (12.1%). Febrile neutropenia was noted in two patients. There was no treatment-related death.

Conclusion
Primary endpoint was not met in this study. However, weekly AMR showed high disease control rate and good tolerability. Weekly AMR is promising in refractory or relapsed non-small cell lung cancer patients.

Background
Although NSCLC patients have a very poor prognosis, they generally need a second line therapy. Studies have shown that both systemic chemotherapy and targeted therapies are useful in this setting. To determine the patients who would get benefit from second line therapy may increase the success rate of the treatment. In this multicenter study, we aimed to evaluate the parameters that determine the benefit of second line treatment in NSCLC.

Methods
Records of NSCLC patients who received second line systemic therapy in 11 centers from Turkey were evaluated retrospectively. Age, gender, histological subtype, stage at diagnosis, performance status, serum hemoglobin level, serum lactate dehydrogenase level, response to first line therapy, platinum sensitivity, and progression free survival after first line therapy were investigated whether they have any role in detecting the usefulness of second line therapy. Additionally, PFS and OS after second line therapy were analyzed.

Results
Overall, the data of 904 patients (31% female and 75% < 65 years old) were evaluated. Median follow up was 13 (2-197) months. The rate of adenocarcinoma, squamous cell carcinoma, and NSCLC-NOS were 47%, 32%, and 23%, respectively. At diagnosis, 22% of patients had stage 3B, and 78% had stage 4 disease. Single agent docetaxel was preferred the most as a second-line therapy (21%). The survival analysis showed that median PFS and median OS were 4 months (SE: 0.2; 95% CI: 3.6-4.3), and 7 months (SE:1: 95% CI: 6-8), respectively. In univariate analysis, performance status, normal hemoglobin level, having stage 3B at diagnosis, response to first line therapy, and PFS of 3 months or longer after first line therapy were found to be significant for overall survival after second line therapy (p values <0.05). In multivariate cox regression analysis, good performance status, normal hemoglobin level, and response to first line therapy were independent prognostic factors for survival (p<0.0001, p<0.0001, and p=0.001, respectively).

Conclusion
Our findings revealed that second-line therapy is beneficial in patients who have good performance status and who responded to the first-line therapy. Detecting the parameters that predict the usefulness of second-line therapy may increase the success rate and guide the selection of patients for this therapy.

Background
Treatment of EGFR mutated NSCLC p with EGFR TKIs in phase III trials has shown improved efficacy to standard chemotherapy.However, it can be difficult to obtain sufficient tumor tissue for analysis of EGFR m status in a large proportion of p. Nevertheless,so far,no data exists for NSCLC p treated according to EGFR m status in serum alone.

Methods
We reviewed our database to identify EGFR mutated p, excluding those for whom status was available in both serum and tissue.We analyzed p treated with an EGFR TKI for whom EGFR mutation status was known in serum only(status in tissue unknown due to insufficient material).At the same time, we reviewed p in whom EGFR m status in tissue was available over the same period in order to compare clinical characteristics and efficacy parameters,PFS,ORR and Overall Survival(OS). EGFR m analysis was performed in cell free circulating DNA(cfDNA)isolated from serum and plasma using the QIAmp DNA blood mini kit.

Results
9 p with EGFR m detected in serum and 33 p with EGFR m in tissue were included. In EGFR mutated p in serum, median age 63; male 55.6%; non-smokers 33.3%; former smokers 44.4%; ECOG PS 0-1 66.7%; adenocarcinoma 77.8%; deletion19 33.3%, L858R 66.7%; EGFR TKI treatment in 1st line 44.4%; 2nd or 3rd line 55.6%. ORR: complete response (CR) 22.2%; partial response (PR) 22.2%; stable disease (SD) 22.2%; progressive disease (PD) 11.1%. 2p had poor PS and died prior to evaluation. mPFS 4.7 months (mo). mOS 18 mo. In p with EGFR m in tissue, median age 61; male 36.4%; non-smokers 75.8%; former smokers 24.2%; adenocarcinoma 87.9%; deletion19 75.8%; L858R 24.2%; 1st line 54.5%; 2nd or 3rd line 45.5%. ORR: CR 15.2%; PR 57.6%; SD 12.1%; PD 15.2%. mPFS 8.9 mo. mOS 32.7 mo. The multivariate analysis for OS considering EGFR m in serum differed according to PS (PS 0-1 16.6 mo vs PS > 2 5.2 mo)

Conclusion
Obtaining sufficient tissue from NSCLC p for analysis of EGFR m status and other molecular alterations can be difficult. Determination of EGFR m in serum alone is feasible, yields similar results to mutation status in tissue, and could permit us to take treatment decisions.

Background
The study aimed to compare overall survival and hospitalization rates for Medicare patients diagnosed with advanced nonsquamous non-small cell lung cancer (NSCLC) and treated with first-line bevacizumab-carboplatin-paclitaxel (BCP) vs. carboplatin-paclitaxel (CP).

Methods
Patients aged ≥65years first diagnosed with nonsquamous NSCLC stage IIIB/ IV between 2006 and 2009 and treated with first-line BCP or CP therapy were identified in the SEER-Medicare database that links cancer registry and Medicare claims data from United States. Outcomes were measured from the treatment initiation date to the end of data availability on 12/31/2010 for hospitalizations and 12/31/2011 for survival. Survival and hospitalization rates are reported from Kaplan-Meier analyses over the follow-up period. Bootstrap methodology was used to test treatment groups differences in median time to death and first hospitalization. Age-stratified survival analyses were conducted using age 75 as a cut point. Inpatient utilization rates are also reported per 100 patient-days for each treatment group and compared in terms of incidence rate ratios (IRR) estimated from negative binomial models adjusted for potential confounders.

Results
Of 1,706 patients, 592 (34.7%) received BCP and 1,114 (65.3%) received CP by inclusion criteria, while 692 (40.6%) were ≥75 years of age. Patient characteristics were balanced between arms for age, sex, disease stage. The BCP group had fewer pre-treatment comorbidities, greater proportion of adenocarcinoma histology, and differences in ethnicity, SEER region, and income compared to the CP group. The median survival time was 10.5 months in the BCP group vs. 8.4 months in the CP group (2.1 months difference, p=0.0007). The difference in median overall survival favoring BCP over CP groups was 1.3 months for patients aged 65-74 years (p=0.11), and 3.3 months for those aged ≥75years (p=0.006). At 6-months and 1 year of follow-up, survival rates for all subjects were, respectively, 70.3% and 43.8% of BCP patients vs. 60.6% and 37.0% of CP patients. After 1 year of follow-up, 69.5% of BCP vs. 75.1% of CP had ≥ 1 hospital admission. Hospitalization rates were significantly lower for BCP patients (adjusted IRRs: 0.82, p=0.003 and 0.77, p=0.002 for hospital admission and hospitalization days). The difference in median time to first hospitalization was 2.1 months (p <.0001). Additional statistics are presented in the Table. Figure 1

Conclusion
In this retrospective analysis of updated SEER-Medicare data, first-line therapy with BCP was associated with longer median survival and reduced hospitalizations compared to CP in patients > 65 years of age.

Background
In a phase III trial, JMDB, the subgroup of patients with nonsquamous histology showed a significant improvement in survival after treatment with first-line pemetrexed + cisplatin (pem 500 mg/m[2] + cis 75 mg/m[2] every 21 days for a maximum of 6 cycles). In PARAMOUNT, a double-blind, placebo-controlled, phase III trial, 539 patients with advanced nonsquamous NSCLC and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 were randomized to maintenance pem or placebo after completing 4 cycles of pem+cis without disease progression.

Methods
We compared patients from the two randomized arms of PARAMOUNT with a selected homogeneous population from JMDB: 346 patients with advanced nonsquamous NSCLC and an ECOG PS of 0 or 1 who completed at least 4 cycles of pem+cis without disease progression. Efficacy outcomes included overall survival (OS) and progression-free survival (PFS) measured from the start of treatment with pem+cis and analyzed by Kaplan-Meier and Cox methods. Rates of toxicities were calculated without formal statistical comparison.

Results
Outcomes for the JMDB homogeneous group were similar to the PARAMOUNT placebo arm (PFS: 6.24 vs 5.59, p=0.117; OS: 14.23 vs 13.96, p=0.979). The PARAMOUNT pem group had statistically superior efficacy compared with the JMDB homogeneous group (PFS: 7.46 vs 6.24 p<0.00001; OS: 16.89 vs 14.23 p=0.003). Patients who received pem maintenance displayed numerically higher incidences of drug-related serious adverse events (SAEs) compared with JMDB patients who received ≥4 cycles of pem+cis (10.6% vs 2.9%); grade 3/4 anemia and fatigue were higher in the pem arm of PARAMOUNT. A comparable number of patients (approximately 2/3) on both arms of PARAMOUNT and on JMDB received post-discontinuation systemic therapy (PDT). Results are summarized in Table 1. Table 1: Summary of survival, post-discontinuation systemic therapy , and selected drug-related adverse events in the PARAMOUNT pem and placebo arms and the JMDB homogeneous group

	PARAMOUNT pem arm (n=359)	PARAMOUNT placebo arm (n=180)	JMDB homogeneous group (n=346)
PFS
Median (95% CI), mos	7.46 (6.90-8.57)	5.59 (5.45-5.95)	6.24 (5.91-6.54)
Cox unadjusted HR (95% CI)	0.66 (0.56-0.77)*	0.86 (0.72-1.04)**
Unadjusted log-rank p-value	<0.00001*	0.117**
OS
Median (95% CI), mos	16.89 (15.77-18.99)	13.96 (12.88-15.51)	14.23 (12.94-15.05)
Cox unadjusted HR (95% CI)	0.75 (0.63-0.91)*	1.00 (0.81-1.24)**
Unadjusted log-rank p-value	0.003*	0.979**
Received any PDT, n %	231 (64.3)	129 (71.7)	207 (59.8)
Patients with ≥1 drug-related SAE, n (%)	38 (10.6)	8 (4.4)	10 (2.9)
Hematologic grade 3/4 toxicities, n (%)
Anemia Hemoglobin decreased Hemoglobin	16 (4.5) 2 (0.6) 0 (0.0)	2 (1.1) 0 (0.0) 0 (0.0)	0 (0.0) 0 (0.0) 10 (2.9)
Neutropenia Neutophils/granulocytes	17 (4.7) 0 (0.0)	0 (0.0) 0 (0.0)	0 (0.0) 18 (5.2)
Nonhematologic grade 3/4 toxicities, n (%)
Fatigue	11 (3.1)	2 (1.1)	5 (1.4)

*PARAMOUNT pem arm vs JMDB homogeneous group; **PARAMOUNT placebo arm vs JMDB homogeneous group. Abbreviations: PDT=post-discontinuation systemic therapy; PFS: progression-free survival; OS: overall survival; SAE: serious adverse event

Conclusion
The PARAMOUNT placebo arm showed results consistent with the JMDB homogeneous group treated with pem+cis. The addition of pem continuation maintenance treatment results in a statistically significant increase in OS and PFS. Although there was an increase in the incidence of grade 3/4 toxicities with longer exposure to pem+cis or maintenance pem, the overall incidence remains low, underscoring the relative safety of these treatment regimens.

Background
Identification of predictive factors is critical for appropriate selection of patients and chemotherapy regimen. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C significantly improved ORR (primary endpoint; 33% vs 25%, P = 0.005), with a trend toward improved OS and PFS in patients with advanced NSCLC. nab-P/C vs sb-P/C was associated with less severe peripheral neuropathy, arthralgia, and myalgia, but more anemia and thrombocytopenia. This exploratory analysis examined the correlation between several key patient and clinical factors and clinical outcomes with nab-P/C vs sb-P/C.

Methods
Patients with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on d 1, 8, 15 or sb-P 200 mg/m[2] d 1 q21d; both arms received C AUC 6 d 1 q21d. ORR and PFS were assessed by blinded, centralized review. P values for ORR were based on chi-square test, and those for OS and PFS were based on log-rank test. Factors, including sex, age (< 70 and ≥ 70 y), histology (squamous and nonsquamous), stage (IIIB/IV), and geographic region (North America, Eastern Europe, and Asia/Pacific), baseline ECOG score, smoking status, diabetes, body mass index, number and location of metastatic sites, were analyzed for association with outcomes; of these, the first 5 were prespecified stratification factors for the trial.

Results
The hazard ratio (HR)/risk ratio favored nab-P/C for ORR, PFS, and OS for most factors analyzed. Significant quantitative treatment-by-predictive factor interactions were noted for several key factors, including number of metastatic sites, diabetes, histology, and age, with respect to outcomes, and the comparative treatment effect was maintained in all other subgroups. In patients with ≥ 4 metastatic sites, significant treatment differences favoring nab-P/C were noted for ORR (response rate ratio [RRR] 3.40; P = 0.003) and OS (HR 0.562; P = 0.009) and trended in favor of nab-P/C for PFS (HR 0.735; P = NS). In patients with diabetes, significant treatment differences favoring nab-P/C were noted for ORR (RRR 1.935; P = 0.046) and PFS (HR 0.416; P = 0.016) and trended in favor of nab-P/C for OS (HR 0.553; P = NS). In patients with squamous NSCLC, significant treatment differences favoring nab-P/C were noted for ORR (RRR 1.68; P < 0.001) and trended in favor of nab-P/C for OS (HR 0.890; P = NS). In patients ≥ 70 y, significant treatment differences favoring nab-P/C were noted for OS (HR 0.583; P = 0.009) and trended in favor of nab-P/C for ORR (RRR 1.385; P = 0.196) and PFS (HR 0.687; P = NS). No treatment differences significantly favoring sb-P/C were observed.

Conclusion
A trend toward improved outcomes was noted with nab-P/C vs sb-P/C in most factors analyzed. Squamous NSCLC, diabetes, age ≥ 70 y, and ≥ 4 metastatic sites were predictive of improved outcomes with nab-P/C vs sb-P/C. These predictive factors should be taken into consideration when selecting the appropriate treatment for patients with advanced NSCLC.

Background
Several studies have suggested a correlation between development of hypertension and response to bevacizumab therapy. Most studies have suggested a prolongation of progression free survival and possibly overall survival in patients who develop emergent hypertension during therapy. Preclinical data suggests an interaction between the renin-angiotensin “RA” system and the vascular endothelial growth factor (VEGF) system. This interaction between the two systems may lead to activation of the RA system when the VEGF system is inhibited. Studies have suggested an activated RA system induces a pro-proliferative response in tumor tissue. We hypothesize that this interaction between the RA and VEGF systems results in a differential response to VEGF therapy when angiotensin modifying drugs (AMD) are used in the treatment of bevacizumab induced HTN.

Methods
We evaluated patients treated at our institution with bevacizumab containing chemotherapy in the first line setting for locally advanced or metastatic non small cell lung cancer and continued bevacizumab therapy until progression, development of adverse events or death. The primary endpoint was Time to Treatment Failure (TTF) defined as the time from initiation of bevacizumab therapy until discontinuation for progression, adverse events or death. Patients were compared based on history of preexisting HTN, emerging HTN, exposure to antihypertensive drugs (AHD) or exposure to AMD (ace inhibitors “ACEi” or angiotensin receptors blockers “ARB”)

Results
75 patients met the inclusion criteria. 38 patients (51%) had preexisting hypertension, 41 (55%) patients were taking an antihypertensive drug prior to the start of chemotherapy and 24 (32%) patients developed emergent hypertension. The median TTF for patients with emergent HTN was 13.1(95% CI: 10.1, 19.9) months versus for those without exposure to AHD was 4.7 (95% CI: 3.5, 5.6) months (p= 0.076). The median TTF for patients with HTN who were treated with AMD was 4.9 (95% CI: 29, 7.5) months compared to 6.2( 95% CI:4.0, 12.3) months for patients treated with all other AHD ( P=0.716) and 4.7( 95% CI:3.5, 5.6) months for patients without exposure to AHD (p=0.438).

Conclusion
We did not observe a statistically significant difference in TTF between any of the groups studied. We specifically did not observe an advantage to using an AMD over other AHDs for the treatment of HTN during bevacizumab therapy. We did observe a trend towards longer TTF in patients who developed emergent HTN commensurate to currently published data.

Background
Oncologists are frequently required to provide estimates of survival time for their patients with advanced cancer. The aims of this study were to determine the accuracy and prognostic significance of oncologists’ estimates of survival time above and beyond conventional prognostic factors.

Methods
Medical oncologists from 26 sites in Australia and New Zealand recorded the “expected survival time in months” for individual patients with ANSCLC prior to randomisation in a trial of first-line chemotherapy with a platinum-based doublet. Blood samples, demographics, tumour and treatment characteristics were collected at baseline along with the oncologist’s rating of each patient using Spitzer’s Quality of Life Index (SQLI). Based on previous studies, we deemed estimates within 0.75-1.33 times observed survival as precise, and expected 50% of patients to live longer (or shorter) than their oncologist’s estimate, 50% to live from half to double their oncologist’s estimate (typical scenario); 5-10% to live ≤¼ of their estimate (worst-case scenario); and, 5-10% to live ≥3 times their estimate (best-case scenario). Associations between estimated and observed survival times in months were assessed with Cox proportional hazards regression before and after adjustment for baseline prognostic factors including age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), cancer extent, histology, co-morbidities, laboratory results and SQLI.

Results
Estimates of survival were available for 244 (98%) of the first 250 patients randomised. Patient characteristics were: median age 64 years; female 40%; adenocarcinoma 64%; ECOG PS 0-1 92%; and distant metastases 71%. After a median follow-up of 21 months there were 172 deaths (69%). The median (interquartile range, IQR) for observed survival was 10 months (5-20) and for estimated survival was 11 months (9-12). Oncologists’ estimates were imprecise (22% from 0.75-1.33 times observed) but well calibrated (47% of patients lived shorter than expected and 53% lived longer than expected). The proportions of patients with observed survival times falling within ranges bounded by simple multiples of their estimated survival times corresponded closely with our a-priori hypotheses: 10% lived ≤1/4 of their estimated survival time, 53% lived from half to double their estimated survival time, and 13% lived ≥3 times their estimated survival time. The oncologist’s estimate of survival time at baseline was the strongest predictor of observed survival in both univariable analysis (HR 0.90, 95% CI 0.86-0.95, p<0.001) and multivariable analysis (HR 0.90, 95% CI 0.86-0.95, p<0.001) accounting for all other independently significant predictors, namely: estimated neutrophil-lymphocyte ratio >5 (HR 3.15, 95% CI 1.76-5.64, p<0.001); haemoglobin <120g/L (HR 1.93, 95% CI 1.3-2.9, p=0.001) and total white cell count >11x10[9]/L (HR 1.55, 95% CI 1.05-2.27, p=0.03).

Conclusion
Oncologists' estimates of survival time were independently associated with observed survival time and provided a reasonable basis for estimating worst-case, typical and best-case scenarios for survival. Oncologists’ estimates provide useful additional prognostic information, above and beyond that provided by established prognostic factors.

Background
Cytotoxic chemotherapy is widely used to palliate malignant pleural mesothelioma (MM) and non small cell lung cancer (NSCLC). While originally considered detrimental to the immune system, there is now abundant preclinical data showing that chemotherapy can enhance anti-cancer immunotherapy. Tregs are immunosuppressive CD4[+] T cells thought to inhibit anti-tumour immune responses; murine data suggests that Treg eradication may augment existing anti-tumour immunity. Cyclophosphamide (CTX) is immunostimulatory and at low doses selectively depletes Tregs in mice and humans. The primary objective of this study is to identify an optimum dose and schedule of iterative low dose oral CTX for Treg depletion in the context of pemetrexed-based chemotherapy, and to determine how treatment affects the function and phenotype of the cellular immune response.

Methods
In this single centre phase 1b study we investigate an optimum dose and schedule of iterative low dose oral CTX for Treg depletion, in the context of pemetrexed-based chemotherapy, and how treatment affects the function and phenotype of the cellular immune response. Thirty-one patients with advanced malignant pleural mesothelioma (MM) or non-small cell lung cancer (NSCLC) received standard doses of pemetrexed ± cisplatin or carboplatin on a 21 day schedule (6 cycles max.). From the second cycle, escalating doses of oral CTX were administered, initially with 50 mg daily. Weekly peripheral blood samples were collected, and the proportion of Tregs within the CD4[+] population (Treg%) determined by flow cytometry, amongst other immunological parameters.

Results
31 participants enrolled on the study (27 MM, 4 NSCLC). The mean number of treatment cycles completed was 4.2 from a potential total of 6 cycles, with 20 participants on-study for at least 4 cycles, and the combination was safe and feasible. Contrary to our initial hypothesis, CTX treatment did not reduce the Treg proportion of CD4[+] T cells in peripheral blood, with baseline Treg (CD127[lo]CD25[+]Foxp3[+]) proportion of CD4+ T cells at 4.44±1.56% and no significant change observed when comparing values from the end of each treatment cycle. Doses above 50/100 mg did not improve depletion. However, analysis of the T-effector cell population has demonstrated an increased frequency of CD38[hi]HLA-DR[hi] cells within the total CD8[+] T cell pool. From the perspective of biological relevance, the ratio of activated T-effector cells to Tregs changes minimally during the first cycle of standard care chemotherapy (baseline = 0.21±0.15 T-effectors per Treg); however, from mid-way through cycle 2 (when CTX treatment begins) onward a notable and variable increase in the proportion of activated T-effector cells is observed (end of cycle 3 = 2.21±3.83 T-effectors per Treg). Detailed immunological data will be presented.

Conclusion
These data suggests that CTX with chemotherapy can increase the proportion of activated T-effector cells, an observation that has the potential to improve anti-tumour immunity or chemo-immunotherapy efficacy. We postulate that CTX may affect the function rather than numbers of Treg cells, decreasing their ability to suppress the proliferation of CD8+ effector T cells.

Background
Lung cancer represents the leading cause of cancer-related death world wide. Several studies have shown that the risk of developing lung cancer is associated with socioeconomic status. Recently a Swedish study showed that socioeconomically disadvantaged groups with NSCLC receive less intensive care. Low education remained an independent predictor of poor survival only in women with early stage disease. Foreign-born people constitute 12.5% of the Swedish population in Sweden.

Methods
A retrospective analysis of all patients with lung cancer at the Department of Respiratory Medicine and Allergy, Karolinska University Hospital - Solna during 030101—061231. In all, 1353 cases of lung cancer were diagnosed in which 157 (11.6%) were immigrants. The mean age in Swedish patients was 69, median 70 and range 38-96 years. The figures for the immigrants was 65, 66 respectively 38-90 years.91,3% of the Swedish and 92,3% of the immigrant patients were either smoker or former smoker. There was no significant differences between the groups.

Results
In 105 (8,8%) Swedish and 7 (4,5%) of the immigrants the diagnosis was clinical Adenocarcinoma was the most common subtype found in both Swedish and immigrant patients 44,7% respectively 40,1%, squamous cell carcinoma 17,5% resp 21,7% and small cell lung cancer 12,2% respectively 14% . No significance differences between the groups.19,1% of the Swedish and 14% of the immigrants were diagnosed as stage I, 2,4% resp 4,4% as stage II, 7,9% resp 7% as stage IIIa and 70,4% resp 74,5% as stage IIIB/IV. Nearly 86% of the Swedish and 84,1% of the immigrants had PS 0-2 and 14,3% resp 15,9% had PS 3-4. Chemotherapy given to 387(32,4%) of the Swedish and 58(36,9%) of the immigrants, concomitant chemo-radiotherapy to 90(7,5%) resp 16(10,2%), radiotherapy against the tumor 8,4% resp 8,3%, SBRT to 2,7% resp 1,3%. Surgery were performed among 9,1% of the Swedish and 10,8% of the immigrants, 5,9% resp 4,5% given adjuvant chemotherapy. Approximately 20% of the Swedish and 15,9% of the immigrants given no therapy at all. There was no significant differences in treatment between the two groups p<0.551.The median survival time for the Swedish patients was 245 days and for other nationalities it was 269 days with no statistical significant difference. For Swedish female patients the median survival time was 273 days and for females from other nationalities it was 329 days with no significant difference.No significant differences in survival and staging between the swedish and the imigrants. There was no significant difference in survival between Swedish and non-Swedish patients within performance status groups.

Conclusion
In this study, we used cohort of patients with lung cancer (except carcinoid), with a focus on ethnicity, to determine whether racial/ethnic disparities exist in overall survival. Another objective of our analysis was to determine whether any differences in survival could be attributed to disease-associated variables. To our best knowledge no previous study has investigated the incidens of lung cancer in immigrants in Sweden. This study showed no significant difference in survival between immigrants and Swedish patients with lung cancer.

Background
Irinotecan and bevacizumab are effective against non-small cell lung cancer (NSCLC) and synergism with non-cross-resistance has been demonstrated in preclinical studies.

Methods
Twenty-four patients having heavily treated metastatic NSCLC were enrolled from March 2011 to November 2012. Sixteen of these subjects had never been exposed to bevacizumab and 8 had received antiangiogenic therapy as part of their first-line (all had achieved a previous response for more than 6 months). Treatment consisted of a 90-min intravenous infusion of 125 mg/m[2] irinotecan on day 1 and 8 plus 7.5 mg/kg bevacizumab on day 1. The treatment was repeated every 3 weeks and all patients underwent genotype evaluation (including EGFR and KRAS mutation screening).

Results
One patient (4.2%) achieved a complete response and six (25%) had a partial response. Objective response rate (ORR) was 29.2% (4.6 months median response duration). Seven patients had stable disease, and disease control rate (DCR) was 58.3%. After a median follow-up of 12.8 months, median progression-free survival (PFS) rate was 4.8 months (95%CI 1.8-9.2) and median overall survival (OS) rate was 19.8 months (95%CI 9.2-30.2). Major toxicity was myelosuppression (grade 3-4 neutropenia occurred in 43% of patients and thrombocytopenia in 8.3%). Two patients experienced febrile neutropenia and non-haematological toxicity was usually mild. One patient suffered grade 4 diarrhoea, and four patients harbouring EGFR mutations had a long-lasting, partial response (>7 months after at least 4 prior lines).

Conclusion
The irinotecan pus bevacizumab combination resulted in favourable activity and manageable toxicity profiles as third or fourth line for patients suffering advanced NSCLC. Our results suggested that such regimen can represent a reasonable chemotherapeutic option, especially for subjects having EGFR mutations. This hypothesis can be partly supported because of topo I activity resulting from increased topo I mRNA and protein expression caused by MET signalling.

Background
Lung cancer comprises 14% of all cancers and 29% of cancer related deaths. Mean age at diagnosis is 60, therefore it’s a disease of elderly. Comorbidities are common in this group of age. Comorbidities can affect survival, quality of life, and patients’ tolerability for therapy, as well. Nevertheless, data on the effects of comorbidities over lung cancer are limited. What we aimed with this study is to use Charlson comorbidity index (CCI) in order to define and stratify the comorbidities of our elderly patients (i.e ≥65 years) with non small cell lung cancer (NSCLC) and analyze its effect over disease-free survival (DFS) and overall survival (OS).

Methods
154 patients with NSCLC aged 65 and over were included in this study. Data were retrospectively collected from patients’ files. Patients’ comorbidities were classified using CCI and its effect on DFS and OS along with other prognostic factors were evaluated.

Results
Mean age of patients for diagnosis in this study was 70 years. Thirty patients (19,4%) had stage I disease, 17 (11%) had stage II, 46 (29,9%) had stage III, and 61 (39,6%) had stage IV disease. Fifty patients had at least one comorbid disease (min; 0 max; 6). CCI scores of the patients were as follows ; 22 patients (14,2 %) had 0 point, 59 patients (38,3 %) had 1 point, 39 patients (25,3 %) had 2 points, 22 patients (14,3%) had 3 points, 8 patients (5,2%) had 4 points, 3 patients (1,9%) had 5 points and 1 patient (0,6%) had 6 points. When patients were classified into 2 groups according to CCI scores (Group 1; CCI 0 and 1, group 2; CCI≥2), DFS of group 1 and group 2 were 13,2 and 16,9 months respectively, and OS were 21,9, and 23,1 months respectively. There was no statistically significant difference between 2 groups (p>0,1 for all comparisons). Survival rates were also similar when compared according to age-adjusted CCI scores of the two groups. The only significant predictors of both dfs and os were disease stage, Eastern Cooperative Oncology Group (ECOG) performance status and the presence of weight loss in multivariate Cox regression analysis.

Conclusion
In conclusion, comorbid diseases stratified according to the CCI were found not to be associated with DFS or OS in elderly patients with NSCLC in our study. The only predictive factors of survival were performance status, weight loss and disease stage. Negative results may be due to low validity of the CCI score in NSCLC, underreporting of comorbidities in patient files or aggressive biology of NSCLC which overrides comorbidities being the most imortant predictor of survival. Prospective studies with larger number of patients are needed to clarify these points.

Background
In advanced non-squamous non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) status is important to determine the treatment. However many previous studies of NSCLC were investigated regardless of EGFR mutation status. Chemotherapy with bevacizumab (Bev) showed higher response rate (RR), and maintenance therapy with Bev or pemetrexed (Pem) showed longer progression free survival (PFS) (E4599, AVAiL, PARAMOUNT). But, there has been few report of chemotherapy with Pem and Bev including maintenance therapy in patients with EGFR-WT. This study is designed to evaluate the efficacy and safety of combination therapy with Pem, carboplatin (Cb) and Bev followed by Pem plus Bev maintenance therapy for non-squamous NSCLC patients with EGFR-WT.

Methods
This study was multicenter, phase II trial. Chemo-naive, stage IIIb/IV or recurrent disease after surgery (rec), non-squamous NSCLC pts with performance status 0-1, and without EGFR mutation in exon 19 deleion or 21 L858R and without brain metastases were eligible. Pts were treated with Pem 500mg/m[2], Cb AUC=6, and Bev 15mg/kg intravenously on day 1 every 3 weeks. After 4-6 cycles, pts who achieved disease control receive Pem 500mg/m[2] and Bev 15mg/kg on day 1 every 3 weeks until progressive disease or unacceptable toxicity. To determine the EGFR mutation, we use the peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp assay. Response was determined by CT scans after every 2 cycles (RECIST ver1.1), and toxicity was assessed with CTCAE ver3.0. Primary endpoint was RR. Secondary endpoint included safety, disease control rate (DCR), overall survival, PFS. We planned the sample size was 47 patients and recruited 52 patients (pts).

Results
Fifty eligible patients were enrolled between July 2010 and July 2012. Of 50 evaluable for analysis, the median age was 64 years (range, 37–74); 40/10 males/females; 6/40/4 with IIIB/IV/rec; 47/1/2 with adenocarcinoma/large cell carcinoma/NSCLC. In the triplet therapy, the median number of cycles was 5. There were 24 partial responses with an RR of 48.0% (95% CI, 33.7-62.6). SD was observed in 21 pts and DCR was 90% and 35 pts (70%) followed by maintenance therapy. NE and PD were observed in 4 pts and 1 pts, respectively. Major adverse event was grade 3-4 neutropenia in 19 pts (38.0%), grade 3-4 thrombocytopenia in 12 pts (24.0%). Although grade 3-4 infection was observed in 2 cases (4.0%). There was no treatment-related death.

Conclusion
This is the first report of treatment with Pem, Cb, and Bev in EGFR-WT pts. This first line chemotherapy regimen demonstrated good efficacy and acceptable toxicity profile , and many pts could transfer to Pem plus Bev maintenance therapy. In the future, we will report the data containing maintenance therapy. Unique trial Number; UMIN000003736

Background
The combination of weekly paclitaxel and every 4 week carboplatin as first-line therapy for advanced non-small cell lung cancer (NSCLC) has been report to result in a median survival time of 8.8 months and a 1-year survival of 39.5%. Retinoids and rexinoids are derivatives of vitamin A with anti-proliferative and differentiation inducing activity in a variety of cancer types, including NSCLC. Preclinical and early clinical work has shown promising results when rexinoids are combined with chemotherapy or targeted agents. We designed a phase I/II study to evaluate the tolerability and activity of the rexinoid, bexarotene in combination with weekly paclitaxel and every 4 week carboplatin to allow for closer interaction between the agents.

Methods
Patients with confirmed stage IIIB or IV NSCLC and adequate organ function were enrolled. Prior chemotherapy was allowed for the phase I portion of this study. All patients were scheduled to receive paclitaxel 100 mg/m[2] weekly for 3 doses every 4 weeks and carboplatin AUC = 6 monthly. Bexarotene oral capsules were administered daily starting on initial day of chemotherapy. Two dose levels of bexarotene were evaluated (300 mg/m[2]/day and 400 mg/m[2]/day). The recommended phase II dose of bexarotene was 400 mg/m[2]/day.

Results
33 patients (pts) were enrolled, 14 pts received 300 mg/m[2]/day and 19 pts received 400 mg/m[2]/day of bexarotene. Patient characteristics: age (median 59), gender (female 39%), stage (85% stage IV), Karnofsky performance status (KPS) (37% with KPS 60-70%), prior chemotherapy (30%), prior radiation (33%), and prior surgery (33%). Hematologic toxicity was mild with grade 3 anemia in 5 pts and grade 3 neutropenia in 7 pts. Non-hematologic toxicities consisted primarily of hyperlipidemia and hypothyroidism which were medically managed. No cases of pancreatitis were observed. With a median follow-up of nearly 9 years, the median survival time (MST) for all pts was 8.5 months with 1-year survival of 43%. MST for the 300mg dose was 6.5 months while the MST for the 400mg dose was 10.2 months. The median survival time for chemotherapy-naive pts (n = 24) was 8.3 months with a 1-year survival of 47%. There was no statistically significant difference in survival between those pts with or without dose modifications for side effects. MST was 8.4 months for the subset of pts who experienced hypertriglyceridemia compared to 4.9 months for the pts who did not develop hypertriglyceridemia.

Conclusion
The 43% 1-yr survival for chemotherapy-naive pts treated with bexarotene in combination with weekly paclitaxel and every 4 week carboplatin is encouraging. However, two reported phase III trials found no benefit from adding bexarotene to conventional chemotherapy. Our study dose confirmed the subgroup analysis for a significant positive correlation between bexarotene-induced hypertriglyceridemia and survival. Thus, our study which utilizes a different chemotherapy should be confirmed in future trials. Further research on biomarkers to identify subsets of patients that may benefit from bexarotene is warranted.

Background
During the past seven years paradigms of advanced lung cancer therapy dramatically changed; Bevacizumab and Pemetrexed, when administered separately in association with platinum salts, demonstrated to improve survival in patients with non-squamous histologies. In the aim to investigate activity and safety of a three-drugs regimen containing both these agents plus cis-platinum, we conducted a multi-institutional phase II trial.

Methods
Eligible criteria were: chemo-naive patients with proven histology of non-squamous non-small celle lung cancer, PS-ECOG-WHO equal or lesser than 2, adequate hematological, liver and renal functions, no previous history of hemoptysis, stage III/B or IV without brain metastases, at least one measurable lesion, no uncontrolled hypertension or other severe comorbidities, no anamnestic episodes of venous thromboembolism. We adopt a two-stage of Simon model as statistical design of the study; the main end-point was overall response rate. No maintenance therapy was allowed.

Results
Thirty-two patients were enrolled; their main characteristics were: male/female: 20/12, median age (years): 59, ECOG-WHO PS 0/1: 21/11. We administered 183 cycles of CPBev: main grade 3 adverse events were neutropenia (28%), emesis (19%), asthenia (9%), and hypertension (9%). In terms of overall response rate we registered 20/32 (62.5%) partial responses, 8/32 (25%) stable diseases and 4/32 (12.5%) progressive diseases, with a clinical benefit rate of 28/32 (87.5%). The median overall survival of the entire series was 16.9 months; 1 and 2-years-overall survival were respectively 61.4 and 32.1%; the median progression-free-survival was 9.3 months, with a 1 and 2-progression-free-survival of 43.2 and 7%, respectively.

Conclusion
On the basis of our data, we may affirm that CPBev regimen have a good toxicity profile and is extremely active iwhen administered to advanced non-squamous, non-small celle lung carcinomas. Data concerning outcome parameters seems to be very interesting: CPBev deserves to be compared to actual standard regimens in a phase III trial in this population of patients.

Background
Epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitor (TKI) responds to approximately 80% of the non-small cell lung cancer (NSCLC) patients with EGFR mutation. In other words, about 20% of the patients with EGFR mutations don’t respond. It was reported that resistance to EGFR-TKI is caused by secondary mutation at codon 790 (exon 20 mutation), Met amplification and hepatocyte growth factor (HGF)-MET signaling. The aim of this study is to explore the type of EGFR mutation, phosphorylated MET and HGF expression in tissues surgically removed for NSCLC with EGFR mutation impact on the sensitivity to gefitinib.

Methods
We studied 44 surgically resected NSCLC from 2001 to 2012. 43 cases were adenocarcinoma and 1 case was large cell neuroendocrine carcinoma. These surgical resections were taken from patients who were treated with gefitinib as first or second or third line therapy for postoperative recurrent cancer. The patients’ age ranged from 27 to 78years old (average 63.1 years old). There were 19 male and 25 female patients. There was 1 case of exon 18 point mutation, 23 cases of exon 19 deletion, 2 cases of exon 20 point mutation, 16 cases of exon 21 point mutation, and 2 cases of both exon 20 and 21 point mutation. We assessed non-responders progression within 2 months. Intermediate responders were considered as being effectively treated (at least stable disease) with gefitinib between 3 and 11 months. And long-term responders were considered to be effectively treated with gefitinib for over 12 months.

Results
Non-responders were 4 cases. Intermediate responders were 26 cases (including 11 cases of ongoing treatment). Long-term responders were 14 cases (including 1 case of ongoing treatment). Non-responders had two secondary mutation, one exon 19 deletion and exon 21 mutation. Intermediate responders had one exon 18 mutation, 14 exon 19 deletion, 10 exon 21 mutation and one both exon 20 and 21 mutation. long-term responder had eight exon 19 deletion, five exon 21 mutation and one both exon 20 and 21 mutation.

Conclusion
In our data, NSCLC with exon 20 mutaiton will respond to gefitinib if this NCCLC with another EGFR mutation. We will report the findings of non-responders excluding analyzed exon 20 mutation phosphorylated MET and HGF expression.

Background
Bone and lung are frequent metastatic sites for adenocarcinoma of lung. Chemotherapy and tyrosine-kinase inhibitor (TKI) are standard first-line therapies for stage IV adenocarcinoma of lung according to the epidermal growth factor receptor (EGFR) mutation status. This study aimed at evaluating the relationship between bone, lung metastasis, with or without classic EGFR mutation, response rate and disease control rate of first-line chemotherapy and TKI therapy.

Methods
We retrospectively reviewed 206 patients who were diagnosed of adenocarcinoma of lung at our hospital. The patients’ bone and lung metastatic status at diagnosis, with or without classic EGFR mutation, response and disease control status of first-line chemotherapy and TKI therapy were collected for chi-square analysis.

Results
Fifty-five (26.7%) patients had bone metastasis and 82 (39.8%) patients had lung metastasis. 107 (51.9%) patients had classic EGFR mutation. There was no significant difference between bone, lung metastatic status and with or without classic EGFR mutation (p=0.65 for bone, p=0.46 for lung). For the patients without classic EGFR mutation and received first-line chemotherapy, 33(57.9%) patients were without response (13, 20 patients were without, with bone metastasis, respectively), 24(42.1%) patients were with response (21, 3 patients were without, with bone metastasis, respectively), p<0.01; 21(36.8%) patients were not controlled (9, 12 patients were without, with bone metastasis, respectively),36 (63.2%) patients were controlled (25, 11 patients were without, with bone metastasis, respectively), p=0.048. For the patients with classic EGFR mutation and received first-line chemotherapy, 27(60%) patients were without response (14, 13 patients were without, with bone metastasis, respectively), 18(40%) patients were with response (16, 2 patients were without, with bone metastasis, respectively), p=0.01; 10(22.2%) patients were not controlled (4, 6 patients were without, with bone metastasis, respectively), 35(77.8%) patients were controlled (26, 9 patients were without, with bone metastasis, respectively), p=0.043. There were no significant difference between response status of TKI and lung metastatic status (p=0.469), control status of TKI and lung metastatic status(p=0.855), response status of TKI and bone metastatic status(p=0.673), control status of TKI and bone metastatic status(p=0.58), response status of chemotherapy and bone metastatic status(p=0.533), control status of chemotherapy and bone metastatic status(p=0.777) in patients without classic EGFR mutation. For patients with classic EGFR mutation, there were also no significant difference between response status of TKI and lung metastatic status(p=0.077), control status of TKI and lung metastatic status(p=0.332), response status of TKI and bone metastatic status(p=0.76), control status of TKI and bone metastatic status(p=0.05), response status of chemotherapy and bone metastatic status (p=0.143), except for control status of chemotherapy and bone metastatic status(p=0.017).

Conclusion
For patients with adenocarcinoma of lung, bone metastasis is associated with decreased disease control rate in those with classic EGFR mutation and received first-line chemotherapy, and lung metastasis is associated with decreased response and disease control rate in those received first-line TKI therapy no matter of with or without classic EGFR mutation.

Background
Denosumab, a fully human monoclonal antibody to RANKL, is expected to improve overall survival better than zoledronic acid when administered in the treatment of bone metastasis from lung cancer. Although the mechanism of prolongation of survival by denosumab for lung cancer patients is unknown, denosumab may have an additional effect other than bone-protective effects. We examined relevance between efficacy of denosumab and EGFR mutation status which is tend to be causal of multiple bone metastasis.

Methods
Patients treated by Denosumab with metastatic lung cancer were eligible for the study. We retrospectively analyzed their histological type, EGFR mutation status, chemotherapy, the change of primary lesion and bone metastasis before and after treatment of denosumab.

Results
From July 2012 to June 2013, there were 18 patients matched in the analysis.Patients’ characteristics: median age 68.5 years, male/female 9/9, PS0/1/2/3 2/10/4/2, adenocarcinoma/others 15/3, EGFR mutation status Ex19del./L858R/wt or unknown 9/2/7). Seven patients were treated by gefitinib, and in the three of them, reossifications by computed tomography were observed without ostalgia.In none of 11 patients treated by other anticancer drug or followed-up, reossification was seen. Figure 1Figure 2

Conclusion
Patients treated with gefitinib may be beneficial by denosumab treatment. Further investigation exploring synergistic effect of denosumab and gefitinib is warranted.

Background
IP is commonly concomitant disorder with lung cancer. Because IP sometimes deteriorates and results unfavorable clinical course, patients with IP are excluded from most cancer clinical trials. S-1 is a novel active oral fluoropyrimidine anticancer agent consisting of tegafur, gimeracil and oteracil potassium. Although most anti-cancer agent has pulmonary toxicity, post marketing surveillance reported S-1 has lower pulmonary toxicity incidence. We have conducted feasibility study of S-1 and carboplatin combination for patients with advanced or ineligible for other treatment modality of NSCLC patients.

Methods
Patients with confirmed NSCLC, clinical and radiological diagnosed interstitial pneumonia, aged 80 years old or younger, performance status 0-2 and chemo-naive patients were eligible for the study. Carboplatin (AUC 5) was administered on day 1 and S-1 (80mg/m[2]/day) on day 1 to 14 for four to six cycles. Study objectives are safety estimation especially pulmonary adverse events, and efficacy evaluation as tumor response and survival. Pulmonary adverse events were evaluated by CTCAE ver.4.0 and acute exacerbation criteria.

Results
From March 2009 to December 2011, 21 patients were enrolled. Male/female: 19/2, age: 67(55 to 77), adeno/squamous/adenosquamous: 10/10/1, stage IIB/IIIA/IIIB/IV/rec.: 1/2/10/4/4, PaO2 at rest: 70.6(51.4 to 96.7) mmHg, %VC: 91.0 (69.0 to 119.0), %DLco; 63.4(48.1 to 90.4). Treatment delivery cycles 1/2/3/4/5/6: 3/3/2/10/2/1. PR/SD/PD/NE: 7/7/4/3 (RR 33%, DCR 67%), the median progression free survival was 4.0 months and the median overall survival was 10.4 months. During the treatment, two patient experienced moderate level of acute deterioration of IP, one patient experienced infectious pneumonia, all these patients recovered from the event. Acute exacerbation rate were estimated as 9.5% with 22.1% of upper limit of 95% C.I. There was no treatment related death. After first line treatment, four patients experienced acute exacerbation of IP, two during second line treatment, one during immune therapy, and another during no treatment period. From begging of first line chemotherapy, 6 out of 21 patients (29%) experienced some forms of acute exacerbation of IP during any treatment or observational periods. Besides pulmonary toxicity, the profile of hematological and non hematological toxicities was similar to past studies.

Conclusion
First and largest prospective trial for the patients with IP and NSCLC was completed. The study revealed S-1 and carboplatin combination was feasible and active even in patients with IP and NSCLC who are usually excluded from clinical trials. Acute exacerbation of IP was observed during not only fist line treatment but also latter line or observational period.

Background
In recent clinical trials for non-squamous non-small cell lung cancer (NonSq-NSCLC), platinum regimens with bevacizumab (BEV) resulted in better prognosis and acceptable toxicity profile. However, there have been few studies on their feasibility or efficacy of BEV in NonSq-NSCLC patients who were previously treated with a platinum regimen. Therefore, we conducted a prospective study of combination therapy with vinorelbine (VNR) and BEV in NonSq-NSCLC patients who were previously treated with a platinum regimen.

Methods
Eligible patients had recurrent NonSq-NSCLC, PS 0-1, and adequate organ functions. The primary endpoint was feasibility. Secondary endpoints were response rate and safety. Patients received combination therapy with VNR (25mg/kg on day 1, 8) and BEV (15mg/kg, day 1). The treatment cycles were repeated every 3 weeks until progressive disease (PD)

Results
From June 2011 to January 2013, 15 NSCLC patients were eligible for this study. The patients consisted of 7 men and 8 women, and their median age was 68 (range 57-82) years. The patients received the treatment with a median of 4 (range 1-12) cycles. The histological classification was adenocarcinoma in all. The PS (ECOG) was 0 in 2, 1 in 11, and 2 in 2, respectively. The incidence of grade 3-4 neutropenia, anemia, thrombocytopenia and febrile neutropenia was 26.7%, 6.7%, 6.7%, and 13.3%, respectively. Response rate and disease control rate in the overall study population (n=15) were 26.7% and 73.3%, respectively. Median PFS was 2.8 months. Grade 3-4 phlebitis occurred in 3 patients; phlebitis improved by central venous catheter in 1, and by administration with corticosteroid in other two patients.

Conclusion
Combination therapy with VNR and BEV was safe and effective in NonSq-NSCLC patients who were previously treated with a platinum regimen. However, a few patients had a risk of developing phlebitis.

Background
Rearrangements at chromosome locus 2p23 encompassing the Anaplastic Lymphoma Kinase (ALK) gene in non-small cell lung carcinomas (NSCLC) drive expression of the oncogenic ALK encoded protein and provide a target for crizotinib and other ALK inhibitors. A companion diagnostic assay, fluorescence in-situ hybridization (FISH) using conventional formalin-fixed paraffin-embedded (FFPE) tissue samples, was approved for identifying patients eligible for treatment and has been the commonly employed method for identification of ALK rearrangements. The FISH assay assessing ALK rearrangments may fail due to absence of enumerable FISH signals, insufficient number of tumor cells, or autofluorescence obscuring specific FISH signals, especially for cytoblocks obtained as part of staging or diagnostic fine needle aspiration (FNA) biopsy. FISH performed on liquid based ThinPrep slides (ThinPrepFISH) may represent a robust alternative to conventional FFPE-FISH.

Methods
ThinPrep slides obtained by FNA biopsy from 156 patients with advanced NSCLC were evaluated at Cleveland Clinic by ThinPrep-FISH using a standard ALK break-apart two color probe set (Abbott Molecular Vysis, Des Plaines; AMV). Cell pellets were not available for preparation of FFPE cytoblocks from the cell pellet in 7/156 (4%), and the FFPE cytoblock slides did not contain tumors cells for evaluation in 33/156 (21%) despite the presence of abundant tumor cells in the ThinPrep slide. Given the failure rate for FFPE-FISH using cytoblocks (>30% in our preliminary experience) we chose to use ultrasensitive immunohistochemistry (IHC) for ALK expression in corresponding cytoblocks {D5F3 antibody (Cell Signaling) coupled with enhanced detection sensitivity (OptiView with signal amplification (Ventana; Tucson)} as the reference data set [J Mol Diagn 2013 May; 15(3):341-6] The same ThinPrep slide used for cytopathology diagnosis was probed using ThinPrep-FISH. Specific areas of the ThinPrep-FISH slide having abundant tumor cells were etched with a diamond tip pen on the reverse side of the slide prior to removal of the cover slip; all areas of the ThinPrep slide were screened qualitatively and signals enumerated selectively for tumor cells. Interpretative criteria used for ThinPrepFISH were the same criteria as is used for the IVD AMV probe set.

Results
ThinPrepFISH ALK signals were robust and not compromised by nuclear truncation inherent in FFPE tissue FISH in 155 / 156 cases. One of 156 cases displayed no signals, but was probed 11 months after the ThinPrep slide had been prepared. Overall, 9/156 cases (6%) were ALK rearranged. For 116 ThinPrep slides successfully paired with FFPE cytoblocks containing tumor cells, 7/116 cases (6%) were ThinPrep-FISH positive and IHC positive for ALK rearrangements/expression, 2/116 cases (1.7%) were ThinPrep-FISH positve but IHC negative, and 107/116 cases were ThinPrep-FISH negative and IHC negative (sensitivity 100%, specificity 98.2%, overall agreement 98.3%).

Conclusion
Detection of ALK gene rearrangements in liquid cytology ThinPrep slides prepared from fine needle aspiration cytopathology specimens derived from patients with NSCLC can be confidently used for clinical ALK molecular testing.

Background
Stage IIIA NSCLC represents a relatively heterogeneous group, which the relative roles of treatment modalities are not clearly defined. Adjuvant chemotherapy remains the most important treatment for stage IIIA NSCLC after radical operation, but the drug-related toxicities limit its use and benefits for patients. The tyrosine-kinase inhibitor might provide a promising treatment for NSCLC patients with EGFR19 or 21 exon mutation. In the OPTIMAL study comparing first-line erlotinib with carboplatin/gemcitabine in advanced NSCLC patients with EGFR activating mutations, the primary analysis showed significantly prolonged progressive free survival in erlotinib treatment in comparison to carboplatin/gemcitabine (p<0.0001). The aim of this study is to investigate the efficacy and safety of erlotinib in comparison to vinorelbin plus cisplatin (NP) chemotherapy as adjuvant therapy in post radical operation stage IIIA NSCLC patients with EGFR19 or 21 exon mutation to explore a new treatment strategy for this subset.

Methods
The study was designed as a prospective, open-labeled, randomized, multicenter phase II clinical trial. Patients aged between 18 and 75 with ECOG PS 0–1 IIIA NSCLC confirmed by histopathology or cytology after radical operation and with EGFR exon 19 deletion mutation or exon 21 L858R single base substitution were enrolled (n=94). Within 4 weeks post radical surgery, the enrolled patients would randomly allocated for adjuvant therapy, receiving either erlotinib (n=47) 150mg/day for 2 years or NP (n=47) chemotherapy (vinorelbine 25mg/m2 on day 1, 8 and cisplatinum 75mg/m2 on day 1 of a 3-week schedule ) for 4 cycles. Duration of trial recruitment is estimated to 18 months. Primary endpoint is 2-year disease free survival rate (DFSR). Secondary endpoints are disease free survival (DFS), 3-year and 5-year overall survival (OS), Quality of Life (QOL) and Safety. Biomarker profile will be the exploratory research. Patients after surgery and therapy will receive long-term follow-up including chest and abdominal CT scan every 3 months, brain MRI every 6 months and bone scan every 12 months for up to 2 years.

Results
Current recruitment: twenty-five patients have been enrolled since FPI in August, 2012.

Conclusion
Adjuvant erlotinib therapy in IIIA-N2 NSCLC with EGFR activating mutation is a promising strategy.

Background
For advanced NSCLC patients who benefited from prior EGFR-TKI therapy, the choice of a second TKI therapy has gradually become a new strategy for the treatment. Some investigators recommend that the second therapy should be continued with the original TKI; however, other investigators recommend the administration of another TKI. This study aims to discuss which choice is more reasonable.

Methods
In retrospect, patients with advanced NSCLC or with postoperative relapse of advanced NSCLC achieved CR, PR or SD in prior Gefitinib therapy, PFS≥3 months. They received repeated Gefitinib or Erlotinib at an interval of at least one month. The analysis was carried out with respect to efficacy and optimal population of the two groups.

Results
A total of 61 patients were enrolled into the study, 30 in Gefitinib group and 31 in Erlotinib group. Baseline characteristics of the two groups were comparable. Among these patients, overall response rate was 16.4% (10/61), disease control rate was 67.2% (41/61), median PFS was 3.5 months (95%CI 3.0-4.0 months), median OS was 8.5 months (95%CI 7.0-11 months). In the comparison between patients treated with Gefitinib and with Erlotinib, no statistical differences were seen for response rate (10% vs 22.6%, P=0.3006), disease control rate (60% vs 74.2%, P=0.2378), median PFS (3.0 vs 3.5 months, P=0.4945), or median OS (8.3 vs 8.5 months, P=0.1408). Multivariate analysis showed that in the initial dose of Gefitinib, PFS≥6 months (HR 0.317, 95%CI 0.102-0.984, P=0.0469). With an interval ≥3 months (HR 0.224，95%CI 0.071-0.713,P=0.0113) between two doses of TKI, the risk of disease progression was reduced; but if with an interval ≥3 months (HR 0.262, 95%CI 0.097-0.705,P=0.0080), the risk of death was reduced.

Conclusion
Advanced NSCLC patients who benefited from prior Gefitinib therapy can benefit again either with the original drug Gefitinib or the alternative drug Erlotinib when a second TKI therapy is resumed. Such benefit is related to PFS of initial TKI therapy and time interval between two doses of TKI.

Background
The PI3K pathway has been implicated as a mechanism for cell survival and resistance to chemotherapy. PI3K may be an important target in NSCLC based on genetic alterations such as PIK3CA amplification, PTEN loss and PI3K mutations. Preclinical NSCLC models show that concurrent dosing of GDC-0941 improved activity of taxanes, platinums, and anti-VEGF therapy. This Phase 1b study aims to establish the safety and tolerability of GDC-0941 in combination with four frontline standard of care regimens in patients with advanced NSCLC.

Methods
This study contains two Carbo/Pac containing arms: Arm A (GDC-0941 + Carbo + Pac), open to squamous (Sq) patients and Bev-ineligible non-squamous (NSq) patients; and Arm B (GDC-0941 + Carbo + Pac + Bev) for NSq patients. The study also aims to evaluate two Cis/Pem containing arms in NSq patients: Arm C (GDC-0941 + Cis + Pem + Bev); and Arm D (GDC-0941 + Cis + Pem). Study objectives are to evaluate safety and pharmacokinetics (PK), and to determine the maximum tolerated/administered dose (MTD or MAD) of GDC-0941 in combination with chemotherapy regimens in all arms. Patients received GDC-0941 with 4-6 cycles of chemotherapy every 3 weeks (Q3W): Pac (200 mg/m[2]), Carbo (AUC 6 mg/mL·min), Cis (75 mg/m2), Pem (500 mg/m2), and Bev(15 mg/kg) . In all arms, GDC was given PO qd on Days 1-14 of a 21-day cycle. GDC-0941 +/- Bev were given until progression or toxicity.

Results
As of 1 February 2013, Arms A, B and C have completed enrollment, with 18, 24 and 13 patients, respectively; no patients have been enrolled in Arm D to date. The most common Grade 3/4 treatment-related adverse events (TAEs) reported in ≥10% of patients were as follows: Arm A: neutropenia (50%), anemia (17%), febrile neutropenia (17%), leukopenia (11%) and thrombocytopenia (11%); Arm B: neutropenia (38%), lymphopenia (13%); Arm C: fatigue (31%), dehydration (15%) and hypertension (15%). The MTD/MAD in Arms A, B and C is 340 mg GDC-0941 in combination with either Carbo + Pac +/- Bev or with Cis + Pem + Bev, respectively. PK characteristics in all Arms were similar to historical profiles for the respective chemotherapy agents, as well as to the single-agent GDC-0941 profile. Confirmed partial responses (PRs) for patients with at least one post-baseline scan are as follows: 6 of 10 (60%) Sq patients; 11 of 28 (39%) NSq (Arms A and B) and 9 of 12 (75%) NSq patients (Arm C).

Conclusion
The combinations of GDC-0941 with either Pac + Carbo (+/- Bev), or Cis + Pem + Bev have been well tolerated at doses consistent with target PK exposures based on preclinical activity. Promising responses rates have been observed with all combinations evaluated. Evaluation of GDC-0941 + Cis + Pem is ongoing. A randomized Phase 2 study of GDC-0941 + Pac + Carbo (+/- Bev) in NSq and Sq patients is ongoing.

Background
Pemetrexed (Pem) and bevacizumab (Bev) have each been shown to improve survival in patients (pts) with advanced non-squamous non-small-cell lung cancer (NSCLC) (Scagliotti JCO 2008, Sandler NEJM 2006). Recent evidence suggests these agents can be safely combined and given with carboplatin (Cb) in the first-line setting with encouraging activity (Patel, ASTRO 2012). However, the efficacy and safety of these agents in pts with poor performance status (PS) are unknown. Herein, we report a prospective randomized phase II study of first-line pem v. pem/bev v. cb/pem/bev in pts with advanced NSCLC and poor PS.

Methods
Key eligibility included: pts with newly diagnosed advanced non-squamous NSCLC (IIIB or IV), an Eastern Cooperative Oncology Group (ECOG) PS of 2, and measurable disease per RECIST v.1.1. Pts were randomized 1:1:1 to receive either Pem 500mg/m[2] IV (Arm 1), Pem 500mg/m[2] IV and Bev 15mg/kg IV (Arm 2), or Pem 500mg/m[2] IV, Bev 15mg/kg IV, and Cb AUC=5 IV (Arm 3). Cycles were 21 days, with reimaging every 2 cycles. Pts on Arm 3 received a maximum of 4 cycles (12 weeks) of Cb. All pts continued Pem or Pem/Bev until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety.

Results
Between June 2009 and May 2013, 155 pts were randomized. Summary demographic data are available for 142 pts (median age: 72 years, adenocarcinoma, 80%, males, 59%) in Arms 1, 2, and 3; 97%, 98%, and 88% of pts were current or former smokers, respectively. The most common treatment-related grade 3/4 toxicities are presented below. ORRs for Arms 1, 2, and 3 were 15%, 24%, and 40%, respectively. While modest efficacy was observed in Arm 1, recent data (Lilenbaum, et al. 2012) suggesting a significant OS advantage in pts receiving Pem in combination with Cb vs. Pem alone led to closure of this arm in early 2013. A subset analysis examining pts older or younger than 70 years found that the younger population treated on Arm 1 had inferior ORRs to older pts treated on Arm 3 (7% v. 26%, respectively).

Grade 3/4 Toxicity	Arm 1 (N=48)	Arm 2 (N=49)	Arm 3 (N=45)
Hematologic
Hemoglobin	5 (10%)	1 (2%)	5 (11%)
Leukocytes	0	1 (2%)	4 (9%)
Neutrophils	3 (6%)	4 (8%)	8 (18%)
Platelets	0	2 (4%)	10 (22%)
Non-hematologic
Anorexia	1 (2%)	0	0
Cardiac ischemia/infarction	0	1 (2%)	0
CNS ischemia	0	1 (2%)	1 (2%)
Deep vein thrombosis	0	1 (2%)	1 (2%)
Dehydration	2 (4%)	2 (4%)	0
Diarrhea	0	2 (4%)	1 (2%)
Dyspnea	0	2 (4%)	2 (4%)
Fatigue	10 (21%)	9 (18%)	9 (20%)
Epistaxis	0	1 (2%)	0
Hypertension	0	2 (4%)	2 (4%)
Muscle weakness	4 (8%)	3 (6%)	4 (9%)
Nausea	0	0	2 (4%)
Proteinuria	0	0	1 (2%)
Pulmonary embolism	1 (2%)	1 (2%)	2 (4%)
Vomiting	0	2 (4%)	1 (2%)

Conclusion
This is the largest prospective trial of bevacizumab in poor PS pts with advanced NSCLC. All three regimens were safe and well-tolerated. ORRs with Pem/Bev +/- Cb were encouraging and comparable to historical outcomes in patients with better PS. PFS and OS data will be presented.

Background
Over the last decade, incorporation of new cytotoxic chemotherapeutics, introduction of maintenance therapy, and integration of targeted therapies have altered treatment paradigms for patients with metastatic NSCLC (mNSCLC). In a disease that was largely treated empirically, therapy is now tailored based upon histology and MB. We sought to analyze whether outcomes of clinical trials in mNSCLC reported over 10 years at the ASCO Annual Meeting reflected perceived gains in the treatment of patients with mNSCLC.

Methods
Data were collected from ASCO abstracts of Phase II–IV clinical trials for patients with mNSCLC from 2004–2013. Trials in Progress abstracts were excluded. Data collected included author names, histology and MB selection criteria, phase, primary endpoint, outcomes, and drugs used. We hypothesized that rates of positive clinical trial outcomes would increase over time and that trials using MB selection criteria would have higher rates of positive outcomes. Statistical comparisons were made using Fisher’s exact test with two-sided p-values. Trends were compared using Spearman’s rank correlation.

Results
711 of 2,540 identified mNSCLC category abstracts met selection criteria. Over 50% were published by the top 10% of 841 unique first/last authors. Annual abstracts fitting selection criteria declined from 107 to 41 from 2004–2013. Common primary endpoints were: not specified (31%), response rate (24%), progression-free survival (PFS, 22%), and overall survival (OS, 14%). Few phase II trials had primary endpoints of PFS or OS (20.4%, 6.0%). The proportion of trials with positive PFS outcomes increased from 3.7% to 26.8% despite decreases in total annual abstracts (correlation coefficient = –0.67, p=0.033) (see Figure). Positive OS outcomes increased from 0.9% to 4.9%. Trials with MB selection criteria (5.6%) or non-squamous (NS) histology (13% of trials without MB selection) increased from 0% to 22% and 18% annually, respectively, and were more likely to result in an improvement in PFS (20.0% vs. 9.2%, p=0.0482 and 23.0% vs. 7.3%, p=0.0001, respectively). These criteria had no significant association with OS or QOL outcomes. Figure 1

Conclusion
Despite fewer phase II–III clinical trials presented at ASCO annually, there was a significant increase in those with positive PFS outcomes. Increases in trials selective for MB or NS histology may account for the improved PFS results. These data suggest better trial design and efficient use of resources. These data may also reflect bias in selecting abstracts for presentation, which could result in missed learning opportunities for future trial design. Additionally, it is unclear whether PFS endpoints are as meaningful as OS.

Background
EGFR-TKI has been widely used in the treatment of advanced NSCLC with positive EGFR mutation. However, tumor tissues may not always be available in patients with inoperable NSCLC. Although peripheral blood can be used to test the mutations, but the sensitivity are not satisfactory.Studies have found that the CEA level are higher in patients with positive EGFR mutation. And it also have been reported that the variation of CEA level before and after EGFR-TKI therapy was closely related with therapy efficacy. So if we use high CEA level to predict the EGFR mutation, could we get a higher sensitivity than use peripheral blood to test the mutation? Are the variation types of CEA related with the efficacy of EGFR-TKI? To solve these questions, we designed this study and hope to find a marker to predict EGFR mutation and efficacy of EGFR-TKI.

Methods
70 cases of newly diagnosed non-smoking adenocarcinoma of NSCLC were included in the study. We detected their EGFR mutation status, record their clinical characteristics and test CEA level. The patients with positive EGFR mutation receive EGFR-TKI treatment. The EGFR mutation status of these patients’ blood was analyzed by HRM and ARMS. Then we tested their CEA level on the third, seventh, fifteenth and thirtieth day after EGFR-TKI treatment respectively. We evaluated the efficacy on the first month and confirm it on the second month.

Results
44/70 cases were found with EGFR gene mutations.Including 25 cases of exon19,18 cases of L858R mutation and 1 case of exon20 mutation. EGFR mutation rate of serum CEA high-level group was significantly higher than low-level group (EGFR gene mutation rate of patients with serum CEA level <5ng/ml vs. ≥ 5ng/ml was 40.9% vs. 70.8%, p=0.017). Multivariate analysis showed that CEA high-level is independently associated with EGFR gene mutation rate. (p=0.020,OR=3.508, 95%CI：1.223-10.059).The sensitivity, positive predictive value and accuracy of high CEA level to predict EGFR mutation is 79.1%,70.8% and 67.1%.The sensitivity of HRM and ARMS is 13.9% and 51.2% respectively. 43 patients received EGFR-TKI treatment, 2 patients quit the study due to severe adverse reaction. We evaluate the efficacy and follow up their PFS.The total ORR is 41.9%, DCR is 74.4%.We divided the patients through the variation types of CEA into three groups: descending type, first increased then decreased type and ascending type. Analysis the relevance between clinical characteristics and efficacy of EGFR-TKI shows that the variation types of CEA is the only influencing factor (P=0.001). Univariate analysis of NSCLC patients who received EGFR-TKI first-line treatment shows that patients with descending type have longer PFS (P=0.001, HR 6.981, 95%CI: 2.534-19.237). Multivariate Cox proportional hazards model analyses of various factors affecting PFS shows the same result (P=0.001, HR 9.82, 95%CI: 3.322-26.031).

Conclusion
Patients with high CEA levels have a higher rate of EGFR mutations in NSCLC. Using high CEA level for predicting EGFR mutation is more sensitive than using peripheral blood to test EGFR mutation; the variation types of CEA could help us to predict the efficacy of EGFR-TKI for a short time (one month).

Background
EGFR mutations have previously been reported in 10-15% of non-squamous NSCLC in European populations. The rate of mutations and the proportion of mutations considered to be classical activating, known to confer resistance or unusual is yet to be determined in the Australian population. The influence of unusual mutations on disease progression is not yet clear.

Methods
We conducted a retrospective audit of cases of non-squamous NSCLC lung cancer presenting to two metropolitan multidisciplinary teams in Sydney, Australia. All had EGFR testing conducted between October 2010-March 2013. EGFR mutations were identified using PCR and DNA sequencing.

Results
134 patient samples were tested for EGFR mutation. Samples were obtained by surgical resection (n=50), FNA (n=31), Core Biopsy (n=31), pleural fluid aspirate (n=3) and EBUS FNA (19). Of these, 32 (24%) were positive for an EGFR mutation. 23/32 had classical activating mutations, with 16/32 Exon 19 deletions and 7/32 Exon 21 L858 substitutions. 4/32 had non-activating/resistance mutations, with 3 exon 20 insertions and 1 exon 20 T790M (L858 + T790M complex de novo mutation). The remaining 6/32 had unusual mutations (1 Exon 20 ala 767-Val769 duplication, 1 Exon 21 p. Pro848Leu, 2 Exon 18 p. G719x, 1 exon 20 S761, D770 insertion and 1 exon 20 deletion V774 insertion). 72 patients in the cohort were female. 8 were Asian, 8 were Pacific Islander, 1 was Indian and 15 were Caucasian. Smoking history was confirmed in all cases. 18/32 were non-smokers, 3/32 were Asian and 24/32 were female. Of the patients with EGFR mutation positive tumours, 16/32 received TKI as first-line therapy, 5/32 received TKI as second-line therapy, 6/32 did not receive TKI and 5/32 were lost to follow-up in other institutions. Of the 6 who did not receive TKI, 5 cases were early-stage treated surgically; the other case received palliative radiotherapy but co-morbidity prevented TKI therapy. Information regarding disease progression was available in 20/32 cases. Of these cases 11/20 had classical activating mutations, were treated with EGFR TKI and, to date have a mean (SD) progression free survival (PFS) of 315 (± 208) d. Those with other mutations had a PFS of 117 (±86) d. This difference was statistically significant at p<0.01(Mantel-Cox).

Conclusion
EGFR mutations occur more commonly in an Australian population of non-squamous NSCLC than previously reported in European populations. Most in this series have classical activating mutations. Almost one third of this series had a mutation other than classically activating and in all of these cases the PFS was significantly reduced. We report six unusual mutations of unclear clinical significance, which are also associated with poor PFS.

Background
Background: EGFR-activating mutations are predictive of high response rates and overall survival gains in patients (pts) with pulmonary adenocarcinomas, treated with EGFR- tyrosine-kinase inhibitors (EGFR-TKIs), as erlotinib. Our objectives in this study were to analyze the efficacy and safety of erlotinib as first-line therapy or later in pts with adenocarcinomas harbouring EGFR-activating mutations.

Methods
Methods: It is a prospective, observational study on all consecutively pts whose tumors were genotyped for EGFR-activating mutations. All studied pts were treated in a single institution (ICESP) with erlotinib 150 mg PO daily. Tumor samples were formalin-fixed and paraffin-embedded. Tumor areas were selected and macrodissected, followed by whole DNA extraction and amplification by PCR. EGFR genotyping was performed through DNA sequencing (exons 18, 19, 20 and 21) by Sanger´s methodology.

Results
Results: 49 pts were treated with erlotinib from Nov/2010 to May/2013, as first-line (11 pts, 22%), second-line (31 pts, 63%) or third-line therapy (7 pts, 14%). Erlotinib was administered during a median time of 4 mo. (0.2-23.6 mo.). Among these 49 pts, 38 (78%) were diagnosed with adenocarcinomas harbouring EGFR-activating mutations: 26 with exon 19 deletions, 10 with L858R mutation in exon 21 and one presented a rare mutation in exon 18 (G719S). As expected, erlotinib was well tolerated, and acneiform rash and diarrhea were the most commonly observed toxicities. No treatment-related deaths were seen. Tumor response assessment was done in 42 pts: progressive disease was observed in 15 pts (36%) and 27 pts (64%) presented either partial response or disease stabilization. In a mean follow-up of 14 mo., 13 pts were dead. Median overall survival was not reached for the 38 pts with EGFR-mutated adenocarcinomas, and 1-year overall survival rate was 94% in these pts. In those pts with wild-type EGFR tumors, median overall survival was 15.6 mo (HR 0.17; 95% CI 0.02-0.33, p=0.0004). No difference in overall survival was observed between pts with EGFR-mutated adenocarcinomas if treated with erlotinib either as first-line therapy or later (HR 1.11; 95% CI 0.20-6.15, p=0.895). No difference in overall survival was observed between pts with EGFR-mutated adenocarcinomas according to the type of mutations (exon 19 deletions or others, p=0.147).

Conclusion
Conclusions: High rate of disease control (64%) and an impressive 1-year overall survival rate (94%) were observed among pts with metastatic pulmonary adenocarcinomas harbouring EGFR-activating mutations, as expected, with a favorable toxicity profile. These results do reinforce the importance of the correct identification of this subgroup of pts with EGFR-activating mutations and their treatment with an EGFR-TKI as a targeted therapy.

Background
NSCLC patients having an activating EGFR mutation initially responded well to EGFR TKI but most of them experienced progressive disease due to various resistance mechanisms including T790M (~50% of cases) mutation. HM61713 is an orally active, novel EGFR mutant selective inhibitor showing a strong anticancer activity in many lung cancer cell lines including T790M mutation harboring cell line. Therefore, HM61713 might provide the potential clinical benefit to those who have an activating EGFR mutation but have failed previous EGFR TKI treatment.

Methods
This is a phase I study using a standard 3+3 dose escalation scheme. NSCLC Patients with activating EGFR mutation and progressed after at least 2 prior chemotherapy regimens including EGFR TKI were eligible. The objective of this study is to determine the recommended phase II dose as well as to assess the preliminarily efficacy.

Results
To date, a total of 23 patients were treated with at doses of 75-250 mg/day. One patient at a dose of 200 mg/day experienced grade 3 drug induced idiosyncrasy and grade 4 elevation of amylase. The drug induced idiosyncrasy was skin rash of non-EGFR TKI type. The most common drug-related adverse events were desquamation, diarrhea, pruritus, and nausea; most were grade 1 or 2. The maximum tolerated dose (MTD) and recommended phase II dose were not determined yet. Plasma concentration of HM61713 reached the peak 2-4 hr after administration and declined with the half-life of 8-12 hr. Among 21 evaluable patients, 2 patients achieved partial response (PR) and one of them had confirmed T790M mutation while 12 patients had stable disease (SD) including 11 patients showed tumor shrinkage. Accrual to this study is ongoing and updated data will be presented at the meeting.

Conclusion
HM61713 showed good safety profile and promising anticancer activity in NSCLC patients with EGFR mutation who failed to prior EGFR TKI therapy. These results support the therapeutic potential of HM61713 for NSCLC patients with activating EGFR mutations after development of resistance to EGFR TKI therapy.

Background
Afatinib, an irreversible ErbB Family Blocker, displayed nanomolar inhibitory activity in proliferation assays using lung adenocarcinoma cell lines expressing mutant EGFR[L858R/T790M] (NCI-H1975 EC~50~ 92 nM).[1] In NSCLC patients with prior erlotinib/gefitinib failure and one/two previous lines of chemotherapy, 50mg afatinib once daily produced confirmed objective responses in 7% of patients and a median PFS of 3.3 months.[2] Preclinical models suggested that administering afatinib using a high-dose intermittent (HDI) schedule, leading to higher maximal plasma concentrations, may provide an alternative means to block T790M-harbouring cells effectively. It may also potentially reduce wild-type EGFR-mediated adverse events noted with continuous dosing of EGFR TKIs. In this ongoing open-label study, the maximum tolerated dose (MTD), safety and pharmacokinetics (PKs) of HDI afatinib are being assessed in Part A in patients with advanced solid tumours. The MTD of HDI afatinib will be evaluated in Part B in patients with T790M-mutated advanced NSCLC following prior EGFR TKI therapy. Preliminary results from Part A are presented.

Methods
In Part A, patients with metastatic/unresectable solid tumours and adequate organ function were administered 90–200mg afatinib on Days 1–3 every 14 days in each 28-day cycle using a 3+3 dose-escalation design. Doses are escalated until MTD (primary endpoint), defined as the dose at which less than two of up to six patients develop dose-limiting toxicities (DLTs) in Cycle 1. PK sampling was conducted on Days 1–3, 8, 15–17, 29, 43 and 57, with C~max~ of afatinib on Day 3 of Cycle 1 being the secondary endpoint. In Part B, the MTD cohort will be expanded to specifically include EGFR TKI-pretreated advanced NSCLC patients with T790M mutations. Exploration of baseline and on-therapy plasma levels of detectable T790M is planned.

Results
To date, 16 patients have been recruited in Part A (90mg n=6; 120mg n=3; 150mg n=4; 200mg n=3; male/female n=8/8; median age 65 years; never smokers/ex-smokers n=10/6; primary tumour site lung n=9; known T790M mutation n=7). The most common drug-related adverse events (DRAEs) were diarrhoea, rash, dermatitis acneiform and nausea. DRAEs of Grade ≥3 were seen in one patient at 90mg (Grade 3 worsening cellulitis [Cycle 1; DLT] and urosepsis [Cycle 2]) and one patient at 150mg (Grade 3 dehydration, hypokalaemia, hypophosphataemia, diarrhoea [Cycle 2]). Preliminary response data on evaluable T790M-mutated NSCLC patients will be presented as available. Preliminary PK analyses suggest 150mg afatinib once daily for 3 days is sufficient to achieve total plasma C~max~ concentrations at or above the predicted IC~50~ value for T790M. Afatinib trough plasma concentrations will also be presented.

Conclusion
HDI afatinib elicited a manageable safety profile up to 200mg on Days 1–3 every 14 days. Total plasma C~max~ concentrations at or above the predicted efficacious threshold for T790M inhibition were already achieved in the 150mg cohort. Treatment in the 200mg cohort is ongoing. Additional cohorts may be included to explore shorter drug-free dosing periods. 1. Solca F, et al. JPET 2012;343:342–50. 2. Miller V, et al. Lancet Oncol 2012;13:528–38.

Background
MET, a receptor tyrosine kinase, and its ligand, hepatocyte growth factor (HGF), play a key role in cancer progression and prognosis. Aberrant activation of the HGF/MET pathway can enhance invasion, proliferation, and survival of cancer cells, providing a rationale for developing therapeutics that block MET activation. Onartuzumab was engineered as a unique recombinant humanized one-armed anti-MET monoclonal antibody that inhibits HGF-induced MET signaling without agonistic activity.

Methods
This 2-stage study was the first in Japanese patients to evaluate efficacy, safety, and pharmacokinetics (PK) of onartuzumab or onartuzumab in combination with erlotinib. In Stage 1—a 3+3 dose-escalation stage—patients with advanced solid tumors, refractory to the standard of care or for which there is no standard of care, received onartuzumab at doses of 4, 15, or 30 mg/kg IV once every 3 weeks until disease progression. In Stage 2—a combination stage—onartuzumab at a dose of 15 mg/kg IV once every 3 weeks was given in combination with erlotinib 150 mg/day to patients with advanced MET-positive non–small-cell lung cancer who had received at least 1 prior platinum-containing regimen (as regards EGFR-TKI, only 1 regimen was permitted); this regimen was continued until disease progression. Exploratory biomarker analyses were also conducted.

Results
In Stage 1, 9 patients (male/female: 6/3) were enrolled. Median age was 68 years. There were no dose-limiting toxicities (DLTs) and the maximum tolerated dose was not reached at 30 mg/kg. Hypoalbuminemia (33.3%) and constipation (33.3%) were the most frequent adverse events (AEs). Hypoalbuminemia was the only AE occurring at grade 3 severity, indicating that onartuzumab was well tolerated up to 30 mg/kg. In Stage 2, 6 patients were enrolled (male/female: 1/5; adeno/squamous: 5/1; EGFR wild type/mutant: 3/3; median age 69 years). There were no DLTs. The most frequent AE was diarrhea (83.3%). Grade 1/2 AEs occurred in all patients. There was one grade 3 case of each of deep vein thrombosis, pulmonary embolism, rash, hypoxia, dermatitis acneform, diarrhea, and neutropenia. No grade 4/5 AE was observed. PK analysis from patients in Stages 1 and 2 indicated dose proportionality of C~max~ and AUC. No drug–drug interaction between onartuzumab and erlotinib was observed. In Stage 2, progression-free survival was beyond 6 months in 2 patients (7.2 and 12.2 months); 1 patient achieved a partial response. Median circulating HGF concentration after onartuzumab was elevated to approximately three times the baseline level.

Conclusion
Onartuzumab alone or with erlotinib was well tolerated in Japanese patients. The PK profile of onartuzumab was not affected by co-administration with erlotinib.

Background
In the UK approximately 35,000 people die from lung cancer annually, the majority from NSCLC. Chemotherapy is one of the main treatments for advanced NSCLC but those treated will still only live for an average of 9 or 10 months after diagnosis. Chemotherapy damages tumour cell DNA, and NSCLC tumours that respond to chemotherapy are less able to repair this damage. Olaparib blocks the Poly (ADP-ribose) polymerase (PARP) enzyme which is essential for DNA repair. It is hypothesized that if DNA repair is prevented then this will cause cancer cell death. The UK National Cancer Research Institute Lung Clinical Studies Group, as part of the National Cancer Research Network/AstraZeneca initiative, have developed this clinical trial to investigate whether or not giving Olaparib following chemotherapy will benefit patients with NSCLC who have responded to initial chemotherapy treatment by prolonging the time before the tumour re-grows. The study is funded by a research grant from Cancer Research UK (C16728/A14917) and an investigator sponsored grant and free drug from AstraZeneca. The trial is sponsored by Velindre NHS Trust, and coordinated by the Wales Cancer Trials Unit, Cardiff, UK.

Methods
A UK multicentre randomised phase II trial. Eligible patients include histological diagnosis of stage IIIB/IV squamous/non-squamous non small cell lung cancer, ECOG PS0-1, age>=18, chemonaive and having given informed consent. Figure 1 Patients are initially registered before induction chemotherapy after which if there is evidence of radiological response (partial or complete) they will be randomised to either Olaparib (300mg po bd q21) until disease progression, or placebo. Those with stable disease or progression will not be eligible for the main trial and will receive local standard treatment. The primary endpoint of the randomised trial is progression-free survival based on RECIST v1.1 with secondary endpoints of safety, tolerability, feasibility of use, response, overall survival and tumour volume reduction. The median PFS for patients with CR/PR after 3 – 4 cycles of induction chemotherapy treatment is expected to be 3 months. With 90% power and a one-sided α of 0.2, 114 participants are required to demonstrate statistical significance between the arms if the true hazard ratio for Olaparib compared to placebo is 0.65, based on the logrank test. We therefore aim to recruit 57 participants into each arm, over a 12 month accrual period, with minimum participant follow-up of at least 6 months. The primary analysis of data will be performed after 98 PFS events.

Results
Not applicable

Conclusion
Not applicable

Background
We evaluated the risk of clinical trial failure and the cost of drug development for patients with NSCLC between 1998 and 2012

Methods
For assessment of drug development we used trial disclosures from publically available resources, such as clinicaltrials.gov and others. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use clinically significant, treatment-relevant endpoints, such as response rate, progression-free and overall survival. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. A compound that had completed a phase I clinical trial was classified as successful if there was an ongoing, completed, or currently recruiting phase II clinical trial found. A compound that had completed a phase II clinical trial was similarly classified as successful if there was an ongoing, completed or currently recruiting phase III found. A compound that had completed a phase III clinical trial was classified as successful if there was an official FDA approved indication in our study population. In addition, a phase I/II trial was classified as a phase II trial and a phase II/III trial was classified as a phase III trial for analysis purposes. Follow up was completed until January 1, 2012. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD).

Results
2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11% (less than the expected industry aggregate rates of 16.5%). The biggest obstacle for approval was the success of phase III trials: success rate was only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development with biomarkers was US$1.4 billion, a 26% reduction when compared to overall lung cancer drug development costs of US$1.89 billion, which is within industry expectations. Potential savings may be even higher if fewer clinical trials are required for successful development.

Conclusion
Physicians that enroll patients in NSCLC trials should prioritize their participation in programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.

Background
EGFR tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with advanced NSCLC who harbor activating EGFR mutations. No large prospective trial has compared gefitinib, erlotinib and afatinib face-to-face. We did a network analysis comparing the three drugs against chemotherapy and among themselves.

Methods
We searched PUBMED, EMBASE, google scholar databases and abstracts from ASCO, ESMO and WCLC abstracts between 2000 and 2013 using relevant search terms. Prospective, randomized clinical trials comparing erlotinib, gefitinib, or afatinib to chemotherapy or one another as first-line therapy in patients with non-small-cell lung cancer were selected. Studies were included if they included only patients with EGFR activating mutations or if they reported relative efficacy within the EGFR positive subgroup. Endpoints of interest were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). Direct and indirect meta-estimates were generated in the context of linear mixed effects models, similar to the model of DerSimonian and Laird, with fixed effects for each relative comparison and random effects for each study. Heterogeneity across studies was tested using chi-squared and I[2] statistics in the manner of Higgins and Thompson. Confidence (CI) and Predictive intervals (PIs) were calculated using the study-to-study variance estimates from each linear mixed-effects model. Results were considered statistically significant if the CI and PI did not cross unity.

Results
Eight studies fulfilled search and inclusion criteria: OPTIMAL, EURTAC, LUX-Lung 3, LUX-Lung 6, IPASS, West Japan, North-east Japan, and First-SIGNAL. The pooled hazard ratio (HR) meta-estimate for PFS were as follows: erlotinib vs. chemotherapy - 0.25 (95% CI 0.14-0.43; 95% PI 0.11-0.58), afatinib vs. chemotherapy - 0.44 (95% CI 0.25-0.77; 0.19-1.03), gefitinib vs. chemotherapy - 0.43 (95% CI 0.29-0.63; 95% PI 0.21-0.90), erlotinib vs. afatinib - 0.57 (95% CI 0.26-1.23; 95% PI 0.21-1.55), erlotinib vs. gefitinib - 0.58 (95% CI 0.30-1.13; 95% PI 0.23-1.46), and afatinib vs. gefitinib - 1.02 (95% CI 0.52-2.00; 95% PI 0.41-2.58). The test of heterogeneity (for PFS) indicated moderately high study-to-study variability with Q = 17.7 on 5 degrees of freedom (p = 0.003) and I[2] of 72%. For ORR, The pooled odds ratio (OR) meta-estimate for erlotinib vs. chemotherapy was 8.2 (95% CI 4.5-15.1; 95% PI 3.9-17.5), afatinib vs. chemotherapy was 5.5 (95% CI 3.4-8.8; 95% PI 2.9-10.5), gefitinib vs. chemotherapy was 4.1 (95% CI 2.7-6.3; 95% PI 2.3-7.6), erlotinib vs. afatinib was 1.5 (95% CI 0.7-3.3; 95% PI 0.6-3.7), erlotinib vs. gefitinib was 2.0 (95% CI 0.9-4.1; 95% PI 0.8-4.7), and afatinib vs. gefitinib was 1.3 (95% CI 0.7-2.5; 95% PI 0.6-2.8). The test of heterogeneity indicated moderate study-to-study variability with Q = 7.32 on 5 degrees of freedom (p = 0.198) and I[2] of 32% (For ORR). There were no statistically significant differences for overall survival.

Conclusion
Erlotinib, gefitinib and afatinib improved clinical outcomes when compared with chemotherapy. There were no statistically significant differences in the comparison among erlotinib, afatinib, and gefitinib.

Background
The outcomes of brain metastasis (BM) from non-small cell lung cancer (NSCLC) remain poor even with optimized option of stereotacic radiosurgery (SRS), whole brain radiotherapy (WBRT), surgery, chemotherapy or a combination. We purposed to identify the efficacy of tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) using with conventional therapy on BM patients from NSCLC and clarify the association between treatment outcome and EGFR gene mutation status.

Methods
Totally 282 cases treated basically with conventional therapy alone or in addition to TKI were enrolled in our study from 2003-2012. Among these patients, 178 cases were treated with conventional therapy (Non-TKI group) and 104 cases were treated with TKI plus conventional therapy (TKI group). EGFR mutation analysis was performed in 107 patients with tissue samples.

Results
With a median follow-up of 28 months (range, 22-34 months), the median overall survival (MOS), median progression-free survival of intracranial disease (MPFSI), and median progression-free survival for extracranial disease (MPFSE) in TKI group was 31.9, 19.8, and 19.6 months compared with 17.0 (P<0.0001), 12.0 (P<0.0001), and 12.3 (P<0.0001) months in Non-TKI group, respectively. Within TKI group, patients harboring EGFR mutation had longer time of 20.4 months to extracranial disease progression than 14.1 months in EGFR negative patients (P=0.032). In additional, EGFR positive patients had nonsignificant but potential improvements of 37 and 22.7 months for MOS and MPFSI compared with 23.4 and 16.9 months in EGFR negative patients (P=0.094, P=0.382 respectively).

Conclusion
Administration of TKI agents with conventional therapy might be benefit for patients with BMs from NSCLC on MOS, MPFSI and MPFSE compared with conventional therapy. Patients harboring EGFR mutation not only had significant improvement for PFSE with TKI plus conventional treatment compared with EGFR negative patients, but also non-significantly better outcome of OS and PFSI as well.

Background
In non-small cell lung cancer (NSCLC), the well-developed epidermal growth factor receptor (EGFR) is important therapeutic target. EGFR activating gene mutations have been proved strongly predictive of response to EGFR-tyrosine kinase inhibitors in NSCLC. However, both in daily clinical practice and clinical trials, patients with unknown EGFR gene status (UN-EGFR-GS) are very common. In this study, we assessed efficacy and tolerability of sequential treatment of first-line pemetrexed followed by icotinib in Chinese advanced lung adenocarcinoma with UN-EGFR-GS.

Methods
We retrospectively analyzed 15 patients with advanced lung adenocarcinoma, who were treated first-line chemotherapy with pemetrexed and sequential using icotinib. The clinical characteristics, toxicity and survival status were collected through reviewing medical records, electronic preserved data, interviewing with patients or their family members. The overall survival (OS) was defined as the time of starting pemetrexed treatment to death or lost to follow up. The clinical course of included patients and treatment were prospectively monitored.

Results
Totally, 15 patients with advanced lung adenocarcinoma were included, 9 females, 6 males. The median age is 57 years old (ranges: 40-73y). Of the 15 patients, 11 were non-smokers and 4 were smokers. All the patients at least received one cycle of pemetrexed chemotherapy, and then were administered with icotinib. Four cases were received pemetrexed combined with carboplatin, 8 combined with cisplatin, and 3 as single use. The mean cycles of pemetrexed given to patients were 3.8(1-6cycles). The response rate to pemetrexed was 20.0% (3/15), stable disease 33.3% (5/15), progressive disease 40% (6/15). The icotinib use of 4 patients was for the purpose of maintenance therapy, 11 for second line. The response rate to icotinib was 40% (6/15), stable disease 26.7% (4/15), progressive disease 33.3% (5/15). There was no grade 3-4 toxicities observed during icotinib treatment phase. The most common grade 1-2 toxicities were rashes (26.7%), diarrheas (30%), elevated aminotransferase (13.3%) and elevated BUN (6.7%). At the end of follow up, 8 patients were dead, 7 alive. The median OS was 22.6 months. Two patients were still on icotinib treatment.

Conclusion
The sequence of first-line pemetrexed-based chemotherapy followed by icotinib treatment is a promising option for advanced lung adenocarcinoma with UN-EGFR-GS in China. The sequence yielded promising results with acceptable toxicity. The role of the sequential model for advanced NSCLC patients with adenocarcinoma histology should be further investigated in studies with larger sample sizes.

Background
Central European countries are among those with the highest incidence rates of lung cancer and most of these cancers are smoking-related. The INSIGHT observational study aimed at assessing prevalence and treatment of patients with EGFR mutations in clinical practice in Central Europe. Here we report on the overall findings of this study.

Methods
Patients with NSCLC and tested for EGFR mutations between 15 November 2011 and 31 March 2013 in 14 centers from 6 Central European countries (Austria, Czech Republic, Hungary, Poland, Slovakia, Slovenia) were enrolled. EGFR mutations were determined by sequencing, PCR or other techniques.

Results
Here we report data on 1009 NSCLC patients who had been enrolled into the INSIGHT study. The patients had the following characteristics: median age 64 (range 29-93), 62% male, 38% female, 99.9% Caucasians, ECOG performance status 0-1, 2 and 3-4 in 79%, 17% and 4%; 19% never-smokers, 46% former smokers, 35% current smokers; 79% adenocarcinomas, 2% adenosquamous carcinomas, 7% squamous cell carcinomas, 9% NSCLC NOS and 3% others; tumor stages I-II, III and IV in 15.5%, 24% and 60.5% of the patients. EGFR mutations were found in 163 (16%) patients. Patients with mutations had the following characteristics: age median 66 (range 34-89) years, 46% male, 54% female, 47% never-smokers, 38% former smokers, 15% current smokers; performance status was recorded in 153 patients and was 0, 1, 2 and 3 in 30%, 50%, 14% and 6% of the patients. The mutation-positive tumors had the following characteristics: 85% adenocarcinomas, 4% adenosquamous carcinomas, 4% squamous cell carcinomas, 2% NSCLC NOS, and 5% others. Among patients with mutations, exon 18 mutations were seen in 7% of the patients, exon 19 mutations in 50% of the patients including deletions in 39%, exon 20 mutations in 12%, exon 21 mutations in 39% including L858R in 28% of the patients. Detailed data on systemic treatment were available for 122 patients with advanced EGFR mutation-positive NSCLC and most of these patients received EGFR-directed tyrosine kinase inhibitors during the course of their disease.

Conclusion
The INSIGHT observational study demonstrated that EGFR mutation testing has been established in the participating centres in Central Europe. The mutation rate of 16% is on the upper limit of the range seen in Western European countries but a potential selection bias for testing of patients with higher likelihood of harboring EGFR mutations cannot be excluded. Systemic treatment in patients with EGFR mutations is similar to treatment patterns observed in other countries. This study was supported by Boehringer Ingelheim Regional Center Vienna.

Background
The INSIGHT observational study aimed at assessing the management of NSCLC patients with EGFR mutations in clinical practice in 10 centres from 6 Central European countries. As part of this project, the treatment strategies used in these patients have been determined.

Methods
Between 15 November 2011 and 31 March 2013, EGFR mutations were determined by one of the established methods in 1009 patients with NSCLC. The systemic treatments of patients with EGFR mutation positive NSCLC were assessed.

Results
Comprehensive data on systemic treatment were available for 122 patients with EGFR mutation-positive tumors. Mutations were located in exon 19 (52.5%), exon 21 (38.5%), exon 20 (10.7%), and exon 18 (6.6%). In 8 patients, mutations were present in 2 or 3 exons. Patients with mutation-positive tumors had the following characteristics: median age 66 (range 41-83) years; 58 (48%) males, 64 (52%) females; 51 (42%) never smokers, 51 (42%) former smokers, and 19 (16%) current smokers; performance status at diagnosis ECOG 0, 1, and equal or above 2 in 28 (23%), 60 (49%), 20 (16.5%) of patients; in 14 (11.5%) patients PS was not recorded; adenocarcinomas 98 (80%), adenosquamous 6 (5%), squamous 7 (6%), not otherwise specified 2 (2%) and 9 (7%) patients had other types of carcinoma. A total of 116 patients presented with stage IIIB or IV and received the following first-line therapy: gefitinib in 66 (57%), erlotinib in 4 (3%), chemotherapy in 43 (37%), and chemotherapy plus bevacizumab in 3 (3%) patients, respectively. In 22 (19%) patients EGFR test results were obtained after initiation of first-line therapy and the majority of these patients (n=20) received chemotherapy as first-line therapy. For patients tested before the first-line treatment initiation, median time between the date of test result and initiation of first-line therapy was 16 days. Regardless of the lines of treatment, EGFR-directed tyrosine kinase inhibitors were administered to 90 out of 116 (78%) patients. No major differences in treatment strategies between various countries were observed.

Conclusion
The INSIGHT observational study demonstrated that most patients with advanced EGFR mutation-positive NSCLC had been treated with EGFR-directed tyrosine kinase inhibitors either in the first- or second-line setting. This study was supported by Boehringer Ingelheim Regional Center Vienna.

Background
RET fusions were recently identified in non-small cell lung cancer (NSCLC) and considered to be a druggable target of NSCLC. There are several small molecules which can potentially inhibit RET kinase activity. Among them, sorafenib, sunitinib and vandetanib are clinically available, and sorafenib is the most promising agent which showed potent anti-RET activity (the IC50 against RET is 0.0059-0.047 μM) in preclinical studies. However, it is difficult to evaluate the efficacy of this agent in RET-positive NSCLC in large clinical trials, because RET-positive NSCLC makes up only 1% to 2% of NSCLC cases. Therefore, we conducted a pilot study to evaluate the efficacy and feasibility of sorafenib treatment in a small number of patients with RET fusion-positive NSCLC.

Methods
Eligible patients had advanced or recurrent NSCLC, were more than 20 years old, had undergone treatment with one or more previous chemotherapy regimens, had an ECOG performance status (PS) 0–2, adequate organ function and provided informed consent. The RET fusion gene was confirmed by a split FISH assay. Patients received 400 mg of sorafenib orally twice daily. The treatment was continued until disease progression or unacceptable toxicity.

Results
From March 2012 to April 2013, three patients were enrolled. The first patient was a 62-year-old female who had stage IV NSCLC and had received three prior chemotherapy regimens (pemetrexed with cisplatin, docetaxel and erlotinib) and two courses of palliative radiation (thorax and whole brain) before being enrolled this study. The second patient was a 38-year-old male who had recurrence after thoracic surgery and had received two prior chemotherapy regimens (pemetrexed with cisplatin and docetaxel) and whole brain radiation before enrolling this study. The third patient was a 75-year-old female who had recurrence after thoracic surgery and had received one prior chemotherapy regimen (Docetaxel). The pathological diagnoses were adenocarcinoma in two patients and NSCLC not otherwise specified in one patient. Their tumors did not demonstrate any EGFR mutations or ALK fusion. The RET partner genes were KIF5B in two patients and unknown in one patient. All three patients were treated with sorafenib at 400 mg orally twice daily. Unfortunately, there was no response. The best responses to sorafenib in the patients were PD, SD and SD. In the third patient, sorafenib treatment was continued for over seven weeks. The most common toxicities were hand-foot syndrome, hypertension and diarrhea. The third patient needed a dose reduction to 400 mg once daily due to grade 3 hand-foot syndrome.

Conclusion
Sorafenib seems to have some efficacy for the RET fusion-positive NSCLC, but no dramatic response was observed.

Background
Locally advanced (III A-bulky N2, III B) lung cancer is often treated with chemotherapy with or without radiotherapy. The VEGF inhibitor bevacizumab has demonstrated clinical activity in advanced lung adenocarcinoma. To explore the role of bevacizumab in the neoadjuvant setting, we performed the phase II trial to assess the safety and efficacy of neoadjuvant bevacizumab plus pemetrexed and carboplatin followed by surgery in conventionally unresectable, locally advanced (III A-bulky N2, III B) lung adenocarcinoma. Here we report interim outcomes.

Methods
The single-center, single-arm, phase II study investigates neoadjuvant bevacizumab (7.5mg/kg) plus pemetrexed (500 mg/m[2]) and carboplatin (AUC=5) followed by surgery for patients with unresectable, locally advanced (III A-bulky N2, III B) lung adenocarcinoma. Four cycles of neoadjuvant therapy were planned and neoadjuvant therapy was administered on day 1 of every 21-day cycle. Patients’ resectability was assessed by a medical team (including thoracic surgeons, medical oncologists, and radiologists) and surgery was scheduled 3-4 weeks after last neoadjuvant therapy. Primary and secondary endpoints were resectability rate and perioperative complications.

Results
20 patients were enrolled. All patients received bevacizumab plus pemetrexed and carboplatin. Neoadjuvant-related toxicities included: epistaxis (5%), fatigue (30%), infusion reaction (5%), nausea (5%), diarrhea (10%), insomnia (5%), headache (5%); neutropenia (25%), anemia (10%), thrombocytopenia (5%). Grade 3 or above toxicities included fatigue (10%); neutropenia (5%), thrombocytopenia (5%). Complete response was observed in 1 patient, partial response in 8, stable disease in 10, and progressive disease in 1. After neoadjuvant therapy, 14 (70%) patients underwent surgery. Median time between last neoadjuvant therapy and surgery was 25 days (22-28). R0 resection was achieved in 10 patients. No patient died in the perioperative phase. Postoperative complications were manageable and included pneumonia (1 patient), atelectasis (1), subcutaneous emphysema (2), arrhythmia (1). No perioperative hemorrhage events, thromboembolic events and wound-healing problems were observed.

Conclusion
The treatment modality of neoadjuvant bevacizumab plus pemetrexed and carboplatin followed by surgery appears to be safe and feasible in patients with unresectable, locally advanced (III A-bulky N2, III B) lung adenocarcinoma. Clinical trial information: NCT01588704.

Background
Study NCT01203917 assessed the efficacy and safety/tolerability of the EGFRTKI gefitinib in Caucasians with EGFR mutation-positive NSCLC (previously reported). Here we report post-hoc EGFR mutation analyses of plasma-derived, circulating-free DNA (cfDNA), including efficacy (objective response rate [ORR] and progression-free survival [PFS]) by mutation subtype (Exon 19 deletions; L858R point mutations).

Methods
Patients: Caucasians; ≥18 yrs; PS 0-2; histologically confirmed Stage IIIA/B/IV EGFR mutation-positive NSCLC eligible for first-line treatment. Treatment: 250mg gefitinib once-daily until disease progression. Primary endpoint: ORR (investigator assessment); secondary endpoints: disease control rate, PFS, overall survival, and safety/tolerability (previously reported). Mandatory tumor and plasma samples were collected at baseline (all screened patients). Post-hoc exploratory analyses: correlation between clinical characteristics and baseline plasma cfDNA EGFR mutation status; concordance of plasma cfDNA mutation subtype determination (Exon 19 deletions; L858R) with tumor; gefitinib efficacy by plasma cfDNA mutation subtype (Exon 19 deletions; L858R).

Results
Of 1060 screened patients with NSCLC, 118 presented with activating, sensitizing EGFR mutations, 106 of whom were enrolled and treated with gefitinib (Full Analysis Set; 71% female; 97% adenocarcinoma; 64% never-smoker). Mutation rate for samples with known mutation status: 14% (118/859) in tumor, 10% (82/784) in plasma. Among 784 patients with baseline plasma samples of known mutation status, histology (adenocarcinoma vs non-adenocarcinoma; odds ratio [OR] 5.54; p=0.0012), smoking status (never- vs ever-smoker; OR 4.39; p<0.0001), and gender (female vs male; OR 2.68; p=0.0004) independently predicted plasma cfDNA mutation status. Concordance in 652 matched tumor and plasma- Exon 19 deletions: 96% (confidence interval [CI]: 95-98); L858R: 98% (CI: 96-99). Using tumor mutation status as reference, EGFR mutation test sensitivity in cfDNA (Exon 19 deletions) was 68% (CI: 56-78), specificity was 100% (CI: 99-100); positive predictive value: 100% (CI: 93-100); negative predictive value: 96% (CI: 94-98); results were similar for L858R, with numerically lower sensitivity (62%; CI 44-78%). ORR for patients with both EGFR mutation-positive tumor and plasma for Exon 19 deletions (n=45): 82% (CI: 69-91); L858R (n=20): 65% (CI: 41-85) (Table). Median PFS for patients with both EGFR mutation-positive tumor and plasma for Exon 19 deletions (25 events): 10.3 months (CI: 8.5-12.4); L858R (11 events): NC. Table

ORR with gefitinib: baseline tumor vs plasma samples
	Tumor				Plasma
	N	Responders	ORR, %	95% CI	N	Responders	ORR, %	95% CI
All mutations	106	74	70	61-78	65	50	77	65-86
Exon 19 deletions	69	50	73	61-82	45	37	82	69-91
L858R point mutations	33	21	64	47-78	20	13	65	41-85
Median PFS with gefitinib for baseline tumor vs plasma samples
	Tumor (FAS, N=106)				Plasma (N=65)
	Events, N	PFS, months	95% CI		Events, N	PFS, months	95% CI
All mutations	61	9.7	8.5-11.0		36	10.2	8.5-12.5
Exon 19 deletions	41	9.6	8.0-11.0		25	10.3	8.5-12.4
L858R point mutations	19	NC	NC		11	NC	NC

NC, not calculated

Conclusion
EGFR mutation status assessment of common mutations from plasma-derived cfDNA can be considered when tumor tissue is unavailable. In this context, cfDNA might be used to guide treatment decisions with EGFRTKI therapy, as patients with mutation-positive cfDNA, regardless of mutation subtype, appear to have similar ORR to tumor mutation-positive patients.

Background
Advanced NSCLC patients have an extremely poor prognosis with a 5-year survival rate of less than 5%. In 2009, the European Medicines Agency approved gefitinib, a reversible EGFR tyrosine kinase inhibitor, at the dose of 250 mg daily for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR activating mutations. As the first-line EGFR mutation positive data at that time were mainly in Asian populations a prospective phase IV, open-label, single-arm study of first-line gefitinib in Caucasian patients was presented: this trial confirmed the activity and efficacy of gefitinib in 106 Caucasian patients (Douillard EMCTO 2013). In the same way, we initially collected retrospectively, continuing then prospectively, the data of NSCLC EGFR-mutation positive Italian patients treated with first-line gefitinib, with the aim to evaluate the therapeutic outcomes and the approaches beyond progression in a “real life population”.

Methods
We collected data of patients who started gefitinib from June 2009 until May 2013. Primary endpoint was the evaluation of first line outcomes, in terms of: objective response rate (ORR), duration of treatment, progression-free survival (PFS), overall survival (OS) and safety. Secondary endpoint is the evaluation of the outcomes beyond progression to gefitinib. Here we report the results of first-line gefitinib of a large number of Caucasian patients.

Results
Data of 203 patients from 23 Italian Institutions were collected. The main patients characteristics were: median age 67 (range: 33-87), male/female 76/127, ECOG performance status (PS) 0/1/2/3/4 in 89/92/18/2/2 patients, 90.6% adenocarcinoma (in our study the percentage of carcinoma non otherwise specified was 1.5%), never/former/current smoker in 129/64/10, del19/L858R/uncommon in 128/57/18. In one case a T790M mutation ex novo was found in association with the deletion of the exon 19 (not all the patients were tested for this mutation at baseline). A median time for obtaining the EGFR test result was 8-15 days (more than 30% of the patients got the results in less than one week). Patients evaluable at the time of data lock were 168, of these 3 (1.8%) patients achieved a complete response, 72 (42.9%) a partial response for an ORR of 44.7%, 54 (32.1%) patients were stable. Median treatment with gefitinib was 38 weeks. Main toxicities were: grade 3-4 skin rash and diarrhea in 1.8% and 4.2%, respectively. Treatment was definitely stopped due toxicity in 4.2% of patients. After progression in 5 cases a re-biopsy was performed and 94 (56%) received a second-line treatment.

Conclusion
BE-Positive is the first study reporting results of first-line gefitinib in a large "real life population" of Caucasian patients. Data were firstly collected in a retrospective fashion, than in a prospective way. This study shows that Caucasian patients reported lower ORR when indirectly compared to Asian counterparts, but this is probably due to the partial analysis of the patients, excluding at this time those who are still on treatment. However, the tolerability profile was excellent and the median time of treatment is quite overlapping to literature data. The outcomes of PFS, OS and treatment beyond gefitinib progression will be reported when mature.

Background
Radiation therapy (RT) is a principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in the central nervous system, it is uncertain whether upfront brain RT is necessary for EGFR mutated lung adenocarcinoma patients with BM treated with EGFR-TKIs.

Methods
We identified all patients treated from 2006-2012 with EGFR-mutated NSCLC with BM at our institution. We evaluated the clinical outcomes of these patients who developed brain metastases and received EGFR-TKI and/or CNS radiotherapy. Endpoints included intracranial progression (ICP), extracranial progression (ECP) and overall survival (OS). All endpoints were measured from development of BM.

Results
222 patients were identified. Patients were excluded if they were on an EGFR-TKI prior to the development of BM (n=57), if they possessed a de novo EGFR-TKI resistance mutation (n=6), or if there was incomplete data (n=48). Of the remaining 111 patients, 64 were treated initially with erlotinib, 32 with whole brain RT (WBRT), and 15 with partial brain radiation (PBI). Median follow-up was 20 months (mos). Median age was 61 years (range 26-89). Patients were predominantly female (68%), stage IV at diagnosis (92%), never-smokers (61%), RPA class II (87%), and neurologically asymptomatic (82%). Patients had a median of 4 BM (range 1-30) with a median largest diameter of 10mm. In the erlotinib group, erlotinib was given as monotherapy in 91% and combined with chemotherapy in 9% of patients. 38% of these patients (n=24) eventually received WBRT or PBI a median of 17 mos after diagnosis of BM (range 5-40 mos). Median OS for the whole cohort was 29 mos with a 2-yr OS of 59%. There was no significant difference in OS between the WBRT (median 35 mos) and erlotinib (median 26 mos) groups (p=0.59 by Cox model) though patients treated with PBI had a longer OS (median 64 mos). On univariate analysis, KPS (p<.001), RPA class (p<.001) and PBI (vs. erlotinib, p=.005) were significant, with only RPA class (p=.007) and KPS (p<.001) remaining significant on multivariate analysis. Median time to intracranial progression (ICP) was 17 months for the entire cohort. There was a longer time to ICP in patients who received WBRT (median 24 mos) vs. erlotinib upfront (median 16 mos, p<.05), though this effect was no longer significant on multivariate analysis. Patients in the erlotinib or PBI group were more likely to fail intra-cranially as a component of first failure (58% and 71%, respectively), while upfront WBRT patients were more likely to fail extracranially first (76%).

Conclusion
The survival of EGFR-TKI naïve patients with EGFR-mutated NSCLC with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, but this effect is potentially due to other confounding variables. Though retrospective, this analysis suggests that deferring brain RT in favor of EGFR-TKI is a reasonable strategy for patients with EGFR-mutated NSCLC with BM.

Background
RET fusions are novel targetable drivers in non-small cell lung cancers. While the clinicopathologic profile of patients with RET fusion-positive tumors has been described in early-stage disease, little is known regarding clinical behavior in advanced unresectable disease.

Methods
Patients with advanced unresectable (stage IIIB/IV) pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, MAP2K1, ERBB2, PIK3CA, and AKT, and fusions of ALK or ROS1) were screened for RET fusions via dual-probe break apart FISH testing. Upstream partners were identified via RT-PCR and next-generation sequencing whenever possible. A retrospective review of patient records was conducted to determine response to systemic therapy and overall survival (OS). OS was calculated from diagnosis of metastatic disease and compared to patients with ALK and ROS1 fusion-positive, and EGFR- and KRAS-mutant lung cancers. Survival curves were estimated using the Kaplan-Meier method. Differences in survival between groups were assessed by the log-rank test.

Results
A RET fusion was found in 16% (n=12/76, 95%CI 8%-24%) of pan-negative tumors and 19% (n=10/48, 95%CI 10%-33%) of pan-negative tumors from never-smokers. Patients with RET fusion-positive tumors were predominantly never-smokers (83%, n=10/12, 2 patients with 7 and 10 pack-year histories, respectively) with advanced-stage disease at diagnosis (92%, n=11/12 stage IIIB/IV). Fusion partners were identified in 6 patients (4 KIF5B-RET, 1 TRIM33-RET, 1 NCOA4-RET). Eight patients (67%) received first-line platinum-based therapy, 6 of whom (50%) received maintenance pemetrexed and/or bevacizumab. Partial responses (PRs) were seen in 3 patients (38%) and stable disease (SD) in 5 patients (62%). 1-year OS on chemotherapy and median progression-free survival were 47% and 7.3 months, respectively. 1-year and 2-year OS for patients whose tumors harbored RET, ROS1, or ALK fusions, or EGFR or KRAS mutations is summarized below (Table). OS was not significantly different between RET, ROS1, ALK, or EGFR cohorts when RET was compared to each of the latter three cohorts separately. The presence of a RET fusion was associated with improved OS compared to the presence of a KRAS mutation (HR 0.39, 95%CI 0.21-0.74, p=0.004). Of the 11 patients with RET fusion-positive lung cancers, 4 patients (36%) were treated with cabozantinib on a phase 2 protocol (NCT01639508) with disease shrinkage of -66%, -32%, -23%, and -19% via RECIST v1.1.

Driver Detected	OS 1-year [95%CI]	OS 2-year [95%CI]
RET (n=12)	100%	71% [25%-92%]
ROS1 (n=9)	88% [39%-99%]	88% [39%-99%]
ALK (n=44)	91% [77%-97%]	73% [55%-85%]
EGFR (n=102)	85% [76%-91%]	58% [47%-67%]
KRAS (n=117)	60% [50%-66%]	26% [18%-35%]

Conclusion
Response to platinum-based first-line therapy in patients with RET fusion-positive tumors is comparable to historical controls. Survival in patients with RET fusion-positive disease is comparable to patients with EGFR mutations and other recurrent gene fusions (ROS1 and ALK) and improved compared to patients with KRAS mutations. Cabozantinib is worthy of further study in RET fusion-positive lung cancers.

Background
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib, are used to treat non-small cell lung cancer with EGFR sensitive mutations. The response rates to EGFR-TKI for mainly adenocarcinoma patients with EGFR mutations are very high, ranging from 62-85%, with a median progression-free survival (PFS) of 8.0-13.1 months and a median overall survival of 21.6-35.5 months. EGFR mutations can also be detected in a few non-adenocarcinoma tumors, however, the response of such cases to EGFR-TKIs is controversial. This study assessed the effectiveness of EGFR-TKIs in non-adenocarcinoma non-small cell lung cancer (non-adeno NSCLC) with EGFR mutations.

Methods
Nine institutions of the Lung Oncology Group in Kyushu (LOGIK) joined in this study. The primary endpoint was the response rate (RR), and the secondary endpoints were the disease control rate (DCR), overall survival, duration of disease control and the incidence of adverse events. A total of 43 cases of non-adeno NSCLC who were treated with EGFR-TKIs were retrospectively enrolled in this study.

Results
This study included 28 males and 15 females, and 18 of the 43 were never smokers. The ages of the patients ranged from 42 to 83 years, with a mean of 67 years. The pathological types were squamous cell carcinomas in 26 patients, adenosquamous cell carcinomas in six, large cell carcinomas in six, and others in five patients. Of these 43 cases, 18 with EGFR mutations were included in the analysis. The incidence of EGFR mutations was significantly higher in females than in males (80.0% vs. 21.4%, p<0.01), and in never smokers than in smokers (72.2% vs. 20.0%, p<0.01). The EGFR-TKIs administered were gefitinib in 27 patients and erlotinib in 16. In the patients with EGFR mutations, the RR and DCR were 83.8% and 93.8%, which were significantly superior to the rates in patients without EGFR mutations, which were 4.1% and 20.1%, respectively (p<0.01).

Conclusion
Even in patients with non-adeno NSCLC, the mutation of EGFR gene was a predictive factor for the response to EGFR-TKI treatment. In this meeting, we will show a detailed report based on the pathological analysis performed by the pathological committee of the LOGIK.

Background
Erlotinib is an EGFR tyrosine kinase inhibitor with promising efficacy in treating lung adenocarcinoma. However, after the failure of two lines of EGFR-TKI and chemotherapy, the remaining treatment choices are few. The purpose of this study is to demonstrate the efficacy of erlotinib as ≥ third-line treatment in this kind of patients.

Methods
We retrospectively reviewed the chart records of our stage IV pulmonary adenocarcinoma patients who were diagnosed and treated in our hospital between July 2004 and June 2013. Clinical data, type of response to the treatment, time to disease progression, the duration between starting erlotinib treatment and end of first line EGFR-TKI treatment, and overall survival time were collected.

Results
Seventy-four patients were enrolled and they all had been treated with EGFR-TKI, either as a first-line therapy or following platinum-based chemotherapy. Thirty-nine patients had response to initial EGFR-TKI treatment and thirty-five of them did not. The median progression free survival (PFS) of front-line EGFR-TKI is 8.2 months. All received erlotinib as salvage treatment after they had disease progressed to both chemotherapy and front-line EGFR-TKI. The median PFS of erlotnib as salvage treatment for patients with and without response to front-line EGFR-TKI are 5.1 months and 4.9 months (p=0.768), respectively. Detailed data of subgroup analysis regarding EGFR mutation status and clinical characteristics will be presented in the meeting.

Conclusion
In pulmonary adenocarcinoma patients who were heavily treated, erlotinib is still a choice whether or not the patient was responsive to previous EGFR-TKI.

Background
Since the IPASS-study was published in 2009, EGFR-TKI has been the recommended first line treatment for EGFR-mutation positive (EGFR-m[+]) non-small cell lung cancer (NSCLC) patients. In Sweden, the indication for EGFR-mutation testing of NSCLC, based on national and regional consensus guidelines, has gradually shifted from clinical characteristics (age, sex and smoking status) to histological subtypes (non-squamous cell lung cancer). The aim of this study was to characterise the EGFR-mutation spectrum in a representative Swedish NSCLC cohort in relation to patient demographics, histology, prognosis and sample quality parameters. We also wanted to assess the adherence to guidelines regarding molecular testing and treatment recommendations.

Methods
NSCLC patients tested for EGFR mutations 2010-2012 (n=669) were identified in records at the molecular pathology unit in Uppsala that serves five regional hospitals in central Sweden. Histopathology and molecular reports were reviewed, and age, sex, stage, smoking, performance status and overall survival data were retrieved from regional and national lung cancer registries. For the EGFR-mutated sub-group a medical chart follow-up was performed to evaluate TKI-treatment and chemotherapy response. In addition, for estimation of potential clinical selection bias and true molecular testing coverage, we compared the study cohort, referred for EGFR-analysis, to the entire source NSCLC population (n=2527) in the five covered counties.

Results
The EGFR-tested cohort consisted of 83% adenocarcinomas (AdC), 5% squamous cell carcinomas (SqCC), 11% large cell carcinomas not otherwise specified (LC) and 1% where histology was not reported. The EGFR mutation frequency was 10% (n=66), with an expected frequency distribution within exons 18-21. Mutations were enriched in women, never smokers and AdC. The analysed tissue was collected using bronchoscopic px (29%), core needle biopsy (46%), cytology (1%), and surgical specimens (22%), with mean tumor cell fraction of 30% (range 5–85%). With regard to the subgroup in focus for TKI-treatment, i.e. patients in stage IIIb/IV with non-squamous histology, 36% were referred for EGFR-testing, with an increasing trend between 2010 and 2012 (27.9–40.1%). Of the patients with EGFR-m[+] and advanced disease 38% received EGFR-TKI in first line, 46% in later lines and 16% had not received EGFR-TKI at time of follow up. There was a trend for worse overall survival in the subgroup not receiving TKI-treatment, however this difference did not reach statistical significance.

Conclusion
The results regarding the EGFR mutation frequency and patient demographics is similar to previously published data on western populations. Surprisingly, despite guidelines regarding molecular testing, the majority of patients in advanced stage with non-squamous histology were not referred for EGFR-analysis and only a minority of the EGFR-m[+] patients received TKI-treatment in first line. Our results highlight the need for follow-up of treatment and diagnostic algorithms in population-based real life patient cohorts combining quality registries, pathology review and clinical records.

Background
Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) have demonstrated dramatic response rate and prolonged progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutation. However, PFS and overall survival (OS) among those patients who were treated with EGFR TKIs are variable. In this study, we evaluated predictors of clinical outcome in EGFR mutant NSCLC patients treated with EGFR TKIs.

Methods
From January 2008 to December 2010, a total of 148 patients who had metastatic or recurrent NSCLC with activating EGFR mutation treated with either erlotinib or gefitinib as a first-line (n=10) and a second-line or more treatment (n=138) were retrospectively reviewed. The first analysis with a total 148 patients and subgroup analysis with patients who had received EGFR TKIs as second-line treatment (n=105) were undertaken to identify any difference in the clinical and molecular features among those patients who were treated with EGFR TKIs.

Results
Median follow-up duration was 21.9 months (range, 1.1-62.5) and median number of cycles was 7 (range, 1-44). The median PFS and OS for a total 148 patients were 10.6 months (95% CI, 9.0-12.2) and 21.8 months (95% CI, 18.5-25.1), respectively. The survival outcomes were similar between first-line and second-line or more line of treatment of EGFR TKIs (p=0.512 for PFS, p=0.699 for OS). A high number of metastasis sites (3-6 versus 1-2) was associated with shorter PFS and OS (median PFS 9.9 vs. 11.9 months, p=0.019; median OS 16.4 vs. 22.2 months, p=0.021, respectively) in univariate analysis, but not in multivariate analysis. According to the clinical and molecular markers by multivariate analysis, there were no significant differences in PFS. When PFS was dichotomized by median 11 months for 105 patients treated with EGFR TKIs as second-line therapy, no significant differences in any clinical or molecular features were found between longer PFS and shorter PFS groups.

Conclusion
Despite the heterogeneity in PFS among EGFR mutant patients treated with EGFR TKIs, no significant differences of clinical features were noted, suggesting more understanding of the variability of underlying biology should be needed.

Background
In patients with non-small cell lung cancer (NSCLC), the development of liver metastasis (LM) is a poor prognostic factor that compromises survival time. Whether combine systemic treatment with local treatment for liver metastases has benefit for NSCLC patients with LM is unknown. How to select a suitable patient for receiving local treatment is also unclear.

Methods
We retrospectively reviewed 713 pulmonary adenocarcinoma patients and 85 patients that developed LM at any time point in the course of the disease were identified for analysis. We use radiofrequency ablation (RFA) for local treatment of liver metastases. The indication of RFA were liver metastases number less than three with maximal size less than 5cm. RFA was performed with real-time ultrasonography guidance. Dynamic computed tomography (CT) scan was done 1 month after RFA for evaluating local therapeutic efficacy. An SPSS version 19 statistical software package (SPSS INC, Chicago, IL, USA) was used for data analysis.

Results
The independent prognostic factors after LM were Performance status、epidermal growth factor receptor (EGFR) mutation and LM numbers. There were 47 patients (54.7%) have LM nodules number less than three. The median overall survival (OS) in patients with LM nodules number less than three was 7.9 months comparing with 2.9 months in patients with nodules number over three ( P < 0.001). The independent prognostic factors for LM nodules number less than three patients were performance status and presence of brain metastasis. There were total six patients received RFA. Patients who received RFA treatment had better median OS after LM than those not ( 19.1 v.s 6.0 months, P = 0.04)

Conclusion
We recommend patients with better performance status (ECOG <2) without brain metastasis can consider RFA for liver metastases.

Background
Decreasing tumor burden may reduce/delay cancer-related symptoms experienced by patients with NSCLC and favorably impact global health-related quality of life (HRQoL). Dacomitinib is an irreversible small-molecule inhibitor of all catalytically active members of the human epidermal growth factor receptor (HER) family of tyrosine kinases (EGFR/HER1, HER2, and HER4), and has shown anticancer activity and manageable toxicity in NSCLC clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012; Mok et al 2012]. Qualitative assessment of the adverse event (AE) burden from the patient’s perspective helps to provide a greater understanding of the overall impact of treatment-related AEs than grading of AEs alone. Here we report the impact of dacomitinib on core lung cancer symptoms in patients with previously treated, advanced NSCLC in three phase II clinical trials [Janne et al 2009; Park et al 2010; Ramalingam et al 2012].

Methods
Dacomitinib was evaluated in advanced NSCLC, in patients who had received prior chemotherapy and erlotinib (study 1002; n=66) [Janne et al 2009], in Korean patients who had received prior chemotherapy and erlotinib or gefitinib (study 1003; n=43 in phase II) [Park et al 2010], and in comparison with erlotinib in patients who had received prior chemotherapy (study 1028; n=188) [Ramalingam et al 2012]. In each of the trials, HRQoL was evaluated using validated patient-reported outcome (PRO) measures. Disease/treatment‑related symptoms were recorded using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core module (EORTC QLQ-C30) and its lung cancer module (LC13). Scores were summarized using the mean (and 95% CI) for each group and plotted over time. Mean changes from baseline were also reported.

Results
On-study questionnaire mean completion rates were high (>90% of patients answered at least 1 question across treatment cycles) in each of the studies. Across the three trials, patients reported a rapid onset (typically ≤3 weeks of starting therapy) of improvement in key lung cancer symptoms (e.g. cough, pain in chest, and pain in arm/shoulder) relative to baseline scores, with symptomatic improvements remaining durable over the course of therapy. Diarrhea and sore mouth were the most commonly reported class-related AEs (for dacomitinib in studies 1002 and 1003, and for both dacomitinib and erlotinib in study 1028). These AEs peaked at weeks 3–6, were manageable, and remained stable or improved over time with intervention. Compared with erlotinib in study 1028, clinically meaningful improvements from baseline (>10 points difference on a 0–100-point scale) in key NSCLC symptoms (cough, dyspnea, pain in chest, pain in arm/shoulder, fatigue, and physical function) were reported by patients receiving dacomitinib. The difference in mean change from baseline was more favorable with dacomitinib at most time-points.

Conclusion
Dacomitinib demonstrated consistent improvements in common NSCLC symptoms across three clinical trials in pretreated patients with advanced NSCLC. PROs such as cough and pain improved within 3 weeks of initiating treatment, with benefits sustained throughout the course of therapy. Dacomitinib also demonstrated greater improvements in key NSCLC symptoms than erlotinib.

Background
Overall survival (OS) in lung cancer is poor but not without heterogeneity. Molecular pathways and “driver mutations” have been identified in the struggle to improve prognosis and treatment outcome. Some constitute predictive factors for the use of new drugs: tyrosine kinase inhibitors (TKI) such as erlotinib and gefitinib target mutations within the EGFR-gene and crizotinib ALK-translocations. The presence of the two molecular features are usually mutually exclusive. Crizotinib is a newly registered drug in Sweden. Our aim was to define the clinical importance of molecular pathological testing for ALK-EML4-translocations in non-small lung cancer (NSCLC).

Methods
We have retrospectivly examined all histological and cytological sampling for molecular testing on NSCLC-patients at Karolinska University Hospital since 2010. 3 complementary methods to identify ALK-EML4-translocations were used: fluorecense-in-situ-hybridisation (FISH) with Vysis ALK break apart probe, immunohistochemistry (IHC) with ALK-EML4 specific AB and real time PCR with an in-house developed method able to detect the five most common fusiontranscripts with inversion INV(2)(p21p23).

Results
211 FISH-test were conducted, whereof 70 performed on 160 consecutive surgically removed NSCLC. A total of 30 ALK-EML4-translocations were identified, 3 of which amongst the 70 surgical samples. No case of concomittant ALK-EML4-translocation and mutation in the EGFR-gene was identified. The characteristics of ALK-EML4 positive patients were as follows: 19 were women and 11 men with an average age of 58.2 years. 20 were never smokers, 1 current smoker, 9 ex smokers with an average time of 20.5 years since smoking cessation. Adenocarcinomas represented 29 cases and adenosquamous cancer 1 case (currently smoking woman). Staging according to IASLC 7[th] edition showed : 4 patients in stage I, 1 in stage II, 7 in stage III and 18 in stage IV. 16 patients, all with metastatic disease, were treated with crizotinib (15 with 250mg 1x2 and 1 patient with 200mg 1x1). Crizotinib was given to: 0 patients as 1[st] line, 4 patients as 2[d] line, 6 as 3[d ]line, 5 as 4[th] line and 1 as 5[th] line. At time of data collection 9 patients had discontinued crizotinib-therapy. 7 patients had ongoing treatment with an average duration of 125 days. 12/16 patients obtained partial remission, 3 stable disease and 1 disease progression. 3/9 discontinued crizotinib-therapy due do severe side effects: 1 due to persistant visus toxicity grade ≥2, 1 due to pneumonitis occuring at treatment day 42 and 1 due to liver toxicity with CTCAE grade ≥2 occurring at treatment day 37. Only the case with pneumonitis resultated in death at day 43. No QTc-syndromes and no hematological toxicity CTCAE grade ≥3 occurred.

Conclusion
Identifying patients with ALK-EML4-translocations, the predictive factor for crizotinib-treatment, offers new treatment options and realistically balanced hope in the severe setting of metastatic NSCLC. In our experience, the predictive value of a positive ALK-EML4-test is high on histological material and crizotinib offers good treatment outcomes after progression on platinum-based chemotherapy but for shorter time than what is expected for TKIs in patients with activating EGFR-mutations.

Background
To date, three EGFR Tyrosine Kinase inhibitors (TKIs) gefitinib (G), erlotinib (E), and afatinib (A) have been compared to standard chemotherapy as first line treatment in patients with advanced NSCLC harboring EGFR mutations. We performed a systematic review and meta -analysis in order to estimate through indirect comparisons the relative risk benefit associated to each drug.

Methods
The major databases were searched for published and unpublished randomized control trial up to March 2013. Data extraction was performed by two independent reviewers and focused on benefit (ORR, PFS) and selected harm outcomes (diarrhea, rash, nail disorders, hypertransaminasemia). The adjusted indirect comparisons were performed using the random effect method described by Bucher and Glenny approach for Hazard Ratio (HR) for PFS and relative risk (RR) for the other outcome measures.

Results
All EGFR TKIs fared better when compared with chemotherapy in terms of PFS: overall HR 0.40 (95%CI 0.30-0.54); G vs E HR 1.34 (95%CI 0.63-2.86), G vs A HR 0.74 (95%CI 0.53-1.04), E vs A HR 0.55 (95%CI 0.31-0.99). The relative probability of ORR was G vs E 0.96 (95%CI 0.69-1.34), G vs A 0.79 (95%CI 0.49-1.28), E vs A 0.82 (95%CI 0.49-1.38). Indirect comparisons for safety showed RR for diarrhea G vs E 0.8 (95%CI 0.63-1.01), G vs A 0.32 (95%CI 0.20-0.51), E vs A 0.38 (95%CI 0.24-0.62); for rash G vs E 1.0 (95%CI 0.82-1.22), G vs A 0.31 (95%CI 0.15-0.65), E vs A 0.31 (95%CI 0.15-0.65); for hypertransaminasemia G vs E 2.29 (95%CI 1.63-3.23). Nail disorders affected 57% of patients treated with A, 15% with G, and 4% with E.

Conclusion
Results of our analysis showed that all treatments have similar activity and efficacy while the toxicity profile was less favorable for A with a significant higher risk of diarrhea, rash, and nail disorders. Based on these safety results, we suggest that A may not be the first choice for upfront treatment in EGFR mutated patients. Confirmation is warranted by ongoing prospective head to head RCTs.

Background
Lung cancer is the leading cause of cancer death in the world, and the non-small cell lung cancer accounts for more than 80% of the lung cancer. Among patients with non-small cell lung cancer, tumor epidermal growth factor receptor (EGFR) activating mutations were mostly found in patients with adenocarcinoma and were associated with a better prognosis than EGFR wild-type tumors. The relationship between EGFR activating mutations and their primary tumor location in the lungs was not reported before.

Methods
We retrospectively reviewed the data of our pulmonary adenocarcinoma patients who had received complete staging and received tumor EGFR mutation analysis. The association between EGFR mutation status, patients smoking status, patient’s gender and primary tumor location were analyzed.

Results
205 cases were reviewed. There are 126 patients with tumor EGFR mutations, including 115 patients with classic EGFR mutations (exon 19 deletions or L858R), and 79 patients were without EGFR mutation. There are statistically significant association between tumor EGFR mutations and primary tumor location in right upper lobe (P=0.007); especially in RB1 segment (P=0.018), and primary tumor location of exon 19 deletions occurred more frequently in right upper lobe (P<0.001). There were no significant associations between patients smoking status and primary tumor location(P=0.659), nor was patients gender and primary tumor location (P=0.473).

Conclusion
There are statistically significant association between EGFR mutation and primary tumor location in right upper lobe of patients with adenocarcinoma of the lungs.

Background
CNS metastasis happens not infrequently in patients with non-small cell lung cancer, reaching upto 25%. The presence of CNS metastasis is a major decision factor of planning primary treatment. Furthermore, predictors for CNS metastasis could be used for selecting patients who may get the potential benefit of prophylactic cranial irradiation.

Methods
We retrospectively analyzed the clinicopathologic data of 233 patients with non-small cell lung cancer who underwent brain MRI at the time of diagnosis between Jan 2008 and Dec 2012. Chi-square analysis and multivariate logistic regression model was used to find risk factors for CNS metastasis.

Results
Forty-five (19.3%) patients had initial CNS metastasis (41 brain parenchymal metastasis and 4 leptomeningeal seeding). Chi-square analysis revealed that never-smoking (28.7% vs. 13.7%, P=0.005), lung metastasis (29.6% vs 14.8%, P=0.009), bone metastasis (35.7% vs 13.1%, P<0.001), adenocarcinoma (24.8% vs 10.9%, P=0.008), and EGFR activating mutation (44.4% vs 18.3%, P=0.004) were associated with CNS metastasis. However, pleural, pericardial, adrenal, liver metastasis, gender, age, and T/N staging did not have correlation with CNS metastasis. Multivariate analysis indicated that only EGFR activating mutation status (adjusted HR, 4.3; 95% CI, 1.6-11.2; P=0.003) and bone metastasis (adjusted HR, 4.0; 95% CI, 1.5-10.6; P=0.005) had independent association with CNS metastasis.

Conclusion
In the current study, EGFR activating mutation status and presence of bone metastasis are independently associated with initial CNS metastasis. Initial staging work-up for patients with these clinicopathologic features should include brain MRI. Results of this study can be used for selecting candidates for prophylactic cranial eradiation or adjuvant EGFR tyrosine kinase inhibitor treatment.

Background
Lung cancer is the leading cause of cancer deaths globally, and NSCLC comprises 85% of lung cancers. Patients with advanced (stage IIIB or IV) NSCLC have a poor prognosis. Current second-line chemotherapeutics demonstrate a median overall survival (OS) of 8 months and 1-year survival of 30%. Factors that may influence clinical activity include age, ECOG performance status (PS), number of prior therapies, and EGFR- and KRAS-mutation status. The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation upon interaction with its ligands PD-L1 and PD-L2. Nivolumab, a fully human IgG4, PD-1 receptor blocking monoclonal antibody, was evaluated in a phase 1 study (CA209-003; NCT00730639) in patients with various tumors, including previously treated advanced NSCLC. In this study, treatment with nivolumab demonstrated durable objective responses and prolonged stable disease in a portion of patients from this NSCLC cohort (Topalian S, et al. N Engl J Med. 2012;366:2443-54). We present the updated findings from assessment of clinical activity to nivolumab in subpopulations of the NSCLC cohort from this study.

Methods
Patients received nivolumab (1–10 mg/kg IV Q2W) for ≤12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. An analysis of clinical activity by select patient characteristics was performed from the NSCLC cohort of this trial.

Results
129 patients with NSCLC (non-squamous [n=74], squamous [n=54], unknown histology [n=1]) received nivolumab at 1, 3, or 10 mg/kg as of March 2013 (Table). Association of clinical activity with baseline characteristics will be assessed for the following subgroups: age ≥70 and <70 years, gender, ECOG PS 0 and ≥1, number of prior therapies 1–2 and ≥3, prior tyrosine kinase inhibitor (TKI) therapy, EGFR-mutation status, and KRAS-mutation status.

Table

Baseline characteristic[a]		NSCLC patient population (n=129)
Median age (range), y		65 (38–85)
Gender, n (%)
	Male	79 (61)
	Female	50 (39)
ECOG PS, n (%)
	0	27 (21)
	1	100 (78)
	2	2 (2)
Number of prior therapies, n (%)
	1	25 (19)
	2	34 (26)
	3	27 (21)
	≥4	43 (33)
Prior therapy, n (%)
	Platinum-based chemotherapy	128 (99)
	TKI	36 (28)
[a]Data on EGFR- and KRAS-mutation status are pending.

Conclusion
Nivolumab demonstrated encouraging clinical activity in patients with previously treated advanced NSCLC. Clinical activity by patient subgroups may provide insights into the influence of patient and tumor characteristics on response to nivolumab. An update of the data regarding clinical activity of nivolumab therapy in these subgroups of the NSCLC cohort will be presented.

Background
Background. Antitumor immunotherapy to target tumor antigens is considered reasonable and promising in lung cancer (LC). In our early phase of clinical investigation, the safety and efficacy of dendritic cell (DC) based vaccine therapy in patients with non-small-cell lung cancer (NSCLC) have been shown. Following successful early phase results, we designed a phase III trial of DC- vaccine in IIB-IIIA stage NSCLC patients to investigate clinical benefits as the primary endpoint, and immune response markers as secondary endpoint.

Methods
One hundred and twenty eligible patients with IIB-IIIA stage NSCLC, ECOG 0-1, without autoimmune disorders were enrolled into the study. Patients were randomly allocated into two groups: 1 st - patients who received DC-vaccine as immunotherapy after surgery (lobectomy or pneumonectomy), 2nd - comparison group of patients who received surgery only. Original construction of DC-vaccine have been used: autologous DCs of monocytic origin loaded with mechanically heterogenized microparticles of tumor cells. Maturation state and functional activity of DCs were evaluated by the expression of cell surface markers CD83/86, HLA-DR and IL-12 p35/p40 mRNA levels. DC in amount 4,62±0,37x106 per injection were injected intravenously in 1-3 courses with 6 months interval. One course consisted of 5 injections with one-month interval. Clinical and immunological monitoring of DC-vaccine immunotherapy was performed.

Results
The table summarizes median overall survival (OS) and disease free survival rates at 1, 2, 3, 4 and 5 years for NSCLC patients. Figure 1 Hazard ratio (HR) for recurrence: 0.384; 95:CI = 0.1736 - 0.8510; p = 0.018. The most pronounced changes in the immune system have been defined only after fourth DC-vaccine administration. These changes consist in the significant reduction of T-reg number and their ability to secrete TGF-β, significant increasing the CD8[+]IFN[+] CTL number and functionality and CD4[+] memory cell number, Th1–polarization of immune responses, significant increasing of the RANTES/MIP-1α mRNA ratio (p<0,001). ROC analysis revealed that CD8[+]IFN[+] number (Se=66,67%;Sp=100%; AUC=0,83; p=0,0066), CD4[+] memory cell number (Se=100%;Sp=75%; AUC=0,875; p=0,0094), TGF-β mRNA level (Se=75%;Sp=100%; AUC=0,889; p=0,017), RANTES/MIP-1a mRNA ratio (Se=100%;Sp=83,33%; AUC=0,83; p=0,0066) are the most important immune response markers which associated with clinical outcome after DC-vaccine therapy in NSCLC patients.

Conclusion
Adjuvant therapy with DC-vaccine in IIB-IIIA stage NSCLC patients is highly effective approach for prevention metastasis development and recurrence of disease in post-operative period. Patients with low volume disease constitute a target group for the development of effective immune and clinical responses after DC-vaccine therapy.

Background
Ipilimumab is a fully human IgG1 monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4) and augments antitumor T-cell responses. In a global phase 2 study in subjects with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), ipilimumab administrated in a phased schedule in combination with paclitaxel/carboplatin, improved immune-related progression-free survival with an acceptable safety profile. A pronounced benefit was observed in squamous NSCLC. We conducted the phase 1 study of ipilimumab in combination with paclitaxel/carboplatin in Japanese patients with NSCLC.

Methods
Target population was Japanese subjects with stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC. Patients received ipilimumab 3 mg/kg or 10 mg/kg (starting at Cycle 3) in addition to paclitaxel 175 mg/m2 and carboplatin AUC=6 every 3 weeks for up to 6 cycles. Dose limiting toxicity (DLT) was evaluated during the first two cycles of ipilimumab administration (Cycle 3 and Cycle 4). The recommended dose (RD) was defined as the highest dose at which no more than 2 out of 6 ipilimumab-treated patients experienced a DLT.

Results
A total 15 patients were enrolled and 12 patients received ipilimumab (female/male=1/11, range of age =53-70, stage IIIB/IV/recurrent=0/9/3, squamous/non-squamous= 1/ 11, ipilimumab 3 mg/kg / 10 mg/kg=6/6). DLTs were observed in 2 out of 6 ipilimumab-treated patients in ipilimumab 3 mg/kg arm (febrile neutropenia, amylase increased / 1patient, thrombocytopenia / 1patient) and 1 out of 6 ipilimumab -treated patients in ipilimumab 10 mg/kg arm (entercolitis, total-bilirubin increased, lipase increased). Of 10 patients evaluable for tumor response based on RECIST criteria, partial response and stable disease were achieved in 6 and 4 patients, respectively.

Conclusion
For Japanese patients with NSCLC, the RD of ipilimumab in combination with chemotherapy was identified as 10 mg/kg and it demonstrated acceptable safety profile and potential efficacy. Two global Phase 3 studies are ongoing in subjects evaluating ipilimumab 10 mg/kg in combination with chemotherapy in advanced squamous NSCLC (with carboplatin/paclitaxel) and extensive stage SCLC (with etoposide/platinum).

Background
In the ongoing global randomized phase III study PROFILE 1007, the oral ALK inhibitor crizotinib improved progression-free survival, response rate, and global quality of life compared with single-agent chemotherapy in patients with advanced, previously treated ALK-positive NSCLC. While hematologic toxicities were more common with chemotherapy, a greater number of non-hematologic toxicities were reported with crizotinib. Several factors may have complicated the comparison of AEs, including longer treatment duration with crizotinib, standard use of prophylactic medications with chemotherapy but not with crizotinib, and a higher rate of continuing treatment beyond RECIST-defined progressive disease with crizotinib. Here we examine whether differences in treatment duration may have impacted the incidences of selected AEs and non-fatal serious AEs (SAEs) observed in this study.

Methods
In PROFILE 1007, 172 patients received crizotinib 250 mg orally BID and 171 patients received chemotherapy (pemetrexed 500 mg/m[2] or docetaxel 75 mg/m[2], both IV q3w). AEs were classified and graded using CTCAE v4.0. For this analysis, AEs of interest included those occurring in ≥10% of patients with ≥5% absolute difference between treatment groups, as well as non-fatal SAEs. To evaluate the potential impact of differential treatment duration on these AEs, exposure-adjusted incidence rates were calculated using person-years of exposure (PYE; the sum of the individual person-years at risk for a particular AE).

Results
Median treatment duration was almost three-fold longer with crizotinib (31 weeks) versus chemotherapy (12 weeks). Incidences and exposure-adjusted incidence rates of AEs of interest are shown in the table below. After accounting for treatment duration, the rates of nausea, constipation, elevated transaminases, edema, upper respiratory infection, dizziness, pulmonary embolism, hypokalemia, and non-fatal SAEs were comparable between the crizotinib and chemotherapy groups. The rates of diarrhea, vision disorder, vomiting, dysgeusia, and syncope were significantly higher with crizotinib. Exposure-adjusted incidence rates for other AEs, as well as additional analyses to account for treatment duration will be presented.

	Crizotinib (n=172)			Chemotherapy (n=171)
AE	Incidence (%)	Incidence rate/1000 PYE		Incidence (%)	Incidence rate/1000 PYE	P value[a]
Diarrhea	60	1848		19	592	<0.0001
Vision disorder[b]	60	2449		9	268	<0.0001
Nausea	55	1577		37	1527	0.842
Vomiting	47	1083		18	561	0.001
Constipation	42	832		23	789	0.789
Elevated transaminases[b]	38	716		15	470	0.056
Edema[b]	31	568		16	473	0.430
Dysgeusia	26	463		9	269	0.045
Upper respiratory infection[b]	26	419		13	401	0.865
Dizziness[b]	22	346		8	236	0.195
Pulmonary embolism[b]	6	78		2	62	0.686
Hypokalemia	5	70		2	63	0.846
Syncope	3	39		0	0	0.025
Non-fatal SAEs	29	440		21	640	0.105

[a]For differences in incidence rates, two‑sided.[b]Clustered term.

Conclusion
This initial analysis suggests that differences in treatment duration between two drugs may have a significant impact when comparing AE profiles. Depending on the safety profiles of the two drugs, analyses to account for treatment duration may be appropriate when a large disparity has been observed.

Background
Erlotinib is a key treatment option in all advanced or metastatic non-small cell lung cancer (mNSCLC) subtypes regardless of epidermal growth factor receptor (EGFR) status. Despite side effect advantages over cytotoxic chemotherapy, a shortcoming of erlotinib is pH-dependent absorption. Recent evidence highlights this inconsistency further by showing reduced plasma levels of various oral tyrosine kinase inhibitors (TKIs) in the presence of acid suppression therapy. Given the prevalence of gastroesophageal reflux disease (GERD) and diseases that use acid suppression, goals of this study are to determine if coadministration of acid suppressants and erlotinib affected clinical outcomes in advanced NSCLC patients.

Methods
A cohort of patients with mNSCLC from 2007-2012 who received erlotinib through our institution was retrospectively reviewed. In addition to stage, age, gender, performance status, and NSCLC subtype, patients were then identified as receiving acid suppression (AS) if their pharmacy records included either proton pump inhibitors (PPIs) or histamine blockers (anti-H2). Patients were considered taking these medications concomitantly if dates for acid suppressants overlapped their erlotinib prescription by ≥ 20% of the treatment duration. Patients who received erlotinib for ≥ 1 week were analyzed for progression free survival (PFS) and overall survival (OS).

Results
544 stage IIIB/IV NSCLC patients were identified. Of those, 507 were eligible for review. Median age was 64 years, gender 235 male, and 272 female. By subtype, 318 were adenocarcinoma, 106 squamous, 43 poorly differentiated, 11 large cell, and 29 not otherwise specified (NOS). 124 patients received concomitant AS therapy with the most common type being PPIs. Analysis unselected for EGFR mutational status yielded median PFS and OS in the AS versus no-AS group as 1.4 v 2.3 months (p<0.001) and 12.9 v 16.8 months (p=0.003), respectively. In multivariate analysis with gender, NSCLC subtype, and performance status, Cox proportional hazards ratios for PFS and OS for AS and non-AS groups were 1.83 (95% CI 1.48-2.25) and 1.37 (95% CI 1.11-1.69) respectively. Subgroup analysis by subtype in the AS and non-AS groups was significant in the following types (p<0.05): adenocarcinoma, PFS 1.8 v 2.7 months, OS 13.2 v 17.5 months; squamous PFS 1.5 v 2.3 months, OS 13.4 v 15.9 months; poorly differentiated PFS 0.8 v 2.0 months, OS 7.6 v 15.5 months, and NOS PFS 1.2 v 1.7 months, OS 10.8 v 14.5 months. Effects of AS in EGFR mutated patients are being studied.

Conclusion
Despite limitations of retrospective analyses, this large population based study demonstrates erlotinib efficacy is dependent on gastric acidity and OS can be adversely affected. This is the first study the authors are aware of that demonstrates an impact on clinical outcomes by co-administration of acid suppression and TKI therapy. Caution should be taken with co-administration of other TKIs and acid suppressive therapy.

Background
The echinoderm microtubule-associated protein like-4—anaplastic lymphoma kinase (EML4--ALK) fusion oncogene defines a novel molecular subset of non-small cell lung cancer (NSCLC). Crizotinib (Xalkori) has been approved for patients with locally advanced or metastatic NSCLC that is ALK positive. However, the clinicopathological characteristics of patients with the EML4-ALK gene have not been identified completely.

Methods
The clinicopathological characteristics of 200 Chinese patients with advanced NSCLC were analyzed retrospectively．Clinical factors including age, sex, smoking history, pathological type, biopsy method, site of biopsy and interval between biopsy and the identification of EML4-ALK fusions and the status of epidermal growth factor receptor (EGFR) mutation were analyzed to investigate possible correlations with EML4-ALK fusions.

Results
Among the 200 patients with NSCLC enrolled, 56 (28.0%) harbored the EML4-ALK gene in this retrospective study. EML4-ALK fusions could not be detected in 22 of 200 patients (11.0%) because of insufficient tissue. The median age was 53 as a whole. The median ages of ALK positive and negative groups were 48 and 55 years, respectively. Patients with the EML4-ALK gene were significantly younger than patients without EML4-ALK (p＜0.001). The detection rate of EML4-ALK rearrangement in patients with tumor or metastatic lymph nodes resection was significantly higher than patients with needle biopsy(p=0.003). If the interval between biopsy and the identification of EML4-ALK fusions was less than 48 months, the detection rate of EML4-ALK rearrangement was significantly higher compared with the interval more than 48months(p=0.020). Among the 200 patients, 103(51.5%) patients had received EGFR mutation detection. Only 1 case harbored both EML4-ALK rearrangement and EGFR mutations. The incidence of EML4-ALK rearrangement in patients with EGFR wide type（42.5%,37/87）was significantly higher than EGFR mutant type（6.3%,1/16）. No significant difference in the distribution of sex, smoking history, pathological type, and site of biopsy(lung tumor compared with metastatic lymph nodes) was observed between ALK positive and negative groups (p = 0.140, 0.103, 0.438 and 0.217, respectively).

Comparisons of patient characteristics according to genotype

		EML4-ALK gene
Characteristics	Total,n	Positive,n	Negative,n	P value
		56	122
Age(years)
Median	53	48	55	＜0.001
Range	25-76	25-74	27-76
Sex
Male	78	20	58	0.140
Female	100	36	64
Smoking history
Never/light smokers	143	49	94	0.103
Smokers	35	7	28
Pathological type
Adenocarcinoma	161	52	109	0.438
Non- adenocarcinoma	17	4	13
Biopsy method
Tumor and metastatic lymph nodes resection	158	49	109	0.003
Needle biopsy	20	7	13
Site of biopsy
Lung tumor	99	27	72	0.217[$]
Metastatic lymph nodes	72	26	46
Pleura	2	1	1
Others	5	2	3
Interval between biopsy and the identification of EML4-ALK fusions (months)
≤48	167	55	112	0.020
＞48	11	1	10
EGFR mutation(n=103)
Mutant type	16	1	15	0.005
Wide type	87	37	50

$:lung tumor compared with lymph nodes

Conclusion
We identified younger age and EGFR wide type as clinicopathological features of patients with advanced NSCLC harboring EML4-ALK fusion genes. The detection rate of EML4-ALK rearrangement was significantly higher in patients with tumor or metastatic lymph nodes resection and the interval less than 48 months between biopsy and the identification of EML4-ALK fusions.

Background
Progression-free survival (PFS) and response rate (RR) to EGFR tyrosine kinase inhibitors (TKIs) vary in P with NSCLC driven by EGFR mutations, suggesting that other genetic alterations may influence oncogene addiction. In our experience, high BRCA1 mRNA expression negatively influenced PFS among EGFR mutant P treated with erlotinib. We hypothesiszed that since olaparib can attenuate and/or prevent BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these P.

Methods
This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics (PK), and clinical activity of orally administered olaparib in combination with gefitinib in EGFR mutant advanced NSCLC. In a standard 3+3 design based on toxicity, P were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Steady state Cmax and AUC (AUC0-12) were determined following dosing on Day 7 and 14 of the study and the Day 14:Day 7 treatment ratio calculated to assess the impact on olaparib steady state exposure of dosing in combination with gefitinib

Results
22P have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (6) and 250mg TDS (7). Median age, 65 (range 39-84); male, 6P; PS 0-1, 20P; EGFR TKI treatment-naïve, 13P; Most toxicities were G1-2, including anemia, leucopenia, nausea, diarrhea, asthenia, rash and anorexia; G3 drug-related events included lymphopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 3 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions for both drugs were needed. 1P died due to pulmonary embolism unrelated to study treatment. 19P were evaluated for response: For those not previously treated P, partial responses (PR) were observed in 8P (72,2%), stable disease (SD) in 3P (27,27%) and no progressive disease (PD) (0%). In previously TKI treated P, 3 (37,5%) PR were observed, 3 (37,5%) SD, and 2 (25,5%) PD. Durable PR and SD were observed in both EGFR TKI-naïve and previously treated P.10P are still on treatment. The derived PK parameters were the following: 100mg bid: Olaparib Cmaxss(ug/ml): Day 7:4.60; Day 14:3.53; TR(range) 0.77. AUCss(ug.h/ml) Day 7:24.4; Day 14:18.9; TR:0.79. 200mg bid: Cmaxss(ug/ml): Day 7:7.68; Day 14:6.60; TR:0.89. AUCss(ug.h/ml) Day 7:48.6; Day 14:40.0; TR:0.85; 200mg tds: Cmaxss(ug/ml): Day 7:8.35; Day 14:8.01; TR:0.96. AUCss(ug.h/ml) Day 7: 34.9*; Day 14: 32.7*; TR: 0.94; 250mg tds: Cmaxss(ug/ml): Day 7:9.85; Day 14:9.46; TR:0.97. AUCss(ug.h/ml) Day 7: 44.2*; Day 14: 43.3*; TR: 0.99. *AUC quoted is AUC0-6 not AUCss.

Conclusion
This phase IB trial of gefitinib plus olaparib, confirms the tolerability of the combination and the anti-tumor activity seen warrants further exploration in treatment-naïve patients. MTD of olaparib was 200mg TDS. Co-administration of gefitinib does not appear to have altered steady state exposure to olaparib. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC is planned to start in 2013. The final recommended dose of olaparib will be 200 mg TDS

Background
HER2 amplifications and/or mutations are rare genetic alterations in NSCLC accounting for approximately 4%. Preliminary clinical data suggested efficacy of trastuzumab in patients with HER2 IHC3+ status or FISH positivity. The heat shock protein HSP90 is a molecular chaperone that modulates stability and/or transport of intracellular client proteins including HER2. In breast cancer HSP90 inhibition has shown anticancer activity in HER2-positive patients after trastuzumab failure. Here we are investigating the efficacy of the combination of trastuzumab and the HSP90 inhibitor AUY922 in lung cancer patients with aberrant HER2.

Methods
This phase II study recruits metastatic NSCLC patients with HER2 overexpression (immunohistochemistry, DAKO-score 3+) or amplification (fluorescence in situ hybridization) or activating mutation after at least one previous standard treatment. In the first part of the study, patients are treated with trastuzumab only. CT scans are scheduled every 6 weeks during treatment. In case of disease progression, patients receive the combination of trastuzumab and AUY922.

Results
The study was initiated this year and NSCLC patients are screened within the Network of Genomic Medicine Lung Cancer on HER2 overexpression, amplifications and mutations. Until now, we tested 720 tumor samples by FISH and 63 by genomic sequencing. We identified 55 patients with HER2 amplification, 34 with HER2 overexpression (Dako score 3+) and 7 patients showed a mutation in the HER2 gene (1 exon 19; 6 exon 20).

Conclusion
HER2 overexpression, amplification or mutation is a rare genetic alteration in NSCLC patients. Data on treatment with HER2 antibody trastuzumab and HSP90 inhibitor AUY922 will be presented.

Background
Lung cancer is the second most common cancer in United States. However, new molecular information whether arising from identification of key mutations, or Next Gen Sequencing (NGS) has lead to the fragmentation of this common disease into multiple and often very rare molecular subtypes. Even though this has enabled us to substantially improve survival in specific molecular subtypes with targeted agents, having sufficient numbers of patients to demonstrate the effectiveness of novel targeted therapies for each subtype has therefore become challenging, essentially impeding progress.

Methods
Use of sample size determination software allows for comparison of phase II trials with a target survival proportion at a given time T based upon Kaplan-Meier (KM) versus exponential (E) survival methods. This comparison was made in instances where the exponential distribution assumption is valid.

Results
The use of exponential survival fitting methods, in lieu of the currently implemented KM trial designs, to single arm phase II studies can routinely reduce patient numbers by 25-40% (Table) without compromising the statistical power. Another substantial advantage is that the variability in the survival information for the exponential fit estimate both before and after the median survival points is reduced. Since patient accrual is staggered ,this reduced variability allows for obtaining robust survival information with shorter follow up times T. Any additional follow-up beyond T only further improves the E estimate, but not the KM estimate. Thus, compared to the KM approach, the E approach will allow us to do single arm phase II trials with smaller numbers of patients without compromising statistical power. Robust survival estimates can also be achieved with shorter follow up periods. Figure 1

Conclusion
When conducting single arm phase II clinical trials with rare molecular entities of lung cancer, the exponential survival fitting method could replace the current standard approach. Robust survival information can be obtained with smaller numbers of patients and with shorter survival times. Detailed examples and analysis will be presented.

Background
Erlotinib and pemetrexed are novel agents used for the treatment of patients with advanced-stage NSCLC. Both are frequently used for the treatment of patients after failure of first-line chemotherapy. Sequential treatment strategies have become a very interesting topic in current oncology research. The role of sequential treatment in NSCLC has not been elucidated yet. Thus, we conducted this retrospective study to compare the efficacy of second-line pemetrexed monotherapy followed by third-line erlotinib (P-E) to treatment with the reverse sequence (E-P).

Methods
Clinical data of 57 patients with advanced (IIIB/IV) lung adenocarcinoma harboring wild-type epidermal growth factor receptor (EGFR) gene were analysed. 31 patients were treated with P-E and 26 patients with E-P sequence. Genetic testing was performed using PCR direct sequencing. The terminations of PFS and OS, as well as the estimations of survival probabilities, were performed using Kaplan Meier survival curves; all point estimates were accompanied by 95% confidence intervals. The differences in survival were tested using the log-rank test.

Results
The median progression-free survival (PFS) for patients treated with the P-E sequence was 3.6 months compared to 7.8 months for patients treated with E-P sequence (p=0.029). The median overall survival (OS) for patients treated with P-E sequence was 7.9 months compared to 26.3 months for patients treated with E-P sequence (p=0.006).

Conclusion
The study results proved significant improvement of both PFS and OS for patients treated with the E-P sequence as compared to the P-E sequence. Although the study was limited, its findings could have a great impact on the treatment of advanced-stage NSCLC. Thus, the role of the sequential treatment of NSCLC should be confirmed in a prospective randomised study in the future.

Background
Afatinib, an irreversible tyrosine kinase inhibitor of ErbB-family, has shown clinical benefits and prolonged progression free survival in EGFR mutated patients. Adverse effects related to afatinib such as diarrhea, stomatitis and rash can negatively impact on QoL and survival by interrupting treatment. Dose of TKI´s of EGFR are fixed regardless of weight or body surface (BS), which could affect the severity of treatment related toxicity.

Methods
We prospectively studied patients with advanced Non-small cell lung cancer (NSCLC ) treated with afatinib in order to determine if malnutrition and clinical factors are associated to higher incidence of severe toxicity. This study was approved by Ethics and Investigation Committees Prior treatment with afatinib (40mg), 84 patients was assessed. Nutritional status was assessed by Subjective Global Assessment (SGA) and muscle volume was determined by CT scan analysis using L3 as anatomic landmark (-29 +150 HU). Toxicity was obtained during 2 cycles by CTCAE 4.0, severe toxicity is defined as grades 3 and 4.

Results
Mean age was 59.3±14.8 years, 70.2% were women, 94% had adenocarcinoma, 91.7% had a good performance status (ECOG 0-1). Median weight and BS were 59.8±13.4 kg and 1.6±0.21 m[2]). Afatinib was indicated as 2[nd], 3[rd] and 4[th] line of treatment in 54.8%, 38.1%, and 7.12% of patients, respectively. Sixty percent of patients had some grade of malnutrition (SGA B+C). Severe diarrhea, mucositis and overall GI toxicity were present in 38.9%, 28.8% and 57.5% respectively. Fifty percent of patients required dose reduction, only 6 patients presented severe diarrhea and mucositis simultaneously with no statistical association (p=0.929). Factors associated to severe diarrhea, mucositis, overall gastrointestinal toxicity and dose reduction are shown in Table 1. Table 1 Related factors to Afatinib toxicity.

	Diarrhea G3/4 (%)	Mucositis G3/4 (%)	All GI toxicity G3/4 (%)	Dose reduction %
Female Male p	44.4 22.2 p=0.094	33.3 15.8 p=0.146	64.8 36.8 p=0.034	59.3 36.8 p=0.092
ECOG 0-1 >1 P	36.9 57.1 p=0.419	24.2 71.4 p=0.018	53.1 100 p=0.017	53.0 57.1 p=0.836
BMI ≤18.5 >18.5 P	47.1 31.6 p=0.179	38.5 17.6 p=0.05	55.9 59 p=0.79	50 56.4 p=0.584
Body surface ≤1.7m[2 ] >1.7m[2 ] p	40.7 33.3 p=0.572	0 38.9 p=0.001	36.8 64.8 p=0.0034	36.8 59.3 p=0.092
Malnutrition SGA A SGA B+C p	36.3 29 p=0.136	16.1 38.1 p=0.04	38.7 71.4 p=0.005	32.3 69 p=0.002
Hemoglobin(mg/dl) <12mg/dl >12mg/dl p	68.8 30.4 p=0.005	28.1 31.2 p=0.804	50.9 81.2 p=0.03	47.4 75 p=0.05

GI: Gastrointestinal. SGA : Subjective Global Assessment. ECOG: Eastern Cooperative Oncology Group Performance Scale.

Conclusion
The performance status, malnutrition and body surface are independent factors related to severe gastrointestinal toxicity to Afatinib. The only independent factor associated with dose reduction was malnutrition. This study suggests that for the initial dose selection of TKI´s of the EGFR these factors should be considered in order to reduce the risk of severe toxicity.

Background
Approximately 15% of patients with NSCLC are diagnosed with stage IIIA-N2 disease, the treatment modalities of which are not clearly defined due to its heterogeneous character. Patients with stage IIIA N2 NSCLC have poor outcomes with 5-year survival rate of approximately 15% after treatment with surgical resection or chemo-radiotherapy. Tyrosine kinase inhibitor mono-therapy as the first line treatment could significantly improve tumor response rate and disease progression free survival (PFS) for metastatic NSCLC patients with activating EGFR mutation. The objective of this trial is to explore the efficacy and safety profile of erlotinib as neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with activating EGFR mutation.

Methods
This is a prospective, single arm, phase Ⅱ clinical trial. Patients with Endobronchial Ultrasound(EBUS) confirmed stage ⅢA-N2 NSCLC with activating EGFR mutation in exon 19 or 21 will be enrolled into the study. All the recruitment patients will be treated by erlotinib 150mg orally per day for 56 days for neoadjuvant period. Patients will be assessed after erlotinib treatment and those who get response from neoadjuvant therapy and are technically resectable will undergo surgery treatment. The adjuvant regime is decided by the investigator taking patients’ benefits into consideration. The primary endpoint is radical resection rate. The secondary endpoints are pathological complete resection rate(pCR), objective response rate(ORR), disease free survival(DFS), overall survival(OS), quality of life(QoL) and safety profile. Patients after surgery and therapy will receive long-term follow-up including regular chest CT and ultrasound examination.

Results
Eighty-eight(88) patients have been screened and 15 patients have been enrolled since first patients in (FPI) on 30th April, 2011. Excluded reasons including ineligible pathological diagnosis (n=23), ineligible stage (n=36), without EGFR mutation (n=10) and poor compliance (n=4). Ineligible stage including T1-3N0M0 (n=11), T1-3N1M0 (N=8), T1-3N3M0 (N=8), T1-3N2M1 (N=7) and T4N2M0 (N=2). 41% patients who were diagnosed with stage IIIA-N2 non-small cell lung cancer when in chest CT examinations were not in the stage after endobronchial ultrasound(EBUS) , and became the main reason for screening failure in this study. Seven patients had partial response, 3 patients with stable disease and 2 patients were still on treatment (DCR 66.6%). 3 patients with progress disease. Due to active hepatitis and technical infeasibility, 2 patients with partial disease didn’t receive surgery. However, one stable disease patient and five partial response patients (40%) received R0 surgery.

Conclusion
Neoadjuvant erlotinib therapy might be a promising treatment for IIIA-N2 NSCLC patients with EGFR activating mutation. EBUS helps the judgment of mediastinal lymph node metastasis and is better than CT scan.

Background
Driver gene mutation in lung adenocarcinoma varies greatly among different populations, and lacks of large sample study on Chinese population. The purpose of this study was to identify driver gene mutations or translocations, and to evaluate their association with clinicopathological features and prognosis in Chinese lung adenocarcinoma.

Methods
Gene mutations or translocations were detected by fluorescence quantitative PCR in tumor tissues of 762 lung adenocarcinoma patients, including mutations of EGFR, KRAS and BRAF, and translocations of ALK and RET. The correlation of gene mutations/translocations with clinicopathological features was retrospectively analyzed by Chi-square test and logistic regression. Kaplan-Meier survival curves were used to evaluate the correlation of these genes with disease-free survival(DFS) in 314 patients and overall survival(OS) in 564 patients respectively.

Results
In the 762 patients with lung adenocarcinoma, the positive rate of gene mutations/translocations involving EGFR, KRAS, ALK, RET and BRAF was 49.6%, 10.0%, 4.5%, 1.7%, 0.5%, respectively, among which there was no mutations of polygenes. This study showed that EGFR mutations were more common in non-smokers or light smokers, lepidic predominant invasive adenocarcinoma subtype, and patients without distant metastasis. KRAS mutations were more common in heavy smokers, mucinous invasive adenocarcinoma subtype, and early stage patients. ALK translocations were more common in patients younger than 55 years old, with solid predominant invasive adenocarcinoma subtypes. RET translocations were more common in patients younger than 52 years old, with solid predominant invasive adenocarcinoma subtypes and patients who have family history of lung cancer. BRAF mutations were more common in mucinous invasive adenocarcinoma subtype. The survival analysis showed that the median OS of EGFR-mutant group was shorter than wild-type group among stage IIIB-IV paitents without targeting therapy(P=0.019); Although KRAS gene mutations in patients with early stage was not related to disease recurrence and survival either, KRAS mutations in stage IIIA patients do contribute to shorter DFS and OS(P=0.018, 0.039); ALK translocations in each stage subgroup were not related to recurrence and survival; Patients with mutations of either EGFR, KRAS, or translocations of ALK as a group showed no significant difference in DFS and OS as compared to those without involvement of any of these genes.

Conclusion
The overall driver gene positive rate in this series detected by Q-PCR is 66.3%. Each type of drive gene corresponds to different clinical and pathological features. Patients with ALK or RET gene translocations are more younger, and more likely to be solid predominant invasive adenocarcinoma. EGFR-mutant group has shorter OS than wild-type group among stage IIIB-IV paitents without targeting therapy. KRAS mutations implicate poor prognosis only in patients with stage IIIA.

Background
Half of the patients who have a complete lung cancer resection have a recurrence. However, advances in radiographic modalities and chemotherapy enable physicians to achieve better outcomes for postoperative lung cancer recurrence. Yet, for cases with recurrence, postoperative follow-up methods have not been adequately assessed and there is currently no evidence-based postoperative surveillance method. We evaluated cases with postoperative recurrence and the personalized postoperative surveillance periods and methods used.

Methods
Follow-up after surgery consisted of a regular outpatient clinic check-up, including physical examination, history taking, blood tests, and chest X-ray, which were done three or four times per year for five years. During the follow-up period, annual chest and brain computed tomography scanning was done. If the patients were completely followed for 5 years, then surviving patients continued to be followed using chest X-ray or CT. Between May 2004 and December 2011, 547 patients had completely resected lung cancers in our institution. We retrospectively reviewed their prospectively collected database.

Results
We selected 106 patients (19.4%) who had a postoperative recurrence for an analysis of associations between recurrence and clinical factors. Regarding pathological stages, 24 of 257 (9.3%) with stage IA, 23 of 115 (20.0%) with stage IB, 18 of 61 (29.5%) with stage IIA, 10 of 25 (40.0%) with stage, IIB 30 of 50 (60.0%) with stage IIIA, and 1 of 2 (50.0%) with stage IV developed a recurrence. Sixty-eight patients (64%) were found to have a recurrence during follow-up surveillance and 38 patients (36%) were found to have a recurrence based on symptoms. The median time to recurrence was 12 months (1–72 months). Cumulative recurrence rates after surgery were 53% at 1 year, 81% at 2 years, and 98% at 5 years. Multivariate analysis showed that an advanced stage (stage II-IV; p < 0.01) and lymphovascular invasion positive (LVI; p = 0.01) were independent factors for earlier recurrence. Comparing those patients who were advanced stage and LVI positive with those who did not have these factors, 90.8% of high-risk patients had a relapse and 55.1.% of the other patients had a relapse within 2 years after surgery (p < 0.01). Five-year survival after surgery for patients with recurrence was 31.6% and 5-year survival after recurrence was 9.0%. Multivariate analysis showed that recurrence with symptoms (p < 0.01) and shorter time to recurrence (< 24 months; p < 0.01) were independent prognostic factors after recurrence.

Conclusion
Although this study was retrospective and included some biases, advanced stage and LVI positive patients should be intensively followed-up. Personalized follow-up programs for resected lung cancer patients should be considered.

Background
To evaluate the midterm results of percutaneous cryoablation for medically inoperable stage I non-small cell lung cancer.

Methods
Between January 2004 and June 2010, 160 patients underwent computer tomography guided percutaneous cryoablation for lung tumors at our institution. Of these patients, histologically proven stage I primary lung cancer patients with more than one year of follow-up, were retrospectively reviewed. All of these patients were considered to be medically inoperable. Follow-up was based primarily on computed tomography.

Results
There were 22 patients with 34 carcinoma who underwent 25 sessions of cryoablation treatment. Complications were pneumothoraces in 7 treatments (28%, chest tube required in one treatment), and pleural effusions in 8 treatments (31%). The observation period ranged from 12 to 92 months, average 44±22 months, median 38 months. Local tumor progression was observed in two carcinomas (3%). Mean local disease progression-free interval was 88±8 months. Median local disease progression-free interval was not achieved. The overall 3-year survivals were 90.7%. Mean overall survival was 88±8 months. Median overall survival was not achieved. The disease-specific 3-year survivals were 100%. Mean overall survival was 81±14 months. Median overall survival was not achieved. The disease-free 3-year survivals were 77%. Mean disease-free survival was 64±19 months. Median disease-free survival was 89 month. Pulmonary function tests were done in 16 patients (18 treatments) before and more than 3 months after cryoablation. Percentage of predicted vital capacity, and percentage of predicted forced expiratory volume in 1 second, did not differ significantly before and after cryoablation (93±23 versus 90±21, and 70±11 versus 70±12, respectively).

Conclusion
Although further accumulation of data is necessary regarding efficacy, cryoablation may be a feasible option in inoperable stage I primary lung cancer patients.

Background
Stage IV non-small cell lung cancer (NSCLC) patients are considered incurable and mainly treated for palliation. The purpose of this study is to investigate the overall survival (OS) and disease free survival (DFS) of NSCLC patients, diagnosed with synchronous oligometastatic disease treated with curative intent of the intrathoracic disease as well as the metastasis.

Methods
Patients treated between 2008 and 2013 were included in this retrospective analysis. Main inclusion criteria were: synchronous presentation of NSCLC and oligometastatic disease at diagnosis with only 1 extra-thoracic metastasis, and multidisciplinary consent on a radical treatment of both the intrathoracic disease and the solitary metastasis. Treatment of the intrathoracic disease consisted of radical radiotherapy (> 55 Gy biological effective dose) or surgical resection. Treatment of the metastasis consisted of radical/stereotactic radiotherapy or surgical resection or radiofrequency ablation (RFA).

Results
Twenty-two patients, 13 men and 9 women, were included. The mean age was 61 years (range 41-79) and all were in good condition (WHO 0-1). The sites of the solitary metastases were brain (13), bone (6), liver (1), soft tissue (1) and adrenal gland (1). The intrathoracic tumor stage (ignoring M-status) was IA in 2 patients, IB in 1 patient, IIA in 4 patients, IIB in 1 patient, IIIA in 8 patients and IIIB in 6 patients. Nineteen patients were treated with radiotherapy and 3 patients had a surgical intervention for the primary tumor. Eighteen patients (82%) received chemotherapy, 3 concurrently and 15 sequentially. The metastases were treated with ablative/stereotactic radiotherapy (19), surgical intervention (2) and RFA (1). The median follow-up was 47 months (95% CI 24-69). Seventeen patients developed recurrent disease of whom 12 died. Only 2 recurrence occurred within the irradiated area. Both infield recurrences were brain metastasis after a stereotactic irradiation of 15 Gy and 18 Gy. The other recurrences where mostly pulmonary (7) and brain metastases (6). The median DFS was 14 months (range 1-47, 95% CI 9 – 19) and the median OS was 32 months (95% CI 12– 52). The 1- and 2-year OS was 78.7% (95% CI 52.7-91.5) and 59.5% (95% CI 32.8-78.5), respectively. The 1- and 2-year DFS was 54.5% (95% CI 30.5-73.2) and 24.9% (95% CI 8.1-46.3), respectively.

Conclusion
Radical treatment of a highly selected group of NSCLC patients in good condition presenting with a single synchronous extra-thoracic metastasis resulted not only in adequate local control, but also in favorable long-term DFS and OS.

Background
By 2010, the estimated number of percutaneous radiofrequency ablation (RFA) procedures to treat solid thoracic malignancies approached 150,000 per annum. But limited data exists regarding factors that impact local recurrence following RFA of solid lung tumors in non-surgical patients. The objective of this meta-analysis was to compare pooled estimate data of LTP for small (<3cm diameter) versus large (≥3cm diameter) solid lung tumors following CT-guided percutaneous RFA. Moreover, sensitivity analyses were used to consider whether lung lobular site (RUL, RML, RLL, LUL, lingula, and LLL), histology (primary versus metastatic), and adjuvant chemotherapy modified local tumor recurrence.

Methods
Study design: Based on meta-analysis. Evidence was gathered from PubMed, the Cochrane Library, EMBASE, and CANCERLIT databases from January 2000 to December 2012; additional interrogation of abstracts from scientific meetings, bibliographies of identified studies, and clinical trial registries [e.g., clinicaltrials.gov] was undertaken in an effort to identify all available evidence. Blinded duplicate screening was used to extract data from captured clinical studies involving patients with non-surgical solid lung tumors, both primary and/or metastatic. Aggregate effect estimates from constituent studies for single outcome (local tumor progression; [LTP]) was the basis for comparing pooled estimates. Population: non-surgical patients with solid lung tumors, either primary and/or metastatic. Intervention: RFA +/- PAC. Comparators: small (<3cm diameter) versus large (≥3cm diameter) tumors. Outcomes: LTP at 1 year follow-up; sensitivity analyses for tumor location in lung lobules, tumor histology, and post ablation chemotherapy (PAC).

Results
Pooled estimate analysis involved 87 small tumors versus 96 large tumors; 106 primary versus 48 metastatic. LTP 6% for small tumors versus 19% for large tumors following percutaneous RFA at 1 year follow-up; odds ratio (OR) 4.7 (95% CI: 1.5-14.9, p=0.009). Tumor location and histology did not significantly perturb LTP (p>0.1). RFA plus PAC yielded LTP of 15% over median follow-up of 31 months [range 12 to 59]) whereas RFA alone yielded 19% over median follow-up of 21 months [range 12 to 29]); OR 0.73 (95% CI: 0.61-0.86, p<0.05) at 1 year follow-up.

Conclusion
RFA is a relatively new tool for local control of solid lung tumors. To our knowledge, our meta-analysis is the first to purposely demonstrate factors that impact the management of solid lung tumors by percutaneous RFA in non-surgical patients. Our pooled analysis revealed that locoregional control of lung malignancy by percutaneous RFA is most effective for tumors <3cm in diameter, is independent of lung lobular site and tumor histology, but is optimized with a therapeutic strategy of RFA plus PAC. Patients most likely to benefit from a RFA plus PAC strategy would be non-surgical candidates with solid lung tumors that have a relatively good performance status and could tolerate RFA plus PAC.

Background
AIM: New classification of adenocarcinoma subtypes cannot be discriminated by PET/CT findings. The aim of this study was to evaluate the features of operable adenocarcinoma patients according to PET/CT findings.

Methods
METHODS: Medical records of 49 adenocarcinoma patients to whom PET-CT was applied for clinical staging between November 2009 and December 2011 were evaluated retrospectively.

Results
RESULTS: Mean tumor size was 3,51±1,70 and mean tumor SUV max value was 8,18±4,50. Tumor size and tumor SUV max values were not different between subtypes. Seventeen of the patients had positive and 8 had suspicious positive mediastinal lymph nodes, however only 16 of the positive N2 lymph nodes were determined to be pathologically positive by mediastinoscopy or thoracotomy. Tumor SUV max values were found to be correlated with tumor size (r=0,493, p<0,001). The most frequent subtype was unclassified (32 patients). The others were mixed (6), acinar (4), lepidic (3), mucinous (2), solid (1) and papillary (1) subtypes.

Conclusion
CONCLUSION: We need studies involving more patients to evaluate the differences between PET/CT uptakes of adenocarcinoma subtypes, although we observed an association with tumor size and SUV max values of the adenocarcinomas regardless from the histopathological subtypes.

Background
AIM: Staging of lung cancer determines the choice for treatment. Currently, PET/CT has been used widely in the staging NCSLC. We aimed to investigate the changes in clinical staging of NSCLC patients after PET/CT procedure.

Methods
METHODS: Clinical and pathological data of 124 operable NSCLC patients to whom PET-CT was applied for clinical staging between November 2009 and December 2011 were evaluated retrospectively. PET-CT was positive for N2 lymph nodes in 60 of 124 patients. Thirty of them underwent mediastinoscopy, 4 underwent mediastinotomy and 2 underwent thoracotomy and the remaining 24 were operated without any prior invasive procedure for the evaluation of mediastinal lymph nodes. Among the 64 PET/CT negative patients 59 were directly operated, 4 underwent mediastinoscopy and 1 to thoracotomy.

Results
RESULTS: Stage 3A was the most frequent stage in both clinical and pathological staging. T staging was the same for both clinical and pathological stages in 48%of the patients, while this was 58% for mediastinal lymph nodes. Overall clinical and pathological stages were the same in 42% of the patients, while in 34% clinical staging was lower and in 24% higher than the pathological staging. The most compliant stage between clinical and pathological stages was 1A while the least one was stage 1B.

Conclusion
CONCLUSION: Clinical staging with the assistance of PET/CT was observed to be moderate compliant with pathological staging in most of the patients. Therefore, clinical staging with PET/CT should not replace pathological staging in NSCLC

Background
Adjuvant cisplatinum-based chemotherapy is recommended for routine use in patients with stages IIA, IIB, and IIIA of non small-cell lung cancer (NSCLC) after radical resection. Results in stage IB were not conclusive. Vinorelbine is a preferable drug in this indication and a randomized study proved the comparable effectiveness and tolerability of vinorelbine given both orally or intravenously (i.v.) in advanced NSCLC, meanwhile oral vinorelbine gives better comfort to patients. Only few studies evaluated the position of vinorelbine in doublet with carboplatin (CBDCA) none of them used oral vinorelbine in this doublet as adjuvant chemotherapy (ACT).

Methods
This prospective multicentre study evaluates the feasibility, toxicity and short time survival of ACT based on CBDCA (AUC 5) with oral vinorelbine after radical resection. Vinorelbine was applied orally 80 mg/m[2] D1 and D8 after the first cycle of 60mg/m[2]. ACT (4 cycles of 21 day regimen) was applied to patients with stage IB, II, and IIIA of NSCLC (6[th] TNM revision) in 16 centres. Therapy was applied from the 1[st] of April 2009 to the 28[th] of February 2010. Median of follow-up period was 31 months Histology of tumor, type of surgery, grading, visceral pleura and angio-invasion were evaluated as potencial predictors of survival.

Results
ACT was applied to 104 eligible patients (72 men, 32 women, median of age 64 years). Out of them 41 were smokers, 57 ex-smokers and 5 non smokers. Surgically determined stages were IB in 32 pts, II in 36 pts and IIIA in 36 pts. Altogether 399.5 cycles (mean no 3.82) were administered, 86,5 % of patients finished four cycles of planned ACT. The reasons for 14 (13.5%) patients ending ACT prematurely were hematological toxicity in 8 pts, non-hematological toxicity in 3 pts, other reasons in 3 pts . Relative dose intensity (RDI) was 80.8% for vinorelbine and 95.4% for CBDCA. The most frequent WHO grade 3/4 of toxicity were neutropenia in 10.6%, leucopenia in 5.6%, anemia in 1.3%, thrombocytopenia in 1.3%, alopecia in 3.3%, nausea in 4.8%, neurotoxicity, nephrotoxicity, diarrhoea and mucositis in 0.3%. During the median of follow-up period, 45 (43.2%) pts died and 38 (36.5%) out of them died on lung cancer. Median DFS was 29.1 months, 2-year survival was 70.6%, 2.5-year survival was 63.9%. Predictors of significantly better DFS and 2.5 year survival were stage IB (p = 0.0045) and lobectomy (p = 0.0465). Trend of better DFS and 2.5 year survival was observed in cases without angioinvasion and pleural invasion.

Conclusion
Applied ACT had excellent tolerability, high RDI was achieved and preliminary parameters of survival are acceptable. Study is ongoing and long term survival results will be evaluated in the future. This study was supported by Grant NT- 13569 and NS-9959-3 of the Czech Ministry of Health

Background
CDPD and lung cancer sometimes occurs simultaneously. COPD has been recognized as an inflammatory disease mainly by smoking effects and may potentially affect biology of the accompanying tumor. It is not fully understood whether presence of CDPD influences clinical characteristics, pathological findings and/or clinical outcomes in patients with operable ES-NSCLC.

Methods
Retrospective and consecutive data were collected from the medical records of patients who underwent surgical resections of lung cancer at Kinki-chuo Chest Medical Center, Japan, between January 2009 and December 2010. CDPD status was classified as absence of COPD, stage I and II COPD based on the criteria of Global Initiative for Chronic Obstructive Lung Disease (GOLD2009). Histology, vascular / lymphatic invasion and the status of epidermal growth factor receptor (EGFR) were determined using the surgical materials.

Results
A total of 319 surgical cases was included in this study with median age of 67 (range, 36 - 89). There were 81 cases of relapse and 40 cases of death during the median follow up of 28 months (11 days to 49 months). According to the subgroups of no COPD, stage I and II COPD, the median age, the number of case in gender (male/female), performance status (PS, 0/1), histology (squamous cell carcinoma [SQ] /non SQ), smoking status (never/ever), and EGFR status (wild type/mutant) were as follows respectively; 67, 72, 72 (p<0.001) and 105/110, 48/12, 38/6 (p<0.001) and 170/40, 53/7, 27/14 (p=0.029) and 31/184, 12/48, 14/28 (p<0.001) and 89/122, 7/53, 2/39 (p=0.002) and 47/37, 21/3, 9/3 (p=0.013), respectively. No significant difference was observed in disease-free survival (DFS, log-rank p=0.411) and overall survival (OS, log-rank p=0.127) between the patients with and without COPD. In multivariate analysis adjusted for age, gender, PS, histology, smoking status, pathological stage, vascular / lymphatic invasion and EGFR status, presence of COPD did not affect DFS (HR=1.457, p = 0.279) nor OS (HR=0.993, p = 0.990).

Conclusion
Although COPD was significantly associated with the elderly, male gender, presence of symptoms, SQ histology, ever smoking, and wild type EGFR, it did not add values of prognostic factors in patients with operable ES-NSCLC.

Background
The prognostic importance of positron emission tomography (PET) standardized uptake value maximum (SUVm) scores for patients with early stage non-small cell lung carcinoma (ES-NSCLC) treated with stereotactic body radiotherapy (SBRT) is unclear. This study aims to address this uncertainty.

Methods
Records of patients diagnosed with ES-NSCLC and treated with SBRT between September 2007 and May 2012 were retrospectively reviewed. Mediastinoscopy was used to stage patients with synchronous primary lesions, centrally located lesions, and those larger than 3 cm. SBRT was delivered via 3-5 fractions to a dose of 40-60 Gy, with the vast majority of patients receiving 54 Gy in 3 fractions. Univariate and multivariate Cox proportional hazards analyses were used to compare disease progression and overall survival on the basis of pre- and post-SBRT SUVm, absolute change in SUVm, age, tumor size, and histology.

Results
127 patients with a median follow-up of 14 months were identified. Median age was 73.9 years and 54% were male. Histology was adenocarcinoma in 39%, squamous cell carcinoma in 20%, unspecified NSCLC in 20%, and unbiopsied in 21%. Pre-SBRT PET was available in 98% and median pre-SBRT SUVm was 4.8. Post-SBRT PET was performed in 33% and median post-SBRT SUVm was 2.3. SUVm declined by a median of 3.7 units post-SBRT. There were 5, 4, and 12 local, regional, and distant failures, respectively. On multivariate analysis, older age, tumor size, and squamous histology predicted for higher rates of any failure (p=0.034, <0.001, 0.016, respectively). Conversely, larger absolute reduction in SUVm post-SBRT predicted for improved rates of disease control (p=0.005). Median OS was 14.65 months. On multivariate Cox proportional hazards analysis of predictors of overall survival, higher pre-SBRT SUVm, larger size, squamous cell histology, and staging mediastinoscopy predicted for worse OS (all p<0.05).

Conclusion
PET is a powerful tool in the work-up of newly diagnosed NSCLC. SUVm values appear to also have prognostic importance, as absolute change in SUVm after SBRT predicts for failure and pre-SBRT SUVm predicts for overall survival.

Background
A standardized definition of visceral pleural invasion (VPI) has been incorporated into the 7th edition of TNM, and the recommendations include the use of elastic stains to determine the VPI. PL0, defined as a lack of pleural invasion beyond the elastic layer, is not regarded as a T factor. In tumors of 3 cm or less, PL1 was defined as invasion beyond the elastic layer, and PL2 was defined as invasion to the surface of the visceral pleura, both of which are classified as indicators of T2 disease. The purpose of this retrospective study was to evaluate the validity of this definition.

Methods
We retrospectively reviewed 493 NSCLC patients with pathological N0M0 with a size of 5 cm or less with PL0-2 who underwent curative resection by lobectomy or segmentectomy between 1999 and 2013. We evaluated the disease-free survival (DFS) and overall survival (OS) in relation to the grade of VPI.

Results
The median follow-up for overall survival was 39 months after the operation. There were 282 males and 211 females included in the study. The age of the patients ranged from 31 to 90 years, with a mean of 69 years old. There were 347 patients in stage IA and 146 in Stage IB, and the histological type was adenocarcinoma in 374 patients (75.8%), squamous cell carcinoma in 91 patients (18.4%) and others in 28 patients (5.8%). The 5-year survival rates by PL grade were as follows: 85.0% for PL0 (n=425), 73.3% for PL1 (n=50) and 70.8% for PL2, respectively. In patients with tumors 3 cm or less in diameter, the 5-year survival rates and 5-year DFS rates were as follows: 87.9% and 88.2% for PL0 (n=342), 71.6% and 86.9% (n=30) for PL1 and 90.7% and 80.0% (n=11) for PL2, respectively. The 5-year survival rate of cases with PL0-T2a (> 3 cm, ≤ 5 cm) was 71.2%, and that for PL1-T2a was 71.6%, which did not differ significantly. Postoperative recurrence was observed in 47 patients (9.5%). Distant metastases were observed in 3.1% of PL0 patients, 10.0% of PL1 patients and 11.1% of PL2 patients, which showed significant difference between PL0 and PL1/2. However, no difference was found in the local recurrence rates between PL0 and PL1/2 patients.

Conclusion
The grade of VPI defined by the TNM 7th edition is reasonable. Namely, PL1 indicates visceral pleural invasion, and can be regarded as T2a disease.

Background
Despite receiving curative treatment, a significant proportion of patients with locoregional non-small cell lung cancer (NSCLC) will develop recurrent disease. The role of routine surveillance imaging following curative treatment remains controversial, as there is no definitive evidence that early detection and treatment of asymptomatic metastases improves survival. The aim of this study was to explore the patterns of recurrence in stage I-III NSCLC patients treated in routine clinical care.

Methods
Retrospective analysis of 218 patients across two tertiary centres in Melbourne, Australia, who underwent surgical resection of stage I-III NSCLC over a 5-year period. Patients who died within 30 days of surgery or with no follow-up data were excluded. Clinicopathologic, treatment and outcome data were collected.

Results
Between July 2006 and June 2012, 206 patients underwent surgical resection, with a median follow-up of 30 months. Median age was 69 years (range 46–84), with a male:female ratio of 65 vs 35%. There were 113 (55%), 52 (25%) and 39 (19%) stage I, II and III tumours respectively. One patient had a pathologic complete response to neoadjuvant chemoradiotherapy. Adjuvant chemotherapy was delivered to three (3%), 20 (39%) and 28 (72%) patients with stage I, II and III disease respectively. Nine of 39 (23%) stage III patients received adjuvant radiotherapy. 73 of 206 (35%) patients relapsed at a median of 10.5 months from surgery (range 0.7–46.4). A further 15 (7%) patients were diagnosed with new primary lung cancers and four (2%) with second, non-pulmonary malignancies. Relapses were more frequent in patients with higher stage tumours (Table 1). Of the patients receiving adjuvant or neoadjuvant chemotherapy, 55% developed recurrent disease. Among patients who recurred, 46 (63%) were symptomatic, with 32 of these (70%) requiring emergency or early clinical reviews. In contrast, new primary tumours were significantly more likely to be detected on routine surveillance imaging (87% vs 29% of recurrences, p=0.0001). One-year post-relapse survival was 40% for disease recurrences vs 53% for new primary lung cancers.

Table 1 – Clinicopathologic features and patterns of relapse in 206 patients with resected stage I-III NSCLC[1]

	Total N	Disease-free n (%)	Relapsed NSCLC n (%)	New primary lung cancer n (%)
TOTAL	206	104 (51%)	73 (35%)	15 (7%)
Stage 0 I II III	1 113 52 39	1 (100%) 70 (62%) 21 (40%) 10 (26%)	0 25 (22%) 21 (40%) 25 (64%)	0 10 (9%) 2 (4%) 3 (8%)
Chemotherapy receipt Yes No	53 145	17 (32%) 84 (58%)	29 (55%) 42 (29%)	3 (6%) 12 (8%)
Histology Adenocarcinoma Squamous cell Large cell Other	112 57 15 21	53 (47%) 32 (56%) 6 (40%) 13 (62%)	41 (37%) 18 (32%) 8 (53%) 6 (29%)	9 (8%) 5 (9%) 1 (7%) 0
Method of relapse detection[2] Routine imaging Symptomatic	34 51	N/A N/A	21 (62%) 46 (90%)	13 (38%) 2 (4%)
[1]Data for second non-pulmonary malignancies not shown [2]Method of relapse detection not documented in six patients

Conclusion
The goals of routine surveillance imaging following curative treatment of NSCLC are two-fold; early detection of: 1) asymptomatic disease recurrence and, 2) new primary lung cancers. Our data demonstrate that the majority of disease recurrences are symptomatic at the time of diagnosis, thus negating the value of routine imaging. In contrast, the high proportion of asymptomatic new primary cancers detected on surveillance imaging supports this approach for patients fit for curative-intent treatment.

Background
The brain is a common site of relapse following curative treatment of stage I-III non-small cell lung cancer (NSCLC). Retrospective series estimate actuarial risk of brain recurrence at ~10% for stage I-II and ~30% for stage III tumours. Possible risk factors are young age, non-squamous histology and higher tumour/nodal stage, with survival typically dictated by the presence of extracranial disease. The aim of this study was to review patterns and treatment of brain metastases in patients with relapsed stage I-III NSCLC.

Methods
Retrospective analysis of 218 patients with surgically resected stage I-III NSCLC at two tertiary centres in Melbourne, Australia over a 5-year period. Patients who died within 30 days of surgery or with no follow-up data were excluded. Treatment and outcome data for patients who subsequently developed brain metastases are reported.

Results
206 eligible patients underwent surgical resection between July 2006 and June 2012. None received prophylactic cranial irradiation. At a median follow-up of 30 months, 73 (35%) patients had relapsed. Twenty-two (30%) had intracranial metastases, ten with brain-only metastases at the time of relapse. The other 12 had concurrent extracranial disease. Median time to brain relapse was 7.7 months (range 0.7-38.6). The incidence of brain relapse increased with higher stage: 6%, 13% and 21% of patients with stage I, II and III disease respectively (Table 1). Relapses occurred at a median of 10.9 (stage I), 8.8 (stage II) and 6.4 (stage III) months from surgery. Brain metastases were noted more frequently in patients with adenocarcinoma. Although 18/57 patients with squamous cell histology relapsed, none were noted to have intracranial metastases. In five patients, asymptomatic brain metastases were detected on routine surveillance imaging and treated with palliative whole-brain radiotherapy. Three of the five had coexistent extracranial disease and died within four months of relapse. The other two had brain-only metastases and remain alive at nine and 16 months from relapse. For all patients, one-year survival following diagnosis of brain metastasis was higher in those with brain-only disease (50%) compared to those with concurrent extracranial metastases (9%).

Table 1 – Clinicopathologic features in total and brain relapse populations

	Total population N	Brain relapse n (%)
TOTAL	206	22 (11%)
Median age (yrs)	69 (46-84)	69 (50-84)
Sex M F	134 72	15 (11%) 7 (10%)
Stage 0 I II III	1 113 52 39	0 7 (6%) 7 (13%) 8 (21%)
Histology Adenocarcinoma Squamous cell Large cell Other	112 57 15 21	16 (14%) 0 3 (20%) 3 (14%)
Chemotherapy Adjuvant Neoadjuvant None	50 3 145	6 (12%) 1 (33%) 14 (10%)
Radiotherapy Adjuvant Neoadjuvant None	12 2 185	5 (42%) 0 16 (9%)

Conclusion
In this small retrospective series, the majority of patients who developed brain metastases after curative treatment for NSCLC were symptomatic at the time of relapse. Post-relapse survival was worse in patients with coexistent extracranial disease. None of the incidentally detected asymptomatic brain metastases could be treated curatively, suggesting a limited role for including brain imaging in routine surveillance for resected NSCLC.