Virtual Library

Background
Induction therapy for non-small cell lung cancer has given promising results in a select group of patients, but no prognosis of these patients makes the future uncertain. Using a technique revild EGFR mutations and expression of ALK translocation with follow targeting induction chemotherapy increased the possibility of this technique, even in previously unresectable patients

Methods
From 2008 to 2013, 78 patients with potentially unresectable NSCLC was held from 2 to 4 courses of standard (platinabased) induction chemotherapy and 5 patients of targeted chemotherapy with the identification of mutations in EGFR or ALC traslocation. Subsequently assessed resectability of the tumor and in the case of regression of tumors - lung resection

Results
In the first group (standard) was 29 patients with adenocarcinoma. Tumor regression was achieved in 3 (10%), partial response in 5 (17%), the rest had stable or progress desease. Toxicity grade 3-4 was observed in 45% of patients. Resectability was achieved in 5 patients (17%). In the second group (target), complete response was achieved in 60% of cases, partial in 1 (20%) and stabilization in 1 patient (20%). Toxicity of chemotherapy is not more than grade 3. Resectability rate was 80%. In operated patients - time to progression was 9 months in the (standard) and 1 year 4 months in the second group (target). Median survival was 11 months versus 18 months.

Conclusion
Using the induction of targeted therapy in patients with previously unresectable NSCLC is promising, since the best results were found tolerability, objective response rate and better survival rates of patients.

Background
newly diagnosed patients with Non-small cell lung carcinoma (NSCLC) presented with advanced stages IIIA and IIIB were randomized to receive 3 protocols of neoadjuvant chemotherapy aiming at determining of both (pathologic response, and local-regional control) before undergoing surgery according to the response.

Methods
85 enrolled Patients treated from Jan 2009 till Dec 2011 with neoadjuvant chemotherapy. 75 pts males and 10 pts females.48 patientsts (56,5% ) had less than 60 years. 58 patientsts (68,2%) had Squamous cell carcinoma subtype (SCC) , while the other 28 patients (31,8%) had (Non SCC). All patients underwent pretreatment evaluation at AL BAYROUNI University cancer center. Some patients (32%) had complete mediastinoscopy staging, and all were believed to be poor candidates for up-front surgery because of the bulky disease. Different chemotherapeutic protocols were employed (Gemcitabine/cisplatin)(Docetaxel/cisplatine) and( vinorelbine/cisplatine). Study end points included resectability, pathologic response, local-regional control,and the best chemotherapy regimen . An exploratory comparison between pathologic response and both histology and age was performed. On the other hand,An exploratory comparison between the three different regimens of chemotherapy was also done.

Results
Of the 85 patients, 26 (30,5%) were deemed surgical candidates after induction therapy however 7 patients of which (8,2%) refused surgery, were 27/85 males and 2/10 females had good downstaging P value (0.0001) and (0.0003) respectively with T downstaging 20/85 (23.5%), and N downstaging 18/85 (21.2%) but T+N downstaging was seen in only 9 patients (10.6%)P value (0,0001).The response to induction chemotherapy was 30/85 patients (35.2%) with one patient only (1.2%)` in a complete response . furthermore, 26/85 patients were in objective response (30.5%) and while 3 patients (3,5%) had a stable disease.Regarding responders' age, there were 18/48 patients (37%) aged 60 years and less, and only 8/37 patients (21.6%) were over 60 years.Depending on response to histology, 21/58 patients (34.5%) of SCC had got a response to preoperative chemotherapy, P value (0,0015), while 10/27 patients (37%) had no SCC,P value ( 0,0295).50/85 patients (58.8%) treated by (Gemcitabine / Cisplatin) protocol with 15 responders( 30%) P value (0,0197 ),24/85 patients (28.2%) treated with (Vinorlbine / Cisplatin) protocol with 11 responders (45.8%) P value(0.0125) . And finally,11/85 of pts (12,9%) treated by (docetaxel / cisplatin) protocol showed four responders (36.4%) P value ( 0,0332 )

Conclusion
The preoperative chemotherapy gives a good response for a possible surgery in patients with stages IIIA and IIIB NSCLC. this response was better in patients under 60 years , P value ( 0,0055 ). With response was better seen in Vinorelbine and Cisplatin arm . However , regarding histology based response, there was no preference.the former results lead us to use neoadjuvant chemotherapy in locally advanced NSCLC,but we still need a larger trials to reach the best protocol.

Background
Half of non-small cell lung cancers are diagnosed in locally-advanced stages (LA-NSCLC), and warrant multidisciplinary treatments. Inductive and adjuvant therapies obtain the same survival benefit after surgery, but the first ones also provide prognostic information. Mediastinal downstaging and pathologic complete response preclude a better outcome. However, the value of minor pathologic features has been scarcely analyzed. We report the impact of lymphovascular invasion (LVI) and tumor necrosis (TN) on the prognosis of resected LA-NSCLC after inductive chemotherapy (iCT) or chemoradiation (iCRT).

Methods
We retrospectively reviewed 50 resected LA-NSCLC treated with iCT or iCRT in our center from October-2004 to June-2012. Three patients died due to early surgery complications and were not analyzed. The impact of ILV, TN, pneumonitis, extracapsular (EI) and pleural invasion (PI) on disease free (DFS) and overall survival (OS) was analyzed in the remaining patients

Results
Our series included 42 men and 5 women aged between 47-82 years. Non-specified NSCLC was diagnosed in nine, adenocarcinoma in two, and squamous carcinoma in 36. Thirty-seven received cisplatin-based and 10 carboplatin-based chemotherapy. Concurrent radiation was administered in 21. Pneumonectomy was performed in 15, lobectomy in 26, and segmentectomy in 6. The presence of pneumonitis, EI, or PI in the resected specimens did not impact on the outcome of the patients. However, DFS and OS clearly worsened when LVI (34.1 vs. 14.1 months, p= 0.01; and 43 vs. 29, p= 0.005; respectively), and absence of TN (31.6 vs. 24.3, p= 0.045; and 42 vs. 33, p= 0.041, respectively) were found. Radiation, cis- or carboplatin administration, and treatment length did not modify LVI and TN incidence

Conclusion
Minor pathologic features as LVI and TN significantly impact on the prognosis of resected LA-NSCLC after iCT or iCRT. Implications of that should be further analyzed. Figure 1. DFS and OS Kaplan-Meier curves according to the presence of LVI. Figure 1

Background
Half of non-small cell lung cancers are diagnosed a locally advanced stage (LA-NSCLC) and are treated by combining chemotherapy, radiation, and surgery (S). However, many patients are not able to receive complete multidisciplinary therapies due to previous respiratory dysfunctions. We report the feasibility and efficacy of inductive chemotherapy (iCT) or chemoradiation (iCRT) followed by S or consolidative radiation (RT) in LA-NSCLC patients with normal (NRF) and reduced respiratory function (RRF)

Methods
We retrospectively reviewed 100 LA-NSCLC ECOG-0-2 patients treated with iCT or iCRT followed by S or RT in our center between October-2004 and June-2012. No patient was excluded to receive treatment due to RRF, but all those without initial determination of basal forced expiratory volume in the first second (FEV1) were not analyzed. Patients were classified into two groups according to initial FEV1: 1) NRF FEV1≥ 60%, and 2) RRF FEV1< 60%. A comparison of toxicity, compliance, treatment modality, and outcome between these groups was performed

Results
Seventy-two patients initially presented NRF, and 28 RRF. Seventy (97.2%) patients with NRF completed curative treatments (20 iCRT+S; 20 iCRT+RT; 19 iCT+S; and 11 iCT+RT). Twenty-six patients (92.8%) with RRF completed curative treatments (3 iCRT+S; 14 iCRT+RT; 3 iCT+S; and 6 iCT+RT). The rest of them progressed during inductive treatment and did not receive curative approaches. Any patient interrupted the treatment due to toxicity. Resection rate was lower among patients with RRF (55.7% vs. 23%, p= 0.004), but tolerance to S was similar to those with NRF (p= 0.72). RT was applied in 44.2% and 76.9% of patients with NRF and RRF, respectively. Incidence of grade 3-4 toxicities was similar in both groups of patients (13.9% vs. 11%; p= 0.72). There were no significant differences in disease free survival (16 vs. 21.8 months, p= 0.689), but overall survival paradoxically trended to be better in patients with RRF (27.4 vs. 37.3 months, p= 0.066)

Conclusion
RRF does not necessarily contraindicate a multidisciplinary curative approach for LA-NSCLC. In our series, iCT and iCRT were followed by S in 23% of patients with RRF, and by RT in 77%. Outcome of patients with RRF receiving an intentionally curative treatment was at least as good as that of patients with NRF. Figure 1. Kaplan-Meier DFS and OS curves according to initial FEV1. Figure 1

Background
Lung cancer is the most frequent cause of cancer-related death worldwide. Brain metastasis is an important issue because its incidence of 20-40% in non small cell lung cancer (NSCLC) patients and association of significant mortality and morbidity. There are several therapeutic modalities for CNS lesions such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and metastasectomy. It is well known that conventional chemotherapy is not effective for brain metastasis because of blood brain barrier (BBB). On the other hand, tyrosine kinase inhibitors (TKI) have showed efficacy in patients with brain metastasis from activating epithelial growth factor receptor (EGFR) mutant NSCLC. We assumed that SRS for brain metastasis could be delayed for the patients with activating EGFR mutation on taking gefitinib or erlotinib.

Methods
We retrospectively identified patients with brain metastasis from NSCLC harboring a sensitizing mutation of EGFR who were treated with SRS for the brain metastasis combined with TKI. EGFR mutations in exons 18, 19, 20 and 21 were analyzed by direct sequencing. SRS treatment was indicated for brain metastasis less than 6 lesions and not exceeding 4cm each of them. The patients in SRS first group were treated by SRS for brain metastasis, and then TKI was administrated. The other patients were treated with TKI before SRS and they were assigned to TKI first group. Progression free survival time was compared with each group.

Results
Forty-three patients were eligible (SRS first: 29, TKI first 14). Twenty-nine patients of them (67.4%) were women, median age was 56 (range 36-78). Most of them were adenocarinoma, except 1 squamous cell carcinoma and 1 NSCLC NOS. All patients have activating EGFR mutations, 2 patients had also T790M mutation known as TKI resistant mutation. TKI was used as 2[nd] line treatment for twenty five patients (58.1%). WBRT and brain metastasectomy were additionally employed for 9 and 6 patients. Although eight patients complained headache after SRS, it was self-limited. The median duration of TKI treatment were not different from each group (13.4 months in SRS first group, 14.7 months in TKI first group, p=0.986) As a result, the median progression free survival time was prolonged in SRS first group than in the TKI first group (12.6 months versus 2.3 months, p<0.001). And there was no significant adverse effect related with SRS in both groups.

Conclusion
It is better to consider SRS for brain metastasis as soon as possible, even if TKI is effective for patients with brain metastasis from activating EGFR mutant NSCLC. Also, the combined treatment of TKI with SRS was well tolerated by all patients in this study.

Background
Annually 63,000 approximately new patients of lung cancer are diagnosed in India, with two-third of them in advanced stage at presentation.. Radiotherapy with concurrent chemotherapy has shown survival benefit and is the standard of care for this group of patients in western literature.

Methods
One hundred seventy four consecutive patients Of Non Small cell Lung cancer (NSCLC) were treated with radical (chemo)-radiotherapy at Tata Memorial hospital from January 2008 to December 2012, . Detailed study of patient, tumour and treatment related factors were performed. Outcomes in the form of progression free survival (PFS) and overall survival (OS) at two years were calculated. Follow-up and analysis of data was performed in February 2013. Univariate and multivariate analysis was performed to see the impact of patient related factors like age, smoking, KPS, presence of comorbidity, tumour related factors including T stage, N stage and stage group and treatment related factors chemotherapy timing , total dose, duration of radiotherapy and response to treatment on PFS and OS.

Results
Of 174 patients, Males were 154(88.5%) with median age of 58 years (range 30-84 years) and 121(69.5%) were smokers. Median KPS was 80 (range 60-100) and 59 patients had significant comorbidity. Cough was the commonest presenting symptom (28%) followed by chest pain (27%) and haemoptysis (24.7%). Most common histology was squamous carcinoma 47.1% followed by adenocarcinoma in 41.4%. Stage III (A+B) constituted 90.2% of the patients. All patients received thoracic radiotherapy using 3D Conformal technique using 6/15 MV photons to a median dose of 60Gy (range 4-66Gy) over a median duration of 44 days(2-85 days) .Of 174 patients 166 patients (95.4%) completed the planned treatment. Median GTV and PTV volumes were 132 cc (16.7-741cc) and 538 cc(56-5680 cc) respectively. The median lung-PTV volume was 2599cc and V20 Gy was 23.79 %. Out of 174 patients 76% patients received concurrent chemotherapy, while 11.5% received sequential chemotherapy also. Response assessment using WHO criteria was done at 2 months post treatment, 63 (36.1%) had complete response whereas 64patients (36.8%) had partial response or stable disease and 7 patients(3.4%) had progressive disease . At last follow-up of with mean follow up 9.3 months (range 0-37 months), 32 patients had loco-regional recurrence and 33 patients had distant metastases. Acute pneumonitis grade I and II was observed in 87(50%) and 13(7.4%), acute oesophagitis grade II and III was seen in 56(32.1%) and 7(4%) patients respectively as per RTOG grading. Median PFS and OS were 20 months and 23 months with the estimated 2 year PFS & OS was 35% & 47.4%respectvely.On Univariate analysis, complete response to treatment (p=0.000) had favourable impact on PFS whereas smoking (p=0.009), advanced T stage (p=0.002) and less than complete response (p=0.000) had negative impact on OS.

Conclusion
Even under resource limited conditions patients who were treated with an intensive (chemo) radiation with supportive care had an acceptable treatment compliance and comparable treatment outcomes. , Patients with advanced stage and smokers did worse. Patients treated with concurrent chemoradiation and complete responders had better OS.

Background
The study was aimed to evaluate association between number of chemotherapy (CT) cycles and prognosis in stage IIIB non-small cell lung cancer (NSCLC) patients treated with thoracic radiotherapy (TRT) and concurrent CV CT protocol given in 1-3 cycles according to the toxicity or patient preference.

Methods
A total of 475 18-70 years old stage IIIB NSCLC patients, who received 60-66 Gy TRT concurrently with at least 1 cycle CV (q21) regimen between January 2007 and December 2011 were retrospectively evaluated. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS) and locoreginal PFS (LRPFS).

Results
Median follow-up time was 21.7 months (range 17-24.1). Histolopathologic subtype was squamous cell in 51.8%, and adenocarcinoma in 48.2% of cases. Treatment-related mortality was reported in 6 (1.3%) patients. There was no grade-4 non-hematological toxicity but grade-4 hematological toxicity was observed in 59 (12.4%) patients. Respective grade-3 non-hematological and hematological toxicity rates were 14.5% (n=69) and 24.6% (n=117), with leukopenia (9.3%) and esophagitis (17.3%) being the most common toxicities. Median OS, PFS and LRPFS for whole group were 20.7 (%95 CI: 19.4-22.0), 9.9 (%95 CI: 9.9-10.4) and 13.4 months (%95 CI: 12.6-14.2), respectively. Comparative median OS, PFS and LRPFS results for groups receiving 1 (n=44), 2 (n=68) and 3 (n=363) cycles of chemotherapy were 13.2 vs. 19.3 vs. 21.9 months ( p≤0.001), 6.1 vs. 9.7 vs. 10.5 months (p≤0.001), 6.6 vs. 12.8 vs.14.2 months ( p≤0.001), respectively. For all survival parameters, there were significant difference between patients receiving 1 cycle and 2 or 3 cycles of chemotherapy (p<0.05 for each) but there was no difference between those receiving 2 and 3 cycles of chemotherapy (p≥0.05 for each). T-satge (T1-2 vs T3-4) and N-stage (N2 vs N3) were the other factors influencing OS (p<0.05 for each) on univariate analyses. However, only T-stage (p=0.004) and Number of chemotherapy cycles (p≤0.001) retained prognostic significance on multivariate analyses.

Conclusion
Our results revealed that CV protocol was a relatively well-tolerated chemotherapy regimen given concurrently with TRT in stage IIIB NSCLC cases, and number of chemotherapy cycles than could be given during TRT course was an important prognostic indicator in such patients. Although results of randomized trials are needed, findings of superior survival in cases receiving 2 or 3 cycles of chemotherapy during TRT and similar survival results between 2 and 3 cycles suggest that 2 cycles of chemotherapy may potentially reduce toxicity rates, which results in increased treatment tolerability and quality of life, without compromising efficacy of treatment.

Background
The standard of care for patients with a good performance status and inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (1–3). Carboplatin and paclitaxel is an alternative to the cisplatin-based doublets that have been used traditionally (4). Early-phase studies with small numbers have been reported (5–7) but a randomised phase 3 comparison has not been performed. The objective of this study was to assess outcomes in a large cohort of patients treated with curative-intent radiotherapy and concurrent carboplatin and paclitaxel chemotherapy.

Methods
Consecutive patients between March 2004 and May 2012 with stage III NSCLC undergoing curative-intent 3D-conformal radiotherapy to 60-66 Gy in 30-33 daily fractions with concurrent weekly carboplatin (45mg/m[2]) and paclitaxel (AUC=2) were identified from a prospective database. Consolidation chemotherapy was not given. Individual medical charts, radiology and laboratory investigations were reviewed retrospectively. Baseline clinico-pathologic, treatment, outcome and toxicity details were recorded. A minimum follow-up of three months after completion of treatment was required unless death occurred sooner. Median follow-up and survival times were calculated from date of first contact using the Kaplan-Meier method.

Results
One hundred and sixteen patients were identified and baseline characteristics are provided in Table 1. Nine patients were excluded as the chemotherapy regimen changed after at least one cycle and the remaining 107 patients were analysed. Median follow-up was 43.5 months. Imaging at three months post-treatment demonstrated a complete response in 4 (4%) patients and a partial response in 68 (64%) patients. Nine (8%) patients had already died. Median progression free survival and median survival were 15 and 22 months, respectively. Locoregional control was 53%. Failure at any site occurred in 75 (70%) patients. Isolated distant failure occurred in 24 (22%) patients with 9 in the brain. Adjustments to chemotherapy dose or number of planned cycles were required in 29 (27%) patients. Fifty two (49%) patients were admitted during treatment. Seven patients experienced an acute hypersensitivity reaction to paclitaxel. Grade 3/4 neutropenia, thrombocytopenia, nephrotoxicity, oesophagitis and pneumonitis were observed in 15%, 1%, 3%, 11% and 9% of patients, respectively. There was 1 episode of fatal radiation pneumonitis.

Table 1. Patient characteristics. ECOG= Eastern Co-operative Group; FEV-1= forced expiratory volume in one second; PET= positron emission tomography; NOS = not otherwise specified.
Total number of patients (%)	116	(100)
Age, years
Median	65
Range	32-80
Sex: number (%)
Male	78	(67)
Female	38	(33)
Performance status: number (%)
ECOG 0	45	(39)
ECOG 1	62	(53)
ECOG 2	7	(6)
Unknown	2	(2)
Smoker: number (%)
Never	3	(3)
Current or ex-smoker (≥10 pack-years)	111	(96)
Unknown	2	(2)
Smoking history, pack-years
Mean	53.4
Range	0-250
FEV-1, litres
Mean	2.05
Range	0.62-4.25
Loss of weight: number (%)
None	98	(84)
≥10%	18	(16)
Stage: number (%)
IIIA	75	(65)
IIIB	41	(35)
PET-staged before treatment: number (%)
Yes	113	(97)
No	3	(3)
Histology: number (%)
Adenocarcioma	43	(37)
Squamous cell carcinoma	45	(39)
Carcinoma NOS	22	(19)
Other	3	(3)
Unknown	3	(3)

Conclusion
This review of a large, single institution series of patients with inoperable Stage III NSCLC treated with curative intent demonstrates that the concurrent administration of carboplatin and paclitaxel with radiotherapy is feasible. Survival and toxicity outcomes compare favourably to those reported with concurrent cisplatin and etoposide (4).

Background
Pemetrexed platinum regimens, unlike other regimens, can be given at full systemic doses with thoracic radiation therapy (TRT) in locally advanced stage III nonsquamous non–small cell lung cancer (NSCLC). Study JMIG was initiated to determine if this finding would translate into a survival advantage versus contemporary standard of care.

Methods
Study JMIG randomized patients with stage III unresectable nonsquamous NSCLC to experimental Pem+Cis (pemetrexed plus cisplatin and concurrent TRT for three 21-day cycles, followed by consolidation pemetrexed) or to control Etop+Cis (etoposide plus cisplatin and concurrent TRT for two 28-day cycles, followed by consolidation chemotherapy regimen of choice [excluding pemetrexed]). The primary objective was overall survival of Pem+Cis compared with Etop+Cis with safety as a secondary objective using Common Terminology Criteria for Adverse Events (CTCAE). Adverse event incidences were analyzed using Fisher’s exact test (2-sided α=0.05).

Results
Of 598 randomized patients, 555 received treatment: 283 Pem+Cis and 272 Etop+Cis. Baseline characteristics were similar (Pem+Cis/Etop+Cis); age (mean±SD) 59.2±9.5/58.7±9.3 years; women, n=114 (40.3%) / n=105 (38.6%); stage IIIB, n=153 (54.1%)/n=138 (50.7%); Eastern Cooperative Oncology Group performance standard of 1, n=138 (48.8%)/n=137 (50.4%); and planned target volume (mean±SD) 628.9 ±463.3/581.2±417.0 ml. Pem+Cis mean weekly dose intensities were 95.9% for both pemetrexed and cisplatin; Etop+Cis dose intensities were 96.4% and 94.1% for etoposide and cisplatin. TRT therapies were similar (Pem+Cis/Etop+Cis); TRT median (range) of 66.0 (2.0–66.3) gray (Gy)/66.0 (2.0–66.0) Gy, mean (SD) number of fractions 31.4 (4.3)/31.1 (5.2), V20 of 27.5% (6.5%)/26.7% (7.3%). Table 1 summarizes AEs during the concurrent phase by treatment. Few patients (n≤4) had grade 3 or 4 CTCAE of mucositis/stomatitis or rash. Pem+Cis had fewer SAEs of febrile neutropenia and pneumonia but increased vomiting compared with Etop+Cis. Nine patients died during the concurrent phase (not included in this safety analysis by treatment to preserve the integrity of final efficacy analysis).

Table 1. Summary of Common Terminology Criteria for Adverse Events Grade 3 Plus 4 Occurring in ≥2% of Patients Randomized and Treated
CTCAE (Grades 3 and 4)	Pem+Cis N=283 n (%)	Etop+Cis N=272 n (%)	p-value
Patients with ≥1 CTCAE*	170 (60.1)	186 (68.4)	0.042
Neutrophils/granulocytes*	52 (18.4)	78 (28.7)	0.005
Leukocytes*	44 (15.5)	65 (23.9)	0.014
Esophagitis	42 (14.8)	47 (17.3)	0.488
Lymphopenia	48 (17.0)	37 (13.6)	0.290
Hemoglobin	14 (4.9)	20 (7.4)	0.289
Febrile neutropenia	9 (3.2)	18 (6.6)	0.075
Dysphagia	18 (6.4)	16 (5.9)	0.861
Platelets	15 (5.3)	16 (5.9)	0.854
Vomiting	12 (4.2)	13 (4.8)	0.839
Hypokalemia	6 (2.1)	12 (4.4)	0.153
Infection—lung (pneumonia)*[a]	1 (0.4)	9 (3.3)	0.010
Dehydration	11 (3.9)	8 (2.9)	0.643
Nausea	13 (4.6)	8 (2.9)	0.376
Anorexia	10 (3.5)	7 (2.6)	0.625
Fatigue	9 (3.2)	6 (2.2)	0.603
Hyponatremia	5 (1.8)	6 (2.2)	0.768
Thrombosis/thrombus/embolism	7 (2.5)	5 (1.8)	0.772
Abbreviations: Cis = cisplatin; CTCAE = Common Terminology Criteria for Adverse Events, Version 3.0; Etop = etoposide; N = number of patients dosed; n = number of patients with at least one CTCAE; Pem = pemetrexed.
* Statistically significant; p<.05 based on Fisher’s exact test.
[a] CTCAE was defined as Infection (clinical/microbio)—Gr3/4 neutrophils—Pulmonary/upper respiratory—Lung (pneumonia).

Conclusion
During the concurrent treatment phase, patients with stage III locally advanced nonsquamous NSCLC in either treatment arm received comparable systemic therapy; however Pem+Cis had significantly lower incidences of some toxicities. Further toxicity differences may emerge with longer follow-up.

Background
The epidermal growth factor receptor (EGFR) mutational status is an important biomarker in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the frequency and clinical significance of EGFR mutation in patients with potentially curable locally advanced NSCLC (LA-NSCLC) who are eligible for definitive chemoradiotherapy (CRT).

Methods
Between Jan 2001 and Dec 2010, we conducted analysis for the presence of EGFR mutations, in consecutive non-squamous NSCLC (mainly in adenocarcinoma) patients who were eligible for CRT. The response rate (RR), progression-free survival (PFS), 2-year progression-free rate, first recurrent sites, and overall survival were investigated according to the EGFR mutational status.

Results
A total of 528 patients received CRT at the National Cancer Center Hospital during the study period, of which 274 were diagnosed as having non-squamous NSCLC (mainly adenocarcinoma). Sufficient specimens for mutational analyses could be obtained from 198 patients, and EGFR mutations were found at a frequency of 17% in these patients. In addition to the well-known characteristics of NSCLC patients carrying EGFR mutations (female, adenocarcinoma, and never/light smoker), the proportion of cases with smaller (T1/2) primary lesions was also higher in the patients carrying mutated EGFR than in those carrying wild-type EGFR. Patients carrying mutated EGFR showed similar RR (79% vs. 76%), median PFS (11.8 m vs. 10.6 m) and 2-year progression-free survival rate (22% vs. 30%) as compared to those carrying wild-type EGFR. Local recurrence as first relapse occurred less frequently in patients carrying mutated EGFR than in those carrying wild-type EGFR (4% vs. 21%). A majority of the patients with mutated EGFR showing disease progression received EGFR-TKIs (55%), and these patients showed a longer post-progression survival and a higher 5 year survival rate (50% vs. 34%) than the patients with wild-type EGFR.

Conclusion
Among the LA-NSCLC patients eligible for definitive CRT who were included in this analysis, 17% harbored EGFR-activating mutations in the carcinoma specimens. Although definitive CRT was similarly effective in both patients with mutated EGFR and wild-type EGFR, substantially lower frequency of local relapse was noted in the patients carrying mutated EGFR. Among the LA-NSCLC patients harboring EGFR mutations who developed disease progression, those treated with EGFR-TKIs showed a longer post-progression survival and overall survival as compared to those who did not receive EGFR-TKIs.

Background
The RAS/RAF/MEK/ERK signalling cascade has a central role in cancer proliferation and in modulating response to treatment. RAS mutations can confer a radiation-refractory phenotype and MAPK signaling can be stimulated by treatment with ionizing radiation in non-small cell lung cancer (NSCLC). Selumetinib (AZD6244; ARRY-142886) is an orally available inhibitor of MEK1/2 which was shown to enhance the effect of radiotherapy in preclinical studies. This effect was due to the ability of selumetinib to directly sensitize tumor cells to the cytotoxic effect of radiation and to modulate tumor vessel functionality by reducing VEGF-A expression. In a Phase II study, selumetinib given in combination with docetaxel showed promising activity in NSCLC patients with KRAS activating mutations. Aim To determine the recommended Phase II dose (RP2D) of selumetinib in combination with standard dose thoracic radiotherapy (RT) in NSCLC.

Methods
Selumetinib (Hyd-Sulfate capsule) was administered orally twice daily as a single agent for one week and then in combination with thoracic RT for 6 to 6.5 weeks (60 to 66 Gy in 30 to 33 fractions) in a single institution, open label Phase I trial using a modified Fibonacci sequence. Prior standard chemotherapy was permitted with a minimum interval between day8 of the last cycle of chemotherapy and day1 of administration of selumetinib of ≥ 2weeks. Other eligibility included: histologic or cytologic diagnosis of NSCLC, stage III not suitable for concurrent chemo-radiotherapy or stage IV with dominant thoracic symptoms, disease encompassable within a radical RT treatment volume, ECOG PS 0-1., no prior RT or investigational agents.

Results
A total of six consecutive patients with inoperable stage III (n=3) or stage IV (n=3) NSCLC were given selumetinib 50 mg twice daily (dose level 1) with concomitant thoracic RT (59.8-66 Gy in 30-33 fractions). All patients completed the combined treatment. Selumetinib delivery was > 80%. Four out of the six patients had dose interruptions of 2-3 days due to expected adverse events (AEs). Skin rash (6/6), diarrhoea (5/6) and fatigue (4/6) were the most common toxicities. Grade 3/4 AEs included hypertension (2/6), diarrhoea (2/6), skin rash (1/6), pulmonary embolism (1/6), fatigue (1/6) and pericardial effusion (1/6). Pulmonary embolism (grade 3) was considered not related to the study treatment. One patient experienced dose limiting toxicity (DLT) consisting of a combination of diarrhoea (grade 3) and fatigue (grade 3). Response to treatment was assessed 4 weeks post RT. Distant recurrence was seen in 1 patient; 3 patients had SD, 1 patient experienced a PR and 1 a CR. Median duration of response was 2 months (range 1-4 months).

Conclusion
Selumetinib given at 50 mg twice daily with concomitant radical thoracic RT was tolerated with no unexpected toxicities or enhancement of expected RT toxicities. Although the protocol-defined criteria to further escalate the selumetinib dose were met, because of the heterogeneous and small patient cohort and AEs encountered further evaluation of the 50 mg twice daily was preferred in order to obtained additional safety data. An expanded cohort of 15 patients having additional FLT-PET scans.

Background
Pemetrexed plus platinum recommended as first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC) were more effective in East Asian patients. Few studies have evaluated the role of radiotherapy in combination with pemetrexed in advanced NSCLC. We hypothesized that pemetrexed plus platinum at full dose in combination with early radiotherapy can improve the clinical efficacy in advanced NSCLC, especially for selected patients.

Methods
Patients of stage IIIB or IV non-squamous NSCLC with unknown epidermal growth factor receptor (EGFR) mutation status were treated with pemetrexed plus platinum at full dose as first-line chemotherapy. All patients underwent concomitant chemoradiotherapy for primary cancer with or without radiotherapy for metastases. No patients had maintenance therapy with TKI after chemotherapy.

Results
Figure 1From January 2009 to July 2012, 43 patients were included, 21 of which were stage IIIB diseases (19 with stage N3- IIIB). In the 22 patients with stage IV disease, 17 had oligometastases (≤5) and 5 had polymetastases. The median chemotherapy cycles was 4.27 patients (62.8%) received ≥ 4 cycles of chemotherapy and 16 patients (37.2%) received <4 cycles. 36 patients (83.7%) received radical dose radiotherapy (≥60 Gy) and 7 patients (16.3%) received palliative dose to primary tumor. The median radiation dose was 60Gy. The median follow-up time of survival patients was 17.0months (range, 5.8 to 45.2 months). The median progression free survival (PFS) was 12 months. 12-, 18- and 24-months PFS rate were 50.4% （95%CI, 35.3-65.5%）, 25.1% (95%CI, 21-39.2%) and 21.5% (95%CI, 7.8-35.2%), respectively. 12-, 18- and 24-months overall survival (OS) rate were 90.1% (95%CI, 75.8-96.2%), 72.2% (95%CI, 54.2-84.1%) and 65.7% (95%CI, 44.3-80.5%), respectively. The median OS was not reached. Toxicities were better tolerated except one death of radiation-induced pneumonitis.

Conclusion
Pemetrexed plus platinum as first-line treatment in combination with early radiotherapy had encouraging short term efficacy with acceptable toxicity in selected patients with advanced NSCLC. Although the long-term efficacy needs further observation, the result showed potential advantage of early radiotherapy in Asian patients with advanced non-squamous NSCLC, especially stage IV.

Background
Treatment of stage III NSCLC involves surgery, radiation therapy and chemotherapy. This treatment varies, depending on the size and location of the primary tumor and lymph nodes as well as the clinical status of the patient. Evaluation of these patients should take place in a multidisciplinary clinic, where all treating physicians and pulmonary medicine provide a unified treatment plan.

Methods
We performed a retrospective analysis of all patients with Stage III NSCLC seen at the Lehigh Valley Health Network (LVHN) between March of 2010 and March of 2012. We compared the initial treatment of patients seen in our TMDC with those patients whose treatment was arranged outside the TMDC.

Results
Thirty-five patients were seen in the TMDC (34 treated at LVHN) and forty-four patients were seen outside the MDC (34 treated at LVHN). The 11 patients not treated at LVHN either were not treatable or were treated elsewhere. Of patients with stage III NSCLC, 37.5% were seen in the TMDC year 1 (March 2010 – March 2011) as compared year 2 (March 2011 – March 2012) during which over 61% of patients seen in the TMDC (p = 0.05). Patients were seen by physicians from at least two specialties 100% of the time when seen in the TMDC, but only 64.7% of the time when seen outside the TMDC (p < 0.001). Mediastinal staging by either endoscopic bronchoscopic ultrasound (EBUS) or mediastinoscopy was performed more frequently in patients seen in the TMDC; 58.9% compared to 23.5% outside the TMDC (p = 0.009). The LVHN clinical pathway for stage III NSCLC recommends initial therapy with concomitant weekly chemotherapy and radiation either in the neo-adjuvant setting or as definitive treatment. Eighty-eight percent of patients seen in the TMDC followed our clinical pathway while 46% of patients seen outside the TMDC conformed to the clinical pathway (p < 0.001). The time from first contact with a treating physician to initiation of treatment was reduced by almost 30% (29.03 days outside the TMDC; 20.62 days at the TMDC).

Conclusion
All patients with stage III NSCLC should be seen in a multidisciplinary setting. At LVHN we saw an increase in these patients being referred to our TMDC over time. These patients were more likely to have mediastinal staging and enjoyed quicker initiation of their therapy. They were more likely to have at least two physicians involved in their initial treatment plan and were more likely to conform to our clinical pathways.

Background
In this study, prognostic role of age in stage IIIB non-small cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (CRT) was investigated.

Methods
Medical records of 942 18-70years old stage-IIIB NSCLC patients treated between January 2007 and December 2011 were retrospectively evaluated. Patients received 60-66 Gy radiotherapy concurrently with 1-3 cycle cisplatin-based (q21) chemotherapy. Patients were divided into groups [Group 1= ≤45 years(N=145), Group 2= 45-70(N=680) and Group 3=70-80(N=117)] according to the cut-off ages defined in the literature. Moreover, a further age cut-off point that might potentially influence survival was researched from ROC analysis, and comparatively analyzed with other factors. Primary end point was the evaluation of association between treatment duration and overall survival (OS), and secondary end points were progression-free survival (PFS) and locoregional PFS (LRPFS).

Results
Median follow-up for alive patients was 30.8 months (range 17.4-38.2), there was no statistically significant difference between groups in terms od demographic characteristics (p>0.05). Overall treatment was well-tolerated, and treatment-related mortality was reported in only 7 (0.7%) cases, which was not different between groups (%1.4 vs. %0.6 vs. 0.9; p=0.87). The most common grad 3-4 hematological and non-hematological toxicities were leukopenia (%37.3; %35.9 (n=52) vs. %36.2 (n=243) vs. %45.3 (n=53); p=0.26), and eosophagitis (%20.6 (n=194); %17.2 (n=25) vs. %20.7 (n=141) vs.%23.9 (n=28); p=0.36), respectively. Median OS for whole group was 23.6 months (%95 CI: 22.8-24.3). Results of comparative survival analyses between 3 groups were given in Table, and there was no statistically significant survival difference between groups in all survival measures. Moreover, no significant age cut-off that might be used to evaluate age as prognostic factor could be determined from ROC analyses. Table: Comparative survival analyses

Survival	Group 1 ≤45 years (N=145)	Group 2 45-70 (N=680)	Grup 3= 70-80 (N=117)	P
Overall Survival Median (%95 CI) 2 years 3 years 4 years 5 years	24.8 (22.3-27.3) 51.9 38.0 24.2 24.2	23.4 (22.5-24.3) 46.8 30.2 23.2 19.2	21.2 (17.3-25.1) 47.5 27.6 14.3 14.3	0.32
Locoregional Progression-free Survival Median (%95 CI) 2 years 3 years 4 years 5 years	15,7 (12,2-19,2) 33.3 25.5 12.2 12.2	14,7 (14,2-15.2) 22.1 18.5 15.6 12.6	14.7 (13,9-15.5) 27.4 26.4 9.2 9.2	0.13
Progression-free Survival Median (%95 CI) 2 years 3 years 4 years 5 years	12.0 (9.9-14.1) 24.3 18.2 11.2 11.2	10.6 (10.1-11.1) 17.5 15.1 13.4 12.5	10.6 (10.0-11.1) 20.3 18.2 7.3 7.3	0.18

Conclusion
Results of this study has demonstrated that age was not a prognostic parameter that could be used alone to predict outcomes in stage IIIB NSCLC treated with CRT. The observation that patients >70 years old could also tolerate aggressive CRT protocols, treatment of elderly patients with good performance status and no comorbidity with protocols similar to younger counterparts is recommended

Background
Purpose of this study was to evaluate the association between pretreatment thrombocyte count (TC) and prognosis in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with concurrent chemoradiotherapy (CRT).

Methods
Medical records of 792 LA-NSCLC patients, who had been treated with definitive CRT at our department between dates January 2007 and December 2011, and whose pretreatment TC values are available, 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 two groups according to their pretreatment TC: Group-1: normal (130.000-400.000; n=639) and Group-2: high (>400.000; n=153). Primary and secondary end points were overall survival (OS), and progression-free survival (PFS), respectively.

Results
At a median follow-up of 23.1 months (range 18.8-24.6), Median PFS and OS for whole group were 10.1 (%95 CI: 9.7-10.5) and 20.9 months (%95 CI: 20.9-22.9), respectively. On comparative survival analyses, patients with high pretreatment TC had inferior OS (23.2 vs. 15.6 months; p≤0.001) and PFS (10.6 vs. 7.8 months; p<0.001) than those with normal TC. Similarly, 3-years OS was significantly lower in Group-2 patients (8.9 vs. 33%, p<0.001). TC cut-off value determined from ROC curve analysis was 278.000, and median OS (18.7 vs. 24.5 months; p<0.001 and PFS (9.1 vs. 11.3 months, p<0.001) was significantly lower in patients with TC above this cut-off point. On univariate analyses, T-stage (T1-2 vs. 3-4), N-stage (N2 vs. N3), pretreatment TC (130.000-400.000 vs. >400.000), and ROC TC cut-off (<278.000 vs. ≥278.000) were the significant prognostic factors (p<0.05 for each), which retained their significance on multivariate analyses as well (p<0.001, 0.022, <0.00, 0.01, respectively).

Conclusion
Results of this study has shown that pretreatment TC may be a relevant and independent prognostic factor that can potentially be used besides other well-known factors to predict treatment outcomes in LA-NSCLC patients treated with definitive CRT.

Background
The optimal treatment for stage IIIA non-small cell lung cancer (NSCLC) disease is not well established with only 15% of 5-year survival rate, probably due toalready micro-metastatic lesion at the diagnosis. Thus, neoadjuvant therapy might be a good choice for IIIA NSCLC patients. The treatment modality of EGFR (TKI) intercalated with chemotherapy has been demonstrated to significantly improve objective response rate (ORR), progression free survival(PFS) and overall survival (OS) in advanced NSCLC patients with or without activating EGFR mutations. The objective of this study is to assess the efficacy and safety profile of intercalated erlotinib with gemcitabine/cisplatin as neoadjuvant treatment in stage IIIA NSCLC.

Methods
This is a single arm, multi-center, clinical phase II trial. Patients with untreated stage IIIA bulky N2 NSCLC and ECOG PS 0/1 were enrolled to received up to 2 cycles of gemcitabine 1,000 mg/m[2] on days 1 and 8 and cisplatin 75 mg/m[2] on day 1 or carboplatin AUC=5 d1, followed by oral erlotinib (150 mg, once a day) on days 15 to 28 as neoadjuvant therapy. A repeat computed tomography (CT) scan evaluated the response after induction therapy and eligible patients would undergo surgical resection. The primary endpoint was ORR, and secondary endpoints included pCR, resection rate, DFS (disease free survival) and OS , safety, QoL and biomarker analyses. Subgroup analysis of ORR by EGFR mutation status was also performed

Results
Between March 2011 and December 2012, a total of 39 patients were enrolled in the study, in which 36 patients (92.3% ITT population) have completed 2-cycle neoadjuvant treatment. According to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 18 patients achieved partial response (PR) (ORR=46.2%) and 18 patients achieved stable disease (SD) (DCR=92.3%); 22(56.4%) patients underwent resection with 18 R0 (46.2%), 2 R1(5.1%),1 R2(2.6%),1 NE(2.6%). Fifteen patients have had EGFR mutation test, with 7 EGFR mutation and 8 EGFR wild type. ORR in patients with EGFR mutations and wild type was 85.7%(6/7) vs. 50%(4/8), respectively. Common toxicities included myelosuppression (38.5%), rash (28.2%), neutropenia (5.1%), alanine transaminase (ALT) elevation(5.1%), diarrhea(5.1%) , fatigue(2.6%) and alopecia(2.7%) . Five (12.8%) patients suffered from CTCAE ≥3. No CTCAE ≥4 complications were recorded perioperatively.

Conclusion
Two cycles of intercalated administered gemcitabine/cisplatin with erlotinib as an induction treatment is a feasible and efficacious approach for stage IIIA NSCLC, which provides evidence for the further investigation.

Background
Metastasis of Lung cancer to Brain is associated with poor prognosis despite aggressive treatment. Available treatment options are limited beside radiotherapy as most drugs do not penetrate the blood brain barrier. Temozolamide has a good safety profile and crosses the blood brain barrier. One of the novel methods of delivering temozolamide is to use metronomic dosing which also has anti angiogenic properties, other than cytotoxic properties.

Methods
Eligible patients had to have confirmed Non Small Cell Lung Cancer (NSCLC) with no prior radiotherapy or radio-surgery for brain metastasis; with multiple brain metastasis. All patients were treated with Temozolamide 20mg in empty stomach twice a day continuously. Radiation was given to these patients as standard procedures. This was compared only to standard whole brain radiation. All patients continued on standard planned chemotherapy which was paclitaxel + carboplatinum and patients who had received Temozolamide were continued either till progression or unacceptable toxicity.

Results
41 patients - 24 men and 16 women with proven advanced Non Small Cell Lung Cancer (NSCLC) who were on treatment and developed brain metastasis, which was not operable or amicable to stereotactic radiotherapy.

	Radiotherapy (n=20)	Radiotherapy & Low Dose Temozolamide (n=21)
Median Karnofsky Score	> 60	> 60
Response Rate	7 (35%)	12 (57%)
Complete Response	1 (5%)	5 (24%)
Partial Response	4 (20%)	7 (33%)
Stable Disease	3 (15%)	3 (14%)
1 year survival rate	6 (30%)	14 (67%)
Median Overall Survival	9.2months	17.6months
Thrombocytopenia Grade III/IV	3 (15%)	5 (24%)
Neutropenia Grade III/IV	1 (5%)	2 (10%)
Anemia Grade III/IV	3 (15%)	6 (29%)

Conclusion
Metronomic dosing of temozolamide with concurrent whole brain radiation is an effective option in treatment of brain metastasis from Non Small Cell Lung Cancer (NSCLC). The median survival time is almost doubled. Side-effects are manageable.

Background
Concomitant chemoradiotherapy is the standard treatment of unresectable stage IIIA/IIIB non- small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is still controversial. Therefore; we conducted this prospective clinical trial to evaluate the efficacy and safety of pemetrexed and carboplatin when given concomitantly with thoracic radiotherapy followed by consolidation therapy of pemetrexed and carboplatin in elderly patients with locally advanced non-squamous NSCLC

Methods
Thirty seven patients with previously untreated, unresectable stage IIIA or IIIB non-squamous NSCLC with ECOG PS of ≤2, ≥65years old, and had adequate organs functions were enrolled into the study between August 2010 and April 2013. Patients received pemetrexed 500 mg/m[2] and carboplatin area under the curve (AUC) 5 on day 1 repeated every 3 weeks concomitant with thoracic radiotherapy 60-66 Gy over 6-6.5 weeks, followed by pemetrexed and carboplatin for 3 cycles as consolidation therapy. Treatment response, toxicity, progression free survival and overall survival were evaluated.

Results
The median age was 71 (range 65-79). Twenty seven patients (73%) were men. Twenty four patients (65%) had Stage IIIB and 13 patients (35%) had stage IIIA. Performance status was measured by ECOG and it was 0 in 23 patients (62%), 1-2 in 14 patients (38%). Eight (22%) patients had a complete response, 22 (59%) patients had partial response, while 5 (14%) patients had a stable disease and 2 (5%) patients had a progressive disease. The overall response rate (81%, 95% confidence interval (CI): 68-96%).The median PFS was 11 months (95% CI: 9.8-12.9 months).Grade 3/4 toxicity were reported as neutropenia in 12 (32%) patients; thrombocytopenia in 9 (24%) patients; anemia in 7 (19%) patients; vomiting in 3 (8%) patients; dysphagia in 2 (5%) patients, radiation pneumonitis in 2 (5%) patients and fatigue in 3 (8%) patients. No treatment related deaths (neither due to sepsis nor bleeding) were reported in the study.

Conclusion
Concomitant chemoradiotherapy using full doses of pemetrexed and carboplatin for treatment of elderly patients with locally advanced non-squamous NSCLC is a safe and effective regimen and it needs enrolling more patients to confirm the current results.

Background
On 2005 began the EGFR gene mutations determination in our Centre. We want to know the survival of patients with locally advanced non-small cell lung cancer treated with radical intention and to determine if there is a dependency for the EGFR gene mutation status.

Methods
We have treated 399 patients with locally advanced non-small cell lung cancer from 2005 until now. Mean age is 63,38 years (range 26-86). By gender, 346 patients were males (87%) and 53 were females (13%). All the patients were treated in our Department of Radiation Oncology. Squamous cell carcinoma was found in 188 patients (47%), adenocarcinoma in 169 patients (42%) and 42 patients (11%) had large cell or undifferentiated carcinomas. The majority of cases of radical treatment received concomitant radiotherapy and chemotherapy. Radiotherapy in stage IIIA (222 patients) was adjuvant to surgery in 53 cases, preoperatory in 1 patient and was administered with curative intent, with or without chemotherapy, to the rest of patients of stage IIIA. All the patients in stage IIIB disease (177 patients) received curative radiotherapy with or without chemotherapy. Conventional daily 3-D radiotherapy at standard fractionation was used and median dose of radiotherapy was 50 Gy in adjuvancy and 66 Gy (range 2-70) in curative intention. EGFR gene mutation determination was performed in 99 patients.

Results
Five-year overall survival for all patients is 22.8%, with a median survival of 22 months. By stage, 5-year overall survival is 29% for stage IIIA (median survival of 26 months) and 16.2% for stage IIIB (median survival of 20 months). Five-year overall survival for non-surgical stage IIIA disease is 17.1%, being the median survival 18 months and showing no difference with patients with stage IIIB disease. For the 99 patients analyzed for the EGFR gene status, the mutation was present in 9 patients while 90 patients were wild type. The overall 5-year survival for the patients whom the EGFR mutation was determined is 24% (median of 30 months) and there is no difference with the survival found for all patients. The EGFR gene status mutation does not imply a difference in survival.

Conclusion
The survival for stage III non-small cell lung cancer remains about 15% at 5 years and there is no difference for inoperable stages IIIA and IIIB. Median survival has achieved 20 months, which is better than the previous observed in the last decade of twentieth century. Given the small size of the sample with EGFR gene mutation (9 cases) we cannot conclude whether or not this factor has a prognostic value.

Background
Stage III non-small cell lung cancer (NSCLC) typically represents up to one third of all new NSCLC diagnoses, and can be a technically difficult and controversial group of patients to definitively manage. In 2004, the National Health and Medical Research Council published a set of evidence based clinical guidelines for the management of lung cancer in Australia. This study aims to investigate adherence to these national guidelines in the treatment of Stage III cancers and identify factors associated with the receipt of guideline recommended therapy (GRT) and patient survival.

Methods
A retrospective cohort of newly diagnosed, Stage III NSCLC was identified from the South Western Sydney (SWS) Local Health District Clinical Cancer Registry. Cases were diagnosed between 2006 and 2011 and resided within SWS local postcode boundaries. Pre-2010 diagnosed “wet” stage IIIB cases with malignant pleural effusion were excluded from analysis. GRT was assigned to each case based on stage group and performance status (ECOG) at diagnosis. Significant factors associated with adherence to GRT and the effect these factors had on patient survival was determined using univariate analysis and Cox proportional hazards regression model.

Results
Of 316 eligible cases identified, 19 patients (6%) had no ECOG documentation found, and were excluded from the analysis. Median age of the remaining cohort was 69 years, and 64% were male. Disease stage distribution was 58% for IIIA cases and 42% for IIIB. 85% of patients were identified as having Good ECOG (0-2) at diagnosis. Overall 55% of the total; 63% of IIIA and 46% of IIIB patients received GRT. 24% of IIIA patients received surgery alone in combination with chemotherapy and/or radiotherapy. 31% of IIIB patients received either concurrent or combination chemo-radiation. On univariate analysis, the receipt of GRT was associated with patient age (p <0.001), disease stage (p 0.003), and performance status (p <0.001). Morphological subtype was trending (p 0.056). Overall median survival was 11.4 months. Patient survival was not significantly improved with the receipt of GRT.

Conclusion
Adherence to GRT was associated with tumour stage, patient age and performance status. In this cohort of patients, the receipt of GRT did not have a significant impact on survival.

Background
Although pretreatment evaluations are well defined for the diagnosis of stage III NSCLC, we have very little data about the follow-up of these patients after completion of therapy. No documented standards for surveillance were set in the NCCN, ACCP or ESMO guidelines. To determine if there is a survival difference in stage III NSCLC patients who were followed by PET/CT or CT after chemoradiotherapy.

Methods
Data from 50 patients who were treated with CRT in Marmara University Medical Oncology clinics between 2003-2012 were retrospectively reviewed. All patients were followed-up by CT or PET/CT. Median age was 57 (range 29-73 years), 90% were male, and PS was 0 in 74%. Adenocarcinoma was seen in 28% and squamous cell carcinoma in 48%. PET/CT was done in 86% of patients during metastatic workup. Median follow-up was 17 months. Median overall survival for all patients was 26 months (range 3-70 months) and progression free survival was 10 months (3-63 months).

Results
PET/CT was used in 58% of the patients to evaluate response and was done a median of 6 months after the first treatment. Eight patients had complete, 23 had partial response and 4 had progressive disease. Median survival was 18 months in patient who were followed by CT scans, whilst the survival in the group who had PET/CT was 30 months (p:0.098). Thirtythree patients relapsed on follow-up; of these 28 presented with symptoms, 17 was detected with CT, 5 with MRI of brain and 12 with PET/CT.

Conclusion
Response evaluation with PET/CT after CRT in stage III NSCLC might prolong survival in this selected group of patients. But during the follow-up period PET/CT might not be as beneficial as expected, because most of the patients present with symptoms on relapse. Further clinical well designed studies should be done in this field, because usage of PET/CT for follow-up is increasing in the entire world. PET/CT might be unnecessary in the follow-up of stage III NSCLC patients after initial response evaluation.

Background
The standard treatment for unresectable stage IIIA/IIIB NSCLC patients with good PS is concurrent chemo-radiotherapy. However, local tumor control remains suboptimal and distant metastases remain the major failure. Moreover, the treatment related toxicities limit application. EGFR-targeting agents including tyrosine kinase inhibitor (TKI)such as erlotinibwere demonstrated to sensitize tumor cells to radiation by a variety of mechanisms in preclinical studies. Subsequently, Phase I/II studies forcombination of TKI with radiotherapy in different cancer types have been conducted. Based on those findings, the RECEL study is comparing efficacy and tolerability of erlotinib versus etoposide plus cisplatin with concurrent radiotherapy in unresectablestage III NSCLC with activating mutation of epidermal growth factor receptor (EGFR) in exon 19 or 21.

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 0–1IIIA/IIIB NSCLCconfirmed by histopathology or cytology and clinically unresectablewith activating mutation ofEGFR in exon 19 (loss) or 21 (L858R point mutation)will be enrolled (n=100). The enrolled patientswould be randomly assigned (1:1) into two arms: erlotinibarm(erlotinib 150mg/day taken orally for up to 2 years which begin on day 1 of radiation) or EP chemotherapy arm(etoposide50mg/m[2]I.V. on days 1-5 and days29-33,cisplatin50mg/m[2]I.V. after etoposideon days 1,8,29,36. 28-day schedule for 2 cycleswhich begin on day 1 of radiation).Concurrent radiotherapy in both arms is prescribed at 200cGy/day, 5 days/week for a total of 30-33 fractions, total dose of 6000-6600cGy. Duration of the recruitment will be 36 months. Patients will receive long-term follow-up including chest and upper-abdominal CT scan every 3months, brain MRI every 6 months and bone scan every 12 months. Primary endpoint is progress free survival (PFS). Secondary endpoints areobjective response rate(ORR), local control rate (LCR), overall survival (OS), quality of life (QoL) and safety.Biomarker profile will be the exploratory research.

Results
Till June 2013, 24 patients were screened for EGFR mutation, and 4patient has been enrolled.

Conclusion
Concurrent erlotinib with radiation therapy might be a promising treatment strategy.

Background
We report the interim-analysis result of the BEST trial, which examines efficacy and safety of second- or third-line chemotherapy with erlotinib (E) and bevacizumab (B) for the Japanese patients (pts) with non-squamous, non-small cell lung cancer.

Methods
E was administered initially at 150 mg/day orally and B was administered at a dose of 15 mg/kg on the first day of each 3-week cycle. The primary endpoint was objective response rate (RR). The secondary endpoints included overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and incidence of adverse events. This trial was planned to accrue 80 pts based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status was planned (Trials. 2011; 12: 120).

Results
Total of 28 pts enrolled in 2 years from November, 2010. One patient was excluded due to thrombosis in lower limb and 27 pts (15 men and 12 women) with a median age of 67 (43-82) were analyzed; 18 pts had a PS of 0; all had adenocarcinoma; 11 pts had EGFR mutation; 1 patient had stage IIIB, 23 pts had stage IV and 3 pts had recurrences after surgery; 21 pts received as second-line and 6 pts received as third-line chemotherapy. RR was 18.5% (p=1.00; one-sided); DCR was 77.8%. Median PFS was 5.6 months (m); OS data were not yet mature (median follow-up time was 11.9 m). Grade 3/4 non-hematologic toxicities were mainly acne (11.1%) and hypertension (11.1%). The subset analysis according to EGFR showed significantly higher RR (p=0.02) and better PFS (p=0.03) in mutant group than in wild group. RR in mutant group was compared with 20% null hypothesis using the same binomial test (p=0.056).

Conclusion
Combination therapy of B and E had mild adverse effects but did not increase anti-cancer effect.

Background
There has been no randomized controlled study for comparing tumor response, toxicity and survival between belotecan- and topotecan- monotherapy in patients with SCLC. To aim of this study is to assess and compare tumor response, toxicity and survival between belotecan- and topotecan- monotherapy in patients with SCLC.Therefore, we try to help physicians to select drugs through a comparison of the efficacy and toxicity for both drugs in this study.

Methods
The clinical data of 94 patients treated with belotecan- (n=59, total 188cycles) or topotecan- (n=35, total 65cycles) monotherapy were reviewed retrospectively from September 2003 to December 2011. Hematologic and Nonhematologic toxicities were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Statistical significance of Time to progressive disease (TTPD), chemotherapy-specific survival (CSS) and overall survival (OS) between the 2 chemotherapies were evaluated by the Kaplan-Meier analysis.

Results
There were no significant differences in baseline characteristics between belotecan- and topotecan- monotherapy except the line of chemotherapy. The overall response rate was 12.7% in patients treated with belotecan monotherapy and 5% in topotecan monotherapy. Thrombocytopenia was developed in 42% and 61.5% of cycles in belotecan- and topotecan- monotherapy, respectively (P = 0.007). In nonhematological toxicities, grade 4 or 5 in lung infection, headache, grade 4 or 5 in elevation of liver enzyme developed in 3.2% and 10.8% (P=0.003), 3.2% and 10.8% (p=0.017), 0.5% and 4.6% (p=0.023) of cycles in belotecan- and topotecan- monotherapy, respectively. The median TTPD, CSS and OS were 14 months and 11.6 months (P=0.646), 10 month and 7 month (P=0.179), 34.5 months and 21.4 months (P=0.914) in belotecan- and topotecan- monotherapy, respectively.

Conclusion
In our experience, belotecan monotherapy seemed to be efficient compared with topotecan monotherapy in small cell lung cancer, with acceptable toxicity, especially in thrombocytopenia, severe lung infection and elevation of liver enzyme.

Background
Epidermal growth factor receptor (EGFR) mutation alone may be insufficient to predict clinical outcomes in the response to EGFR-tyrosine kinase inhibitor (TKI) therapy. The secondary mutation T790M and MET amplification are mechanisms of acquired resistance to EGFR-TKI in approximately 50% of patients, but the remaining mechanisms are unknown.

Methods
Eight metastatic lesions and specimens from 41 non-small cell lung carcinoma (NSCLC) patients harbouring activating EGFR mutations who underwent surgical resection and EGFR-TKI therapy were available. Immunohistochemistry was used to evaluate E-cadherin, β-catenin, and PTEN. Chromogenic in situ hybridisation and silver-enhanced in situ hybridisation were used to evaluate EGFR and MET amplification.

Results
Patients with E-cadherin/β-catenin alteration showed a poor objective response rate (ORR) (p=0.005) and shorter overall survival (p=0.059). Additionally, β-catenin alteration was associated with a poor ORR (p=0.012). In the metastatic tumours, 3 cases (37.5%) showed the acquisition of altered E-cadherin/β-catenin and PTEN loss, and 2 cases (25.0%) demonstrated MET/EGFR amplification.

Conclusion
Altered E-cadherin/β-catenin expression in NSCLC harbouring EGFR mutations was associated with a poor response to EGFR-TKI. During metastatic progression, changes in E-cadherin/β-catenin were found. These results may suggest that E-cadherin/β-catenin alteration is related to poor TKI response and resistance.

Background
African Americans (AA) have a higher rate of lung cancer than Caucasians per 100,000 population (74.7 versus 64.4) but are underrepresented in randomized clinical trials. In the PointBreak study, AAs were enrolled at the same rate as the US incidence of non-small cell lung cancer (NSCLC) for AAs in 2011 (13%; now 15% in 2013). Post-hoc analyses of the AA subgroup were conducted from this study to evaluate efficacy and safety, as well as these outcomes by treatment center.

Methods
All patients (N=939) were chemonaive with an ECOG performance status (PS) of 0/1. AAs were analyzed against Caucasians for efficacy/safety in the pemetrexed (Pem) arm only. Subgroup analyses of AAs alone were conducted for efficacy/safety (between arm comparisons) as well as academic versus community settings (pooled two treatment arms). Hazard ratios and p-values were derived from a multivariate Cox-PH model, adjusting for disease stage, gender, PS and measurable/nonmeasurable disease. Response rates and adverse events (AEs) were compared using the exact test.

Results
Patients had stage IIIb (with pleural effusion)/IV nonsquamous NSCLC, according to AJCC edition 6. There were 94 AAs (42 = Pem arm; 52 = Paclitaxel [Pac] arm) and 805 Caucasians in the treated population. Demographics were statistically comparable between AAs and Caucasians in the Pem Arm, respectively: 62%/53% male, 71%/53% ≤65 years, 98%/89% ever smokers, 81%/90% Stage IV disease, with ECOG PS of 0/1, 33%/67%, versus 44%/56%. Median OS was similar between AAs and Caucasians in the Pem arm at 12.4 versus 12.3 months. Median PFS for AAs and Caucasians was 4.6 months versus 6.0 months (HR 1.229 (0.864 – 1.749; p=0.251). Overall response rate (ORR) for AAs was higher, though not statistically, at 38.1% versus 33.3% (p=0.607). Efficacy among AAs was fairly similar with median OS for Pem arm at 12.4 versus 13.7 months for Pac arm (p=0.1208). Median PFS by arm was 4.6 versus 5.1 months (p=0.6699). ORR among AAs was 38% in both arms. AAs showed a heavy trend (80%) for enrollment in community centers (n=74) versus academic center (n=20). Efficacy among AAs by setting showed a higher median OS at academic sites at 16.5 months versus 11.4 months, p=0.1906 (HR=0.6605; 95% CI: 0.355 – 1.229). Median PFS was also higher at academic sites at 6.9 months versus 4.6 months, p=0.9149 (HR =0.9690; 95% CI: 0.544 – 1.726). Drug-related grade 3/4 AEs in the Pem arm showed higher percentages for Caucasians with the exception of neutropenia, as follows: anemia (7.3%/15.9%), thrombocytopenia (9.8%/25.5%), fatigue (4.9%/11.5%), neutropenia (31.7%/25.3%), febrile neutropenia (0%/1.6%). Among AAs in the Pem/Pac Arm respectively, drug-related grade 3/4 AEs were: anemia (7.3%/0%), thrombocytopenia (9.8%/4.0%), fatigue (4.9%/4.0%), neutropenia (31.7%/44.0%), and febrile neutropenia (0%/4.0%).

Conclusion
There were no significant differences between AAs and Caucasians for OS, PFS, and ORR. Among AAs, median OS was not superior for either arm. PFS and OS were similar for academic and community settings among AAs. Caucasians had a significantly higher incidence of Grade 3/4 thrombocytopenia (p=0.0217), but this should be interpreted with caution due to the sample size for the AAs.

Background
Bv is a novel anti-angiogenic agent used in many advanced solid tumours, including non-squamous NSCLC. In contrast to clinical studies where enrolled pts are fit, many elderly NSCLC pts suffer from co-morbidities and often have history of a CVD

Methods
Medical records of 2672 pts diagnosed with NSCLC between 2001-2012 were screened. We identified and examined pts ≥75 yrs old treated with bev, for their demographics, clinical data and treatment (Tx) details. We focused on those elderly pts with stable pre-existing cardiovascular disease.

Results
356/2672 NSCLC pts received Bv at any Tx line. 33/382 (8,6%) were ≥75 yrs old. Of those, 29 had various co-morbidities including 19 pts with stable CVD on medical Tx. In the 19 pts with CVD the male:female ratio was 17:2 and mean age 77 yrs (range 75-86). 8/19 pts had impaired renal function. All pts were of Performance Status ECOG 0/1. Median number of Bv cycles was 5 (range 2-11). 17/19 pts experienced ≥1 side effects (11 epistaxis and haemoptysis, 5 proteinuria, 4 hypertension) which led to treatment discontinuation in 5 pts. No major/fatal adverse events were noted. 8/19 pts (42%) showed radiological partial response and 5 (19%) stable disease (total disease control rate 61%). Median survival from initiation of Bv till death/last follow up was 7 months (range 2-28, 95% CI 5.14-12.55).

Conclusion
Treatment with Bevacizumab seems to be safe and effective in elderly NSCLC patients with controlled pre-existing cardiovascular disease and good PS. These patients might benefit from participation in clinical trials similarly to younger NSCLC patients.

Background
Although the 2012 version of the clinical practice guidelines for lung cancer published by the Japan Lung Cancer Society recommends performing a tegafur-uracil (UFT) compound drug therapy on cases of non-small cell lung cancer for stage 1A and 1B tumors measuring > 2 cm in diameter after surgery, we often encounter cases of recurrence. Therefore, we obtained data on T2a tumors (> 3 cm but < 5 cm in diameter) treated with UFT as postoperative adjuvant chemotherapy at our hospital and examined their recurrence predictors.

Methods
Among 2,724 cases of total surgical removal of non-small cell lung cancer performed between January 1997 and December 2007, we examined 168 cases with stage 1B T2a tumors treated with UFT to clarify the recurrence predictors in these cases. We examined age, sex, tumor diameter, vascular invasion, lymphatic involvement, pleural invasion, histologic degree of differentiation, tissue, and CEA.

Results
The age range was 38 to 85 years (median 66 years), and there were 108 men and 60 women. The 5-year recurrence-free survival rate was 72.7%. In cases of recurrence, the median time to recurrence was 662 days in 48 of the 168 cases (28.6%). On univariate analysis, vascular invasion (p < 0.001), male sex (p = 0.045), and non-differentiation (p < 0.002) were identified as significant recurrence predictors. On multivariate analysis, vascular invasion (p = 0.009) was found to be a significant recurrence predictors. Please confirm this part as the changes were made based on the original Japanese text.

Conclusion
It was inferred that vascular invasion is a primary recurrence predictor in cases receiving UFT as postoperative adjuvant chemotherapy. We need to consider a more careful follow-up during UFT administration as postoperative adjuvant chemotherapy in stage 1B T2a tumors.

Background
Non-small cell lung cancer (NSCLC) is the most common cancer worldwide. Majority of the patients present with advanced disease. For patients with good performance status, palliative chemotherapy consisting of a platinum-containing doublet has become Standard of care. Cisplatin plus gemcitabine is a viable option in the treatment of metastatic NSCLC. Biweekly use of this regimen has been found to be effective and tolerable in various cancers. Moreover, this schedule offers a more convenient way of administration. We retrospectively evaluated the efficacy and tolerability of this regimen in advanced NSCLC patients.

Methods
Medical records of advanced NSCLC patients who were treated with first-line biweekly cisplatin + gemcitabine chemotherapy were analyzed retrospectively. Cisplatin 50 mg/m2 and gemcitabine 1000 mg/m2 were given on day 1 of every 14 days of the cycle. Response rates, survival outcomes and toxicities were recorded.

Results
A total of 109 patients were evaluated in six centers of Anatolian Society of Medical Oncology. Of those, 94 patients were men (86%) and 15 were women (14%). The median age was 58 years (range, 25-82). Most of the patients had adenocarcinoma (n=62, 57%). All of them had ≤2 ECOG PS. Median 7 cycles therapy were given (range, 2-12). Patients were evaluated for response usually after every 4 cycles. There was no complete response. Forty-five patients (41%) achieved partial response (PR). Stable disease was observed in 27% of the patients leading to an overall clinical benefit rate of 68%. Median progression-free survival (PFS) was 5.9 months. Median overall survival (OS) was 12.6 months. Eight patients died due to progression during therapy. The most common non-hematologic toxicities were nausea and vomiting. Grade 3/4 toxicity was detected in eight (7%) patients. They were four anemias, two neutropenias, one vomiting and one nephropathy. In all grades, the most common hematologic toxicity was anemia (48%). Neutropenia was seen in 21% of the cases, but only one patient had febrile neutropenia. One patient had to discontinue therapy due to grade 2 nephropathy.

Conclusion
Biweekly cisplatin and gemcitabine is an effective and tolerable regimen in the first-line treatment of NSCLC.

Background
Previous publications have demonstrated the efficacy of pemetrexed (PEM) as first-line, second-line and maintenance therapy in advanced non-small cell lung cancer (NSCLC). A recent study found skin toxicities compromised continuation of PEM treatment. The purpose of this study is to investigate the clinical significance of hyperpigmentation (HP) in advanced non-squamous (NS) NSCLC receiving PEM-based therapy in China.

Methods
Medical records of patients with advanced NS NSCLC who received PEM-based treatment in our hospital were retrospectively studied. Chi-square test, Pearson’s test as well as Kaplan-Meier method and Cox Proportional Hazards model were performed for statistical analysis.

Results
A total of 101 patients were collected with a median age of 58 years old. Among them, 53 (52.5%) were female and 65 (64.4%) were nonsmokers. 52 (51.5%) patients received first-line treatment. Presence of HP was associated with better ORR (22% vs 7.1%, p=0.043), higher DCR (84.7% vs 54.8%, p=0.001), and had longer PFS (186 days versus 96 days, p<0.0001). There were no significant differences according to grade of HP in ORR, DCR and PFS. There was a higher incidence of hyperpigmentation in patients who received first-line treatment (73.1%% vs 42.9%, p=0.023) and doublet chemotherapy (43.1% vs 74.0%, p=0.002). However,multivariate analysis demonstrated HP was not an independent factor for better clinical outcomes (vs absence, Hazard Ratio [HR] 0.417, 95% Confidential Interval [CI] 0.255-0.690, p=0.493).

Conclusion
HP due to PEM is frequent in advanced NS NSCLC receiving PEM. It might be a predictive factor for better clinical outcomes in Pemetrexed-treated advanced NS NSCLC in China.

Background
One of the therapies for the advanced Non-Small Cell Lung Cancer (NSCLC) is chemotherapy. The success therapy is measured by 1-year survival, 2-year survival and progression free survival (PFS). The success is influenced by many factors such as resistant to the cytostatic, dosage, administer intensity, chemotherapy regiment, type of histology, stage, performance status, comorbidity and socioeconomics. In Indonesia, chemotherapy expense is one of the problem for the treatment which docetaxel is much expensive than etoposide. Purposes this study are to determine the survival and PFS difference between the NSCLC patients that were treated with Cisplatin-Etoposide (EC) against Cisplatin-Docetaxel (DC).

Methods
The study was using the retrospective cohort study with survival analysis. The patients that included to this study were the advanced NSC Lung Cancer (at least stadium IIIa) who came to Dharmais Cancer Hospital and Cipto Mangukusumo Hospital during January 2006 until December 2010 for their first chemotherapy until finished the cycle (6 times) and had 2-year monitoring. Data was analyzed by SPSS 16.0 by cox regression analysis, and featured on the Kaplan Meier Curve.

Results
Fifty five patients were using EC and the other 55 patients were using DC. There were significant difference in survival: 1-year survival of EC group was 30.9% and DC group was 47.3% (p 0.030); 2- year survival of EC group was 0% and DC group was 5.5% (p 0.003); median time survival of EC group was 27 weeks and DC group was 38 weeks (p < 0.016). Compared to DC group, chemotherapy in EC group increased the death risk (HR 1.684; CI 95% 1.010-2.810). Moreover, twenty four weeks PFS in EC group (54.5%) was better than DC group (32.7%) with p < 0.022.

Conclusion
The survival and PFS with cisplatin-docexatel is better compare to cisplatin-etoposid. But we can still give cisplatin etoposide if patients have financial problem.

Background
Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the dramatic therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non–small cell lung cancer (NSCLC); however, there are no studies investigating clinical indicators that affect the likelihood of survival benefit from EGFR-TKI in selected patients with EGFR mutations. We evaluated the progression-free survival (PFS) and overall survival (OS) according to response and tumor shrinkage pattern among EGFR-mutated NSCLC.

Methods
Among 145 EGFR-mutation positive patients treated with EGFR-TKI, 68 patients were selected for the present analysis.

Results
Of those 68 patients, six patients achieved complete response (CR), 42 patients partial response (PR), and 14 patients stable disease (SD). The PFS and OS of CR/PR group was significantly longer than that of the SD group. A multivariate analysis demonstrated that response (CR/PR) to EGFR-TKI significantly correlated with both PFS and OS. Among CR/PR group, the median maximum tumor change from baseline was -56%, and the median time to response (TTR) was 4.2 weeks. No trend toward more favorable PFS and OS benefit was seen in the subset of patients who had experienced rapid tumor regression (TTR < 4.2 weeks) as well as high degree of tumor shrinkage (< -56%) compared with those who showed slow tumor regression (TTR > 4.2 weeks), or low degree of tumor shrinkage (> -56%) among CR/PR patients.

Conclusion
Response (CR/PR) may represent the optimal surrogate for efficacy among EGFR mutation-positive patients treated with EGFR-TKI patients.

Background
Presence of activating EGFR mutations is known to be predictive of a favorable response to treatment with EGFR-TKIs in non-small cell lung cancer (NSCLC) patients. Indeed, in clinical practice, EGFR-TKI treatment in patient with NSCLC harboring EGFR mutations sometimes yields a progression-free survival (PFS) of more than 2 years. The aim of this study was to evaluate the clinicopathological features of patients showing long-term (in the context of this study, more than 2 years) PFS.

Methods
Data of 194 consecutive patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs between May 2003 and May 2011 were reviewed. PFS was measured from the date of start of EGFR-TKI treatment to the date of documentation of disease progression, death or the last follow-up.

Results
The characteristics of the 194 patients were as follows, male/female: 70/124; median age: 65 years (range 36-88); PS 0-1/2-3: 170/24; adenocarcinoma/non-adenocarcinoma: 189/5; advanced/recurrent: 104/90; EGFR-TKI 1st line/2nd or 3rd line: 120/74; gefitinib/erlotinib: 170/24; Exon 19 deletion/L858R/other mutations: 98/86/10. The median progression-free survival was 9.7 months. Of the 194 patients, 32 (16%) showed long-term progression-free survival. The results of univariate analyses revealed significant associations between the PFS and the PS and site of EGFR mutation. The EGFR-TKI treatment line (1st line/2nd or 3rd line) and specific EGFR TKI used (gefitinib/erlotinib) exerted no significant influence on the PFS. Multivariate analysis with a Cox proportional hazards model identified PS0-1 and Exon 19 deletion as independent favorable prognostic factors for PFS. The median PFS in patients with PS 0-1 and Exon 19 deletion (n=88) was 13.2 months, and 20 of the 88 patients (23%) showed long-term progression-free survival.

Conclusion
Patients with good PS and Exon 19 deletion appear to have a higher likelihood of showing long-term progression-free survival. Therefore, the site of EGFR mutation, in addition to the PS, may be useful as a stratification factor in future clinical trials.

Background
S-1, a 5-fluorouracil derivative, and pemetrexed (PEM) are antimetabolites that both mainly target thymidylate synthase. S-1 received approval as a therapeutic drug for treating non-small cell lung cancer (NSCLC) in Japan in December 2004, and has been primarily used as a single agent for salvage chemotherapy. To our knowledge, there has been no clinical evidence whether the activity of S-1 is influenced by PEM resistance.

Methods
Patients with pretreated NSCLC who underwent S-1 monotherapy were identified from an institutional database. This study was approved by the institutional review board. Eligible patients were classified into three groups; patients with non-squamous NSCLC pretreated with PEM (PEM+) or not (PEM−), or those with squamous cell lung cancer (SQ). Progression-free survival (PFS) and overall survival (OS) from S-1 administration were estimated using the Kaplan-Meier method and the log-rank test was used for inter-group comparisons. Impacts of prior PEM therapy on PFS and OS were examined using Cox proportional hazards modeling with variables including number of prior chemotherapy regimens, histological subtype of NSCLC, sex and age (<70 vs. ≥70 years).

Results
We identified 125 patients who underwent S-1 monotherapy for pretreated NSCLC. Median age was 69 years (range, 39-86 years), with 31% female. Histological subtype was 82 (66%) adenocarcinoma, 33 (26%) squamous cell carcinoma and 10 (8%) NSCLC not otherwise specified. Number of prior chemotherapy regimens was one in 32 (26%), two in 54 (43%), three in 26 (21%) and four or more in 13 (10%) patients. Among 108 patients with measurable disease, response rate was 12% and disease control rate was 45%. Response rates for S-1 monotherapy as second-, third- and fourth-line chemotherapy were 19% (5/27), 13% (6/45) and 9% (2/23), respectively. Forty-eight patients had received PEM-based chemotherapy prior to S-1 administration. Median PFS were 2.0 months for the PEM− group (reference), 2.1 months for the PEM+ group (crude hazard ratio (HR) 1.11, 95%CI 0.73-1.69, p = 0.6), and 2.2 months for SQ group (crude HR 0.72, 95%CI 0.44-1.15, p = 0.2). Median OS were 4.5 months for the PEM− group (reference), 5.9 months for the PEM+ group (crude HR 0.65, 95%CI 0.41-1.03, p = 0.07), and 8.4 months for SQ group (crude HR 0.76, 95%CI 0.47-1.23, p = 0.3). Multivariate analyses revealed that only female sex was associated with longer PFS (HR 0.59, 95%CI 0.38-0.91, p = 0.02) and OS (HR 0.58, 95%CI 0.36-0.91, p = 0.01), with history of PEM therapy or histological subtype exerting no influence.

Conclusion
Activity of S-1 is unaffected by prior PEM therapy. These results are compatible with recent preclinical findings. Further study is warranted.

Background
To evaluate the efficacy and safety of nab-paclitaxel single agent and in combination with nedaplatin in elderly patients who have had prior treatment in the recurrent or metastatic NSCLC setting.

Methods
Elderly (age ≥ 65) advanced NSCLC patients with ECOG PS 0-1 were recruited and 1:1 randomized to Abraxane single agent arm (arm A) or Abraxane plus nedaplatin arm (arm AP). In arm A Abraxane was 130 mg/m[2], d1, 8, q3w and in arm AP nedaplatin was added by 20 mg/m[2], d1-d3, q3w. The primary endpoint was ORR and secondary endpoints were DCR, PFS, OS and safety.

Results
From October 2009 to January 2013, 48 patients were enrolled, 24 patients in each arm. In arm AP, 1 patient was lost to follow up and 1 patient withdrew from study. The median treatment cycle number was 4 and more than 80% of patients finished 4 cycles. The overall ORR of all patients was 21.3% and DCR was 55.3%, median PFS was 4.5 months, and median OS was 12.6 months. There was no significant ORR difference between arm A and AP (16.7% vs 26.1%, P=0.665) as well as DCR (54.2% vs 56.5%, P=0.871). The median PFS was 3.3 months (95% CI: 1.74-4.86) in arm A and 5.5 months (95% CI: 1.59-9.41) in arm AP, with no significant difference (P=0.738). Median OS was 12.6 months in arm A (95% CI: 3.70-21.50) and 15.1 months in arm AP (95% CI: 6.71-23.49), with no significant difference (P=0.770). There was no significant difference of ORR between squamous cell carcinoma and adenocarcinoma subgroups within arm A or AP (P>0.05). There was no ORR difference between subgroups pretreated with or without solvent-based paclitaxel within arm A or AP (P>0.05). Most adverse events were grade 1-2. Grade 3-4 toxicities included neutropenia, thrombocytopenia, neuropathy, fatigue, nausea and vomiting. The incidence of ≥ grade 3 neutropenia were 62.5% in arm AP and 29.1% in arm A (P=0.020). There was no treatment related death. Table 1 Patients demographics and baseline characteristics (n=48)

Characteristics	All patients (n=48)	Arm A (n=24)	Arm AP (n=24)
Age, years
Mean (range)	70.8 (65-80)	71.0 (65-80)	70.5 (66-79)
Gender, n (%)
Male	31 (64.6)	16 (66.7)	15 (62.5)
ECOG PS, n (%)
0	17 (35.4)	10 (41.7)	7 (29.2)
1	31 (64.6)	14 (58.3)	17 (70.8)
TNM stage, n (%)
IIIb	13 (27.1)	8 (33.3)	5 (20.8)
IV	35 (72.9)	16 (66.7)	19 (79.2)
Histology, n (%)
Adenocarcinoma	32 (66.7)	17 (70.8)	15 (62.5)
Squamous	16 (33.3)	7 (29.2)	9 (37.5)
Smoking status, n (%)
Yes	27 (56.2)	15 (62.5)	12 (50.0)
No	21 (43.8)	9 (37.5)	12 (50.0)
EGFR mutation, n (%)
EGFR (-)	38 (79.2)	18 (75.0)	20 (83.3)
EGFR (+)	10 (20.8)	6 (25.0)	4 (16.7)
Pretreated with solvant-based paclitaxel
Yes	13 (27.1)	6 (25.0)	7 (29.2)
No	35 (72.9)	18 (75.0)	17 (70.8)
Prior treatment
Radiotherapy	7 (14.6)	4 (16.7)	3 (12.5)
Targeted therapy	18 (37.5)	10 (41.7)	8 (33.3)
Chemotherapy	42 (87.5)	20 (83.3)	22 (91.7)
Median treatment cycle, n (range)	4 (1-8)	4 (2-8)	4 (1-6)

Conclusion
Nab-paclitaxel-based chemotherapy is well tolerated in pretreated elderly advanced NSCLC patients and has good ORR and OS. Nab-paclitaxel single agent is more adaptable for elderly patients’ performance status. Nab-paclitaxel can be used in patients formerly treated by solvent-based paclitaxel and there is no significant difference of clinical benefit between squamous cell carcinoma and adenocarcinoma.

Background
Akt, a serine- threonine kinase and a downstream mediator of the phosphoinositide-3-kinase (PI3K) pathway, is a signal transduction protein that plays a key role in tumorigenesis and metastases. Anomalies of Akt regulation including overexpression in lung cancer, impart resistance to conventional chemotherapy and radiation, thereby implicating this kinase as a therapeutic intervention point for this dreadful disease.

Methods
A novel scaffold of Akt inhibitors were assessed through virtual screening of chemical databases available at BITS-Pilani, Hyderabad using GLIDE (Maestro, Version 8.5, Schrodinger). BIA-6, a benzothienopyrimidine derivative was identified as a lead molecule. The compound was tested for in vitro Akt inhibition using a fluorescence resonance energy transfer assay kit (Z-lyte, Invitrogen). Anti-proliferative activity of BIA-6 was studied in NCI-H460, a lung adenocarcinoma cell line, routinely used as a surrogate for lung cancer. Effect of the compound on downstream biomarkers such as pAkt (S473) and p-P70S6K in NCI-H460 cells were determined by western blotting. Bands were quantified using ImageJ (Ver: 1.46, NIH) and normalized to actin.

Results
BIA-6 inhibited Akt1 enzyme activity with an IC~50~ of 0.26 µM with no apparent change in potency upon increasing the ATP concentration 10 fold, indicating allosteric interaction with the kinase. The compound caused a dose dependent reduction in growth of NCI-H460 cells with a GI~50~ of 0.7 µM. Cell cycle analysis indicated that BIA-6 arrested NCI-H460 cells in the G1 phase at <100 nM but led to apoptosis at higher doses. BIA-6 did not affect the viability of normal human tracheal epithelial cells and lung fibroblasts at concentrations upto 40 µM suggesting a high therapeutic window in vitro. Downstream effectors, pAkt and p-p70S6K, were suppressed in a dose dependent manner.

Conclusion
BIA-6 is a novel, allosteric Akt1 inhibitor with potent anti-proliferative activity in lung cancer cell lines and effectively blocks the PI3K/Akt pathway with a high safety margin. Further preclinical profiling of the compound is in progress.

Background
Erlotinib and pemetrexed are recommended for the second-line treatment of non-small cell lung cancer (NSCLC). With the recommended doses determined by our previous phase I study [BMC Cancer 2012;12(1):296], we conducted a phase II study to evaluate the efficacy and safety of combination of the two agents in patients with pretreated non-squamous NSCLC.Erlotinib and pemetrexed are recommended for the second-line treatment of non-small cell lung cancer (NSCLC). With the recommended doses determined by our previous phase I study [BMC Cancer 2012;12(1):296], we conducted a phase II study to evaluate the efficacy and safety of combination of the two agents in patients with pretreated non-squamous NSCLC.

Methods
Patients with stage III/IV or post-surgically recurrent non-squamous NSCLC whose disease had progressed after first-line chemotherapy were enrolled. Patients received 500 mg/m[2] of intravenous pemetrexed every 21 days and 150 mg of oral erlotinib on days 2–16 until disease progression or unacceptable toxicity. The primary objective was the response rate (RR). The secondary objectives were the disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety.

Results
A total of 27 patients, 16 males and 11 females, with the median age of 70 (range, 48–80) were enrolled. They included 21 stage IV diseases and 22 adenocarcinomas. The Epidermal growth factor receptor (EGFR) gene mutations were examined in all patients and only one patient was positive. The median number of treatment courses was 3 (range, 1 to over 19). The RR and DCR were 11.1% and 63.0%. The median PFS and OS were 2.8 months (95% confidence interval (CI); 1.9 to 7.5) and 15.8 months (95% CI; 9.3 to not available), respectively. As for safety, dermal, hepatic, gastrointestinal and hematological disorders were the frequently observed adverse events. Grade 3/4 toxicities observed in more than 15% patients were neutropenia (n = 10), anemia (n = 6), febrile neutropenia (n = 6), ande anorexia (n = 5). One patient experienced grade 3 drug-induced interstitial lung disease.

Conclusion
We could not demonstrate the add-on effect of intermittent erlotinib on pemetrexed in the second-line treatment of non-squamous NSCLC without EGFR mutations.

Background
The TULUNG registry is an independent national non-interventional clinical registry, focused on collection and analysis of epidemiologic and clinical data of non-small cell lung cancer (NSCLC) patients who have been treated with pemetrexed (Alimta®), erlotinib (Tarceva®), gefitinib (Iressa®) and/or bevacizumab (Avastin®) in 10 centers of complex thoracic oncology care in the Czech Republic. The report is based on data analysis of 476 advanced/metastatic non-squamous (adenocarcinoma or large cell carcinoma) NSCLC patients, who had good performance status (PS 0-1), were treated with pemetrexed in the second line of treatment, and whose data were recorded in TULUNG registry as of March 18, 2013.

Methods
There were analyzed baseline demographic data, information about treatment aministered and efficacy and safety clinical outcomes of pemetrexed second line treatment in this selected registry patient population, using descriptive statistics.

Results
In analyzed group of 476 patients slightly prevailed men (56.9%) over women, median age at start of pemetrexed treatment was 62 years (range 27-81 let). Majority of patiens were current smokers and ex-smokers (41.0% and 32.8% resp.). 95% of tumours had adenocarcinoma histology. Vast majority of analyzed patiens (87.4%) had metastatic disease at start of second line pemetrexed treatment, the rest had stage IIIb. 83.8% of patiens had ECOG PS 1 at start of second line pemetrexed treatment and 87.4% of patiens received pemetrexed in monotherapy. At the moment of analysis, pemetrexed treatment was already terminated in 408 patients out of 476 patients (the most frequent reasons for discontinuation of treatment were disease progression in 56.9% and planned completion of treatment in 28.2%), treatment was at moment of analysis ongoing in 68 patients. Median duration of treatment with pemetrexed was 12.3 weeks (corresponds with 4 cycles). When focusing on the subset of patients with finished pemetrexed treatment, the disease control rate (i.e. CR+PR+SD) was reported in 59.6% of patients, while progressive disease (PD) was reported in 33.3%. For 7,1% of patiens there were missing data on treatment response. Median overall survival was 11.3 months (95% CI 9.6 – 13.0) and median progression-free survival was 3.3 months (95% CI 2.7 – 3.8). 1-year survival rate from start of pemetrexed treatment was 47,5%. Adverse events were reported to registry for 21.8% of pemetrexed treated patiens from analysed population. The most frequent (>5% patients) reported adverse events were neutropenia (9.7%), anemia (6.5%), leukocytopenia (6.1%), and fatigue (6.1%).

Conclusion
Reported efficacy and safety outcomes from registry are more favourable than results of published controlled randomized registrational trial. It probably reflects the different methodology of data collection and more prudent approach to patient selection for pemetrexed second line treatment in real clinical practice in the Czech Republic in participating centers. Based on registry data, pemetrexed treatment was in suitable patiens with good PS very well tolerated (78.2% of patiens without reported adverse events in registry) and allowed for reaching disease control in almost 60% of treated patiens, with median OS approaching one year from starting second line therapy.

Background
PM01183 is an inhibitor of transactivated transcription and also acts on the tumor microenvironment. It lacks cross-resistance with platinum (Pt) agents. Evidence of synergism with GEM has been observed preclinically. PM01183 is undergoing intensive clinical evaluation as single agent in phase II studies in pancreatic, ovarian, breast and NSCLC pts. Its primary side effects are reversible myelosuppression and high emetogenic potential.

Methods
Consenting adults with selected solid tumors (including NSCLC), age ≤ 75 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, adequate major organ function and up to 2 prior chemotherapy-containing (CT) lines were included in successive cohorts aiming to primarily define the recommended dose (RD) of PM01183 when combined with GEM, both on Days 1 and 8 every three weeks (q3wk). Prior GEM was not allowed in the metastatic setting. Available results exclusively from the NSCLC population are described here.

Results
Recruitment was closed in December 2012. Overall, 22 of 45 treated pts (49%) had NSCLC. Of these, 73% were males. Median age was 65 years (r: 37-73). Patients received 1, 2 or 3 prior lines, in 64/27/9% of cases respectively. Non-squamous histology was reported in 91% of pts and 18% had known central nervous system (CNS) involvement. Five of 14 pts evaluable for efficacy by Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, responded to therapy [4 PRs and 1 CR], reaching an overall response rate (ORR) of 36% [95% confidence interval (CI): 13-65] in the RECIST evaluable population. Median response duration was 31 weeks (r: 7-52+). Eight of 22 pts were not evaluated for efficacy, as this was not the primary endpoint of the phase Ib study. Nevertheless, on an intention-to treat basis the ORR was 23% (95%CI: 8-45). Severe myelosuppression, G3/4 neutropenia or thrombocytopenia, was observed in 67/42% of pts, respectively. Other toxicities, in ≥ 10% of pts, were generally mild and comprised anemia, ALT/AST or creatinine increases, fatigue, mucositis, nausea/vomiting and anorexia. No alopecia was reported. Serious adverse events included febrile neutropenia (FN), pneumonia, sepsis and shock, and resulted in two treatment-related deaths, both occurred at dose levels over the RD. The RD was established at PM01183 3.0 mg + GEM 800 mg/m[2] on Days 1 and 8 q3wk.

Conclusion
PM01183 and GEM combination resulted in relevant and durable clinical activity in NSCLC pts. Toxicity seems both manageable and predictable at the RD. The novel mechanism of action of PM01183, and particularly its lack of Pt cross-resistance are of special interest in this population. A randomized trial is ongoing to assess the role of this new CT combination in relapsed NSCLC.

Background
Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. 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. Here, we report on the PN profile of 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] q 1 q21d; both arms received C AUC 6 day 1 q21d. PN was assessed by Standardized MedDRA Query (SMQ) for neuropathy (broad scope) unless otherwise indicated. Patient-reported taxane-related neuropathy symptoms were assessed by the Functional Assessment of Cancer Therapy (FACT)-Taxane Additional Concerns scale.

Results
nab-P/C was associated with significantly less PN vs sb-P/C (all grade: 46% vs 62%; P < 0.001) and grade 3/4 treatment-related PN (3% vs 12%; P < 0.001). Grade 4 PN occurred in 2 patients in the sb-P/C arm vs 0 patients in the nab-P/C arm. PN led to taxane dose reductions in 2% vs 7% and delays in 3% vs 8% of patients in the nab-P/C vs sb-P/C arm. Physician assessment of PN based on NCI CTCAE grade showed fewer instances of worsening with nab-P/C vs sb-P/C. At baseline, ≥ 95% of patients in both arms were assessed with grade 0 PN, but at final evaluation, significant treatment differences favoring the nab-P/C arm were observed, with fewer nab-P/C−treated patients shifting from grade 0 to grades 1-4 (38%) relative to the sb-P/C arm (58%; P < 0.001). Fewer patients receiving ≤ 6 cycles (median number of cycles = 6) in the nab-P/C vs sb-P/C arms experienced all-grade PN (41% vs 60%); 2% vs 10% of these patients experienced grade 3/4 PN (no patients in the nab-P/C arm experienced grade 4 PN). Median time to PN onset of any grade was longer with nab-P/C vs sb-P/C, 49 vs 38 days (P < 0.001); grade 2-4, 105 vs 78 days (P = 0.04) and grade 3/4, 121 vs 106 days (P = 0.723). The median time to improvement of grade 3/4 PN to grade 1 was 38 vs 104 days (P = 0.326) with nab-P/C vs sb-P/C. Patient-reported FACT-Taxane PN subscore at final evaluation also demonstrated a statistically significant treatment effect favoring nab-P/C (P < 0.001). Most patients completed the FACT-Taxane questionnaire at baseline (98%) and provided follow-up assessments (94%) at each cycle. Deterioration in patient-reported PN subscore at or after the development of grade 3/4 PN was lower for nab-P/C vs sb-P/C (median change from baseline 4.5 vs 10).

Conclusion
In this trial, nab-P/C was associated with lower rates PN compared with sb-P/C. PN occurred later during treatment with nab-P/C vs sb-P/C, and the majority of patients experienced improvement of PN symptoms within approximately 1 month. Patients receiving ≤ 6 cycles of therapy with nab-P/C had less PN compared with those receiving sb-P/C.

Background
Deletional mutations in exon 19 (Del-19) and L858R point mutation in exon 21 are the most common mutations in the epidermal growth factor receptor (EGFR) gene. In Del-19, several variants actually exist, consisting of different amino acid positions or different sizes. Little evidence has been described whether the variation of Del-19 mutation affects EGFR-tyrosine kinase inhibitor (TKI) sensitivity.

Methods
Between December 2005 and March 2013, we screened 111 patients harboring Del-19 who had received EGFR-TKIs. Efficacies of EGFR-TKI such as response rate (RR), progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated among various patient characteristics (age, gender, ECOG performance status [PS], smoking status, clinical stage, histology, treatment line, types of TKI, initial site of deletion, and presence of insertion). We also performed a multivariate analysis with the proportional hazards model to exclude several confounds. A backward stepwise approach was adopted as our variable selection method for multivariate analyses.

Results
Among these 111 patients with exon 19 deletion mutations, 83 (75%) patients had a deletion from E746 (⊿E746 group), and a deletion from L747 (⊿L747 group) 28 (25%). PFS of ⊿E746 group (12.0 months, 95% confidence interval [CI] 9.27-15.63) was significantly longer than ⊿L747 group (10.0 months, 95% CI 6.43-14.27) (p = 0.0129). Insertion mutations were found in 20 patients (18%), and 91 patients (82%) were without insertions. PFS without insertions (12.0 months, 95% CI 9.27-15.17) was significantly longer than with insertions (10.0 months, 95% CI 3.97-12.67) (p = 0.0173). No relationships were found for RR in all patient characteristics. In univariate analysis, PS (0-1 vs 2-4, p = 0.0001), clinical stage (ⅢB/Ⅳ vs recurrence, p = 0.0408), treatment line (1st line vs after 2nd line, p = 0.0122), initial site of deletion, and presence of insertion were statistically significant factors for longer PFS. PS (p <0.0001), histology (Adeno vs Squamous, p = 0.0134) and treatment line (p = 0.0052) were statistically significant factors for longer OS. In multivariate analysis, PS (hazards ratio [HR] 0.580, 95% CI 0.43-0.80, p = 0.0009) and initial site of deletion (HR 0.696, 95% CI 0.55-0.89, p = 0.0047) remained as significant factors for longer PFS. PS (HR 0.525, 95% CI 0.35-0.78, p = 0.0016), gender (Female vs Male, HR 0.701, 95% CI 0.53-0.93, p = 0.0140) and histology (HR 0.479, 95% CI 0.30-0.83, p = 0.0120) were selected as significant factors for longer OS.

Conclusion
Our data indicated better efficacy of EGFR-TKI in ⊿E746 group than ⊿L747 group. Deletional locations may affect the sensitivity to EGFR-TKI.

Background
The pharmacokinetics (PK) of amrubicin (AMR) in lung cancer patients with impaired hepatic function have not been reported. The objectives of this study were to evaluate the PK of AMR and its major metabolite, amrubicinol (AMR-OH), in lung cancer patients with or without impaired hepatic function, and to assess the validity of dose adjustment of AMR based on hepatic function.

Methods
Eligibility criteria included the presence of histologically or cytologically proven lung cancer, an ECOG PS of 0 to 2, age 20 to 70 years old, and no evidence of hepatitis B virus infection. The dose was adjusted from 25 to 45 mg/m[2]/day (iv, days 1-3, q3w) based on the history of prior treatment and baseline values of total bilirubin (T-bil), AST and ALT (Table 1). Figure 1

Results
Five patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) were enrolled. Terminal half-life (t~1/2~) and clearance of AMR in plasma, and t~1/2~ of AMR-OH in blood did not differ between the two arms. Area under the curve (AUC~0-24~) of AMR in plasma and AUC~0-120~ of AMR-OH in blood in arm I were similar or lower compared to those in arm N (Table 2). The dose-adjusted AUCs of AMR and AMR-OH did not show a tendency to increase with increases in baseline T-bil, AST and ALT. Two deaths occurred in arm I (one due to disease progression, and the other due to an unspecified reason), but the toxicities in arm I were not severe compared with those in arm N. Figure 1

Conclusion
These data show the validity of dose adjustment of AMR in patients with impaired hepatic function.

Background
From the results of recent trials, both EGFR-TKI and platinum doublet are believed to be important for patients with EGFR-mutated NSCLC. However, standard subsequent regimen after the failure of those treatments remains unclear. Some reports suggested high synergistic effect between S-1 (a novel oral fluorouracil derivative) and irinotecan against TKI-resistant cell lines. We therefore conducted this phase II trial of the combination of S-1 plus irinotecan to evaluate the efficacy and safety in EGFR-mutated NSCLC patients resistant to both platinum-based chemotherapy and EGFR-TKI.

Methods
Eligible patients were required advanced or recurrent NSCLC with an EGFR activating mutation, disease progression (PD) during or after second- or third-line EGFR-TKI, and previous chemotherapy including platinum doublet prior to EGFR-TKI. All patients received S-1 (80 mg/m2, day 1 to 14) orally and irinotecan (70 mg/m2, day 1 and 15) intravenously every 3 weeks. The primary endpoint was disease control rate (DCR) at 8 weeks after enrollment. The estimated accrual was 23 patients to confirm a DCR of 60% as a desirable target level and a DCR of 30 % as a lower limit of interest with alpha = 0.05 and beta = 0.10.

Results
From February 2009 to April 2012, 25 patients were enrolled from 6 institutions. The patients comprised 5 males and 20 females with a median age of 62 years (range, 53 to 78 years). ECOG performance status was PS 0 in 4 patients and PS1 in 21 patients. The histological subtypes were: adenocarcinoma 23 patients (92%), squamous cell carcinoma 1 patient, adenosquamous carcinoma 1 patient. EGFR activating mutations were, exon 19 deletion in 17 patients and exon 21 point mutation termed L858R in 8 patients. The current line of treatment in this study was the 3rd in 22 patients and the 4th in 3 patients. The median cycles of treatment was 4 (range 1-12). The objective responses were CR 0, PR 13, SD 8, and PD 4, giving a DCR at 8 weeks of 84.0% (95% CI, 63.9-95.5%). The overall response rate was 52.0% (95% CI, 31.3-72.2%). The median PFS was 5.0 months, whereas the median overall survival was 17.1 months. There was no significant difference in efficacy between the two types of EGFR mutations. Major grade 3 or worse toxicities included neutropenia (52%), anemia (20%), febrile neutropenia (16%), diarrhea (16%), thrombocytopenia (4%), and pulmonary thromboembolism (4%). No treatment-related death was observed.

Conclusion
This combination therapy with S-1 and irinotecan in EGFR-mutated NSCLC that was resistant to both platinum-based chemotherapy and EGFR-TKI showed promising efficacy with manageable toxicities. Further evaluation of this regimen in comparison with other cytotoxic agents or with irreversible EGFR-TKI is warranted.

Background
Lung cancer is a major health problem in Central Europe where some of the countries have the world-wide highest incidence rates of this cancer. The CENTRAL EUROPEAN INITIATIVE AGAINST LUNG CANCER aims at decreasing the burden of lung cancer in this region. The Inaugural Workshop of this Initiative was planned in order develop strategies to achieve this goal.

Methods
Participation at the Workshop was by invitation and more than 100 lung cancer experts from several Central European Countries and Israel did participate. The participants discussed the current status of lung cancer management and suggested strategies for improvement in the various areas of lung cancer management.

Results
The Workshop focused on all aspects of lung cancer. There was agreement that lung cancer is a major health problem in all Central European countries and that improvement in all aspects of lung cancer management must be attempted. Prevention strategies have steadily been improved but remain insufficient in most countries. The potential of screening was recognized but routine implementation of screening was not considered to be feasible in most Central European countries at this time. Access to modern radiological imaging such as PET-CT must be improved in many centers. A future project will assess the accuracy of radiological staging in several hospitals. Molecular diagnosis is increasingly implemented in most countries but patient selection for molecular analyses varies between countries. A major area of discussion was the implementation of standard treatments. Multidisciplinary tumor boards have been established in most centers but participants disagreed on whether all or only selected patients should be presented during tumor board meetings. Concerning stage III NSCLC, great heterogeneity with regard to both staging and treatment has been recognized. A future project plans to assess current management of patients with stage III NSCLC and to define areas for improvement. Access to systemic treatment has improved over the years but timely access to novel and expensive drugs remains challenging in several countries. Strategies to increase the scientific co-operation and education have also been discussed and should increasingly be implemented in the future.

Conclusion
The Workshop did outline the current status including challenges in the management of patients with lung cancer in Central Europe. Next projects will assess staging accuracy and detailed treatment of patients with locally advanced NSCLC. Future events such as the 14th Central European Lung Cancer Congress in 2014 and the 17th World Congress on Lung Cancer in 2016 in Vienna should also have a major impact on decreasing the burden of lung cancer in Central European countries.

Background
Both taxane and pemetrexed have significant activities as salvage chemotherapeutic agents in non-squamous non-small cell lung cancer (NSCLC). The purpose of this study was to compare the efficacy of taxane and pemetrexed according to EGFR activating mutation status in patients with advanced non-squamous NSCLC.

Methods
This retrospective analysis included patients with stage IIIA-IV non-squamous NSCLC given both taxane and pemetrexed in their clinical courses regardless of treatment line. Patients were dichotomized into favorable or unfavorable EGFR-tyrosine kinase inhibitor (TKI) response group. Favorable response group was defined as harboring EGFR activating mutation or partial remission and progression-free survival (PFS) ≥ 4 months with EGFR-TKI.

Results
62 patients were eligible for analysis (24 of favorable and 38 of unfavorable EGFR-TKI response group). Response rate (RR) of taxane based regimen was 37.5% vs. 28.9% (p=0.483) and disease control rate (DCR) was 79.2% vs. 55.3% (p=0.055) in favorable and unfavorable EGFR-TKI response group, respectively. RR of pemetrexed based regimen was 12.5% vs. 34.2% (p=0.057) and DCR was 66.7% vs. 76.8% (p=0.407) in favorable and unfavorable group, respectively. PFS with taxane based regimen was 5.5 months (95% CI 5.0-6.0) vs. 2.6 months (95% CI 1.4-3.8) in favorable and unfavorable group, respectively (p=0.006). PFS with pemetrexed based regimen was 4.1 months (95% CI 2.9-5.3) vs. 4.6 months (95% CI 1.9-7.2) in favorable and unfavorable group, respectively (p=0.361). PFS with taxane vs. pemetrexed based regimen was 5.5 vs. 4.1 months in favorable EGFR-TKI response group (p=0.027), and 2.6 vs. 4.6 months in unfavorable EGFR-TKI response group (p=0.112). The adjusted HR for disease progression of taxane based regimen in favorable EGFR-TKI response group compared with unfavorable group was 0.455 (95% CI 0.252-0.819; p=0.009) in multivariate Cox-regression analysis. However, PFS with pemetrexed based regimen was not associated with EGFR-TKI responsiveness (HR 1.014, 95% CI 0.547-0.877; p=0.966). The overall survival of favorable group vs. unfavorable EGFR-TKI response group was 45.4 vs. 22.8 months (p<0.001).

Conclusion
Favorable response to EGFR-TKI is a predictive marker of taxane activity, but not of pemetrexed in patients with non-squamous NSCLC. Taxane would be the first consideration for patients with disease progression after durable response to EGFR-TKI.

Background
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is treatment of choice in non-small cell lung cancer patients with EGFR mutation, as well as has been recommended in the unselected patients in the 2nd or 3rd line treatment. However, many patients have no response from the EGFR-TKI treatment and there was often a lot of progress in early time of treatment.

Methods
The aim of this study was to analyze clinical features of patients who discontinued EGTF-TKI treatment within two months. We reviewed clinical characteristics of the patients, retrospectively.

Results
. Two hundred and fifty five patients received EGFR-TKIs from January 2010 to May 2013. Sixty nine patients (27%) discontinued within 2 months. The mean age was 64.4 years and smoking rate was 71%. The stages were IIIB 19 patients, IVa 14 (20.3%), and IVb 35 (50.7%), respectively. Forty four (63.8%) patients were adenocarcinoma, 19 (27.5%) squamous cell carcinoma, and 2 large cell carcinoma. In EGFR-TKI treatment, six patients (8.7%) in first line, 43 patients (62.2%) in second line, and 20 patients (30%) in third line or more were treated. Early discontinuation rate of gefitinib was 15.9% (22/138), elortinib 40.1% (47 / 117). EFGR mutation was positive in five patients who all have in exon 19 deletion. The mean duration of EGFR-TKIs was the average 25.5day. Tumor response was no change 42%, progressive disease 39.1%, and non-evaluable 18.9 %. After start of EGFR-TKIs, median survival time was only 68 days. The mean of mass diameter before treatment was 4.7cm, and increased to 5.9 cm when stop the drug. Survival time after EGFR-TKI treatment were significantly different based on ECOG PS (log-rank, p = 0.002), WBC> 10,000/uL (p = 0.007), albumin <3.0 g/dl (p = 0.001), and > LDH 500 IU/L (p = 0.036). Sixty five (94.2%) patients were stopped medication before routine response evaluation with CT scan. The reasons of drug discontinuation were disease progression in 24 (34.8%), serious side effect in 17 (24.6%), patient’s refusal in 3 (4.3%), doctor's decision in 22 (31.9%).

Conclusion
In conclusion, drop-out rate was higher in elortinib treated patients. Patients with poor PS, elevated WBC count, low albumin level, high LDH level have to be careful in the treatment with EGFR-TKI.

Background
Cisplatin with docetaxel (DP) or gemcitabine (GP) is one of standard regimen for advanced non-small cell lung cancer(NSCLC). DP is regarded more toxic compared with GP. There is an increasing interest in a biweekly split administration of DP to reduce its toxicity. Hypothesis here was 1st-line biweekly DP is as safe as GP in elderly or poor performance status (PS) patients (pts).

Methods
Chemotherapy naïve pts with NSCLC (IIIB/IV) who were elderly(>65) or poor PS (ECOG 2) were randomized to biweekly DP or GP by balancing for ECOG (0-1 vs 2), stage (IIIB vs IV) and age (<65 vs >65). DP with docetaxel (35mg/m2)/cisplatin(30mg/m2) iv or GP with gemcitabine (1000mg/m2) /cisplatin(30mg/m2) iv was given on days 1,8 every 3 weeks . Chemotherapy lasted upto 6 cycles or until progression. Primary endpoint was safety (proportion of grade 3/4 toxicities). Planned sample size was 49 pts in each.

Results
From Nov 2009 to Jan 2013, a total of 97 pts were randomized (DP 50/GP 47). Adenoca was 58% in DP and 51% in GP while that of squamous cell ca 34% in DP and 40% in GP. Stage IIIB/IV was 33%/66% in DP and 42%/59% in GP. In DP a total 228 adverse events (AEs) were reported and 27 were grade 3/4 toxicities while 211 AEs and 21 grade 3/4 toxicities in GP. Neutropenia was the most frequent grade 3/4 toxicity in both (DP 8.9%; GP 15.9%). In DP grade 3/4 leukopenia (8.9%), hyponatremia(6.7%), anemia(4.4%) and anorexia (4.4%) were observed while anemia (9.1%) and hyponatremia (6.8%) in GP. In total AEs, anemia was the most common in both (DP 66.7% ; GP 63.6%). Then, in the following order, hyponatremia (53.3%), anorexia (53.3%) and fatigue(40%) were common in DP while anorexia, (56.8%), fatigue(36.4%) and neutropenia(45.5%) were common in GP. Death during treatment was occurred in 1 pt in each. Both regimen showed similar grade 3/4 toxicities with similar profiles. Survivals seemed to be favorable in GP compared with DP with no statistical significance. Progression-free survivals were 3.72 (DP) and 5.56 (GP) months (p=0.341). Overall survivals were 14.93 (DP) and 20.82 (GP) months (p=0.209).

Conclusion
This study showed DP is similar with GP in terms of toxicity and efficacy in treatment of elderly or poor performance patients.

Background
EGFR gene mutations are the important factors predicting a patient’s response to EGFR TK inhibitors (EGFR TKIs). The importance of sensitive methods for the EGFR mutant detection is emphasized. The aim of study is to examine the comparative and concordance analyses among application of direct sequencing, pyrosequencing and peptide nucleic acid (PNA) clamping method to detect EGFR gene mutation using archived cytology specimens.

Methods
A total of 128 cases, which were diagnosed as adenocarcinoma of the lung at 9 hospitals in Korea between 2006 and 2012, were collected. Based on the above three methods, the concordance rates of EGFR mutations for in exon 18, 19, 20, 21 were analyzed and validated in comparative cytology specimens and formalin-fixed, paraffin-embeded (FFPE) tissues.

Results
Comparison of EGFR mutant detection between cytology specimens and concurrent FFPE tissues from the same anatomic site had a concordance rate of 74.7%. The diagnostic performance of pyrosequencing and PNA clamping method in cytology specimen was higher than that of direct sequencing as well as FFPE tissue. In comparison of EGFR mutant detection in cytology specimen and FFPE tissue according to three methods, PNA clamping method showed high concordance rate (93.6%), than other methods. The concordance rate between PNA clamping method and pyrosequencing was high (62.4%) in cytology specimen, whereas direct sequencing and PNA clamping method was as high as 74.5% in FFPE tissue.

Specimen	Cytology
	Direct	Pyro	PNA
Cytology
Direct	-	-	-
Pyro	0.381[*]	-	-
PNA	0.486[*]	0.624[*]	-
	FFPE
	Direct	Pyro	PNA
FFPE
Direct	-	-	-
Pyro	0.509[*]	-	-
PNA	0.745[*]	0.684[*]	-
	Cytology
	Direct	Pyro	PNA
FFPE
Direct	0.546[*]	0.504[*]	0.743[*]
Pyro	0.386[*]	0.735[*]	0.626[*]
PNA	0.491[*]	0.683[*]	0.936[*]
FFPE, formalin-fixed, paraffin-embeded; Direct, direct sequencing; Pyro, pyrosequencing; PNA, peptide nucleic acid (PNA) clamping method [*]k coefficient

Conclusion
Cytology specimens had a diagnostic performance for the detection of EGFR mutations that was comparable to that of FFPE tissues. The high concordance rate among three techniques had good diagnostic performance. Additionally, At least two methods are more likely to improve the detection rate of EGFR mutation than only one.

Background
Genexol-PM is a Cremorphor EL(CrEL)-free polymeric micelle formulation of paclitaxel, which renders higher dose administration with less hypersensitivity. This study was designed to evaluate the efficacy and safety of Genexol-PM and gemcitabine combination in advanced non-small cell lung cancer patients as first line treatment

Methods
This is a prospective single arm, single center Phase II study. Patients with advanced NSCLC received Genexol-PM at 230mg/m2 on day 1 and gemcitabine 1000mg/m2 on day 1 and day 8 of a 3-week cycle as first-line chemotherapy. Six cycles of chemotherapy were administered unless there is a disease progression. The primary endpoint was response rate.

Results
Forty-three patients received the study drugs with median of 4 cycles per patient (range, 1-6). Among 35 patients who received more than one cycle, mean dose intensity of CrEL-free paclitaxel and gemcitabine was 209 mg/m[2]/3-week and 1853mg/m[2]/3-week respectively. Overall response rate was 46.5%. The median progression free survival was 4.0 months (95% CI 2.0-6.0 months) and median overall survival was 14.8 months (95% CI 9.1-20.5 months). 18 patients (51%) experienced grade 3/4 adverse events, including neutropenia or febrile neutropenia (n=7), pneumonia (n=3), asthenia (n=3), peripheral neuropathy (n=2), diarrhea (n=1), skin rash (n=1), myalgia (n=1), pulmonary thromboembolism (n=1), LV dysfunction (n=1), dyspnea with sudden death (n=1). Adverse events leading to drug discontinuation were occurred in 9 patients, among which 2 patients were died of adverse events (pneumonia, dyspnea with sudden death)

Conclusion
CrEL-free paclitaxel in combination with gemcitabine demonstrated comparable antitumor activity with less emetogenicities in non-small cell lung cancer patients. Safety issue should be evaluated cautiously.

Background
Both erlotinib and pemetrexed are second-line treatment options for patients with advanced non-small cell lung cancer. The value of erlotinib in the second-line setting in lung adenocarcinoma with EGFR wild-type and EGFR gene high polysomy or gene amplification remains unclear. Therefore, we undertook this study to investigate the efficacy and safety of erlotinib versus pemetrexed as second-line therapy in treating patients with advanced EGFR wild-type and EGFR FISH-positive (high polysomy or gene amplification) lung adenocarcinoma.

Methods
In this open-label, phase II study, EGFR mutation status was assessed by the amplification-refractory mutation system (ARMS) method and EGFR copy number was assessed by fluorescent in situ hybridization (FISH) method in patients with adenocarcinoma who had progressed during the first-line platinum-doublet. Only patients with EGFR wild-type and EGFR FISH-positive adenocarcinoma were randomly assigned (1:1) to receive erlotinib (250mg, per day, orally) or pemetrexed (500mg/m[2], day 1 of 21-day cycle, intravenously), until disease progression or death, unacceptable toxicity, or a request for discontinuation by the patient. The primary end point was progression-free survival.

Results
A total of 123 patients were enrolled (61 in the erlotinib arm and 62 in the pemetrexed arm). Median progression-free survival was 4.1 months (95% confidence interval [CI] 1.6-6.6) in the erlotinib group versus 3.9 months (95% CI 2.7-5.1) in the pemetrexed group, and the 6-month PFS was 45.1% and 38.8%, respectively. The difference in the progression-free survival between the erlotinib and pemetrexed group was not significant (hazard ratio [HR] 0.92; 95% CI 0.62-1.37; P=0.683). Objective response rate appeared to be higher among patients in the erlotinib arm compared with patients in the pemetrexed arm (19.7% vs 8.1%, P=0.062). Overall survival were similar between the two arms (P=0.970). Both regimens were well tolerated. The three most commonly reported adverse events were rash (54.1%) , fatigue (19.7%) and diarrhea (16.4%) in the erlotinib group, while they were fatigue (25.8%), nausea (24.2%) and anorexia (14.5%) in the pemetrexed group.

Conclusion
Treatment with erlotinib or pemetrexed demonstrated clinically equivalent efficacy and toxicity in the second-line setting for advanced EGFR wild-type and EGFR FISH-positive adenocarcinoma, although objective response rate appeared to be higher among patients in the erlotinib arm. Clinical trial information: NCT01565538.

Background
Both Docetaxel (DTX) and Gefitinib (Gef) have been established as a standard therapy for the treatment of non-small cell lung cancer (NSCLC). Since these active two agents have different mechanisms of action as well as toxicity profiles, the combined use of DTX and Gef could be highly effective for the advanced NSCLC. However, as they are both metabolized by cytchrome P450 (mainly CYP3A4) enzyme, there are concerns about drug-drug interactions. The aim of this study is to assess the influence by the combined use of Gef on DTX's pharmacokinetics (PKs) and toxicity in patients with advanced NSCLC.

Methods
DTX was intravenously administered over 1-hr every 3 weeks on day 1. Gef (250-mg) was co-administrated orally once daily from day 2. The dose of DTX was escalated from 45 mg/m[2] (level 1, n = 6) to 60 mg/m[2] (level 2, n = 6). The total of 20-point PK samplings were performed on day 1 (DTX alone) and day 22 (DTX + Gef) to measure plasma concentrations of DTX using high- performance liquid chromatography (HPLC). DTX PK profile was estimated by non-compartment analysis. Analysis of variance was performed on AUC~0-24h~ to estimate adjusted mean differences between day 1 and 22. DTX clearance (CL), geometric mean (GM) of AUC, adjusted GM ratio (GMR, i.e., the ratio of DTX AUC on day 22 to that in day 1) and 90% CI of the GMR were also calculated.

Results
Twelve patients with advanced NSCLC were enrolled. Two out of 12 patients at dose level 1 withheld the second cycle of treatment (i.e., on day 22) due to progressive disease, and DTX PKs data were available for the rest of 10 patients treated on day 1 and 22. The toxicity profiles of DTX and Gef in this study were generally acceptable, and frequency and severity of hematological toxicity possibly related to DTX were similar to those with historical data in Japanese NSCLC patients. The ≥ grade 3 neutropenia was observed in 66% of patients. GMs of AUC~0-24 ~on day 1 and 22 were 1128 and 1184 ng・h /ml at dose level 1 (n=4), while those were 1827 and 1630 ng・h /ml at dose level 2 (n=6). GMs of DTX CL in all patients on day 1 and 22 were 60 and 63 L/h and GMRs at dose level 1 and 2 were 1.05 (90%CI: 0.96-1.14) and 0.89 (90%CI: 0.82-0.97), respectively.

Conclusion
The above results demonstrate that DTX PKs is not affected by the combined use of Gef in patients with advanced NSCLC. These two active agents can be safely co-administered.

Background
Pemetrexed (Alimta, Eli Lilly) with platinum doublet is an effective drug for first-line treatment of patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC). Innovator products are generally highly priced which limits their utility in developing countries. In India, a generic formulation (Pemgem, Dr. Reddy’s Laboratories) is marketed at 25% the cost of Alimta. Results of a study comparing the pharmacokinetic and safety profile of the two formulations of pemetrexed are discussed here.

Methods
This study was approved by TMC-ACTREC-IRB and registered with Clinical Trials Registry- India (CTRI). Patients were enrolled from a tertiary care cancer hospital in India as per predefined selection criteria mentioned the protocol. Pemetrexed (500 mg/m[2]) was administered as a 10 minute short infusion. All patients received standard premedication. Pharmacokinetic blood samples were collected at predose and 10 minutes (just before end of infusion), 15 min., 30 min., 50 min., 1 hr., 1 hr. 20 min., 2 hrs.,4 hrs.,6 hrs., 8 hrs. and 24 hrs after starting the infusion. Plasma pemetrexed levels were determined by a validated HPLC method. Toxicity was graded using CTCAE v. 4.03. Quality of life questionnaire was taken at baseline and at end of 3rd cycle.

Results
Twenty four patients were enrolled on the study, eight in Alimta arm and sixteen in Pemgem arm. Patient demographics were comparable in the two arms. Mean Area Under the Concentration-Time Curve (AUC~0-24 hr~) was 222.06 vs. 253.7 mg h/L and mean C~max ~was 106.5 and 130.7 mg/L in Pemgem and Alimta arms respectively. Volume of distribution of pemetrexed was 16.59 and 17.56 L, clearance was 3.83 vs. 4.3 L/hr and half-life was 3.29 and 2.43 hr in the two arms respectively. Toxicity was comparable between the groups. However, a higher incidence of grade III/IV hyponatrimia (25%) was observed in our patients which needs to be investigated further. Global health status improved significantly in both treatment arms at the end of 3 cycles compared to baseline. Pooled data of selected Quality of Life indices is shown below. Table 1: Mean difference in selected Quality of Life indices (3rd Cycle Vs. Baseline)

QOL scale	Mean difference	SEM	P value
Global health status	18.39	3.10	0.001
Pain	-7.77	3.46	0.023
Dysponea	-7.77	3.81	0.05
Insomnia	-4.44	3.06	0.017
Haemoptysis	-3.33	2.10	0.043

Conclusion
Pemgem had similar pharmacokinetic and safety profile as Alimta. Generic substitution would be cost effective and likely to yield comparable efficacy.

Background
Lung cancer has one of the highest incidences and mortalities of cancer worldwide, majority being non-small cell lung carcinoma (NSCLC). Platinum-based doublet chemotherapy remains the standard regimen for the treatment of NSCLC, providing an overall median survival of 8-10 months. The most common regimens include cisplatin or carboplatin with gemcitabine, paclitaxel or docetaxel. A multicenter study noted ethnicity to be a particular prognostic factor where significant differences were observed in response rates between Asian and Caucasian patients (65% vs 31% respectively) who all received docetaxel (75 mg/m[2]) and carboplatin (AUC 6). To investigate any such differences in therapeutic response in Bangladeshi patients from previous trials, a retrospective analysis was performed to evaluate survival in Bangladeshi NSCLC patients from a single institution.

Methods
62 patient records, between January 2009 and March 2013, from Square Hospital, Bangladesh were eligible. For the gemcitabine-platinum (GP) arm, 30 patients received either gemcitabine (D1 and D8-1000mg/m[2]) and cisplatin (75 mg/m[2]) or gemcitabine (1000mg/m[2]) and carboplatin (AUC 5). For the docetaxel-platinum (DP) arm, 32 patients received either docetaxel (75mg/m[2]) and cisplatin (75mg/m[2]) or docetaxel (75mg/m[2]) and carboplatin (AUC 5). Median age for GP arm and DP arm were 61 and 57.5 years respectively. All the patients have received a minimum of 3 cycles of the respective regimen. Primary end-point was median overall survival (MOS)

Results
Analysis revealed a MOS of 14 months for GP (95% CI; 8.56-19.43) and 13 months (95% CI; 8.94-17.06) for DP. The 1 year survival percentages were 33.3% and 46.9%% for the GP and DP arms respectively; 2 year survival was only observed in GP arm (6.67%). Adverse neutropenic response was reported in only 4.8% (3) of all patients. This includes 2 cases of Grade III neutropenia in the DP arm and 1 Grade neutropenia in the GP arm.Figure 1

Conclusion
Though no statistical significance (p>0.05) was observed between the two groups, the MOS obtained for both groups were significantly longer than previous trials conducted for the respective regimens, thus confirming our hypothesis and highlighting the potential impact of ethnicity on therapeutic response. Therefore, ethnicity based trials should be conducted in the future to properly evaluate response of any particular therapeutic regimen.

Background
Patients affected by lung adenocarcinoma carrying a EGFR sensitizing mutation of significantly benefit from TKIs in terms of progression free survival (PFS), activity and symptoms control. The potential predictive role of clinico-pathological predictors should be investigated in order to optimize the benefit of the currently available drugs.

Methods
A literature-based meta-regression and sensitivity analyses to investigate the differential effect of TKIs according to demographic and molecular factors, was accomplished, analyzing all RCTs exploring TKIs versus chemotherapy for 1[st]-line treatment of patients affected by EGFR mutant NSCLC.

Results
9 trials (3,741 patients) were identified (EGFR mutant: 1,797). 9 RCTs were evaluable for PFS (1,790 patients) and response (1,733 patients); 7/9 for survival (1,075 patients). With regard to PFS and response, a significant interaction according to ethnicity (Asian versus Caucasian versus mixed, p=0.006 [Cochrane-Q 10.275] and p=0.047 [6.129], respectively), and trial design (retrospective versus prospective EGFR analysis, p=0.024 [5.067] and p<0.0001 [13.633]), was found. No difference was observed in term of survival. A significant interaction for response was found, with an Odds Ratio in favour of afatinib, erlotinib and gefitinib (versus chemotherapy) of 2.70 (95% CI 2.11-3.45), 2.67 (95% CI 1.81-3.93) and 1.81 (95% CI 1.46-4.78).

	Interaction [Cochrane-Q] P value	Interaction [Cochrane-Q] P value
	PFS	Response
Overall (ERL vs GEF vs AFA)	[4.266] p=0.188	[9.924] p=0.007
ERL vs AFA	[3.321] p=0.068	[0.056] p=0.813
ERL vs GEF	[9.714] p=0.054	[5.169] p=0.023
AFA vs GEF	[0.002] p=0.962	[7.351] p=0.007

Conclusion
Although limited by the retrospective nature and the heterogeneity, these data indicate a differential effect of TKIs according to the design and the ethnicity, and in response according to TKIs. These data may constitute the background to develop a clinical predictive model to better estimate the expected benefit when using EGFR TKIs in patients with EGFR mutant NSCLC

Background
Two combination chemotherapy regimens were compared in a Phase 3, randomized, open-label United States only study. The two-drug regimen of pemetrexed/carboplatin followed by maintenance pemetrexed (PemC) was compared to the three-drug regimen of paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab (PCB). The primary endpoint of improved progress-free survival (PFS) without Grade 4 toxicity (G4PFS) for PemC over PCB was not met in PRONOUNCE, as reported by Zinner et al. (ASCO, 2013). No difference in PFS or overall survival (OS) for PemC vs. PCB was observed. Both regimens demonstrated tolerability, but toxicity profiles differed.

Methods
Patients 18+ years of age with Stage IV chemonaïve non-squamous non-small-cell lung cancer (NS-NSCLC) were randomized to PemC (n=182) or PCB (n=179). Safety data were compared for patients who received ≥1 dose of study treatment (PemC:171; PCB:166), and resource use including concomitant medications, transfusions, and hospitalizations was recorded. Measures were compared between arms using Fisher’s exact test, if not otherwise specified. Protocol-defined chemotherapy infusion time was 0.7 hours for PemC and 4-5 hours for PCB. For the primary endpoint of G4PFS, the G4 events were reported regardless of drug causality.

Results
Of 152 G4PFS events for PemC, 37 (24.3%) resulted from first occurrence of a G4 event. Of 144 G4PFS events for PCB, 64 (44.4%) resulted from first occurrence of a G4 event. The safety profile for the entire study demonstrated that patients on PemC experienced significantly more drug-related Grade 3/4 anemia (18.7% vs. 5.4%; p<0.001), Grade 3/4 thrombocytopenia (24.0% vs. 9.6%; p<0.001), and Grade 1/2 nausea (46.8% vs. 28.9%; p<0.001). Patients on PCB experienced significantly more drug-related Grade 3/4 neutropenia (24.6% vs. 48.8%; p<0.001) and Grade 1/2 alopecia (8.2% vs. 28.3%; p<0.001). There was a significantly higher rate of drug-related Grade 1/2 sensory neuropathy (8.2% vs. 30.1%; p<0.001), Grade 1/2 hypertension (0.0% vs. 9.6%; p<0.001), Grade 1/2 hemorrhage in pulmonary/upper respiratory (1.8% vs. 13.3%; p< 0.001) and Grade 1/2 joint pain (1.8% vs. 13.9%; p<0.001) with PCB. Patients on PemC required more red blood cell (RBC) transfusions (34.5% vs. 11.4%; p<0.001), but there was no difference in platelet transfusions (p=0.621). Erythropoietic stimulating agents (ESAs) were used more frequently (19.9% vs. 7.2%; p<0.001) in PemC, and granulocyte colony-stimulating factor (G-CSF) use was significantly higher with PCB (17.0% vs. 30.1%; p=0.005). Requirement for antibiotics (p=0.323) and antiemetics (p=0.574) did not differ between PemC and PCB. There were no differences between PemC and PCB in the number of patients with at least one hospitalization (34.5% vs. 31.9%; p=0.645), and the mean length of stay between PemC (8.2d +/- 6.79) and PCB (8.8d +/- 7.33) did not differ (p=0.682;Wilcoxon rank sum test).

Conclusion
The toxicity profiles of PemC and PCB were consistent with previous reports. Toxicities documented as important to patients were split, with mild-to-moderate nausea more common for PemC and alopecia, infection and neuropathy more frequent for PCB. Resource intense toxicities were also divided. Hospitalizations did not differ between treatments. ESAs and RBC transfusions were more common with PemC, and G-CSF use was more common with PCB. ClinicalTrials.gov identifier:NCT00948675

Background
Patients with advanced/metastatic non-small cell lung cancer (NSCLC) have a poor prognosis and low survival rates. One of the first notable symptoms of advanced lung cancer is unexplained weight loss. We evaluated weight gain (> 5% post baseline), as an early prognostic factor for clinical outcome, in advanced nonsquamous, NSCLC patients.

Methods
This retrospective analysis reports on three randomized phase III studies with survival and response data from a total of 2301 advanced, nonsquamous NSCLC patients who received pemetrexed or other chemotherapy plus a platinum or targeted agent, as first-line therapy. Body weight was recorded before and after treatment by each study’s schedule. Baseline weight was defined as the last non-missing weight measure before first treatment. Post baseline weight was defined as the maximum weight measured after starting treatment. Patients were analyzed using log-rank test and adjusted Cox modeling to assess the relationship between weight gain and overall survival (OS) and progression-free survival (PFS). Logistic regression was used to assess the association between baseline covariates and post-baseline weight gain.

Results
Patients were a mean age of 61 years (range 26 – 86) and most were of Caucasian descent (77.0%). A majority of patients had adenocarcinoma (73.8%), were male (59.8%) with an ECOG performance status (PS) of 0/1/2 (38.5%/60.2%/1.4%). Many patients were smokers or former smokers (55.7%) with Stage IV disease (83.1 %), according to the American Joint Committee on Cancer, editions. 5/6 and had an average weight at baseline of 71.4 kg. A total of 421 (18.3%) patients had a >5% increase in weight (>5% subgroup) after baseline with a statistically significant increase in OS and PFS. Median OS was 16.7 months for patients in the >5% subgroup versus 10.7 months for patients who gained <5% weight (< 5% subgroup; [n=1880]; p<0.001). PFS was 6.9 months for the >5% subgroup versus 4.8 months for <5% subgroup; p<0.001). Differences in overall response rate (ORR = CR + PR) and disease control rate (DCR = CR + PR + SD) were also significant. ORR was 50.8% for >5% subgroup versus 25.4% for < 5% subgroup (p<0.001). DCR was 91.5% for >5% subgroup and 63.6% for <5% subgroup (p<0.001). Cox modeling revealed patients in the >5% subgroup had significantly longer survival (HR=0.56, [95% CI 0.49-0.64]; p<0.001) than patients with <5% subgroup, after adjusting for baseline age (<65 versus 65), sex, ECOG PS (0 versus 1/2), histology (adenocarcinoma versus others), and study. Similar significant results were also found for PFS. Logistic regression indicated a significant association between weight gain and age. More patients aged <65 had a >5% weight gain (p<0.001).

Conclusion
This exploratory analysis showed that substantial weight gain (>5%) occurred after initiation of platinum-based chemotherapy in approximately 20% of advanced/metastatic, nonsquamous NSCLC patients. There was a positive correlation between weight gain and improved, OS, PFS and response in patients treated in these phase III studies.

Background
The combination of pemetrexed /carboplatin / bevacizumab based on previous findings it is possible and has been tested in phase II studies (Patel, ASCO 2008) which showed an increase in progression-free survival to 14.1 months / 7.8m months patients using the combination of pemetrexed / carboplatin / bevacizumab vs pemetrexed / carboplatin, in patients with lung adenocarcinoma. Recent evidence on the combination of pemetrexed / carboplatin / bevacizumab in first line of treatment for NSCLC (Pointbreak study showed no benefit in terms of overall survival asurvival (6.0 vs 5.6months (P = 0.012)) In maintenance therapy esenario AVAPERL study shows a significant Increase in progression-free survival to 10.2 months in patients receiving pemetrexed / carboplatin / bevacizumab versus pemetrexed / carboplatin / placebo, which is data that is unprecedented.

Methods
In the medical oncology department of the Central Military Hospital of Mexico retrospective evaluation was conducted on the records of patients who were treated for NSCLC adenocarcinomas between 2008 and 2011, for those who use the combination of Pemetrexed / Carboplatin / Bevacizumab and Pemetrexed / carboplatin . The primary objectives of this study are an analysis of descriptive and multivartiate statistics on the following variables: Overall survival , progression-free interval, response rate , number of cycles received, toxicity, , diagnosis and smoking history. The results were analyzed using the SPSS program, in which we used Kaplan-Meier for the analysis of Overall survival (OS) and Progression-free-survival and U-MANN-WHITNEY for the correlation between PFS and smoking history and PFS and response rate.

Results
Data were obtained from a review of thirty patients with lung adenocarcinoma stage IIIb and IV treated between the years 2008-2011 (fifteen each arm) with the schemes of Pemetrexed / Carboplatin / Bevacizumab and Pemetrexed / carboplatin with the following results:

VARIABLE	PEMETREXED/CARBOPLATIN (months) n=15	PEMETREXED/CARBOPLATIN/BEVACIZUMAB (months) n=15
OS (GENERAL)	15.2	12.7 (P=0.77NS)
OS SMOKER	12.1	18.0 (NS)
OS NON SMOKER	10.5	13.1 (NS)
PFS (GENERAL)	8.9	8.5 (P=0.69NS)
PFS SMOKER	10.2	8.1 NS
PFS NON SMOKER	8.1	9.5 NS

Conclusion
In this case series shows That adding bevacizumab to first-line treatment with chemotherapy in NSCLC (Adenocarcinoma) based on pemetrexed / carboplatin / bevacizumab not Increased OS and PFS in overall population (OS 15.2 VS 12.7 m, P = 0.77NS), (PFS 8.5 vs 8.0 m P = 0.69 (NS). They found a trend toward increased overall survival in smokers who used Avastin not reached statistical significance.the hematologic and non-haematological toxicity was higher in the PCB arm vs. PC.There were no grade IV adverse events In this series of cases as well as bleeding events or deaths related to treatment

Background
Overall survival (OS) may be confounded by subsequent treatments in advanced NSCLC. To explore the potential effect of newer second-line and subsequent therapies on the results of clinical trials, a systematic literature review was conducted to examine OS and progression free (PFS) data from first line treatment trials published prior to and after the emergence of targeted therapies and newer FDA-approved second-line agents.

Methods
The PubMed database was searched for phase III first line trials in NSCLC over two 2 time frames: 1998 to 2005 and 2006 to 2011. Trials were included if platinum-based doublets were either the investigational or control regimen in previously chemotherapy-naive patients and if published in the English language. Bayesian statistical methods were used in random effects meta-analysis and meta-regression.

Results
13 clinical trials were included from the 1998-2005 and 17 trials from 2006-2011. The median percentage of women and adenocarcinoma included in the two time frames were 28 and 33, and 44 and 52 percentages, respectively. The difference in median survivals for the early and recent time frames (9.35 and 11.03 mo) in the treatment group was found to be significantly different (95% interval being shifted away from 0, Fig 1). However, the difference in the control group (9.74 and 10.59 mo) was not significant. The temporal trend in median survival over the time scale was further examined using meta regression with time as a covariate. The time trends or regression slopes for both the treatment (0.37, 95% interval 0.14 to 0.61) and the control (0.25, 0.06 to 0.43) arms were found to be significantly positive suggesting increasing trends in median survival over time. Only 18 of the 30 trials had PFS data with only 5 from the 1998-2005 timeframe. No significant difference in PFS was found over the two time periods.Figure 1

Conclusion
These analyses suggest longer survival in more recently treated NSCLC patients without a significant difference in PFS. Although this observation may have been influenced by the inclusion of more women and adenocarcinoma patients and improvements in supportive care, in the later time period more effective second and third line therapy may have contributed to longer OS.

Background
Adjuvant vinorelbine/cisplatin (VC) has been demonstrated to increase overall survival in patients with AJCC 6th stage II/IIIA non-small cell lung cancer (NSCLC). Although adjuvant paclitaxel/carboplatin failed to demonstrate its efficacy in a study which enrolled only patients with AJCC 6th stage IB NSCLC, the exploratory analysis showed that patients with large tumor (≥ 4cm) got survival benefits from this regimen. We need to compare the clinical outcomes of these two regimens as adjuvant chemotherapy for NSCLC, since the previous prospective trials used different eligible stage criteria and AJCC stage system was recently updated.

Methods
We retrospectively analyzed patients with surgically completely resected NSCLC between December 2004 and December 2011. They received adjuvant chemotherapy using either paclitaxel/platinum (PP) or VC. Clinicopathological parameters, survivals including disease free survival (DFS) and overall survival (OS) and toxicity between two groups were compared. All tumor stages were updated based on the AJCC 7th edition.

Results
Of the 467 patients with surgically resected NSCLC, 236 received PP (paclitaxel/cisplatin, n=29; paclitaxel/carboplatin, n=206) and 231 patients got VC (n= 231). Two groups were well balanced with regard to demographics, histology, stage and type of surgery. Efficacy was comparable between two regimens: DFS (PP vs. VC: 65 vs. 55 months; p=0.42) and OS (73 vs 58 months; P=0.37). Regarding the adverse events, sensory neuropathy (41% vs. 11%), alopecia (19% vs. 4%), and myalgia (32% vs. 5%) are more frequent in the PP group, while anemia (71% vs. 87%), neutropenia (22% vs. 71%), fatigue (11% vs. 18%), anorexia (19% vs. 41%), and vomiting (9% vs. 19%) are more frequent in the VC group.

Conclusion
Although the adverse event profiles were different, the efficacy data in terms of DFS and OS were comparable between the two adjuvant regimens. Therefore, both regimens are appropriate as the adjuvant chemotherapy for NSCLC, and the selection can be done personally according to the expected profiles of adverse events.

Background
Background: Adjuvant chemotherapy for resected non-small cell lung cancer (NSCLC) is recommended with survival benefit, however low compliance in recent clinical trials. Objectives: We conducted a phase II trial of gemcitabine(G) and carboplatin(C) regimen for patients with completely resected NSCLC and carboplatin is administrated on day 8 to reduce hematological toxicity especially thrombocytopenia.

Methods
Eligibility criteria included: PS(ECOG) 0-1, age≦75 years, p-stage IB-IIIA NSCLC is complexly resected (R0), adequate hematological liver renal and cardiac function. Regimen: G (1000mg/m2) d1 +8 and C (AUC 5, d8) q.3wks. Primary end point of this study is feasibility and secondary end points are toxicity, overall and disease-free survival.

Results
44 patients (20 male, 24 female) were included, median age 63 (40-71) years. Adenocarcinoma in 39, squamous cell ca. in 4, pleomorphic ca. in 1, and pathological stage IB in 25, IIA in 8, IIB in 5, and IIIA in 6 patients. Thirty-three patients (75%) completed the planned 4 cycles of GC therapy and 28 (64%) received the planned doses. Thirty-four percent of the patients had grade 3/4 neutropenia, 2 (6%) had thrombocytopenia, and the other 2 (6%) had anemia. Non-hematological adverse effects were infrequent and no treatment-related death was noted in this study.

Conclusion
Hematological toxicity, especially thrombocytopenia in this study is less than that in the standard administration of CG (C day1) regimen. We conclude that this regimen is feasible with sufficient compliance as adjuvant chemotherapy for completely resected stage IB-IIIA NSCLC patients.

Background
Dramatic response of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) to non-small cell lung cancer (NSCLC) with activating EGFR mutations is known to be followed by subsequent resistance. Although various mechanisms of acquired resistance, such as EGFR secondary mutation (exon 20 T790M), the amplification of mesenchymal-epithelial transition factor, and hepatocyte growth factor overexpression have been reported, their frequency is not globally consistent. The purpose of this study is to retrospectively analyze the frequency of appearance of exon 20 T790M in re-biopsied specimens from NSCLC patients exhibiting acquired resistance to EGFR-TKIs.

Methods
We enrolled 16 patients who were treated with EGFR-TKIs after diagnosis of NSCLC with EGFR activating mutations and were re-biopsied after the resistance acquirement from January 2008 to December 2012 in Keio University hospital. Written informed consents were obtained from all the patients. We detected second mutations (exon 20 T790M) by PNA-LNA PCR clamp.

Results
The median (range) age of the patients was 59 (34-86) years, including 9 male and 7 female. Pathological diagnosis of primary tumors were adenocarcinoma for 14, mixed adenocarcinoma with small cell carcinoma for 1 and NSCLC-NOS for 1, with clinical staging stage IV for 13 and postoperative recurrence for 3 before starting EGFR-TKIs. Five patients were ex-smokers and 11 were non-smokers. Mutations of EGFR are exon 19 deletion for 7 patients, exon 21 L858R for 6, exon 21 L861Q for 2, and unspecified for 1. The median PFS was 306 days (95%CI: 97-514 days) with EGFR-TKIs (6 patients were treated with erlotinib and 10 patients were with gefitinib).For 11 patients, re-biopsy was performed during the treatment or within 2weeks of withdrawal of EGFR-TKIs. The specimens were obtained from primary sites in 6 patients and from metastatic sites in 5 (1 from cerebrospinal fluid, 1 from pleural effusion, 2 from lymph nodes and 1 from the skin). Pathological diagnosis was consistent to the original tumors for all cases, adenocarcinoma, except one with squamous cell carcinoma which was initially diagnosed as NSCLC-NOS. While all specimens remained original EGFR activating mutations, 3 out of 11 exhibited EGFR secondary mutation (exon 20 T790M).On the other hand, re-biopsy was performed long after discontinuation of EGFR-TKIs for 5 patients (median 6 months). All patients received subsequent chemotherapies after EGFR-TKIs. The specimens were taken from primary sites for 3 patients and from metastatic sites for 2 (1 from cerebrospinal fluid and 1 from lymph node). All specimens were adenocarcinoma as was so in initial diagnosis. All specimens kept original EGFR activating mutations, while 2 out of 5 exhibited EGFR secondary mutation (exon 20 T790M).

Conclusion
The frequency of exon 20 T790M in re-biopsied specimens was 27 % in NSCLC patients exhibiting acquired resistance to EGFR-TKIs (under or within 2 weeks after discontinuation of EGFR-TKIs). The other mechanisms behind the acquired resistance to EGFR-TKIs remain to be determined in this population.

Background
Lung cancer therapy has changed in the last decade with the advent of EGFR tyrosine kinase inhibitors (TKI) and newer chemotherapeutics such as pemetrexed. Most of these benefits have been limited to lung adenocarcinoma and not other histological subtypes. In addition, this has translated to improved progression free survival benefits but no apparent overall survival benefits in some of the phase III studies conducted. We hypothesized that the benefits seen in these phase III clinical trials would translate to improved overall survival in the wider population of patients (pts) treated in a cancer center.

Methods
We conducted a survival analysis of all primary stage 3B/4 lung cancer diagnoses available from a cancer center database between 1 Jan 2000 and 31 Dec 2012. The diagnoses were identified based on ICD-9 162 and ICD-10 C34. Recurrent lung cancers were excluded. Histological classification for analysis was based on the IASLC system. Molecular data from adenocarcinoma (AC) was available with routine testing from 2010. Treatment given in the form of pemetrexed and EGFR TKI was also tracked from the pharmacy system from 2001. Vital status was checked against the National Registry of Births and Deaths as at 31 March 2013. The primary endpoint was overall survival (OS) which was defined from the time of diagnosis till death from any cause or last follow-up and estimated using Kaplan-Meier method. Log-rank test was used to compare survivals. Jointpoint regression models were used for trend analyses.

Results
A total of 5320 cases of stage 3B/4 primary lung cancer diagnoses were identified. The cases were predominantly male (65%) and Chinese (81%). The median age at diagnosis and gender distribution among the diagnoses in each year remained stable over time. Non-small cell lung cancer (NSCLC) made up 92% of all diagnoses. NSCLC subtypes were adenocarcinoma (52%), squamous (13%), large cell (2%), and Others (25%). EGFR mutation rate among 708 tested cases was 55%, and ALK translocation rate among 108 tested cases was 9%. The jointpoint regression model identified 2005 as a significant turning point in improvement in median OS. Hence comparing 2001-2005 and 2006-2010, the median OS for the entire cohort improved from 8.0 mths (95% CI, 7.1-8.7) to 9.5 mths (95% CI, 8.9–10.2), p = 0.001. This median OS survival benefit was contributed by OS benefits in AC 10.3 mths (95% CI, 9.3-11.8) vs 13.3 mths (95% CI, 12.1 -14.5). The turning point for improvement for median OS survival coincided with increased usage of EGFR TKI and pemetrexed from 2006 and 2008 respectively.

Conclusion
There is median OS benefit in lung cancer treatment outcomes tracked over a decade. This observed benefit is in tandem with the increased use of drugs that have clinical benefit in adenocarcinoma. Unmet needs remain for both small cell lung cancer and other NSCLC subtypes.

Background
Several prospective studies have demonstrated activating mutations in the epidermal growth factor receptor (EGFR) gene are a predictor of response to EGFR tyrosine kinase inhibitor (TKI). Erlotinib is one of EGFR-TKIs available in Japan. However, there are a few prospective reports on the efficacy and safety of erlotinib therapy in Japanese patients with previously treated advanced EGFR mutation-positive non-small cell lung cancer (NSCLC).

Methods
We undertook a multicenter, open-label, single-arm, phase II study. Patients with performance statuses of 0 to 2 and stage IIIB/IV NSCLC with EGFR-sensitive mutations (exon19 and 21) were eligible if they were treated with one or two prior chemotherapy regimens containing at least one platinum-based doublet. They received oral erlotinib at a dose of 150mg daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), while secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) as well as toxicity. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000002716.

Results
Between November 2009 to July 2012, 29 patients (median age, 68 years; range, 40-77 years) were enrolled. No complete response and 17 partial responses were observed, giving the ORR was 58.6% (95% confidence interval (CI): 38.9-76.5%). Ten patients had stable disease and 2 patients had progressive disease. Thus, the DCR was 93.1% (95% CI: 77.2-99.2%). After a median follow-up of 14.7 months (range, 5.3-37.0 months), the median PFS was 9.5 months (95% CI, 5.9-13.2 months). The median OS has not yet been reached. The most common adverse events were skin rash (96.6%; 13.8% grade ≥ 3), and hepatic function disorder including increased ALT (65.5%) and increased AST (48.3%). No interstitial lung disease events or cases of toxic death were reported.

Conclusion
These results indicate that erlotinib monotherapy could be a potential treatment option with favorable clinical outcomes for Japanese patients with previously treated advanced NSCLC with EGFR mutations.

Background
Adjuvant chemotherapy (CT) improves survival in patients (pts) with completely resected early stage NSCLC. Adjuvant cisplatin/vinorelbine (CV) is considered a standard of care in this population. However many pts relapse and require palliative CT, which may involve platinum doublet CT again. We investigated treatment choices on relapse after prior adjuvant CT, specifically in pts receiving palliative platinum doublet CT, and its impact on response rate (RR) and overall survival (OS).

Methods
With ethics approval, we performed a retrospective chart review of all pts with resected NSCLC who received adjuvant CT from January 2002 until December 2008 at our institution. Baseline pt demographics and cancer stage were recorded, along with treatment decisions upon relapse. The primary outcome was the RR to first-line palliative systemic therapy (ST).

Results
We identified 176 pts who received adjuvant platinum doublet CT (82% received CV). Patient characteristics were: median age 63 years (range 25-82); 55% female: median follow up 4.2 years: the primary surgical procedures were lobectomy (79%) or pneumonectomy (16%). The pathologic stage at surgery was 1A (2%), 1B (30%), 2A (7%), 2B (40%) and 3A (15%). In total 85 pts relapsed (48%), with a median time to relapse of 18.5 (95%CI 15-21.3) months. The variable most strongly associated with a shorter time to relapse was nodal stage (p=0.03); increasing T stage also demonstrated a trend towards shorter time to relapse (p=0.09). Of the 85 relapsed pts, 43 received palliative CT, and 42 received best supportive care (BSC) alone. Of the 43 pts treated, 25 (58%) were re-challenged with platinum doublet CT, with a RR of 28%, versus 17% (p=0.47) in 18 pts receiving other ST (most commonly docetaxel [n=7, 39%] or erlotinib [n=4, 22%). There was a trend towards increased clinical benefit rate (CR+PR+SD) in patients who were treated with a platinum doublet (67% versus 41% p=0.12). For all pts the median OS after relapse was 11.6 months. In pts receiving any CT (n=43), median OS was 15.3 months, compared to 7.8 months in those receiving BSC alone. Pts in the platinum-treated group had a longer survival after relapse than those pts treated with non-platinum regiments (18.4 versus 9.7 months, p=0.041). See Figure 1.Figure 1

Conclusion
In pts previously treated with adjuvant CT, re-treatment with platinum doublet CT upon relapse is feasible and associated with numerically higher response rates and significantly longer survival than those receiving other first-line ST.

Background
There is no single standard doublet combination of platinum chemotherapy for non-small cell lung cancer (NSCLC). In non-inferiority phase III study, cisplatin/pemetrexed showed a significant improvement in survival in patients with non-squamous histology compare to cisplatin/gemcitabine. Recently, continuation maintenance with pemetrexed after cisplatin/pemetrexed was found to prolong overall survival as well. The objective of this retrospective study was to evaluate the efficacy of pemetrexed in combination with cisplatin or carboplatin for stage IV NSCLC at our institution

Methods
We reviewed the medical records of 103 patients with stage IV non squamous NSCLC (between January 2008 and December 2012) treated with pemetrexed in combination with platinum (cisplatin 75 mg/m2 or carboplatin AUC5 on day 1 plus pemetrexed 500 mg/m2 on day 1 every 3 weeks) at our institution. After induction chemotherapy patients received pemetrexed 500 mg/m2 every 3 weeks or best supportive care until disease progression or unacceptable toxicity

Results
From 103 patients, 27,2% were female and 72,8% were male. The ECOG was 0-1 in 80% of patients, and the median age was 63 years old. Smoking status was 39,5% current smokers, 48,9% former smokers, 10,4% never smokers and 1% unknown. Histologic type was 66% adenocarcinoma, 27% large-cell carcinoma and 7% non other. EGFR status was 46% wild type, 49% unknown and 5% mutated. The median cycles of doublet combination of platinum with pemetrexed was four cycles (1-8). 77,7% patients received carboplatin and 22,2% cisplatin. Thirty-three patients (32%) received maintenance therapy with pemetrexed. The median cycles of maintenance pemetrexed was four (1-34). The response rate achieved was 52,1% (Complete Response 4,4% + Partial Response 47,7%) and 21,1% stable disease, so 73,2% with clinical benefit. Median time to disease progression was 6,6 months (95% CI 4,8 to 7,6 months) in all patients. The median time to disease progression was 8,1 months (95% CI 5,9 to 9,9 months) in maintenance pemetrexed group and 4,1 months (95% CI 3,1 to 5,1 months) in best supportive care group (p<0,001). Median overall survival was 9,6 months (95% CI 8,1 to 11 months) in all patients. The median overall survival was 12,4 months (95% CI 10,4 to 17,1 months) in maintenance pemetrexed group and 9,1 months (95% CI 8,2 to 11,1 months) in best supportive care group (p=0,005)

Conclusion
Doublet combination of platinum with pemetrexed and maintenance pemetrexed is effective achieving good response rates and prolonging overall survival. The schema is feasible in patients with non-squamous NSCLC and we reproduced the data from clinical trials in our daily clinical practice. However, there are some questions remaining as the optimal number of induction cycles and most important which biomarkers factors are predicting benefit from maintenance chemotherapy

Background
Diabetes and other age-related comorbidities frequently occur together in patients with NSCLC and may affect treatment efficacy and tolerability. Several studies demonstrated that diabetic patients have worse outcomes than those without diabetes. Additionally, studies have suggested that metformin may enhance the effects of chemotherapy, leading to improved outcomes. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) significantly improved the primary endpoint of overall response rate (ORR) from 25% to 33% (P = 0.005), with a trend toward improved overall survival (OS) and progression-free survival (PFS) vs solvent-based paclitaxel (sb-P) + C in patients with advanced NSCLC. This exploratory analysis examined efficacy and safety outcomes in diabetic patients with advanced NSCLC.

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 determined 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. Multiple sensitivity analyses were performed to confirm treatment differences and to rule out confounding effects from other baseline covariates.

Results
31 patients in the nab-P/C and 30 patients in the sb-P/C arms were included in this analysis. Similar to the intent-to-treat (ITT) population, most diabetic patients were male (75%), white (62%), with ECOG PS 1 (79%), and stage IV disease (85%). In these patients, ORR for nab-P/C vs sb-P/C was 52% vs 27% (response rate ratio 1.935; P = 0.046), median PFS was 10.9 vs 4.9 months (HR 0.416; P = 0.016), and median OS was 17.5 vs 11.1 months (HR 0.553; P = 0.057). Treatment difference in PFS remained significant (P ≤ 0.026) after adjusting for baseline characteristics (including histology, region, stage, and age). For OS, region, stage, race, and age were not observed to be confounding factors on treatment effect. Metformin was concomitantly used in 29% and 37% of diabetic patients in the nab-P/C vs sb-P/C arms, respectively. The percentage of patients experiencing ≥ 1 adverse event (AE) was similar between the diabetic and ITT populations. Among diabetic patients, the most common grade 3/4 AEs in the nab-P/C vs sb-P/C arms were neutropenia (53% vs 55%), anemia (23% vs 10%), peripheral neuropathy (PN, 7% vs 23%), thrombocytopenia (20% vs 7%), and fatigue (7% vs 10%); differences were not statistically significant. Safety findings were similar to those observed in the ITT population; however, the incidence of grade 3/4 PN was slightly higher for both arms in the diabetic population compared with the ITT population (for nab-P/C vs sb-P/C, 3% vs 12%; P < 0.001).

Conclusion
In this analysis, nab-P/C demonstrated improved efficacy and was well tolerated in diabetic patients with advanced NSCLC. These findings warrant further study in a larger diabetic patient population. The relationship between the efficacy of nab-P and glucose level/metformin use also merits additional study.

Background
In the Japanese Clinical Practice Guideline for Lung Cancer, postoperative platinum-based adjuvant chemotherapy in patients with pathological stage IIIA (p-stage IIIA) non-small cell lung cancer (NSCLC) is recommended (grade B). However, the verification of the effect of adjuvant chemotherapy in Japanese patients is not sufficient. In this study, we aimed to validate the effectiveness of platinum-based adjuvant chemotherapy for p-stage IIIA NCSLC.

Methods
Between January 2002 and December 2009, we retrospectively reviewed records of patients with completely resected p-stage IIIA NSCLC in our institution. Exclusion criteria include the patients with oral anticancer drug, tegafur and uracil (UFT), >75 years old, large cell neuroendocrine carcinoma and pleomorphic carcinoma. The primary endpoint of this study was progression-free survival. Cumulative survival curves were estimated with the Kaplan-Meier method and compared with the log-rank test. Multivariable analysis was performed with the Cox proportional hazards regression model to estimate the independent prognostic effect of adjuvant chemotherapy on prognosis by adjusting for confounding factors.

Results
Sixty-seven patients (median age, 63 years; 40 men, 27 women) were eligible. 49 patients had adenocarcinoma and 18 had squamous cell carcinoma. 63 patients underwent lobectomy and 4 patients had pneumonectomy. Of the 33 patients with platinum-based adjuvant chemotherapy regimens, 16 had cisplatin plus gemcitabine, 13had carboplatin plus paclitaxel, and 4 had cisplatin plus vinorelbine. Five-year progression-free survival (PFS) and 5-year overall survival (OS) in the adjuvant chemotherapy group versus in surgery alone group were not statistically significant (5-year PFS rates were 28% and 31%, respectively; p = 0.69, and 5-year OS rates were 54% and 40%, respectively; p = 0.10). Multivariate analysis showed that platinum-based adjuvant chemotherapy did not affect patient prognosis significantly (HR, 0.70; 95% CI, 0.37-1.32; p=0.27).

Conclusion
Our date showed that platinum-based adjuvant chemotherapy in patients with p-stage IIIA NSCLC did not have such impact on our patient’s prognosis as we could understand in daily medical practice. Although there were some limitations of this study, we feel a strong need for searching more effective chemotherapy regimens or individualized treatment strategies.

Background
Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We hypothesized that heat shock protein 70 (Hsp70) would be a biomarker for selecting patients for adjuvant chemotherapy, and evaluated the prognostic or predictive significance of Hsp70 in patients with surgically resected NSCLC.

Methods
Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA between January 1996 and December 2010 were included. We conducted immunohistochemical staining for Hsp70 on surgical specimens and compared survival rates depending on whether of Hsp70 expression and adjuvant platinum-based chemotherapy.

Results
Among 327 patients, Hsp70 expression was positive in 220 (67.3%). For the patients without adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for the patients with adjuvant chemotherapy, patients with Hsp70-positive tumors had longer disease-free survival (DFS; 82.4 vs. 29.7 months; P = 0.004) as well as longer overall survival (OS; 101.9 vs. 73.4 months, P = 0.12) than those with Hsp70-negative tumors. Multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death than those with Hsp70-negative tumors after adjusting for age, gender, performance status, pathologic stage, and histologic types in adjuvant chemotherapy group (DFS: adjusted hazard ratio [AHR], 0.54; 95% CI, 0.36 to 0.80; P = 0.002; OS: AHR, 0.66; 95% CI, 0.42 to 1.05; P = 0.08). Figure 1

Conclusion
Hsp70 is a positive predictive factor in completely resected NSCLC and Hsp70-positive tumors seem to benefit from adjuvant platinum-based chemotherapy.

Background
Pemetrexed maintenance therapy significantly improved survival in patients with advanced nonsquamous non-small cell lung cancer. This study was to investigate the clinical characteristics and to identify the prognostic factors of pemetrexed as continuation maintenance chemotherapy for patients with advanced lung adenocarcinoma.

Methods
Patients with advanced lung adenocarcinoma treated with pemetrexed for continuation maintenance therapy after platinum-based doublet frontline treatment without disease progression were enrolled. The medical records were analyzed for basic characteristics, epidermal growth factor receptor (EGFR) mutation analysis, treatment responses, progression-free survival (PFS) and overall survival (OS).

Results
From September 2009 to September 2012, the medical records of 121 patients with advanced lung adenocarcinoma treated with pemetrexed and platinum as first line chemotherapy were reviewed. Sixty-nine patients treated with pemetrexed for continuation maintenance therapy after 6 cycles platinum-based doublet frontline treatment were included. Thirty-five patients (50.7%) were male. The mean of age was 66 ± 13 years old. Twenty-one patients (30.4%) were current or former smoker. The median cycles of pemetrexed as maintenance therapy was 6 cycles (range from 1 to 36 cycles). Elderly patients (age ≥ 70 years old v.s. age < 70 years old, median PFS: 9.6 months v.s. 4.0 months, p=0.002) and patients with lower glomerular filtration rate (GFR) (GFR ≥ 60 ml/min vs. GFR < 60 ml/min, median PFS: 4.0 months vs. 7.9 months, p=0.03) had longer PFS in maintenance phase of pemetrexed treatment. Other clinical factors, including EGFR mutation status, use of cisplatin or carboplatin, gender, smoking history, and treatment response to first-line chemotherapy, had no eventful effect on PFS. However, there was no significant association between OS and these clinical factors.

Conclusion
Pemetrexed continuation maintenance therapy may be more beneficial for elderly patients and patients who had lower renal function.

Background
Real world evidence for clinical effectiveness, toxicity, and hospitalization costs associated with second-line chemotherapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) is needed to guide clinical practice and reimbursement decision making in China.

Methods
This study retrospectively identified advanced non-squamous NSCLC patients treated with second-line chemotherapy between 2007 and 2012 in four triple-A hospitals. Patients’ baseline characteristics, chemotherapy, clinical response, adverse events, and hospitalization costs were extracted from medical and financial records associated with hospitalizations during second-line chemotherapy. They were compared by treatment using descriptive statistical methods. Kaplan-Meier (KM) survival analysis was conducted to explore the differences in time to progression (TTP) between the treatments. Hospitalization costs were stratified into non-drug costs and non-chemotherapy drug costs, and chemotherapy drug costs. Propensity score methods were used to create matched patients with balanced baseline characteristics to confirm the findings in the unadjusted analyses.

Results
414 patients received pemetrexed singlet (n=57), docetaxel singlet (n=64), docetaxel-platinum doublet (n=119), and pemetrexed-platinum doublet (n=174) as second-line chemotherapy in the four hospitals. The identified patients had similar baseline characteristics except that patients receiving docetaxel-platinum doublet (53.2 years vs. 58.5 years, p = 0.003) or pemetrexed-platinum doublet (54.3 years vs. 58.5 years, p = 0.010) were younger than those treated by pemetrexed singlet. KM survival analysis indicated a non-significant trend suggesting longer mean TTP for pemetrexed singlet than that for docetaxel singlet (95.6 days vs. 53.4 days; p = 0.139), for docetaxel-platinum doublet (95.6 days vs. 52.4 days; p = 0.139), and for pemetrexed-platinum doublet (95.6 days vs. 76.3 days; p = 0.716). The adverse event comparisons demonstrated that pemetrexed singlet had lower incidence rates for neutropenia (8.8% vs. 25.0%, p = 0.035 for docetaxel singlet; 21.9%, p = 0.055 for docetaxel-platinum doublet; 23.0%, p = 0.031 for pemetrexed-platinum doublet) and leukopenia (10.5% vs. 21.9%, p = 0.152 for docetaxel singlet; 28.6%, p = 0.013 for docetaxel-platinum doublet; 26.4%, p = 0.021 for pemetrexed-platinum doublet) and had lower incidence rates for vomiting (35.1% vs. 62.6%, p < 0.001) and nausea (43.9% vs. 69.0%, p < 0.001) than pemetrexed-platinum doublet. Pemetrexed singlet was associated with the lowest hospitalization costs per treatment cycle (3 weeks) for non-drug expenses (RMB 3,949 vs. RMB 5,154 for docetaxel singlet, p = 0.043; RMB 6,067 for docetaxel-platinum doublet, p = 0.002; RMB 5,045 for pemetrexed-platinum doublet, p = 0.029; 1 RMB = 0.16 US$) and non-chemotherapy drugs (RMB 5,471 vs. RMB 8,421 for docetaxel singlet, p = 0.006; RMB 7,874 for docetaxel-platinum doublet, p = 0.015; RMB 7,665 for pemetrexed-platinum doublet, p = 0.009). Similar trends were observed in the comparisons between the treatments in propensity score matched patients.

Conclusion
Advanced non-squamous NSCLC patients treated with pemetrexed singlet for second-line therapy had less toxicity and lower hospitalization costs for non-drug expenses and non-chemotherapy drugs in this Chinese cohort. When compared to pemetrexed singlet, pemetrexed-platinum doublet as second-line chemotherapy was associated with greater occurrence of adverse events and higher hospitalization costs without giving any additional survival benefits.

Background
The aim of this phase II study was to assess the efficacy and safety of paclitaxel combined with carboplatin plus bevacizumab as a second line treatment of elderly patients with advanced NSCLC.

Methods
Twenty one elderly patients with NSCLC who previously received only one line of chemotherapy were enrolled into this study between March 2009 and March 2013. All patients received paclitaxel 175 mg/m[2] followed by carboplatin AUC of 5, and followed by bevacizumab 15mg/kg, all agents were given via I.V infusion on day 1 and the cycle was repeated every 21 days for maximum 6-8 cycles. Patients who attained at least stable disease continued to receive single agent bevacizumab every 21 days until disease progression or unacceptable toxicity developed.

Results
The median age was 73 years old (range 66-82 years); 17 (81%) patients were men; ECOC PS was 0 in 4 (19%) patients, 1 in 9 (43%) patients and 2 in 8 (38%) patients. The objective response rate was 30.3%, while disease control rate was 63.7%, respectively, and the median progression-free survival time was 4. 2 months. Grade 3/4 neutropenia, grade 3/4 thrombocytopenia occurred in 2(10%) patients, while grade 3/4 peripheral neuropathy occurred in 3(14%) patients and grade 3/4 fatigue had occurred in 4(19%) patients. No treatment-related deaths had been reported in this study.

Conclusion
Bevacizumab when given with paclitaxel and carboplatin exhibits activity in previously treated elderly patients with advanced NSCLC and has acceptable toxicity.

Background
We investigated the efficacy and toxicity of a biweekly schedule of docetaxel and cisplatin in high risk patients with unresectable (stages IIIB–IV) non-small cell lung cancer (NSCLC).

Methods
In this study, 48 high risk patients with previously untreated locally advanced or metastatic NSCLC were administered combination chemotherapy consisting of docetaxel 40 mg/m[2] and cisplatin 40 mg/m[2]; both drugs were given biweekly, on days 1 and 15, every 4 weeks in an outpatient setting.

Results
A complete response, partial response, and stable disease were observed in 1 (2.1%), 30 [62.5%, 95% confidence interval (CI): 47.9–77.1%], and 4 (8.3%) patients. The median overall survival was 15.1 months (95% CI: 11.7–18.5) and the median time to progression was 7.5 months (95% CI: 6.4–8.6). The major toxicity was grade 3 anemia in 7 (14.6%) patients. Grade 3/4 neutropenia was observed in 5 (10.4%) patients. Among the non-hematologic toxicities, grade 3 infection and grade 3 diarrhea were observed in 5 (10.4 %) and 4 (8.3%) patients, respectively. No treatment-related mortality was found.

Conclusion
As a front-line chemotherapy for high risk patients with unresectable NSCLC in an outpatient setting, the biweekly schedule of docetaxel and cisplatin showed feasible efficacy with manageable grade 3–4 hematologic toxicities, comparable to the result of previous studies of triweekly or weekly schedules. Additional large randomized studies are needed to optimize the schedule and dosage of combination therapy with docetaxel and cisplatin in high risk patients with unresectable NSCLC.

Background
Patients with advanced non squamous NSCLC benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, pemetrexed or non-pemetrexed doublet. We evaluated the efficacy and safety of pemetrexed maintenance therapy in advanced non squamous NSCLC.

Methods
We used pemetrexed (500 mg/m2 every 21 days) and best supportive care in patients with advanced, non squamous NSCLC who had not progressed after at least 4 cycles of induction chemotherapy. Pemetrexed was administered with folic acid and vitamin B12 supplementation until disease progression or the development of intolerable toxicity.

Results
Eleven patients were enrolled. Patient characteristics were: 9 men, 2 women, median age 60 years (range 44 to 73), 2/4/5 never, former and current smokers, 9 adenocarcinoma, 2 large cell, 3 stage IVa, 8 stage IVb, 100% ECOG PS 1. A total of 87 cyclesof pemetrexed was administered [median 6 (range 2 to 23)], relative dose intensity 91%. Nine pts were evaluable for tumor response 1 PR, 7 SD, 1 PD. Median PFS was 4.14 months (95% CI 3.3 to 9.5 mo). Toxicity was anemia G 1/2 (3/4 pts), neutropenia G 2 (1 pt), fatigue G 1/2 (8/3 pts),nausea-vomiting G 1/2 (5/2 pts), mucositis G 1/2 (2/2 pts), oedema (0 pt).

Conclusion
Pemetrexed maintenace therapy is a well tolerated and an effective option for patients with advanced non-squamous NSCLC. The study is ongoing.

Background
Thirty to forty percent of East Asian patients with non-small cell lung cancer (NSCLC) have epidermal growth factor receptor (EGFR) gene mutations, which are recognized as predictive factors of the response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The most common mutations are the in-frame deletion in exon 19 and a substitution of lysine for arginine mutation at amino acid position 858 (L858R) in exon 21. It has been reported that subtype of EGFR gene mutation affects the efficacy of EGFR-TKIs in Caucasian patients with NSCLC. The deletion in exon 19 was reported to be an independent predictive factor of longer progression free survival (PFS); however, it was not a predictive factor of overall survival (OS).

Methods
We reviewed the records of patients with NSCLC referred to our hospital from May 2007 to May 2013, to clarify the influence of EGFR gene mutation subtype to clinical features.

Results
We found 128 patients with EGFR mutation, involving 124 cases of adenocarcinoma. According to the UICC-TNM ver.7, number of the patients with stage I/II disease was 59, while patients with stage III/IV was 69. We selected 60 patients with non-resectable disease (stage IIIB and IV) for the detailed analysis. The median age of the 60 patients was 74 year-old (range, 41-83). There were 39 female patients, and 39 light or never-smokers. The number of the patients with deletion mutation in exon 19 was 32 (the ratio of E746-A750 del was 78%); while the number of those with mutation in exon 21 was 24 (L858R was 96%). EGFR-TKIs were administered to 52 (86.7%) patients (erlotinib, gefitinib, and both was given in 20, 20, and 12 patients, respectively), including 35 patients without prior chemotherapy. The median duration of observation was 557 days. Any relationship between OS and clinical factor (gender, smoking history, and EGFR gene mutation subtypes) was not seen. In the patients treated with EGFR-TKIs, there was no significant difference in median OS regarding the administered drug (300 days with erlotinib or 285 days with gefitinib). In the patients with the exon 21 mutation, erlotinib-treated group had longer survival time than that of gefitinib group (200 days vs 150 days in median OS, p = 0.079). This observation was not confirmed in the patients with the exon 19 mutation.

Conclusion
Our retrospective analysis showed no difference of OS under subtype of EGFR gene mutation; however, the efficacy of EGFR-TKIs may differ in subtypes of EGFR gene mutation.

Background
Selenite is a trace element, necessary in doses of 40 – 200 microg/day. In these doses it has a reducing, detoxifying effect. However, in human cell-lines in much higher doses, it becomes toxic resulting in apoptosis. Most malignant cell-lines are significantly more sensitive than benignant ones. This indicates that there might be a therapeutic index, so we have started a clinical study.

Methods
This phase I study, the SECAR study has the purpose to find the maximal tolerable dose (MTD) of sodiumselenite. Patients with progressing malignant disease, mainly lung cancer, already treated with established drugs, were included. Treatment was given iv once daily 10 times during 2 weeks. According to a fixed schedule doses were escalated for each new cohort of 3 patients. If a serious adverse event (SAE) was observed 3 more patients were included. If 3/6 patients had an SAE, this dose level was considered too high and MTD was defined as the nearest lower dose.

Results
After 34 patients MTD has been defined to 10.2 mg/m2. Half life is 10 – 16 hours. The most common toxicity was sickness, vomiting and fatigue. However, at higher doses confusion and hallucinations were observed, and the most alarming toxicity was signs of heart ischemia and dyspnea with chock. One patient had a complete remission, but in the rest stable disease and very limited tumour shrinkage was observed at best. Tumour reevaluation is ongoing.

Conclusion
We now have defined the MTD for sodiumselenite. However, we also have got pharmacokinetic data indicating that treatment might probably be optimized. Antitumoural effect has been observed, so the SECAR study will go on at first with an altered treatment schedule.

Background
High serum carcinoembryonic antigen (CEA) levels are an independent prognostic factor for recurrence and survival in patients with non-small cell lung cancer (NSCLC). Its role as a predictive marker of treatment response with chemotherapy has not been widely characterized.

Methods
Two-hundred and fifty patients with advanced NSCLC (stage IIIB or Stage IV), who had an elevated CEA serum level (>10 ng/ml) at baseline and who had no more than one previous chemotherapy regimen, were included. CEA levels were measured after two treatment cycles of platinum based chemotherapy (75%) or a tyrosine kinase inhibitor (25%). We evaluate the change in serum CEA levels and the association with response measured by RECIST criteria.

Results
After two chemotherapy cycles, the patients who achieved an objective response (OR, 30.2%) had a reduction of CEA levels of 97% compared to its basal level. Patients that achieved a decrease in CEA levels> =20% presented and overall response in 72% of cases, stable disease in 26% and progression in 2%. Patients with stable disease and progression have an increase of CEA levels of 12% and 90% from baseline, respectively (p < 0.001).

Conclusion
A reduction of serum CEA level (20%) from baseline after 2 cycles of treatment in advanced NSCLC is an accurate measurement of OR. The comparison de CEA levels (Before and after chemotherapy) in NSCLC is associated with objective response by RECIST and should be part of the routine follow-up of advanced NSCLC patients.

Background
EGFR wild-type non-squamous non-small-cell lung cancer (NSCLC) accounted for the majority of lung cancer patients, but the outcome of its first-line treatment was not satisfactory. INNOVATION study provided a new therapy perspective for those patients. EGFR wild-type subgroup analysis of this study revealed gemcitabine/cisplatin first-line chemotherapy plus bevacizumab showed significant advantage compare with gemcitabine/cisplatin alone (PFS 8.4m vs. 3.4m, OS 18.0 vs. 10.3m), which suggested that gemcitabine/cisplatin plus bevacizumab may be the preferred first-line therapy for EGFR wild-type non-squamous NSCLC. However, no other prospective trail has been preceded to confirm this conclusion in patients with EGFR wild-type non-squamous NSCLC. As a new type of anti-tumor angiogenesis monoclonal antibody, bevacizumab precisely targets VEGF to inhibit angiogenesis for continuous tumor control. We conduct this randomized phase II trial to investigate if gemcitabine/cisplatin first-line chemotherapy plus bevacizumab is a better treatment for advanced non-squamous NSCLC patients without EGFR mutations. This study will also explore plasma biomarkers of bevacizumab efficacy.

Methods
This is an open-label randomized (1:1) 2-arm phase II study. Stage IIIB/IV EGFR wild-type non-squamous NSCLC with performance status (PS) 0 or 1 will be included; patients who have received prior chemotherapy or radiotherapy will be excluded. Patients (N=40) will receive (1:1) gemcitabine/cisplatin orgemcitabine/cisplatinplus bevacizumab (chemotherapy up to 6 cycles) until disease progression, unacceptable toxicity, patient/physician decision to discontinue, or death. Patients in the control arm receive first-line gemcitabine/cisplatin (gemcitabine 1250mg/m[2] IV D1 and D8 plus cisplatin 75mg/m[2] IV D1, every 21-day cycle). Patients in the experimental arm receive gemcitabine/cisplatin plus bevacizumab (7.5 mg/kg IV D1, every 21-day cycle). At the time point of start of chemotherapy and six weeks after chemotherapy, peripheral blood of patients from both arms will be collected to detect plasma VEGF, VEGFR and VEGFR-2 level by ELISA. The primary endpoint is progression-free survival (PFS). Secondary endpoints include response rate, disease control rate, safety of bevacizumab and quality of life. Exploratory objective is biomarker analysis. Recruitment began in February 2013; the estimated final data collection for the primary endpoint is Aug 2014. Further details can be found on ClinicalTrials.gov (NCT01623102).

Results
not applicable

Conclusion
not applicable

Background
This is an ongoing phase III multicenter randomized trial comparing first line pharmacogenomic-driven chemotherapy based on Excision-Repair-Cross-Complementing-1 (ERCC1), Ribonucleotide Reductase subunit M1 (RRM1) and Thymidylate Synthase (TS) gene expression, versus standard first line treatment in elderly patients (pts) with advanced non-small-cell lung cancer (NSCLC). Chemotherapy selection based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the already available cytotoxic drugs. In older pts this is particularly relevant owing to their rapid deterioration of symptoms and their increased propensity to suffer therapy-induced toxicity.

Methods
Pts aged >70 years, with ECOG Performance Status (PS) 0 or 1, previously untreated for stage IV NSCLC will be evaluated. In a 2:1 fashion, pts will be randomized to experimental arm (A) or standard arm (B). They must have measurable disease and EGFR negative mutational status. In arm A, treatment with single or dual-agent chemotherapy will be based on histology, ERCC1 (E), RRM1 (R) and TS (T) expression at the mRNA level. Expression of E, R and T is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. The cut off for high or low expression have been previously defined. Pts with squamous NSCLC who are: E low/R high will be treated with single agent carboplatin, E high/R low with single agent gemcitabine, E low/R low with carboplatin and gemcitabine and E high/R high with docetaxel or vinorelbine. In non-squamous NSCLC pts: E low/T high will be treated with carboplatin, E high/T low with pemetrexed, E low/T low with carboplatin and pemetrexed, E high/T high/R low with gemcitabine and E high/T high/R high with docetaxel or vinorelbine. In arm B treatment will be standard of care at the discretion of the care provider. The primary endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS), disease response according to RECIST 1.1 and tolerability (using CTCAE version 4.0). Feasibility of treatment selection based on pharmacogenomic parameters will also be assessed. Treatment will continue to a maximum of 6 cycles if tolerated or until disease progression. Switch maintenance treatment is not allowed in either arm. Continuation maintenance (one or more of the agents used in the initial regimen) is allowed at the discretion of the investigator. Treatment upon progression is at the discretion of the care provider. Assuming an exponential survival distribution for both treatment arms and a median survival time of 8 months in the control arm we anticipate to detect an improvement of 3 months in the median survival time in the experimental arm. To have 90% power to detect a three-month improvement in median survival at a significance level of 5% (2-sided) and assuming a 10% failure rate in gene analyses or loss to follow up rate, a sample size of 567 patients is planned to be enrolled.

Results
Not Applicable

Conclusion
We hypothesize that such tailored approach will improve survival decreasing the exposure to ineffective toxic agents in advanced NSCLC elderly pts. To our knowledge this is the first pharmacogenomic-driven randomized trial in this population.

Background
Background The cytoprotective chaperone clusterin (CLU) is upregulated in NSCLC and other cancers in response to anticancer therapies, such as docetaxel (DOC). Custirsen inhibits CLU expression, enhances chemotherapeutic activity, and has been shown in vivo to reverse DOC resistance. In a non-randomized, phase 1/2 study, patients with stage IIIB/IV NSCLC who received first-line custirsen with gemcitabine/cisplatin had a median overall survival (OS) of 14.1 months. In early phase studies in castration resistant prostate cancer, custirsen plus DOC was well tolerated and showed encouraging efficacy results. DOC is recommended as second-line chemotherapy for advanced NSCLC with a median OS of only 7-8 months. Treatments that improve OS in advanced NSCLC are greatly needed. ENSPIRIT is designed as a Phase 3 study to assess the clinical benefit of adding custirsen to second-line DOC therapy in advanced or metastatic NSCLC.

Methods
Methods ENSPIRIT was initiated in September 2012. Eligible patients in this phase 3, multinational, open-label trial (planned enrollment: 1100) have failed 1 prior line of platinum (PT)-based therapy and have a life expectancy >12 wks; ECOG score of 0-1; and adequate bone marrow, renal, and liver function. Patients receive 21-day cycles of DOC (75 mg/m[2] IV day 1) or DOC plus custirsen (640 mg IV/wk, preceded by 3 doses during a 9-day loading period) until progressive disease (PD), unacceptable toxicity, or withdrawal. Randomization is 1:1 and patients are stratified by gender, NSCLC histology (squamous vs non-squamous), best overall response to the first-line PT therapy (stable disease [SD], complete response [CR], partial response [PR], vs PD), and ECOG score. The primary efficacy measure is OS. Secondary efficacy measures are progression-free survival, objective response (OR: CR or PR), disease control (DC: CR, PR, or SD), and duration of OR and DC. All efficacy analyses are intent to treat. Adverse events and laboratory results will be assessed. Two interim analyses are planned for stopping the trial early based on inadequate evidence of clinical benefit or futility.

Results
Results Not applicable.

Conclusion
Conclusion This Phase 3 study will assess the potential survival benefit of second-line custirsen and DOC therapy in the treatment of advanced or metastatic NSCLC. This study is sponsored by Teva Branded Pharmaceutical Products R&D, Inc., in collaboration with OncoGenex Pharmaceuticals, Inc.

Background
In the recent years, it has been shown that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), gefitinib or erlotinib, can provide significant benefit to patients with advanced non-small cell lung cancer (NSCLC). A major concern during EGFR-TKI treatment is the development of interstitial lung disease (ILD). The incidence and clinical characteristics of ILD associated with EGFR-TKIs in Taiwanese patients are less well defined.

Methods
Patients with advanced NSCLC in the Taipei Veterans General Hospital were screened and patients who had received EGFR-TKIs were enrolled in this study. The clinical information including medical records and chest images were reviewed. The diagnosis of EGFR-TKI related ILD was confirmed by two pulmonologists according to previously published criteria. Association between ILD development and clinical factors was evaluated.

Results
From February 2008 to July 2012, a total of 1214 patients who received EGFR-TKI as single therapy for NSCLC were screened. Patients who developed severe ILD and needed hospitalization (grade 3-5) were included. Consequently, 9 of 1214 patients (0.7%) were diagnosed to have severe EGFR-TKI related ILD. The median age of the patients with ILD was 61.0 years and 6 were male (66.7%). The median time interval from EGFR-TKIs use to onest of ILD was 31 days (range: 10-75 days). The most common symptom of EGFR-TKIs related ILD was dyspnea (88.9%). The most common radiological manifestation was bilateral ground glass opacity (GGO), which was noted in 5 patients (55.6%). All patients discontinued EGFR-TKIs immediately when ILD was suspected and 8 patients (88.9%) received systemic steroids. Six of nine patients (67%) patients died from ILD.

Conclusion
EGFR-TKIs, both gefitinib and erlotinib may cause fatal ILD in Taiwanese NSCLC patients. Physicians should be aware of this rare but severe side effect of EGFR-TKI and monitor this pulmonary toxicity closely.

Background
We performed a meta-analysis to evaluate the risk of toxic death, treatment discontinuation and grade 3 or 4 (G3/4) adverse events (AEs) of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in the treatment of advanced non-small cell lung cancer (NSCLC).

Methods
Randomized trials comparing EGFR-TKI monotherapy or combination EGFR-TKI-chemotherapy with chemotherapy or placebo were included. We extracted data on toxicity events, and computed pooled relative risks (RR) adjusted for median treatment duration as the ratio of the risks in the EGFR-TKI arm versus the control group. Three treatment comparisons were analysed: EGFR-TKI versus placebo, EGFR-TKI versus chemotherapy, EGFR-TKI-chemotherapy versus chemotherapy. All statistical tests were two-sided.

Results
Thirty-five trials (16,507 patients) were included. EGFR-TKI was associated with 1.7% risk of toxic death (95% CI 1.4-2.0). Compared with EGFR-TKI, we demonstrated no difference in risk of toxic death for placebo (RR 1.15, 95% CI 0.08-1.86, p=0.86) or chemotherapy (RR 0.77, 95% CI 0.50–1.16, p=0.22), but higher risk for EGFR-TKI-chemotherapy compared to chemotherapy (RR 4.23, 95% CI 1.12-14.41, p=0.03). The risks of treatment-related discontinuation and G3/4 AEs were lower for EGFR-TKI than chemotherapy (RR 0.41, 95% CI 0.34-0.50, p<0.001; RR 0.35, 95% CI 0.32-0.38, p<0.001 respectively) but higher for EGFR-TKI than placebo (RR 2.43, 95% CI 1.73-3.40, p<0.001; RR 1.18, 95% CI 1.04-1.33, p=0.008) and for EGFR-TKI-chemotherapy than chemotherapy (RR 1.99, 95% CI 1.66-2.39, p<0.001; RR 1.50, 95%CI 1.32-1.70, p<0.001).

Conclusion
EGFR-TKI therapy in advanced NSCLC has a low incidence of toxic death and similar safety to chemotherapy with fewer serious AEs. Likelihood of benefit and careful consideration of toxicity profiles should inform treatment selection. Improved toxicity reporting in future trials would allow better quantification of EGFR-TKI-associated toxicity.

Background
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are now recognised as the standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harbouring activating EGFR mutations. Many studies consistently demonstrated superior tumour response and progression-free survival (PFS) over chemotherapy. However, there are still ongoing questions whether there are any significant differences in treatment outcomes between patients of different ethnicity, gender, age, performance status, smoking history, tumour histology and different subtypes of EGFR mutation. We performed a meta-analysis to assess the impact of these factors on the PFS benefit of EGFR-TKIs in advanced NSCLC patients harbouring activating EGFR mutations.

Methods
An electronic search of all randomised controlled trials comparing efficacy of first-line therapy of EGFR-TKI vs chemotherapy in advanced NSCLC patients harbouring EGFR mutation was performed. We extracted the published hazard ratio (HR) and the 95% confidence interval (CI) for PFS, if available, or obtained unpublished data, for subgroups defined by each factor. For each subgroup, pooled estimates of treatment efficacy of EGFR-TKI vs chemotherapy were calculated with the fixed-effects inverse variance weighted method. The predictive effect of each factor was analysed by a test for interaction between the factor and treatment effect; P<0.05 was considered statistically significant. All statistical tests were two-sided.

Results
We included 6 eligible studies, with two trials for each of these different EGFR-TKIs - Gefitinib, Erlotinib, and Afatinib – with a total of 1432 patients. As expected, overall the use of EGFR-TKIs in this mutated population significantly prolonged PFS as compared with chemotherapy (HR 0.37, 95% CI 0.32 to 0.43, P<0.001). While mutations at both Exon 19 (deletions) and at Exon 21 (L858R point mutations) were associated with significantly prolonged PFS, the benefit with Exon 19 mutations was greater: HR 0.26, 95% CI 0.21 to 0.31, P<0.001; as contrasted to Exon 21: HR 0.42, 95% CI 0.34 to 0.52, P<0.001 (treatment-EGFR mutation interaction P=0.001). Smoking status also showed differential benefit in this mutated population: never smokers: HR 0.30, 95% CI 0.26 to 0.36, P<0.001; contrasted to current or ex-smokers: HR 0.48, 95% CI 0.37 to 0.61, P<0.001; treatment-smoking history interaction P=0.003). There was also a trend for greater benefit for females with EGFR-TKI therapy as contrasted to males (HR [females] 0.32, 95% CI 0.27 to 0.38, P<0.001; HR [males] 0.42, 95% CI 0.33 to 0.53, P<0.001; treatment-gender interaction P=0.06). Interestingly, several parameters were not significant predictors of PFS benefit with EGFR-TKI treatment in this mutated population: performance status (ECOG 0 and 1 vs 2; interaction P=0.86); age (<65 vs ≥65 years; interaction P=0.58); ethnicity (Asian vs others; interaction P=0.18); and tumour histology (adenocarcinoma vs others; interaction P=0.52).

Conclusion
While EGFR-TKIs significantly prolong PFS in all advanced NSCLC patients harbouring classic activating EGFR mutations when compared with chemotherapy, other molecular and demographic factors have a further influence on benefit. Exon 19 deletions, never-smoking history, and possibly female gender were all associated with longer PFS in these patients when treated with EGFR-TKIs as compared with chemotherapy. These findings should enhance better trial design in future clinical trials.

Background
BVZ combined with carboplatin-paclitaxel as initial treatment followed by BVZ maintenance improves overall survival in advanced non-squamous non-small-cell lung cancer. We conducted a phase II trial in order to study the efficacy and tolerability of a regimen consisting of BVZ-carboplatin-docetaxel in these patients. The objectives were to assess the efficacy and safety of this combination and to evaluate the impact of BVZ in patients who received maintenance BVZ after initial combined treatment compared with patients who did not continue with maintenance BVZ.

Methods
Patients were treated with carboplatin (AUC 5), docetaxel (75 mg/m2), and BVZ (7.5 mg/kg) on day 1 every 21 days, up to 6 cycles. Patients with an objective response or stable disease continued maintenance BVZ (7.5 mg/kg) every 21 days until disease progression or unacceptable toxicity . Performance Status-2, brain metastases, tumor cavitation, central tumors and mild hemoptysis were not exclusion criteria.

Results
Thirty-seven patients were enrolled into the study. 26 male, 11 female. Median age was 64 years (39 – 82). ECOG 0/1/2: 3.5%/70%/27.5%. 34 patients had adenocarcinoma and 3 undifferentiated large cell carcinoma. The median number of cycles for chemotherapy + BVZ was 6 (3-6) and 9 (3 – 22) for maintenance BVZ. All patients were evaluable for efficacy and toxicity. Overall response rate was 70.3% (complete response 2.7%, partial response 67.6%). 21.6% remained in stable disease and 8.15% progressed. Median progression-free survival was 10 months and median overall survival was 19 months. Patients who continued with maintenance BVZ obtained a significant benefit in progression-free survival (10 vs 6 months, p= 0.047) and median survival (20 vs 7 months, p= 0.003). The most frequent grade 3-4 adverse events were neutropenia in 18%, febrile neutropenia in 12%,nausea/vomiting in 12%, diarrhea, hemoptysis in 6% of the patients respectively. Two toxic deaths were observed.

Conclusion
A regimen consisting of carboplatin, docetaxel, and BVZ followed by maintenance BVZ has shown to be feasible and very effective as front-line treatment in a non-selected population. Maintenance BVZ obtains a significant impact in progression-free survival and overall survival.

Background
The control of symptoms to maintain the health-related quality of life continues to be a priority in the treatment of advanced NSCLC. The aim of our study was to assess the evolution of the disease-related symptoms and, due to the lack of evidence, to evaluate its correlation with the response to 1L treatment in p with advanced NSCLC.

Methods
EVEREST is an observational prospective study carried out in 33 Spanish institutions. A total of 155 p with advanced NSCLC initiating standard platinum-based 1L treatment were included. Disease-related symptoms were assessed at baseline and after completing 4-6 cycles of 1L treatment (final visit) with the Lung Cancer Symptom Scale (LCSS) and an ad-hoc specific questionnaire evaluating their frequency. Response to treatment was assessed according to RECIST criteria.

Results
Baseline characteristics of the 155 p enrolled were: 76.1% male, 96.1% Caucasian, 70.3% adenocarcinoma, 16.8% squamous-cell carcinoma; median age was 62 years. ECOG PS 0/1/2: 26.5%/54.8%/14.8%. 65.3% and 12.9% of p maintained or improved the ECOG status during the study, respectively. 118 p completed at least 4 cycles of treatment. Best response to 1L treatment was: 1.7% complete response, 68.4% partial response and 26.5% stable disease. Most frequent disease-related symptoms were asthenia and pain. 1L treatment did not deteriorate disease-related symptoms compared to baseline (LCSS score was reduced 1.4 points) and an improvement in cough was observed (p=0.026). The frequency of cough (p<0.001), dyspnea (p=0.025), pain (p=0.009) and discomfort (p=0.034) were significantly reduced. No significant correlation with response to treatment and the evolution of symptomology between visits was found.

Conclusion
1L treatment was associated with a reduction of the frequency (cough, dyspnea, pain and discomfort) and intensity (cough) of disease-related symptoms in p with advanced NSCLC, irrespective of the response achieved.

Background
Lung cancer is the first cause of death globally. Platinum based chemotherapy is the standard of care for NSCLC. Maintenance therapy and switch therapy with novel agents have shown clinical benefit. The determination of the mutation of EGFR, allowed personalized therapy with tyrosine kinase inhibitors, providing benefit in terms of progression free survival and quality of life to those patient harboring the mutation.

Methods
An observational, analytic and descriptive study was conducted in Venezuela. 36 patients harboring the EGFR mutation were submitted to chemotherapy or tyrosine kinase inhibitors. The primary endpoint was the determination of the clinical benefit in terms of progression free survival according to the first line therapy.

Results
From a total of 296 patients with lung adenocarcinoma, the mutation rate was 12.2%. The EGFR mutation was found more frequently in patients with adenocarcinoma histology, males, less than 65 years old and those who were former smokers or nonsmokers. The most common type of mutation of the EGFR was found in the EXON 21, followed by EXON 19. 31 of these patients received first-line treatment with chemotherapy and 5 with tyrosine kinase inhibitors. The median progression-free survival for patients receiving tyrosine kinase inhibitors was 10 months and for those who received chemotherapy was 6 months. These findings were statistically significant (p = 0.03). Regarding the overall survival, no statistical significance was found, probably due to the crossing-over of the treatment.

Conclusion
The clinical benefit evidenced in Venezuelan patients harboring the EGFR mutation when treated with tyrosine kinase inhibitors in first and second line, was superior to the one shown by patients who received chemotherapy. These results are similar to those evidenced in clinical trials done worldwide. On this basis, we concluded that tyrosine kinase inhibitors should be used as first-line treatment in patients with EGFR mutation or during the course of their disease.

Background
Genetic alterations in anaplastic lymphoma kinase (ALK), including ALK rearrangements, occur in 3–7% of NSCLC. ALK-rearranged (ALK+) NSCLC is sensitive to the tyrosine kinase inhibitor (TKI) crizotinib, but acquired resistance inevitably develops. LDK378 is a novel, potent ALK TKI, with significant preclinical antitumor activity, even in crizotinib-resistant models. An ongoing pivotal Phase I study in Western patients established the MTD as 750 mg/day, with overall response rates (ORRs) of 58% in all patients (n=114) and 57% in crizotinib-resistant patients (n=79), treated at ≥400 mg/day (Shaw, et al. ASCO 2013, Abstr 8010). The primary objective of the present study was to estimate the MTD and/or recommended dose in Japanese patients with tumors harboring ALK alterations; secondary objectives included safety, PK, and preliminary antitumor activity.

Methods
In this multicenter, open-label, dose-escalation study, patients with ALK alterations were enrolled. Japanese patients (ECOG PS 0–2) with locally advanced or metastatic disease that had progressed on standard therapy, or for which no standard therapy exists, were eligible. LDK378 was administered orally at doses of 300–750 mg once daily (21-day cycles, with a PK run-in period). Adaptive dose escalations were guided by a Bayesian logistic regression model with overdose control. Patients were treated until disease progression, unacceptable toxicity, or consent withdrawal.

Results
As of April 29, 2013, the dose-escalation part had enrolled 19 patients (median age 45 years; 11 female), including 18 patients with ALK+ NSCLC (by FISH assay) and one patient with inflammatory myofibroblastic tumor (IMT) harboring an ALK alteration. Fourteen patients with NSCLC had received prior ALK inhibitors (crizotinib, n=9; others [ASP3026 and CH5424802], n=5) and 4 patients with NSCLC were ALK inhibitor-naïve. Patients were treated at 300 mg (n=3), 450 mg (n=6), 600 mg (n=4), and 750 mg (n=6). Two DLTs occurred, at 600 mg (Grade 3 lipase increase) and 750 mg (Grade 3 drug-induced liver injury); the MTD was 750 mg. The most common AEs regardless of drug relationship were nausea (n=18, 95%), diarrhea (n=14, 74%), vomiting (n=14, 74%), blood creatinine increase (n=12, 63%), decreased appetite (n=10, 53%), and fatigue (n=7, 37%). The most common Grade 3/4 AEs were hepatic enzyme increase (n=3) and drug-induced liver injury/abnormal hepatic function (n=2). Among 18 patients with NSCLC (all doses), the ORR (confirmed responses) was 50% (95%CI 26.0─74.0; partial responses [PRs], n=9). PRs were observed in 7/9 crizotinib-pretreated patients (2 unconfirmed). In patients pretreated with other ALK inhibitors, 3/5 had a PR (including 1 who also received crizotinib, and 2/4 who received CH5424802). The patient with IMT also achieved a PR. The preliminary PK profile was similar to that seen in Western patients.

Conclusion
The MTD was 750 mg once daily in Japanese patients. The safety profile was tolerable and comparable to that of Western patients; gastrointestinal toxicities were most common, and the most frequent Grade ≥3 AEs were liver toxicities. LDK378 exhibited antitumor activity against ALK+ NSCLC, in both crizotinib-resistant and other ALK inhibitor-resistant patients. An expansion part will further evaluate oral LDK378 750 mg. ClinicalTrials.gov identifier NCT01634763.

Background
The objective of NIS AVAILABLE was the evaluation of safety and efficacy of Bevacizumab plus platinum-based chemotherapy for the first-line treatment of metastatic or locally advanced histologically confirmed NSCLC in routine practice to complement the data that emanates from pre-authorization randomized controlled trials. The trial also collected data on Bevacizumab dosage, combination partner, duration of treatment and causes for modifications or termination.

Methods
The NIS AVAILABLE was conducted in Germany from October 2007 until June 2013. Patients were recruited in 200 centers, which included office based and outpatient clinics specialized in oncology and pneumology to be widely representative of the NSCLC population. The study aimed to enroll 900 patients receiving chemotherapy and Bevacizumab according to physician’s decision and label instructions. For each patient baseline characteristics, treatment regime and results on efficacy and safety were documented. Progression-free survival (PFS) was estimated with the Kaplan-Meier-method.

Results
Preliminary results of the first interim analysis including 745 patients are presented with focus on baseline characteristics, treatment regimens, dosages and PFS under the perspective of histology and age (≥65/<65 years). The population consisted of 61.3% males, the median age was 62 years (range 29-84), 40.7% of the participants were >65 years of age. At diagnosis 88.6% presented with adenocarcinoma and 82.1% with stage IV disease. 62.0% of the patients had not received any previous treatment (radiation, surgery or chemotherapy) for lung cancer. Bevacizumab was most frequently administered in addition to platinum-based chemotherapy and a third-generation cytotoxic agent. A selection of the most frequently used combination therapies (>6%) and respective PFS values are shown (Table).

Chemotherapy combinations			Patients receiving the combination (%)*	Median PFS in months (95% CI)
Bevacizumab	Carboplatin	Gemcitabine	9.0	5.9 (4.7-9.8)
		Paclitaxel	35.3	6.7 (5.8-7.4)
		Pemetrexed	10.7	6.5 (4.2-8.5)
	Cisplatin	Gemcitabine	12.1	6.0 (4.6-9.9)
		Pemetrexed	9.2	6.8 (3.5-8.4)
		Vinorelbin	6.8	5.9 (4.2-9.1)
* multiple answers were allowed

Conclusion
In the interim analysis of the NIS AVAILABLE Bevacizumab was more frequently combined with carboplatin (64%) than cisplatin (32%) backbone chemotherapy highlighting carboplatin/paclitaxel plus Bevacizumab as the most prominent regime (35.3%). Overall Bevacizumab demonstrated a promising efficacy with a median PFS of 6.7 months in routine practice confirming findings from randomized controlled phase III trials such as E4599 or AVAiL. Although the study was not designed to compare PFS, the results indicate that there might be a difference across regimens.

Background
Radiation therapy is a critical element in the potentially curative treatment of locally advanced NSCLC. Important developments have permitted more precise and effective physical targeting with radiations, an important complement to molecular targeting with drugs. Proton beam therapy (PBT) represents the most advanced physical targeting available thus far. A review of our experiences with proton therapy for NSCLC may serve as a benchmark for technically advanced radiation therapy.

Methods
Patients were enrolled on a protocol to investigate normal tissue effects of proton therapy between 2006 and December, 2010. Patients were excluded if they did not received concurrent chemotherapy, were treated on a phase II study of high dose PBT (JY Chang, PI) or were part of a randomized trial of PBT vs. intensity modulated radiation therapy (IMRT) (Z Liao, PI). They were evaluated before treatment with positron emission tomography (PET) and contrast enhanced computed tomography (CT), studies that were also used for planning treatment. Consultation with thoracic surgeons assured they were not candidates for resection. The mediastinal lymph nodes stations were evaluated with mediastinoscopy and/or fiberoptic bronchoscopy with ultrasound. Treatment planning consistently included motion management with 4D CT simulation and creation of an internal target volume (ITV). Patients were assessed for failure patterns and survival as well as normal tissue effects. Kaplan Meier estimates and Cox regression analysis were used to calculate survival outcomes.

Results
Of the 178 patients enrolled, the median age at diagnosis was 69 yrs (range 37.8 yrs to 94.9 yrs). KPS ranged from 60 to 100, median 80. 43% of patients had squamous carcinoma, and 57% had non-squamous histology. Stage distribution was 15% stage II, 65% III, 5% IV, 15% postoperative recurrence. The median tumor volume was 59 cc (range 4-753 cc) and the median total tumor dose was 74 Gy(RBE). Median follow-up time for living patients was 34.6 mos. Median survival was 32.7 mos. Three year survival rate was 46.5% (49.8% for squamous, 42.1% for non-squamous. Local failure at 3 years was 36.4% for squamous and 48.9% for non-squamous tumors. Distant metastasis-free survival at 3 years was 44.5% for squamous and 55.8% for non-squamous cell histology. Multivariate analysis found age, squamous histology and tumor size adversely affected survival.

Conclusion
Prognostic factors with PBT and concurrent chemotherapy are similar to those seen in series of patients treated with x-irradiation. Favorable median and 3 year survival rates with this relatively large data set suggest superior outcomes with PBT and quite possibly a new platform for physical targeting upon which to build chemical and molecular targeting strategies.

Background
Although NSCLC with activating EGFR mutation is generally sensitive to EGFR-TKI, such as gefitinib or erlotinib, it eventually gets acquired resistance. However, the clinical course after radiological (RECIST-based) “progressive disease (PD) judgment" is highly variable. Some patients are reported to do well with continuation of TKI beyond PD, with or without local therapy. But, prior reports are only on small-numbered and selected cases. The objective of this study is to investigate the clinical course and the actual pattern of care after radiological "progressive disease" to the first-line therapy with EGFR-TKI in such cases.

Methods
Thirty-four institutions in Japan participate in the survey of the patterns of care and outcomes of the patients with EGFRm+ advanced or recurrent NSCLC, who received first-line gefitinib or erlotinib during the period from 2009 to 2011. The primary endpoint is the time from RECIST-based radiological PD to clinical PD in patients who were continuously received EGFR-TKI beyond “RECIST PD”. Clinical PD was defined as one or more of the following events: 1) symptomatic progression, 2) worsening of performance status due to progression, 3) threat to major vital organ(s), 4) multi-organ unequivocal progression. Durations of TKI administration and reasons of discontinuation (RECEIST PD vs. clinical PD vs. toxicity), concomitant administration of chemotherapy and/or local therapy with TKI, occurrence of “flare” phenomenon after TKI stoppage, and overall survival were also recorded.

Results
At the time of the abstract submission, 24 institutions reported the number of patients. There were 1,177 patients (395 in 2009, 397 in 2010 and 385 in 2011) with EGFRm+ advanced or recurrent NSCLC. Among them, 602 (51.1%) received first-line EGFR-TKI. The median number of EGFRm+ patients per institution was 32 (range: 9 to 151). The rates of those who received first-line TKI varied substantially among institutions, ranging from 30% to 88%, and tended to increase over time (41.0% in 2009, 56.9% in 2010 and 55.6% in 2011). In 2009, there were no institutions which administered TKI to every EGFRm+ patient, whereas there were 1 and 3 such institutions in 2010 and 2011, respectively.

Conclusion
In this large observational study, we will collect data on approximately 1,600 patients with EGFRm+ NSCLC, some 800 of them received first-line EGFR-TKI. Since the median progression-free survival of those patients with TKI has generally been reported to be 1 year or less, we will be able to see the pattern of care and outcome after PD in the majority of the cases. Clinical significance of continuation of EGFR-TKI “beyond PD” in the real world will be clarified. This research was conducted by Comprehensive Support Project for Oncology Research (CSPOR) of Public Health Research Foundation. The research fund was provided to CSPOR with support from an Investigator Sponsored Study Programme of AstraZeneca. Trial registry with UMIN#000010538.

Background
Icotinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and a large number of previous studies have demonstrated that icotinib is a safe and efficacious molecule-targeted drug. The treatment of icotinib improves the quality of life and prolongs the survival time for patients with advanced non-small cell lung cancer (NSCLC) who suffer the failure of platinum-based chemotherapy. The aim of this study is to evaluate the efficacy and safety of the treatment of icotinib on patients with advanced NSCLC.

Methods
From August 2011 to March 2013, 196 patients with advanced NSCLC were enrolled for treatment with icotinib including 104 male and 92 female. The age of the patients ranged from 39 to 85 years old, with a median age of 65 years old. There were 66 smokers and 130 never-smokers. By the cytological or histological analysis, all cases were validated as NSCLC which included 159 cases of adenocarcinoma, 22 cases of squamous carcinoma, and 15 cases of other carcinoma. According to the Union for International Cancer Control lung cancer staging system (1997 version), 9 patients were at stage IIIB and 187 patients were at stage IV. Among them, 151 patients had been given one or more chemotherapy regimens, and 45 had not been given any chemotherapy because they were intolerant of or reluctant about chemotherapy. A total of 196 patients received the treatment of icotinib at a dose of 125 mg, 3 times per day. The treatment of icotinib was carried out until the observation of disease progression or the development of unacceptable toxicity.

Results
After the treatment of icotinib for the total of 196 patients with advanced NSCLC，two (1.0%) patients achieved complete remission (CR), 58 (29.6%) patients achieved partial response (PR), 78 (39.8%) patients achieved stable disease (SD), and 58 (29.6%) patients exhibited progression of disease (PD). the overall response rate (ORR) and the disease controlled rate (DCR) of icotinib was 30.6％(60/196) and 70.4％(138/196), respectively. The ORR and DCR were significantly improved in patients with adenocarcinoma compared with those with non-adenocarcinoma (P < 0.05).The median progression-free survival was 5.0 months. Icotinib had a moderate effect for the treatment of brain metastasis of lung cancer. Among 21 patients with brain metastasis, 8 patients achieved PR and 8 achieved SD. The main toxicities were showed to be rash (31.6%, 62/196) and diarrhea of grade I to II (16.3%, 32/196). No bone marrow suppression and impaired renal function were observed.

Conclusion
Icotinib showed a definite efficacy with little toxicity for patients with advanced NSCLC. The treatment of icotinib effectively relieved the symptoms and improved the life quality for patients. Also, patients were well tolerant of the treatment of icotinib. As an EGFR-targeted agent, icotinib represents a new safe and efficacious therapeutic option for patients with tumor relapse or metastasis who are intolerant of or reluctant about chemotherapy.

Background
Gefitinib (Iressa®) is a potent oral non-cytotoxic anthraquinone. It is the active and selective EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor). In the Czech Republic NSCLC patients with EGFR activated mutations were treated with gefitinib in first line from 2/2011 in 10 institutions. This study evaluates treatment outcomes in 74 NSCLC with EGFR activated mutations in exons 19 and/or 21 treated between 2/2011 and 3/2013.

Methods
Patients with advanced NSCLC and with EGFR activated mutations in exons 19 and/or 21 were treated with gefitinib in first line between 2/2011 and 3/2013. Retrospective analyses were carried out to assess the effectiveness of treatment and to evaluate the safety of targeted therapy.This study evaluates treatment outcomes in 74 patients. 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 74 treated patients, 46 had EGFR mutations in exon 19 and 28 had EGFR mutations in exon 21. 53 patients (71.6%) were woman, 21 patients (28.4%) were man. At the time of treatment initiation with gefitinib, the following characteristics were recorded. The median age of patients was 67 years. 9 patients (12.1%) were smokers, 19 patients (25.7%) were former smokers, 46 patients (62.2%) were non-smokers; performance status (PS) was 0 in 16 patients (21.6%), 1 in 49 patients (66.2%) and 2 in 9 patients (12.2%); adenocarcinoma was confirmed in 67 patients (90.5%); most of the patients were in stage IV (64 patients, 86.5%). As on the date of data analysis (18 March 2013), treatment was terminated in 32 patients (43.2%). The median duration of treatment was 19.0 weeks (mean 24.7). Among patients in which treatment was terminated, complete response was not achieved in a single case; partial response was achieved in 10 patients (31.3%), stable disease in 10 patients (31.3%), progressive disease in 7 patients (21.9%) and treatment response was not evaluated in 5 patients (15.6%). Adverse effects during treatment with gefitinib were reported in 23 patients (31.1%). Median progression-free survival from gefitinib treatment initiation is 8.1 months (95% CI: 6.9; 9.3). Median overall survival (OS) was not reached.

Conclusion
In a group of 74 patients with advanced NSCLC and with activated mutations who were treated with gefitinib in first line, the therapy was well tolerated, median progression-free survival from gefitinib treatment initiation is 8.1 months (95% CI: 6.9; 9.3) and median overall survival (OS) was not reached.

Background
BACKGROUND: Lung cancer is second most commonly diagnosed cancer in Canada and commonest cause of cancer related mortality in men and women. It is estimated that it represents 14% of all new cancer diagnoses in 2013. More than half of the patients are diagnosed when they have metastaic disesse. We wanted to study the survival of metastaic non small cell lung cancer patients treated before and after 2005.

Methods
PURPOSE AND METHOD: The purpose of this study was to explore the outcome of metastatic non small cell lung cancer (NSCLC) patients treated at Windsor Regional Hospital Cancer pogram over 7 years. We were specially interested in exploring the influence that advances in systemic management of NSCLC may have had on outcome, in this patient population. A retrospective chart review was conducted on patiets treated from 2003-2009 at Windsor Regional Hospital Cancer Program.Total 483 patients with lung cancer were identified and details of demographics, type of lung cancer, stage, comorbidities and treatment related information was obtained.

Results
RESULT: Total 213 patients with metastatic NSCLC were identified. Mean age at diagnosis was 65.55 ± 10.52 years. 54 % were males. While 93.4 % self identified as smokers 76.5 % were heavy smokers. Most common sites of metastatic disease include brain (23%), bones (21.6%), lung (12.7%) and liver (6.6%). While 31.5 % received first line platinum based chemotherapy only 13.6 % received second line teratment. Median survival was 22 weeks. No difference in survival was found between the two groups of patients treated before or after 2005.

Conclusion
CONCLUSION: Our findings showed that there was no difference in survival between the two groups of patients who were treated before or after 2005. Median survival was noted to be 22 weeks and we speculate this might be related to patients presenting late in the course of disease and therefore had poor performance status and were unable to receieve the second and third line of treatment. Smoking is associated with poor survival and a large number of patients were smokers in this cohort. This was a single institution retrospective study with small number of patients and we may need larger number to assess the difference in survival. Paradigm in treatment of lung cancer is still shifting and may be we need to wait further to observe any meaningful difference in outcome.

Background
The purpose of this study is to evaluate the prognostic value of nodal ratio (NR) and total number of harvested lymph nodes (HLN) in postoperatively node positive Non-small-cell lung cancer (NSCLC).

Methods
Between June 2003 and December 2010, 1192 NSCLC patients had undergone surgical resection at Seoul National University Bundang Hospital. In this study, we excluded patients who had preoperative adjuvant treatments and were revealed to have pathologic T4, N3 or M1. Total 240 patients with N1 or N2 disease were analyzed in this study. According to the number of HLN and NR, we evaluated disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS).

Results
The median follow-up time was 36 months for the surviving patients and median total number of HLN was 23 (range, 6-64). On univariate analysis, patients with more than 20 HLN showed better 3-year DFS (55.6% vs 46.4% p = 0.045) and OS (78.2% vs 61.1%, p = 0.058), respectively. Patients who had NR > 0.1 showed worse 3-year DFS (39.3% vs 64.4%, p = 0.045), LRRFS (72.8% vs 84.0%, p = 0.037), DMFS (45.5% vs 69.6%, p < 0.001) and OS (62.9% vs 79.8%, p = 0.067), respectively. On multivariate analysis, NR > 0.1 showed statistical significance in 3-year LRRFS (p = 0.009) and marginal statistical significance in DFS (p = 0.083) and OS (p = 0.068).

Conclusion
The current nodal classification system does not include the total number of HLN and NR. The results of this study suggest that the total number of HLN and NR could be regarded as important prognostic factors and these factors might be used as decision criteria to postoperative adjuvant radiotherapy for patients with operable NSCLC.

Background
Several studies of erlotinib and gefitinib have shown similar benefit in terms of response and progression-free survival (PFS) for EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, the steady-state plasma trough concentration of erlotinib was approximately 3.5 times higher than that of gefitinib when administered at the respective approved dose. Hence, low-dose treatment of erlotinib may be as effective as gefitinib or erlotinib given at full dose, with reduced toxicity and treatment cost.

Methods
Eligible patients were adults (over 20 years), with advanced or recurrent EGFRm+ NSCLC who had received one to three prior chemotherapy regimens, ECOG PS of 0-2, measurable lesion, and adequate organ function. Erlotinib 50 mg was administered daily until disease progression or unacceptable toxicities. Dose was escalated to 150 mg/day in case of not achieving CR or PR classified by RECIST criteria (i.e., not responded, NR) at the first 4 weeks. The primary endpoint was objective response rate (ORR); SWOG two-stage design with an early stopping rule based on response rate was used. Response was initially judged by the investigators and confirmed by the independent review committee (IRC). Finally, 26 or more responses among 40 eligible patients were to be considered as evidence of sufficient efficacy of this treatment.

Results
Thirty-four patients were enrolled between April 2010 and November 2012: males/females 20/14; median age 67 (range 31-81); PS 0/1/2 16/18/0; Ad/Sq 33/1. EGFR mutation types were: exon 18 and 19/19/21/other 1/21/11/1. One patient was excluded for evaluation because of not having a measurable lesion, therefore, efficacy and safety were evaluated among 33 patients. The study was closed early according to the protocol definition at the time that NR was confirmed in 15 of 33 patients, because it was determined impossible to meet the primary endpoint even if the study was continued. The IRC-judged best responses to the 50 mg/day erlotinib were: PR 18 (54.5%), SD 10 (30.3%) and PD 5 (15.2%). ORR and disease control rate were 54.5% (95%CI: 36.4-71.9%) and 84.8 % (95%CI 68.1-94.9%), respectively. In addition, 4 out of the 10 patients with SD to the initial dose yielded PR after dose escalation to 150 mg/day. At data cut-off (April, 2013), median PFS was 8.6 months (95%CI: 6.7-15.0 months). Toxicities were generally mild, with a few grade 3 or more toxicities. The only grade 3 toxicities were 2 cases with neutropenia and 1 with AST/ALT elevation. No grade 4 toxicity or treatment-related death was observed. There was no treatment-related interstitial lung disease.

Conclusion
Although low-dose erlotinib appeared to have a certain efficacy in this population, this study could not meet the primary endpoint. Because of its relatively lower toxicity and cost, it may be worth further evaluation for elderly or frail patients.

Background
Recently, the elderly population of lung cancer patients is increasing worldwide. Although first-line gefitinib is one of the standard treatments for advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation, few data have been reported on elderly patients. Thus, we conducted a phase II trial to evaluate the efficacy, safety, and quality of life of first-line gefitinib therapy for this specific population.

Methods
Chemotherapy-naïve patients aged 70 years or older with stage IIIB or IV non-small cell lung cancer harboring EGFR activating mutation were enrolled and treated with gefitinib 250 mg daily until disease progression or unacceptable toxicity occurred. Quality of life was assessed by the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy-Lung (FACT-LCS) questionnaire, before and during treatment (at 4, 8, and 12 weeks). The primary endpoint was response rate.

Results
Twenty patients were enrolled between June 2009 and March 2011. The median age was 79.5 years (range: 72-90). All the patients had adenocarcinoma, 13 patients (65%) were female, 12 had exon 19 deletion, and 8 had L858R mutation. Overall response rate was 70% (95% CI, 46 - 88%), and the disease control rate was 90% (95% CI, 68 - 99%). The median progression-free survival was 10.0 months and the 2-year survival rate was 55%. The median follow-up time was 26.4 months and median overall survival time has not been reached yet. The most common adverse events were rash and liver dysfunction, and grade 1 interstitial lung disease developed in one patient. No treatment-related death was observed. The scores of FACT-LCS improved significantly four weeks after the initiation of gefitinib and maintained a favorable tendency during 12 weeks (p = 0.037). Among the seven items of FACT-LCS, especially shortness of breath and cough improved significantly after 4 weeks of treatment (p = 0.046, p = 0.008, respectively).

Conclusion
The present study reveals that first-line therapy with gefitinib is effective and feasible for elderly patients harboring EGFR mutation and improves disease-related symptoms, especially shortness of breath and cough.

Background
Farletuzumab (FAR) is a humanized monoclonal antibody that binds to folate receptor alpha, which is highly expressed in NSCLC, specifically adenocarcinoma. FAR potentially has anti-tumor activity via antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, and was studied in a Phase 2 NSCLC trial.

Methods
This was a global, double-blind, randomized Phase 2 trial in 130 patients with previously untreated FRA-expressing NSCLC. Patient tumors were screened using a FRA immunohistochemical diagnostic assay at a central pathology lab. Subjects could receive carboplatin and paclitaxel, carboplatin and pemetrexed, or cisplatin and pemetrexed for 4 to 6 cycles combined with randomized test product (FAR 7.5 mg/kg every three weeks with chemotherapy, or placebo). Cycle 1 included a loading dose on Day 1 of Week 2. Single agent test product was then continued every three weeks until disease progression. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors, 1.1.

Results
One hundred and thirty patients were randomized. All had adenocarcinoma with one patient having a mixed adeno-squamous histology. All subjects had some expression of FRA in their tumor tissue as assessed by IHC. Median PFS as determined by primary investigator was 5.9 (placebo) and 4.7 (FAR) months with no statistically significant difference between arms (HR=1.22 [95% CI: 0.78, 1.89]). PFS as assessed by an independent evaluator showed a median PFS of 5.9 (placebo) and 6.7 (FAR) months with a HR of 0.91 (95% CI: 0.54, 1.51). The most commonly reported adverse events across arms were those known to be associated with chemotherapy such as hematologic toxicities occurring during combination therapy phase of the study. Preliminary analysis showed that subjects whose serum farletuzumab concentration level was in the top quartile did not reach a median PFS compared to those on placebo. Further investigation is currently on-going.

Conclusion
The study did not meet its primary PFS endpoint. The secondary end point of OS was immature at the time of this analysis. The most commonly reported adverse events across arms were those known to be associated with the study chemotherapy agents. Preliminary pharmacokinetic / pharmacodynamic analysis identified patients with a high serum concentration of FAR that may have benefited from treatment.

Background
The TORCH (“Tarceva or Chemotherapy”) randomized phase III trial demonstrated that first-line erlotinib followed by second-line cisplatin-gemcitabine (N=380) compared to cisplatin/gemcitabine followed by erlotinib (N=380) in unselected advanced NSCLC patients yielded inferior survival, without major differences in first-line global quality of life. We determined the incremental costs and utility between arms, including in the EGFR mutation positive subgroup (N=39).

Methods
Direct medical resource utilization data and EQ5D scores were collected prospectively during the trial. Mean survival and quality-adjusted survival per arm were calculated for the entire study population and the subgroup with documented EGFR mutations. The analysis was conducted from the Canadian public health perspective, using a lifetime horizon. Costs for medications, outpatient visits, investigations and toxicity management including hospitalization were determined, and presented in 2012 Canadian dollars (CAD). The primary outcomes of the analysis included costs and outcomes per treatment arm, and the incremental cost per quality-adjusted life-year (QALY) gained in the EGFR mutation positive subgroup.

Results
The costs per patient in the chemotherapy were higher than in the erlotinib arm, with an incremental mean cost of $4,190 CAD. This was related to longer duration of chemotherapy treatment, associated with higher drug and outpatient visit costs. Higher costs from hospitalization and adverse event management were seen in the erlotinib arm, likely related to disease progression. Mean overall survival in the entire study population was longer in the chemotherapy arm , although mean quality-adjusted survival was similar (0.82 QALY in chemotherapy arm and 0.87 in erlotinib arm). In the EGFR mutation positive subgroup, mean survival was slightly higher in the chemotherapy arm, but quality-adjusted survival was longer in the erlotinib arm (1.19 QALYs versus 1.08 QALYs with chemotherapy). The incremental cost-effectiveness ratio for first-line erlotinib compared to chemotherapy in the EGFR mutation positive subgroup was $32,916 CAD per QALY.

Conclusion
While first-line platinum doublet chemotherapy remains the standard for unselected advanced NSCLC patients, first-line erlotinib appears to be cost effective in the EGFR mutation positive subgroup. This supports routine EGFR genotyping to select first-line therapy in advanced NSCLC, and targeted EGFR TKI therapy for those with EGFR mutation positive NSCLC.

Background
Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, has proven efficacy in second-/third-line advanced NSCLC, and provides superior first-line efficacy to chemotherapy for patients whose tumors harbor activating EGFR mutations. The phase 3, randomized, open-label ENSURE study evaluated erlotinib vs GP in patients from China, Malaysia and the Philippines with EGFR mutation-positive NSCLC.

Methods
Patients ≥18 years with histologically or cytologically confirmed stage IIIB/IV EGFR mutation-positive NSCLC and an ECOG PS of 0–2 were randomized 1:1 to receive either erlotinib (oral; 150mg qd until progression/unacceptable toxicity) or GP (G 1250mg/m[2] iv d1 & 8 q3w; P 75mg/m[2] iv d1 q3w for up to 4 cycles). Patients were stratified by EGFR mutation type, PS, gender, and country). Primary endpoint is progression-free survival (PFS) by investigator, with Independent Review Committee (IRC) assessment for sensitivity analysis; other endpoints include objective response rate (ORR), overall survival (OS), and safety. A pre-planned interim analysis was conducted after 73% of PFS events (cut-off 20 July 2012). An additional exploratory updated analysis (cut-off of 19 November 2012), included all planned PFS events.

Results
In total, 217 patients were randomized: 110 to erlotinib and 107 to GP. Baseline characteristics were similar in both groups. Efficacy data by treatment arm for the interim and updated analyses are presented (Table 1). PFS by investigator in EGFR exon 19 deletion and exon 21 L858R mutation subgroups is also presented (Table 1). Erlotinib was better tolerated than GP, with treatment-related serious adverse events (SAEs) occurring in 2.7% vs 10.6% of patients, respectively. The most common grade ≥3 AEs of any cause were neutropenia (25.0%), leukopenia (14.4%) and anemia (12.5%) in the GP arm, and rash in the erlotinib arm (6.4%). At the updated analysis (19 November 2012), erlotinib remained better tolerated than GP, with treatment-related SAEs occurring in 3.6% vs 11.5% of patients, respectively. Median duration of follow-up was 10.3 months and 11.7 months for the GP and erlotinib arms, respectively, at latest cut-off. OS data are not yet mature.

Efficacy Outcome		Interim analysis (cut-off 20 July 2012)		Updated analysis (cut-off 19 November 2012)
		E	GP	E	GP
Investigator-assessed PFS	Events, n	35	66	61	87
	Median, months	11.0	5.5	11.0	5.5
	HR (95% CI)	0.34 (0.22–0.51)		0.33 (0.23–0.47)
	log-rank p-value	<0.0001		<0.0001
IRC-assessed PFS	Events, n	33	47	51	55
	Median, months	11.0	5.6	11.1	5.7
	HR (95% CI)	0.42 (0.27–0.66)		0.43 (0.29–0.64)
	log-rank p-value	0.0001		<0.0001
ORR	%	62.7	33.6	68.2	39.3
	p-value	0.0001		<0.0001
Disease control rate (DCR)	%	89.1	76.6	91.8	82.2
	p-value	0.015		0.0354
EGFR exon 19 deletion subgroup PFS	Median, months	11.1	4.2	11.1	4.3
	HR (95% CI)	0.20 (0.11–0.37)		0.20 (0.12–0.33)
EGFR exon 21 L858R subgroup PFS	Median, months	8.3	7.1	8.3	5.8
	HR (95% CI)	0.57 (0.31–1.05)		0.54 (0.32–0.90)

p-value significance level: alpha=0.05

Conclusion
These analyses demonstrate that erlotinib provides statistically significant and clinically meaningful improvement in both investigator-assessed and IRC-assessed PFS compared with GP in Asian patients with EGFR mutation-positive NSCLC. Primary efficacy results were also supported by secondary endpoints including ORR and DCR.

Background
The availability of novel therapeutic regimens has led to increase in duration of treatment and utilization of healthcare in non-small cell lung cancer (NSCLC). Although medical resource use and costs were assessed in previous studies, characterization of disease burden exclusively for advanced-stage, in real-world setting is scarce. The aims of our study were to quantify medical costs of stage IIIB/IV NSCLC and identify components of care, that are likely to alter in light of new developments, in Dutch clinical practice.

Methods
A retrospective longitudinal chart review was performed to obtain healthcare utilization of patients, age ≥18 years, with stage IIIB/IV NSCLC (based on the sixth edition of tumor-node-metastasis classification) who received first- and subsequent-line of systemic anti-cancer therapy (SACT). As part of the LUng Cancer Economics and Outcomes Research (LUCEOR), a multi-country retrospective patient chart review, two academic and two non-academic Dutch hospitals participated in the study. Patients who deceased before April 2010 were included. The components of care, from the initiation of first-line SACT until death, were quantified by twelve distinct categories. Total and monthly medical costs attributable to each component were calculated and expressed in 2012 US dollars. Outcomes were fit with statistical models to compare trends. Potential predictors of lifetime NSCLC costs and variability were examined.

Results
A total of 134 patients, 65% (87/134) males, of age 63 ± 9.7 (mean ± SD) years were included. While 34% (46/134) of patients were presented with adenocarcinoma, the proportion of large-cell carcinoma, squamous cell carcinoma and NSCLC not otherwise specified were 33% (44/134), 29% (39/134) and 4% (5/134), respectively. The clinical stage at the start of first-line SACT were 28% (37/134) IIIB and 72% (97/134) IV. Aside from the relatively small subset of patients (12%, 16/134) harboring oncogenic drivers, platinum-based combination chemotherapy regimens were the mainstay of treatment. For a median survival of 7.1 months (95% CI 5.9-8.1), total lifetime costs were averaged to $39,992 ± $20,928 per patient. The influential cost-drivers across all lines of therapy were hospitalizations ($15,521± $16,511) and SACT ($11,628± $7,583), mainly platinum-based gemcitabine or docetaxel. Monthly costs per patient were amounted to $11,932± $14,571. The degree of associations between predictors and outcomes were observed for clinical stage of disease at the start of SACT, administration of prior treatment and smoking history. Although clinically imperative, age and gender were not predictors of variability of healthcare costs at alpha ≤0.05.

Conclusion
Real-world medical costs, in particular hospital admissions and SACT, are substantial in the management of stage IIIB/IV NSCLC in the Netherlands. In a molecularly enriched patient population, biomarker-driven treatments are expected to result in higher likelihood of clinical benefit. Consequently, the average hospitalization costs and long-term management of treatment-related events are likely to reduce. Future research assessing the quantification of disease burden based solely on molecularly targeted agents in daily practice is encouraged. These results may collectively inform decision-making of registration, reimbursement and pricing of interventions in NSCLC.

Background
Novel molecularly targeted therapies are increasingly licensed in conjunction with companion diagnostics to stratify patients with oncogenic aberrations and to help improve patients' likelihood of clinical benefit. Cost-effectiveness analyses (CEAs) are now expected to examine the value of molecular screening as well as traditional costs and benefits of therapeutic choices. The aim of this study was to assess the impact of first-line predictive biomarker screening on the cost-effectiveness of molecularly targeted agents in locally advanced or metastatic non-small cell lung cancer (NSCLC).

Methods
A systematic literature review was performed using MEDLINE, EMBASE and NHS EED. CEAs of epidermal growth factor receptor (EGFR)-, Kirsten RAS (KRAS)-, and anaplastic lymphoma kinase (ALK)-guided screening prior to first-line treatment were appraised according to a priori eligibility criteria. The impact of screening guided patient management was quantified by incremental cost-effectiveness ratios (ICERs) and expressed in 2013 US dollars. Sensitivity analyses were explored to examine the influence of extracted parameters on the ICERs. Methodological quality of the studies was assessed by standardized checklists.

Results
Based on the explicit test-treat combined strategy, eight CEAs met the inclusion criteria. Although six EGFR- and two ALK-guided diagnostic-therapeutic pairings were reviewed, none of the retrieved CEAs explored the potential benefits of KRAS mutation screening on the molecularly targeted agents in the front-line setting. Country-specific decisions regarding utilization of healthcare were conducted from the perspectives of the United States, England and Wales, France, Singapore and China. Efficacy data including biomarker prevalence (ALK: 1.6-4.4%, EGFR: 16.6-60%), sensitivity of the test (ALK: 67-100%, EGFR: 92-100%), specificity of the test (ALK: 93-100%, EGFR: 96-100%) and Quality-Adjusted Life Years (QALY) gained (ALK: 0.009-0.014, EGFR: 0.04-0.5) were extracted. Base-case costs for ALK- and EGFR-guided screening were $98-$1,421 and $105-$516, respectively. The ICERs of EGFR-guided test-treat strategy ranged from being less costly/more effective to unlikely to be cost-effective (ICER range: dominant-$160,123/QALY gained). The ICERs of ALK-guided strategy ranged from likely to be cost-effective to unlikely to be cost-effective (ICER range: $59,240-$213,869/QALY gained). Sensitivity analyses revealed that ICERs of molecularly enriched patient groups were profoundly dependent on the monthly costs of targeted agents (erlotinib, gefitinib, crizotinib) and duration of treatment. Conversely, at low biomarker frequencies, ICERs were influenced by the cost of the screening test. Test specificity, the proportion of advanced NSCLC patients correctly identified as not having EGFR/ALK positivity, was more influential than the test sensitivity. Although clinically imperative, re-biopsy and subsequent therapy were not explored. Furthermore, critical assessment of the CEAs revealed that justification of preferred methods, transparency of input parameters and generalizability of results affected quality.

Conclusion
This study investigates indications of cost-effective screening of 'actionable' molecular aberrations and highlights the impact of clinical and cost parameters on the ICERs. While advancements in mechanisms of resistance and histological transformations will shed light on the future of lung cancer care, CEAs of novel diagnostic-therapeutic pairings will continue to help informed decision-making of all stakeholders.

Background
Background: The GM.CD40L vaccine, an allogeneic tumor cell-based vaccine generated from a human bystander cell line which secretes GM-CSF and expresses CD40L on the surface (GM.CD40L), was developed by our team. It serves to recruit and activate dendritic cells. The mature dendritic cells in turn travel to regional lymph nodes and help to activate T cells which result in systemic tumor cell killing. CCL21 is a chemokine which serves to enhance recruitment of T cells and enrich T cell responses. In NSCLC mouse model, the vaccine combination of GM.CD40L plus CCL21 demonstrated additive effects.

Methods
Methods: We conducted a phase I/II randomized study to evaluate the GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) vaccine in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and 6 month progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses and T-cell responses by ELISpot assay on PBMC. Immune-related response criteria (irRC) determined discontinuation from study treatment at the discretion of the PI/treating physician. Intradermal vaccines were administered in the bilateral axilla and groin every 14 days for 3 doses and then monthly for 3 doses. A two-stage minimax design was used. Survival probabilities over time in each treatment group were estimated using the method of Kaplan and Meier.

Results
Results: Between 4/2012 and 4/2013, phase 1 enrolled 3 patients on GM.GD40L.CCL21, while Arm A enrolled 17 and Arm B enrolled 14 patients. The baseline characteristics, including those in phase I are as follows: median age: 66/68 years, females: 50%/50%, PS1: 64.7%/76.5%, median prior regimens: 2.5/3 for Arm A vs. Arm B, respectively. No DLT’s were observed during phase 1. The most common toxicities for Arm A vs. Arm B were injection site reaction (70.6%/70.6%), fatigue (29.4%/41.2%), anorexia (23.5%/29.4%), and pain in extremity (5.9%/5.9%). Median PFS for Arm A vs. B was 1.9 vs. 4.4 months (p=0.10). All patients who remained on study per MD discretion/irRC, did ultimately demonstrate further progression on subsequent imaging. Treatment was discontinued in all of those patients. In Arm A versus Arm B, stable disease was 4/8 and progressive disease was 8/8, respectively. The disease control rate (DCR) for Arm B compared with Arm A was 50% versus 33%, respectively. ELISpot assay for immune responses and flow cytometry studies on PBMCs are underway.

Conclusion
Conclusion: GM.CD40L plus CCL21 chemokine is well tolerated. The phase II trial including further immune response assays collected pre and post vaccine are underway and updated results will be presented.

Background
Epidermal Growth Factor Receptor (EGFR) has emerged as an important molecular marker with a therapeutic implication in many malignancies including lung cancer. The tyrosine kinase domain is known to be associated with a number of genetic aberrations including deletions, insertions, and single nucleotide polymorphism. TKIs targeting EGFR, including gefitinib and erlotinib, have become the standard first-line therapies for patients with advanced non-small cell lung cancer (NSCLC) who harbour EGFR mutations most often in exons 18-21. The objective of the present study was to explore the EGFR mutational status of a population of lung cancer patients in northern India and evaluate the correlation with clinical characteristics.

Methods
Of the 105 consecutive patients of adenocarcinoma of lung treated in our department between January 2011 and May 2013, information regarding mutational status of EGFR was available for 80 patients. We present the correlation of various clinical parameters with EGFR mutational status for this group of patients. EGFR testing was done on the available biopsy material using a PCR based method.

Results
EGFR mutation status was known in 80 patients with adenocarcinoma lung. Their median age at presentation was 61.5 years with a range of 27 to 87 years. Thirty six (45%) patients were younger than 60 years. The male to female ratio was 2.6:1. The most common biopsy sites, in descending order were: lung mass- 56 (70%), pleura -13 (16%), lymph node – 06 (7.5%), liver- 03 (3.7%) and bone- 02 (2.5%),. All but 2 patients had stage IIIB or IV adenocarcinoma lung. The frequent sites of metastases were- bones (31%), brain (24%), hepatic (14%), adrenals (11%) and contralateral lung (5%). EGFR mutations were detected in twenty two (27.5%) patients. Among the mutant positive cases, the deletions in exon 19 (47%) and exon 21(38%) were most predominant. Out of the entire cohort (N=80), thirty seven (46%) patients had been smokers. Nine (41%) of the mutant patients had history of smoking.

Conclusion
Earlier published data from India had reported an incidence of 51.8% in a group of 220 patients of NSCLC who had been tested for EGFR mutations. At 27.5%, the rate of mutations in our group of patients is lower than that reported in the earlier publication from India. However, this is still higher than the prevalence reported in western literature. The proportion of smokers in the population with EGFR mutations was higher than that reported in other studies (41% in this study vs 22% in a study of Chinese lung cancer patients). This may be on account of retrospective analysis of a smaller sample size and selection bias in subjecting patients to EGFR testing. A prospectively designed trial incorporating a larger population of patients correlating clinical, radiological and other pathological features shall be required to answer various questions linked to EGFR mutational status in lung cancer patients particularly in the Indian sub-continent.

Background
Reovirus is a naturally occurring virus which preferentially infects and causes oncolysis in tumor cells with a Ras-activated pathway. In preclinical studies, reovirus induces cell cycle arrest, acting synergistically with standard cytotoxic agents. We have hypothesized that patients with EGFR-mutated, EGFR-amplified, BRAF or Kras-mutated NSCLC should all have a common downstream activated Ras pathway and should be susceptible to treatment with reovirus.

Methods
We conducted a Fleming, single-arm, phase II study to evaluate safety and the objective response rate (primary end-points), as well as 6-month progression-free and 1 year survival (secondary end-points) of metastatic NSCLC patients treated with reovirus in combination with paclitaxel/carboplatin (P/C). Eligible patients had ECOG PS 0-2, adequate organ function, no prior chemotherapy for metastatic disease, and tumors with the specified above genotype, as per CLIA certified laboratory testing. Prior adjuvant chemotherapy, or erlotinib/gefitinib for pts with EGFR-mutant tumors was permitted. Patients received Reovirus (3 x 10[10 ]TCID~50~) intravenously daily on days 1-5, in combination with P/C at initial doses of P 200 mg/m[2] and C AUC 6, on day 1 of each 21-day cycle. Due to exacerbation of prior colitis and febrile neutropenia (1 each) in the first two pts, doses were subsequently reduced to P 175 mg/m m[2] and C AUC 5.

Results
Overall, 37 patients received 209 cycles (per pt median 4, range 1 to 18). Grade 3-4 toxicity included febrile neutropenia (3 pts), G3 diarrhea (2 pts), G3 anemia (8 pts), fatigue in 6 pts (5 G3, 1 G4), nausea/vomiting and thrombocytopenia (2 pts each), electrolyte abnormalities, and single G3 episodes of arthralgia and transaminitis. Molecular tumor demographics included: 20 Kras (2 G12A, 9 G12C, 1 G12D, 1 G12R, 1 G12S, 3 G12V, 1 G13C, 1 G13R, 1 G12C/V double mutant), 3 EGFR exon 19, 4 BRAF V600E mutations, and 10 EGFR amplified only. Response evaluation showed 11 RECIST partial responses (30%) (EGFR amp 5, BRAF 2, Kras 3, EGFR mut 1), 21 SD, and 4 PD. PFS (by CT and PET) at 6 months for 36 patients with enough follow up to date is 36%, with PET results influencing switching to second line therapy in several patients with SD by CT. Sixteen patients received 6 or more cycles. One year survival was 53%.

Conclusion
Reovirus can be administered safely in combination with P/C and patient selection by Ras-activated pathway is feasible in the clinical setting. Overall clinical efficacy is encouraging. Randomized evaluation is planned.

Background
HM781-36B is an irreversible pan-HER TKI, which showed a strong anticancer activity in many cell lines, including epidermal growth factor receptor (EGFR) TKI resistant ones in preclinical studies. Two phase I studies were conducted to determine the maximum tolerated dose (MTD) in patients with advanced solid tumor.

Methods
Patients with advanced malignancies refractory to standard therapies were eligible. Standard 3+3 dose escalation scheme was used in two phase I studies; a 2-weeks on / 1-week off schedule and a continuous dosing schedule.

Results
A total of 75 patients were enrolled; 55 patients in the 2-weeks on / 1-week off schedule and 20 patients in the continuous dosing schedule. 27 NSCLC patients were enrolled. Among 25 evaluable NSCLC patients, 3 patients achieved partial response (PR) and 10 patients had stable disease (SD). All 3 patients who achieved PR were previously treated with gefitinib, and one of them harbored EGFR T790M mutation. In addition, two of them had been treated with 4 or more regimens. Among 10 SD patients, 5 patients showed some degree of tumor shrinkage. Dose -limiting toxicity (DLT) was grade 3 diarrhea. The MTD was determined as 24 mg/day in the 2-weeks on / 1-week off schedule and 18 mg/day in the continuous dosing schedule. The recommended phase II dose was 16 mg/day (continuous) on the basis of toxicity, pharmacokinetic and pharmacodynamic profiles. Two phase II studies of HM781-36B are ongoing in NSCLC patients with previously EGFR TKI treated and EGFR TKI naive, respectively.

Conclusion
HM781-36B showed good safety profile and anticancer activity in NSCLC patients in two phase I studies. Effectiveness in the gefitinib refractory and heavily pretreated patients supported the potential of HM781-36B as a therapeutic agent for NSCLC.

Background
We recently, concluded a phase II trial (mPEBev trial) aimed to evaluate in metastatic non-small-cell-lung-cancer patients (NSCLC), the toxicity and biological and anti-tumour activity of a newest bio-chemotherapy strategy combining metronomic chemotherapy with fractioned cisplatin, oral etoposide with bevacizumab, an anti-vasculo-endothelial-growth-factor (VEGF) monoclonal antibody. All responsive patients had to continue the treatment with a TKI inhibitor (Erlotinib) until disease progression. The treatment resulted safe and very active with effective anti-angiogenic effects (Correale P, 2011 12(2):112). By considering that this treatment strategy was designed on preclinical results suggesting additive interaction of metronomic chemotherapy with VEGF deprivation and EGFR inhibition, in term of anti-tumor/anti-angiogenic-activity and immune-modulation, we investigated in this patients' population the ability of our treatment to generate immune-biological effects with potential antitumor activity.

Methods
The mPEBev Phase II trial was approved by the Ethical committee of Siena University. All the enrolled patients signed and informant consent. Thirty-five inoperable NSCLC patients (25 males and 10 females) with an ECOG < 1, and median age of 68 years (range 3-75) were enrolled. Twenty-six had an adeno-carcinoma, 6 a squamocellular and 3 NAS carcinoma. All patients received cisplatin (30mg/sqm days 1-3q21 etoposide 50mg/sqm days 1-15/21 and bevacizumab 5mg/kg on the day 3q21). After four treatment courses, all patients who achieved a partial response (PR) or a stable disease (SD) received daily Erlotinib (150 mg/day), starting one week after the end of chemotherapy until disease progression (PD). A cytokine multiplex analysis and an immune-cytofluorimetric analysis was performed on blood samples isolated at the baseline, after 4 bio-chemotherapy courses and 3 months after the end of bio-chemotherapy. Statistical significance (p <0.05) was searched between by comparing the results obtained on the samples taken at baseline and treatment timing as described above.

Results
Our biological multiplex analysis revealed a significant decrease in serum levels of VEGF (68,9 +/-23 vs. 30+/-12 ng/ml), and interleukin (IL)-10 (326 +/-136 vs. 187,6 +/-60 ng/ml) which was maintained along TKI treatment. There was no change in angiopoietin, interferon gamma, IL-12, PECAM and follistatin levels. During TKI maintenance we additionally, recorded an increase in IL-8 (59,2 +/-11 vs. 165,15 +/- 38 ng/ml), and leptine (7275+/- 2202 vs. 11078 +/- 4280 ng/ml) associated with a significant decrease in G-CSF levels (94,3 +/-59 vs. 17,61 +/-3 ng/ml) and angiopoietin levels (1099,9 +/- 123 vs. 603 +/-162 ng/ml). Our immune-cytofluorimetric analysis of patients’ PBMCs showed a significant treatment-related increase in activated (CD3[-]CD11C[+]CD14[+]CD80[+]CD83[+]) dendritic cells [4.3+/-1.5 vs. 8.5+/-2,1%] and activated (CD3[+]CD8[+]CD62L[+]) cytotoxic-T -lymphocytes [2.5 +/-1,2 vs. 5,5 +/-0,259%)].

Conclusion
Our results suggest that this treatment strategy is safe and active in NSCLC patients, and is able to affects their systemic inflammatory status also inducing immune-modulation with potential antitumor.

Background
Non-small cell lung cancer (NSCLC) remains a major cause of death worldwide. Targeting tumour angiogenesis has held great promise in NSCLC based on the ubiquitous role of angiogenesis in NSCLC biology. The monoclonal antibody bevacizumab has shown greatest efficacy when added to first line chemotherapy in the adenocarcinoma subgroup. Small molecule, anti-angiogenic tyrosine kinase inhibitors (AATKIs) have been evaluated in several settings. This review was undertaken to evaluate the benefits and harms of AATKIs when added to chemotherapy for advanced NSCLC.

Methods
We undertook a systematic review of randomised controlled trials (RCTs) of AATKIs added to chemotherapy for advanced or metastatic NSCLC. We searched the electronic databases (MEDLINE/PubMed, EMBASE, The Cochrane Library) in addition to conference proceedings from ASCO, ESMO, IASLC WCLC and Clinical Trials Registries. Data was independently extracted by two reviewers. The primary endpoint was overall survival (OS), with secondary endpoints progression-free survival (PFS), objective response rate (ORR) and ≥ grade 3 common toxicity criteria adverse events (G≥3CTCAE). Meta-analysis of the data was performed to obtain pooled hazard ratios (HR) for OS and PFS, and pooled odds ratios (OR) for ORR and G≥3CTCAE. Statistical analysis was performed using Review Manager v5.2 software (Cochrane). Pre-specified subgroup analyses were performed according to line of chemotherapy, second-line chemotherapy partner and histology.

Results
Fifteen RCTs involving 7904 patients with advanced NSCLC were included in this meta-analysis. In the overall population (N = 7904), the addition of AATKI to chemotherapy significantly prolonged OS (HR 0.93; 95% confidence interval [CI] 0.88, 0.99; P=0.02) and PFS (HR 0.83; 95% CI 0.79, 0.88; P<0.00001). There was no significant heterogeneity between the RCTs. (Chi² = 12.31, df = 14, P = 0.58; I² = 0% for OS. Chi² = 10.64, df = 13, P = 0.64; I² = 0% for PFS). The addition of AATKI to chemotherapy significantly increased ORR (OR 1.64, 95% CI 1.34, 2.02; P<0.00001) and G≥3CTCAEs (OR 1.78, 95% CI 1.41, 2.25; P<0.00001). Used first line (N = 3867), AATKI significantly prolonged PFS (HR 0.86; 95% CI 0.79, 0.93; P<0.0001) but not OS (HR 0.96; 95% CI 0.89, 1.05; P=0.38). Used second line (N=4037), AATKIs significantly prolonged both OS (HR 0.91; 95% CI 0.84, 0.98; P=0.02) and PFS (HR 0.80; 95% CI 0.74, 0.87; P<0.00001). Here, the greatest OS benefit was seen in patients with adenocarcinoma (HR 0.85; 95% CI 0.75, 0.96, P=0.01) and patients receiving docetaxel (HR 0.89; 95% CI 0.81, 0.98; P=0.02). The addition of AATKIs to second line pemetrexed did not improve OS (HR 0.95; 95% CI 0.79, 1.13; P=0.54) nor in patients with squamous histology (HR 1.01; 95% CI 0.87, 1.16; P=0.92).

Conclusion
The addition of AATKIs to chemotherapy in patients with advanced NSCLC prolongs OS, PFS and increases ORR, at the expense of increased toxicity. Greatest benefit is in second line, in adenocarcinomas and in patients receiving docetaxel. Whilst the search for predictive biomarkers of the angiogenic phenotype continues, an individual patient data meta-analysis may clarify subgroups with the most benefit from AATKIs to guide future studies in enriched populations.

Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are used as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) harbouring sensitizing mutations. Transaminitis is a known complication, and may impede the delivery of optimal doses of TKIs. We describe the incidence and severity of TKI induced transaminitis in patients with NSCLC treated with first line EGFR TKI and investigate its association with clinical outcomes. In addition, we review the management of patients who developed Grade 2/3 (G2/3) transaminitis or other TKI toxicity.

Methods
A retrospective study of 127 patients with EGFR mutation positive NSCLC treated at the National Cancer Centre Singapore with TKIs (gefitinib or erlotinib) over seven years (1/1/2006-30/5/2012) was conducted. Transaminitis was graded in accordance with CTCAE v4.0 criteria. Endpoints included dose adjustments, progression free survival (PFS) and overall survival (OS).

Results
Of 127 patients, 85 (66.9%) developed at least CTCAE v4.0 all grade transaminitis (G1/2/3: 75.3/11.8/12.9%) and 39 (30.7%) developed G1/2 bilirubin levels. No patients developed Grade 4 transaminitis. None had encephalopathy suggestive of fulminant liver failure. Median duration to onset of transaminitis was 1.87 months. Of 24 patients who had G2/3 transaminitis (n=21) or stopped TKI therapy due to other TKI toxicity (n=3), 8 switched to alternative regimen and/or therapies (alternative TKI only, n=3; alternative dosing schedule only, n=2; alternative dosing schedule followed by alternative TKI, n=2; switch to chemotherapy followed by alternative TKI, n=1). There was no change in TKI treatment and/or regimen for the other 16 patients. Development of transaminitis was independent of age, gender, smoking status and presence of brain metastases at baseline. Patients who developed transaminitis (all grades) had significantly longer PFS than those who did not (12.4 vs 8.2 months) (p=0.002). Patients with G1 ALT/AST had significantly longer PFS compared to G2/3 (G1/G2/G3: 13.4/3.0/11.9 months) (p=0.034). OS was not significantly affected by the presence and severity of transaminitis.

Conclusion
The incidence of EGFR TKI induced transaminitis in this cohort of patients appears higher than previously reported. Transaminitis, in particular G1, may be predictive of PFS for patients on TKIs. Patients should be monitored for the development of transaminitis, especially during the first two months of TKI treatment. Further studies are recommended to evaluate the role of transaminitis as a marker for TKI treatment efficacy.

Background
Lung cancer is the second most common cancer in Thailand. Oral TKI, Gefitinib and Erlotinib are available for second line and third line treatment in advanced non small cell lung cancer by registration Central Health Informatics for reimbursement. This study aims to compare cost-effectiveness between Erlotinib and Gefitinib by Payer’s perspective.

Methods
A retrospective observational study of Thai patients who were diagnosed advanced non small cell lung cancer and be registered for Oral TKI treatment in either line from 1st Jan 2006-31st Dec 2011. The demographic and clinical data were collected from registered database. The cost analysis data was from reimbursement system. It was analyzed in terms of the direct medical costs during on oral TKI and total direct medical costs through patient’s life time.

Results
Total 1,520 cases database were recruited for analysis. There were 572 and 948 patients in Gefitinib and Erlotinib group respectively. The mean age was 64.8±11.0 years. Most of patients (94.4%) were in ECOG 0-2. The mean overall survival was 15.1 months [95% CI 14.1-16.0]. The mean of the direct medical costs and total direct medical costs of Gefitinib were 623,204.80 baht and 738,441.30 baht, while Erlotinib group were 718,443.50 baht and 837,126.30 baht. The cost effectiveness ratio (CER) in term of overall survival were 581,883 baht per life year gain in Gefitinib group and 688,791.50 baht per life year gain in Erlotinib group.

Conclusion
This long term observational study shows that the effectiveness between Erlotinib and Gefitinib in Non Small Lung Cancer treatment were comparable. Nevertheless, Gefitinib is more cost saving than Erlotinib by payer’s perspective.

Background
Afatinib, an irreversible EGFR-HER2 dual inhibitor, demonstrated superiority versus standard platinum-based chemotherapy as front-line therapy in non-small-cell lung cancer patients (NSCLC) with activating Epidermal Growth Factor Receptor (EGFR) mutations. In pretreated NSCLC afatinib failed to improve survival when compared to placebo in patients refractory to gefitinib or erlotinib and not selected for EGFR status. Aim of the present study was to evaluate clinical efficacy of afatinib in EGFR mutant NSCLC patients (pts) with secondary resistance to reversible EGFR-TKIs.

Methods
We retrospectively analyzed a cohort of 97 EGFR mutant lung cancer pts resistant to EGFR-TKI according to criteria used in the LUX-Lung 1 trial (Miller VA, Lancet Oncol 2012) and treated with Afatinib at the daily dose of 40-50 mg. The drug was given as compassionate use.

Results
The study included individuals with a median age of 62,5 year. The majority were females (N=63/64.9%), never/former smokers (N=94/96,9%), with good performance status (ECOG PS 0-1; N=90/90.2%) and pretreated with > 3 therapy lines (N=68/70.0%). EGFR status was assessed in tumor tissue obtained at the time of original diagnosis. The majority of pts (N=64, 66%) harbored a deletion in exon 19, while T790M mutation was detected in two cases including one case with double exon 19 and T790M mutation. Among the 95 pts evaluable for toxicity, 54.7% had any grade skin rash, including 11.6% with grade 3, and 50,5% had any grade of diarrhea, with grade 3 recorded in 10,5%. Among the 87 pts evaluable for efficacy, response rate (RR) was 11.5%, with a median progression free-survival and overall survival of 3.9 months and 7.3 months respectively. In 25 pts a tumor biopsy was repeated immediately before starting Afatinib therapy and 1 patient out of 5 individuals harboring T790M mutation showed a short extracerebral partial response, with following brain progression.

Conclusion
Our findings suggest that afatinib is modestly effective in EGFR mutant NSCLC with acquired resistance to reversible EGFR-TKIs.

Background
The therapeutic development for advanced stage NSCLC has improved in the past decade, but the poor treatment outcome still poses a major challenge. Investigators have combined conventional platinum-based chemotherapy with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), in the hope of achieving greater therapeutic efficacy. However, current data show that the combination strategy has repeatedly failed to provide a better survival benefit, irrespective of the mutation status of the tumors. However, it might not be true for combination of EGFR-TKI with individual agents which exhibit a variety of anti-cancer actions. Afatinib, a novel irreversible ErbB-family blocker, has shown to provide efficacious effects for advanced stage NSCLC patients. From the Phase I data, afatinib in combination with chemotherapy or anti-EGFR therapy exhibited tumor inhibition response. We present retrospective clinical evidences of patients from Compassionate Usage Program. These patients are treated with continuation of afatinib in combination, alternately, with various chemotherapies or anti-EGFR therapy.

Methods
Between August 2012 to February 2013, 37 patients were enrolled for the program, 11 of these patients died of disease progression either received afatinib for less than 2 weeks or never started afatinib treatment, the remaining 26 patients were included in this analysis. Patient characteristics are median age was 67 (range 46-84), gender (male/female = 8/18), ECOG status (PS 1/2/3: 16/2/4), EGFR mutation status (exon 19 deletion = 10; L858R mutation = 6; exon 18 mutation = 1; wild type = 5; unknown = 5). All of these patients had been previously treated with either gefitinib or erlotinib with no disease progression for more than 6 months. The median TKI-free interval was 125 days (range 0-1,450 days); 8 patients had no TKI-free interval. All patients but 1 started the treatment of afatinib monotherapy (30 mg or 40 mg daily), and subsequently, either paclitaxel (60 mg/m2, day 1, 8, and 15, 4-week cycle), docetaxel (30 mg, day 1, and 8, 3-week cycle), or cetuximab (250mg/m2, every 2 weeks) was added. The combination was alternated or discontinued when patient had disease progression according to RECIST criteria version 1.1, intolerability or severe toxicity.

Results
Of the whole group of patients, 25 received afatinib monotherapy, 11 with 1 afatinib doublet (afatinib/cetuximab = 3; afatinib/paclitaxel = 6; afatinib/docetaxel = 2); 2 with 2 afatinib doublets (afatinib/cetuximab and afatinib/docetaxel = 1; afatinib/cetuximab and afatinib/docetaxel = 1) and 1 with 3 afatinib doublets (afatinib/cetuximab, afatinib/paclitaxel and afatinib/docetaxel). The median duration from administration of frontline systemic treatment to initiation of afatinib was 3 years (range 1 - 10 years). These patients had received 2 to 7 (median 5) lines of treatment before receiving afatinib-based treatment. The median time to treatment failure was 223 days (95% CI: 217, 249) and median overall survival was 288 days (6 events). The toxicities were mild and manageable. There was no correlation between the values of TKI-free interval and duration of afatinib monotherapy.

Conclusion
Integration of afatinib with various treatment agents based on different treatment rationales, the afatinib-based treatment may potentially extend treatment duration and patient survival.

Background
Sunitinib is an oral, selective multi-targeted tyrosine kinase inhibitor (TKI) with antiangiogenic and antitumor activities. The result from a previous study suggested that the treatment of sunitinib might present favorable survival outcomes for the EGFR-TKI pretreated NSCLC Chinese patients. This study was therefore to evaluate the efficacy and toxicity of this therapeutic strategy.

Methods
This is a retrospective review of 30 stage IV NSCLC patients who received sunitinib as salvage therapy in Shanghai Chest hospital, from January 2009 until August 2011. All of the patients had previously been treated with EGFR-TKIs. Kaplan-Meier method was employed to estimate the median progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox proportional hazard regression analyses were carried out to determine the important prognostic risk factors influencing NSCLC survival.

Results
The median PFS of all 30 treated patients was 1.25 months (95% CI: 0.90-1.9 months), and the median OS was 3.40 months (95% CI: 3.00-6.80 months). Of the 29 patients eligible for efficacy evaluation, none achieved partial response. Cox regression analysis suggested that Eastern Cooperative Oncology Group (ECOG) performance status (PS) is predictive of both PFS (p=0.001) and OS (p<0.001). Hand-foot syndrome (53.3%), mucositis (40.0%), rash (36.7%) and diarrhea (33.3%) were most commonly reported adverse events.

Conclusion
In this study, the sunitinib treatment did not demonstrate overall clinical benefits to the EGFR-TKI pretreated NSCLC Chinese patients. Most side effects were mild to moderate. These results need further validation in prospective studies.

Background
AUY922 is a highly potent, non-geldanamycin, HSP90 inhibitor. HSP90 is a molecular chaperone of oncogenic client proteins relevant in NSCLC pathogenesis, including epidermal growth factor receptor (EGFR), which is mutated in 10% of NSCLC cases in the Western population, and in 30% of NSCLC cases in the Asian population. We report here a subgroup analysis of data from the 2 EGFR mutation strata of a Phase II study of AUY922 in patients with previously treated, advanced NSCLC stratified by molecular status.

Methods
Patients with advanced NSCLC who progressed following ≥1 prior line of therapy, received AUY922 (70 mg/m[2]) as a once-weekly, 1-hour infusion. Patients with EGFR-mutant NSCLC were divided into 2 strata: pretreated EGFR-mutant (>2 prior regimens), or less-heavily treated EGFR-mutant (≤2 prior regimens and documented response to an EGFR tyrosine kinase inhibitor [TKI]). The primary endpoint was confirmed response, stable disease at 18 weeks, or no clinical benefit. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety/tolerability.

Results
At the cut-off date of 14 March 2013, 66 patients with EGFR-mutant NSCLC had been treated (median age 58 years; 67% female; 94% adenocarcinoma; EGFR-initial stratum n=35; less-heavily pretreated EGFR-mutant stratum n=31); all patients had been pretreated with an EGFR TKI. Clinical activity of AUY922 was seen, with any responses (investigator assessed), in 12/66 (18.2%) patients. A total of 34/66 (51.5%) patients had a best overall response of stable disease or non-confirmed partial response; of these patients, 11 (32%) had stable disease for ≥18 weeks. The 18-week PFS rate was 39% in all patients with ≤2 prior lines of therapy (n=43), and 28% in all patients (n=21) who had received >2 lines of therapy. The most frequent adverse events (AEs; any grade, regardless of study drug relationship) were diarrhea (73%), nausea (47%), decreased appetite (38%), fatigue (35%), and headache and night blindness (both 29%). Most AEs were Grade 1 or 2; Grade 3 or 4 AEs included diarrhea (9%), and fatigue, decreased appetite, and hyponatremia (all 6%).

Conclusion
AUY922 had an acceptable safety profile. Strong evidence of clinical activity was demonstrated in EGFR TKI-pretreated patients with EGFR-mutant NSCLC. Median PFS, OS and biomarker data for the EGFR-mutant stratum will be presented.

Background
ALK rearrangements are detected in 3%~7% in unselected non-small cell lung cancer (NSCLC) and accurate determination of ALK rearrangements are the key importance to screen appropriate candidates for ALK inhibitor therapy. Previous studies showed that IHC could be a promising prescreening method. However, the correlation between IHC results and clinical outcomes had not been confirmed. This study aimed to elucidate clinical significance of ALK rearrangement in selected advanced NSCLC patients and evaluate a possible association between ALK expression and clinical outcomes in ALK positive crizotinib-treated patients.

Methods
ALK status was assessed by FISH, immunohistochemistry (IHC) and quantitative RT-PCR(qRT-PCR) in 173 selected advanced NSCLC patients who were aiming at undergoing ALK screening for crizotinib therapy. Clinicopathologic data, genotype status and survival outcomes were analyzed. In addtion, we correlated ALK expression with clinical outcomes in crizotinb treated patients including two patients with concurrent ALK rearrangement and EGFR mutation.

Results
ALK positive detection rate was 35.5% (59/166), 36.3% (61/168), 27.9% (34/122) by FISH, IHC and qRT-PCR, respectively. Among the 166 advanced NSCLC patients who were successfully underwent ALK screening by FISH, 20 patients with EGFR mutation, 87 patients with wild type status and 2 (3.4%, 2/59) patients with concurrent ALK rearrangement and EGFR mutation. Of the 59 patients with FISH-positive ALK rearrangement, 45 received crizotinib in the phase II clinical trial (PROFILE 1005), 8 were enrolled in the phase III clinical trial (PROFILE 1014) and 6 did not participate in any clinical trial. ALK-positive patients have distinct clinicopathological features. ALK FISH-positive and crizotinib-treated patients (PROFILE 1005) had a median progression-free survival (PFS) of 7.6 months and longer overall survival (OS) compared with crizotinib-naïve (P<0.0001) or wild type cohorts (P=0.0138), but there was no significant difference in OS compared with EGFR mutation patients(P=0.8959). ALK positive and negative patients divided by qRT-PCR in the ALK FISH crizotinib-treated patients had no different in clinical outcomes. ALK expression was not associated with PFS (P=0.792) and OS (P=0.325). However, when used IHC expression as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P=0.026). The two patients with concurrent EGFR mutation and ALK rearrangement had difference in ALK expression, response to TKIs and crizotinib, and overall survival.

Conclusion
In the era of ALK-targeted inhibitors, enriching NSCLC patients according to clinicopathologic characteristics could highly improve ALK detection rate for molecular target therapy. IHC could be a supplementary method to provide more clues for clinical trial design and therapeutic strategies for NSCLC patients who harbor ALK rearrangement including patients with double genetic aberration of ALK and EGFR.

Background
To evaluate the anti-tumor effect and safety of COX-2 inhibitors through a randomized controlled study by treating advanced non-small cell lung caner (NSCLC) with celecoxib + platinum-based chemotherapy as first-line treatment and celecoxib + icotinib as second-line treatment; to investigate the mechanism of action and efficacy predictors related to COX-2 inhibitors by detecting and monitoring serum VEGF, MMP-9 and E-cardrin in the course of treatment.

Methods
81 untreated patients with stage III-IV NSCLC were randomized into vinorelbine/cisplatin + celecoxib group and vinorelbine/cisplatin chemotherapy group. If disease progression was found in the followed-up visits in the middle or after the end of the 4[th] cycle, the patients would enter second-line icotinib + continued celecoxib group, while the mono-chemotherapy group became the second-line icotinib monotherapy group until the disease progressed. The patients’ serum VEGF, MMP-9 and E-cardrin were detected by ELISA assay at different time points before initial chemotherapy and after chemotherapy.

Results
First-line treatment and second-line celecoxib group showed significant differences in disease control rate (73.2% vs. 65.0%, P=0.036; 56.5% vs. 55.6%, p=0.078). PFS in the second-line celecoxib group was superior to that in the monotherapy group (5.3m vs. 5.0m, p=0.045). One case in the celecoxib group during second-line treatment experienced arrhythmia after continuous use of celecoxib, while the treatment was well tolerated in the other patients. After chemotherapy, serum VEGF, MMP-9 and E-cardrin were decreased, the decline in serum VEGF in the experimental group was significantly greater than that in the control group (p=0.027). Serum VEGF, MMP-9 and E-cardrin in the experimental group after chemotherapy were significantly lower than before chemotherapy (respectively: p=0.025, 0.035, 0.002). The efficacy of chemotherapy in patients with lower baseline serum VEGF and E-cardrin levels in the experimental group was better (p=0.033, 0.047). After chemotherapy, the efficacy of chemotherapy in patients with greater decline in VEGF and MMP-9 levels was better (p=0.038, 0.039). Only baseline serum VEGF was found to be related to the efficacy of chemotherapy in the control group (p=0.023). Baseline serum VEGF levels and the decline after chemotherapy were significantly associated with the patients’ PFS (p=0.019, 0.035).

Conclusion
COX-2 inhibitor celecoxib can improve disease control rate and be well tolerated by patients when combined with either chemotherapy for first-line treatment or targeted therapy for second-line treatment. Serum VEGF level is a good biomarker to predict efficacy and survivals, while serum MMP-9 and E-cardrin are potential biomarkers requiring large-sample studies.

Background
Different therapeutic approaches have been used in the clinical setting in NSCLC p harbouring EGFR mutations progressing to rTKI, although the standard of care in this situation is still not well established.

Methods
A multinstitutional database from five different centers in Spain was review to identify EGFR mut p with acquired resistance to rTKI in order to evaluate the therapeutic strategies after rTKI failure and the effect on the post-progression survival (PPS) of these treatments.

Results
59 p with acquired resistance to rTKI were identified: 61% female; median (m) age 63 ±11 yrs; 96.6% Caucasian; del19 73.7%, never or light former smokers 98.3%; 93.2% adenocarcinomas; 59.4 % received TKI as first line therapy; 87% were initial stage IV. mPFS for the rTKI was 9,9 months (mo) and mOS was 32.8 mo for the entire population. P were treated with a median of 2 therapeutic strategies after the rTKI failure. 6 therapeutic strategies have been identified. As immediate approach, 31p were switched to chemotherapy (CT) with a mPPS of 5,6 mo. 10 p were switched to an irreversible TKI obtaining a mPPS of 4 mo. rTKI plus other drug was maintained in 12 p: rTKI plus CT in 9 p with a mPPS of 5,8 mo and rTKI plus other drug different to CT in 3 with a mPPS of 2 mo. Despite the progression, rTKI was maintained in 3 p, considered slow progressors obtaining a mPPS of 1,4 mo with an OS of 9mo. Furthermore, 3p with oligometastatic progressive disease local therapy was added to rTKI, obtaining mPPS of 1,4mo, but an OS of 17 mo. 4 p were treated sequentially with ≥5 strategies. These p attained a mOS of 45mo.

Conclusion
The combination of different strategies when treating EGFR mut p after rTKI failure may impact the survival especially when p are candidates to receive some of this treatments sequentially. These strategies may reflect different subsets of EGFR mut disease.

Background
Erlotinib, Gefitinib and Crizotinib have been approved by the European Medicines Agency (EMA) for the treatment of molecular defined patient subgroups with advanced EGFR mutation positive (EGFR M+) and ALK translocation positive (ALK +) NSCLC, respectively. In randomized clinical trials for ALK + and EGFR M+ patients comparing standard chemotherapy to TKI treatment so far no significant improvement in overall survival (OS) could be shown, based on the high crossover rate of patients initially treated in the standard chemotherapy arm into the TKI arms upon progression. Since prevention of crossover is obsolete due to ethical reasons, registry data may gain in importance for investigating the impact of new effective targeted drugs on OS in the near future.

Methods
Since January 2010 EGFR sequencing and ALK FISH analysis for lung adenocarcinoma was performed within the Network Genomic Medicine (NGM) as part of a broad genetic screening effort. This included mutation screening for EGFR, KRAS, BRAF and PIK3CA as well as HER2 amplification and recently also translocations of RET and ROS. Clinical and follow-up data were extracted from medical records, directly collected from physicians and patients and additionally matched with data of the Epidemiological Cancer registry of North Rhine-Westphalia, Germany.

Results
So far, we included a total of 44 ALK+ and 143 EGFR M+ patients into our analysis. The median age of the ALK + and EGFR M+patients was 53.5 yrs and 71 yrs, respectively. 39% of the ALK+ patients received crizotinib and 54% of the EGFR M+ patients received an EGFR TKI during the course of their disease. The median OS (mOS) of patients with an initial stage IIIb/IV was 14 months (95% CI 6.2 - 21.8) for ALK+ and 29 months (95% CI 16 - 41) for EGFR M+ patients. Both groups showed a significant difference in mOS when separated by targeted treatment status. ALK+ patients who received crizotinib had a mOS of 23 months (95% CI 12.2 - 33.8) and patients who did not receive crizotinib had a mOS of 8 months (95% CI 0.0 - 17.4) (p = 0.01). EGFR M+ patients who received an EGFR TKI had a mOS of 31 months (95% CI not computable) and patients who did not receive an EGFR TKI had a mOS of 9 months (95% CI 4.9 - 13.1) (p < 0.001). There were no significant differences with regard to treatment of a platinum-containing chemotherapy, age or sex between the two groups.

Conclusion
Screening patients for genetic driver mutations identified patients with EGFR mutations and ALK translocations that were not treated with a kinase inhibitor. Comparing these cohorts of patients that only received standard chemotherapy to those subsequently treated with a personalized approach showed a significant improvement in OS. This confirms the predictive value of ALK translocations and EGFR mutations for treatment with the respective TKIs

Background
Inhibition of signaling pathways interfering with cell proliferation and angiogenesis may increase anti-tumor efficacy. Sorafenib as well as mTOR inhibitors showed preliminary activity in KRAS mutated NSCLC.

Methods
In the dose escalation part, patients with relapsed solid tumors were treated with escalating doses of everolimus from 2.5-10.0 mg daily p.o. in a 14 days run-in phase followed by the combination with a fixed dose of sorafenib 400 mg bid p.o. The extension phase is currently recruiting patients with KRAS mutated NSCLC. The KRAS mutation status is determined by PCR based high resolution melting curve analysis (HRM) on DNA extracted from FFPE material and validated using Sanger sequencing. HRM has now been replaced by multiplex PCR. Pharmacokinetic (PK) analyses are performed during run-in and during the combination. Treatment outcome is validated with CT scans on day 57.

Results
In the dose escalation part, 19 patients were recruited. The dose limiting toxicity (DLT) was not reached. At everolimus dose level of 10 mg/day, increased rates of grade 3 thrombocytopenia (3 patients), leukocytopenia (2 patients) and anaemia (2 patients) occurred after the DLT interval of 29 days. Based on these observations, the dose level of 7.5 mg/day everolimus in combination with 400 mg sorafenib bid was defined as a maximal tolerated dose. The AUC and Cmax values of everolimus at all dose levels were comparable on days 5 and 14. On day 29, AUC and Cmax of everolimus showed a 20 - 40% reduction when co-administered with sorafenib. The best treatment outcome on day 57 was stable disease in 11 patients. Median PFS and OS were 3.7 and 5.5 months, respectively. The extension phase in KRAS mutated NSCLC is currently ongoing. Nine patients have been recruited so far. The CT response at day 57 compared to the baseline of four evaluable patients is ranging from -22% to +5% in the sum of the longest diameter of all targeted lesions.

Conclusion
Treatment of patients with relapsed solid tumors with the combination of 7.5 mg everolimus p.o. daily and 400 mg sorafenib p.o. bid is safe and feasible. Current results of an extension phase in KRAS mutated NSCLC patients show preliminary clinical activity in this patient group with an unfavorable prognosis.

Background
Simultaneious inhibition of several signalling pathways involved in angiogenesis as well as in tumor cell growth regulation by kinase inhibitor combination therapy may increase therapeutic efficacy. Here we evaluate the combination of the mTOR-inhibitor RAD001 (everolimus) and the triple kinase (FGFR, VEGFR, PDGFR) inhibitor BIBF 1120 in a phase I trial in advanced solid tumors. In addition we use DCE-MRI for early identification of patients with benefit from BIBF 1120.

Methods
This is an open-label, monocentric phase I trial with 3 dosage arms in a classical „3+3“-design: Patients in arm A receive 5 mg of RAD001 and 2 x 150 mg BIBF 1120, in arm B 10 mg RAD001 and 2 x 150 mg BIBF 1120 will be administered, whereas in arm C, 10 mg of RAD001 and 2 x 200 mg BIBF 1120 will be given. There is no interindividual dose escalation, and the enrollment of the patients will be performed sequentially. Eligible are all patients with relapsed or refractory advanced/metastatic solid tumors (UICC stage IV) and an ECOG performance state of 0-1 for whom no further standard therapies are available and who have predefined adequate organ functions. All patients will start with a 2-week run-in phase of 2 x 200 mg BIBF 1120. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scans will be performed at baseline staging, on day 3 and day 14. On day 14, there will also be 12 hours-pharmacokinetic (PK) assessment. Combination therapy within the forementioned dosage arms starts on day 15. After two weeks of combination therapy, on day 29, a DCE-MRI scan and 12-hours PK will be performed. Restaging for the evaluation of the efficacy will be performed on day 57. The safety of this combination will be assessed throughout the complete therapy phase using CTC-AE V4.0, with predefined dose-limiting toxicities (DLTs) being assessed until day 42. Patients who experience clinical benefit (i. e., response or stable disease) on day 57 with adequate tolerability of the combination will further receive the medication, as long as the benefit lasts.

Results
10 patients have been enrolled so far. In one patient with FGFR-amplified lung cancer, there was a partial response after six weeks of therapy. No DLTs were detected within the first dosage step. Tolerability of the combination was good, as there were no toxicities of CTC-AE grade 3 or greater. In arm B, there has been one DLT (elevation of transaminases), which turned out to be reversibel.

Conclusion
So far, the combination of BIBF 1120 and RAD001 seems tob e very good tolerated, demonstrating activity in a patient with NSCLC and FGFR1-amplification. Enrollment into the second dosage stage has already started. We expect the termination of the trial by winter 2013/2014.

Background
（Although epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs), gefitinib and erlotinib have shown antitumor activity in patients with non-small cell lung cancer (NSCLC) , it is unclear if progrssion-free survival（PFS）could be a good surrogate endpoint for overall survival(OS) in the clinical trials of first-line EGFR-TKIs treatment in patients with advanced NSCLC, especially with activating EGFR mutation.）

Methods
A PubMed search identified 12 randomized trials comparing first-line EGFR-TKIs treatment with chemotherapy in patients with advanced NSCLC. A total of 1816 patients were enrolled and EGFR mutation status was known in 554 patients. Linear regression analysis was carried out to estimate the correlation of PFS, response rate (RR), and survival post-progression (SPP) with OS

Results
PFS, RR and PPS were all strongly associated with OS（r=0.942, 0.982 and 0.895, respectively, P< 0.01） for all trials. But in trials enolled patients with EGFR mutation, PFS and RR were poor correlate with OS (r =-0.121 and 0.131, respectively, P< 0.01), while PPS strongly associated with OS (r =0.849, P<0.01 ）PFS, RR and PPS were all strongly associated with OS（r=0.942, 0.982 and 0.895, respectively, P< 0.01） for all trials. But in trials enolled patients with EGFR mutation, PFS and RR were poor correlate with OS (r =-0.121 and 0.131, respectively, P< 0.01), while PPS strongly associated with OS (r =0.849, P<0.01 ）

Conclusion
Our findings indicate that PFS is a poor surrogate endpoint for OS in the first line EGFR-TKI treatment in advanced EGFR mutation NSCLC. Further studies are needed to search for appropriate surrogate endpoint for OS.

Background
Health care expenditures have increased dramatically over the past 20 years. Particularly in oncology new technologies may be accompanied by higher costs but a mild health gain. As part of decision-making process, not only effective, but economic value evidence is mandatory in many developed countries. We have recently shown that the combination of carboplatin and pemetrexed improves survival in a dedicated ECOG PS2 population when compared to pemetrexed alone (Zukin et al. J Clin Oncol 2013). Because combination chemotherapy tends to increase toxicity and costs, a cost-effective analysis was performed in that PS2 dedicated trial.

Methods
Clinical data and resource consumptions were obtained from the multicenter phase III randomized trial which tested carboplatin and pemetrexed vs. pemetrexed alone in 205 patients with advanced NSCLC and PS 2. Direct costs were estimated based on Brazilian public health care system. Life time was divided into stable disease stage, progression stage and death. Utilities for each stage were taken from the literature. One-way sensitivity analysis and non-parametric bootstrapping approach were performed to explore the uncertainties regarding the results.

Results
Combination chemotherapy demonstrated a gain in 0.22 life years (LY) and 0.15 quality-adjusted life year (QALY) compared to single therapy at an additional cost of $1,667.28 (in 2012 USD). The incremental cost-effectiveness ratio (ICER) was $7,436.79/LY and $10,949.88/QALY. Estimates of ICER were more sensitive to change by the influence of stable disease utility and pemetrexed cost. The probability of being cost-effective at a threshold of $36,000 (3 times Brazilian GDP per capita) per additional QALY was > 99%.

Conclusion
Adding carboplatin to pemetrexed therapy for advanced NSCLC patients with PS2 status is cost-effective when compared to pemetrexed alone. To the best of our knowledge this is the first report on cost-effectiveness in a dedicated NSCLC PS2 population. This finding adds up to the efficacy data favoring the combination arm and may support health care policies in that subpopulation. This analysis is particularly relevant for countries with limited health care resources.

Background
EGFR mutations define a distinct molecular subset of non-small-cell lung cancer patients (p). Prevalence, baseline clinical characteristics and outcomes for women with lung cancer harboring EGFR mutations would be of interest.

Methods
We analyzed the clinical characteristics of women with lung cancer harboring EGFR mutations included in the WORLD07, a Spanish prospective, multicenter, epidemiologic female-specific e-database.

Results
A total of 2081 newly-diagnosed women with lung cancer from 38 Spanish centers were included in the WORLD07 e-database from October/2007 to October/2012. Overall 915 p were evaluated for EGFR mutation status, and 342 of them were found to have EGFR mutation (16% of all p in the e-database, 37% of p tested). EGFR-mutated p characteristics: median age 64.6 years; 86% had offspring; 8.2% had used oral contraceptives; smoking habit: 72% never smokers, 14% current smokers, 13% former smokers; for those never smokers, second-hand smokers 35%; histology: 91% adenocarcinoma, 1.5% squamous cell carcinoma, 2% large-cell carcinoma, 5% other; EGFR mutation type: 60% deletions in exon 19, 32.5% L858R mutations, 8% exon 20 mutations, 1% exon 18 mutations, 14% unknown. Sixty-nine percent of p had stage IV disease. A total of 184 EGFR mutated p received an oral EGFRTKI as 1[st] line (ECOG PS: 0 in 24%, 1 in 53%, 2 in 13%, 4 in 4%, unknown in 5%) achieving a 59% response rate (RR), 20% stable disease (SD), 10% progression (PD) and 11% not evaluable (NE); with a median follow-up of 12 months, median overall survival for these p was 21 months. A total of 72 p received an EGFRTKI as 2[nd] line with 37% RR, 34% SD, 19% PD and 10% NE. Only 16 p received an EGFRTKI as 3[rd] line, achieving a 38% RR, 19% SD, 31% PD and 12.5% NE. For those EGFR mutated women receiving an EGFRTKI as 1[st] line, RR to an EGFRTKI was 70% in those women harboring deletion in exon 19, and 45% in those with L858R mutation; median overall survival was 24 months in those with deletion in exon 19, and 17 months in those with L858R mutation. Response rate to an EGFRTKI as 1[st] line treatment was 59% in never-smoker p and 53% in current-smoker/former-smoker p with a median overall survival of 23 months and 21 months, respectively.

Conclusion
According to our prospective e-database of women with lung cancer, not selected for clinical trials and including all histologies, a high proportion harbor an EGFR mutation (16% of non-selected women, 37% of those tested). The vast majority of women with lung cancer harboring EGFR mutation are never smokers, have adenocarcinoma histology and outcomes similar to those previously reported in the literature. Additional epidemiologic and treatment data will be presented at the meeting.

Background
Platin-based doublets with a third generation drug are the mainstay of the treatment of fit patients with stage IV non-small cell lung cancer (NSCLC). However, the results reached a plateau at the beginning of the XXIst century with a median survival time of 8-9 months in the randomized trials. Since 2002, personnalized treatment was developed with histology-guided chemotherapy and targeted therapies with a median survival time around 12 months and even 21 months in some patients harboring mutations.

Methods
To ascertain the improvement in survival of patients with advanced NSCLC since the advent of new chemotherapies and targeted therapies, we conducted a retrospective population based-study on a sample of 1047 patients diagnosed with stage IIIb (wet) and IV primary NSCLC in a French department (Bas-Rhin) from 1998 to 2005.

Results
Median age at diagnosis was 65.0 years [26-92]. Patients aged > 70 represented 32.4% of the patients. The proportion of women increased throughout the period with an initial sex-ratio of 3.8/1 in 1998-2001 to 2.5/1 in 2002-2005. Thirteen % of the patients were never smokers. The proportion of adenocarcinomas increased significantly throughout the period at the expense of squamous cell carcinoma subtype. Best supportive care was the sole treatment for only 11.75% of the patients. The use of chemotherapy increased from 74.2% to 87.1% of the patients (p = 0.0021), and type of chemotherapeutic agents have evolved with a significant increased use of carboplatin (while there was a decreased use of cisplatine) and of drugs of third-generation. Among them, vinorelbine was the most frequently used at the beginning of the period (38.8 % versus1.75% paclitaxel whereas during the two last years, the proportions were respectively 18.9% and 22.7%. Use of targeted therapies (gefitinib and erlotinib) began in 2002 with 15% of the patients receiving these therapies in 2004-2005 essentially as 2nd, third or 4th line therapy (only 4 patients as 1st line). Overall survival was 6.5 months [CI 95% 5.8; 7.2]. There was a significant increase from 5.3 months [CI 95% 4.4; 7.2] in 1998-1999 to 7.3 months [CI 95% 6.1;8.6] in 2004-2005. In multivariate analysis of survival, female gender, adenocarcinoma histological subtype were significant independent favorable prognostic factors. Regarding treatment variables, platin-based doublets with third generation drugs, use of targeted therapies were both independent favorable prognostic factors with respective RR of 0.66 (CI95%=0.53; 0.84), and 0.30 (CI95%=0.22; 0.40).

Conclusion
In this population-based study we found the same epidemiological trends recently seen in France (increase in women proportion and of adenocarcinoma histological subtype). Never-smokers were a non negligible fraction of the patients. The introduction of modern chemotherapy schemes and targeted therapies explain probably the slight improvement in survival observed between 1998-1999 and 2004-2005 as in multivariate analysis there were significant independent favorable prognostic factors whreas peiods were not..

Background
Squamous Cell Carcinoma of the lung (SCCLung) has long been recognized as very difficult to treat, with few agents showing effectiveness. Because the combination of P/C and REOLYSIN was shown to be active in 2 trials in SCC of the head and neck, we elected to test this regimen in this Phase 2 trial in SCCLung.

Methods
We conducted a single-arm, open-label phase II study to determine (primary) the Objective Response Rate (ORR) and(secondary) the 6-month Progression-free Survival (PFS) and the Overall Survival (OS) of patients with metastatic or recurrent squamous cell carcinoma of the lung, treated with REOLYSIN in combination with P/C. The study had a two-stage design, with 19 patients in the first stage. The trial would be terminated if 3/19 or fewer patients obtained an objective response. If the trial continued to the second stage, a total of up to 36 patients would be studied. The primary endpoint wouldbe met if patients in both stages had an ORR of at least 35%. Eligible patients had ECOG PS 0–2, adequate organ function, and no prior systemic chemotherapy for their metastatic or recurrent disease. Prior adjuvant chemotherapy or chemo-XRT for treatment of primary disease was allowed, provided it had been ≥ 6 months since the last chemotherapy. Treatment dosages were: paclitaxel 200 mg/m2 IV over 3 hours; carboplatin at a dose of AUC 6 mg/mL minute calculated using standard formula(s)and REOLYSIN 3x1010 TCID50IV over 1 hour daily for 5 days.

Results
32 patients entered the study and received at least one dose of study drug. The patient population included 20 males and 12 females, median age was 62 years (range: 37 to 80 years) and all were Caucasian including one Hispanic patient. Of the 32 entered, 25 patients received more than one Cycle of therapy and a total of 125 cycles were administered in that group (per patient mean=5, median=6, range 2-12). The 7 non-evaluable patients received 1 cycle or less. Of the 25 evaluable patients who received more than one cycle, 12 (48%) had a PR, 10(40%) had stable disease (SD), and 3 (12%) had progressive disease (PD) for overall disease control (CR + PR + SD) in 22/25 (88%). Of 21 patients with >6 months follow-up, 7 (33.3%) have PFS of at least 6 months. The most common adverse events (AEs) seen were those expected with P/C---neutropenia 17 (9=Gr 3-4) and thrombocytopenia 15 (5=Gr 3-4) and those expected with REOLYSIN---fever 6 (1=Gr 3) and fatigue 11 (4=Gr 3). The AE profile of P/C therapy did not appear to be significantly altered by the addition of REOLYSIN. The only serious adverse event reported as unexpected and related to study therapy was reversible Gr 2 elevation of creatinine (and increased BUN) which occurred 3 weeks after Cycle 8 in a 65-year-old woman.

Conclusion
Combination therapy with paclitaxel/carboplatin/REOLYSIN was well-tolerated in patients with recurrent/metastatic SCClung and the response results justify further studies.

Background
Significant progress has been made in the identification of subsets of non-small cell lung cancer (NSCLC) driven by tyrosine kinase gene fusions (including gene fusions of ALK, RET, ROS1 and NTRK1). Despite approval of crizotinib for ALK+ NSCLC there are still significant challenges and high unmet need to develop new agents with durable efficacy against these kinase gene fusions that initiate NSCLCs. In order to address limitations of crizotinib, and to provide treatment option with increased activity against crizotinib resistance mutations and amplified EML4-ALK, TSR-011, a potent, small molecule, second generation ALK inhibitor is undergoing clinical evaluation. TSR-011 was designed using X-ray structure based drug design, and hence has high affinity for the ALK kinase domain (Kd = 0.36 nanomolar, [nM]). TSR-011 inhibits wild type, recombinant ALK kinase activity with an IC50 value of 0.7 nM and exhibits sustained potent inhibition of EML4-ALK-dependent tumor growth in mice. ALK amplification and mutations that are important drivers of tumor cell growth or crizotinib resistance are inhibited by TSR-011 at low nM (IC50 values of 0.1 to 2.2 nM) concentrations. TSR-011 is a similarly potent inhibitor of recombinant TRK kinases including suppressing proliferation of a NTRK1-rearranged colorectal cancer cell line in vitro. Collectively, the selective and potent activity of TSR-011 against ALK, and clinically observed crizotinib resistance mutations, coupled with pharmacologic properties that predict a low clearance, minimal risk for drug interactions, wide distribution and long half life, make TSR-011 a promising 2[nd] generation ALK inhibitor.

Methods
A Phase 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Phase 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Phase 2 dose will be evaluated in Phase 2a in patients required to have ALK+ tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or naïve to, ALK inhibitor therapy.

Results
As of June 2013, patients have been enrolled at oral doses between 30 and 480 mg. Pharmacokinetic parameters have been dose responsive and human drug exposures in excess of that associated with efficacy in murine xenograft models are maintained for the entire dosing interval. Two of the first five patients have SD. A patient with EML4-ALK+ NSCLC with metastatic pericardial thickening and symptomatic disease, who progressed on crizotinib showed clinical improvement in symptoms and thinning of the pericardium by 6 weeks of treatment and continues on study.

Conclusion
Based on tight binding to ALK, potency at inhibiting enzymatic activity, as well as activity against crizotinib resistant mutations and early clinical data, TSR-011 is a promising agent for both ALK-dependent and crizotinib resistant NSCLC.

Background
Several studies suggest that pulmonary resection and gamma knife surgery (GKS) protocol prolong survival in patients with thoracic stage I or II non-small cell lung cancer (NSCLC), without extra-cranial or lymph node metastases, and with a limited number of small synchronous brain metastases. According to the Japanese Lung Cancer Society guidelines published in 2012, stereotactic radiosurgery (SRS) or surgery for a single brain metastatic lesion and SRS or stereotactic radiotherapy (SRT) for 2-4 brain metastatic lesions, less than 3 cm in length, are Grade B recommendations. To validate these recommendations, we retrospectively examined the prognosis of patients with NSCLC who underwent GKS for synchronous brain metastasis and pulmonary resection.

Methods
We retrospectively reviewed the cases of patients with NSCLC and synchronous brain metastasis who underwent GKS preceding pulmonary resection from January 2006 to December 2012 at our institution. The eligibility criteria were thoracic stage I or II NSCLC, a performance status of 0­­­­­­­­­­­­­­–1, a predicted post-operative forced expiratory volume in 1 second of >600 ml/m[2], no extra-cranial metastasis, and brain metastatic lesions of < 3 cm.

Results
In total, 253 patients underwent pulmonary resection for NSCLC between January 2006 and December 2012. Six patients with NSCLC and synchronous brain metastasis underwent GKS preceding pulmonary resection, and received postoperative adjuvant systemic chemotherapy or molecular targeted therapy. All of them were Japanese, 4 were male and 2 were female. The mean age was 63 years (range, 47–78 years). Four patients had neurologic symptoms. The mean size of the primary lung lesion was 35 mm (range, 22–59 mm). The median number of brain metastases was 1 or 2 (range, 1–8) and the mean size was 16 mm (range, 7–28 mm). GKS was performed before pulmonary resection in all patients. The median time between GKS and thoracotomy was 2 weeks (range, 2–8weeks). Combined pulmonary resection was performed in 2 patients because of inter-lobar pleural invasion and lobectomy was performed in 4. Postoperative complications occurred in 1 patient: (thoracic empyema with bronchopleural fistula). Histologically, 4 patients had adenocarcinoma and 2 had large cell carcinoma. None of the patients showed evidence of lymph node metastasis after pulmonary resection (pN0). All patients received either platinum-taxol doublet therapy or molecular targeted therapy as postoperative adjuvant chemotherapy. One patient died 28 months after surgery because of new brain metastasis, and 5 were alive at 15, 18, 30, 66, and 88 months after pulmonary resection.

Conclusion
The pulmonary resection and GKS protocol resulted in long-term survival in 5 of 6 patients with synchronous brain metastasis from NSCLC. Although only a small number of cases were studied, this report may provide promising data with regard to a multidisciplinary therapeutic strategy for patients with newly diagnosed thoracic stage I or II NSCLC with brain metastasis. Further analysis and clinical studies are necessary to validate our findings.

Background
Although the incidence of peripheral squamous cell carcinomas (SqCCs) of the lung has increased over recent years, clinicopathological factors influencing prognosis of resected peripheral lung SqCCs remain to be elucidated.

Methods
We reviewed the clinical data of 186 patients who underwent complete resection of peripheral lung SqCCs in our institute and analyzed the clinicopathological features in relation to their overall survival (OS) and recurrence free survival (RFS).

Results
The enrolled patients ranged in age 40 to 91 years, with a median age of 69 years. Multivariate analysis revealed that nodal metastasis (OS; Hazard ratio (HR) = 2.47, P = 0.02), vascular invasion (OS; HR = 1.93, P < 0.05, RFS; HR = 2.07, P = 0.01) and pleural invasion (OS; HR = 2.27, P = 0.02, RFS; HR = 2.30, P < 0.01) were independent unfavorable prognostic factors. Among pathologically confirmed stage I peripheral SqCCs patients, high serum squamous cell carcinoma antigen (SCC) levels (OS; HR = 3.91, P < 0.01, RFS; HR = 2.30, P < 0.01), vascular invasion (RFS; HR = 2.68, P = 0.02) and pleural invasion (OS; HR = 4.44, P = 0.01, RFS; HR = 4.57, P < 0.01) were strongly correlated with poor prognosis.Figure 1

Conclusion
Pleural and vascular invasions were independent poor prognostic factors for completely resected peripheral SqCC. Adjuvant chemotherapy might be beneficial for patients having SqCC with pleural and vascular invasion.

Background
The pretreatment ratio of neutrophils to lymphocytes has recently been reported as a prognostic factor in non-small cell lung cancer (NSCLC). However, the mechanism behind this is unclear. Therefore, we separately investigated the influences of neutrophil and lymphocyte counts on prognosis in completely resected NSCLC.

Methods
We conducted retrospective analyses of patients diagnosed with NSCLC who underwent surgery involving complete resection at Tsukuba University Hospital between 2000 and 2009. Patients with preoperative treatment, suspicion of granulocyte colony-stimulating factor-producing tumor, and unmeasured differential leukocyte count were excluded. Univariate analysis was performed using the Kaplan-Meier method, and statistical significances were assessed by the log-rank test. The cut-off values of neutrophil and lymphocyte counts were defined as the maximal log-rank statistical values. Then, we divided the patients into two groups according to the optimal cut-off values to investigate the association with clinicopathological factors. Chi-square test was used for categorical variables and t test was used for continuous variables. To assess the independent predictive values, Cox proportional hazards model was used. The result was considered to be significant when the P value was less than 0.05.

Results
A total of 328 patients were evaluated. There were 217 men and 111 women. The patients’ age at the time of operation ranged from 29 to 89 years (mean, 67.0 years). The mean follow-up was 41.0 months (range, 1-118 months). Two hundred and ten patients were classified as Stage I, 72 patients as Stage II, and 46 patients as Stage III. The overall 5-year survival rate of all 328 patients was 71.1%. As for the neutrophil count, the maximum log-rank statistical value was 11.456 (P < 0.001) when the cut-off value was 5200 mm[-3]. The overall 5-year survival rates were 74.2% for the low-neutrophil-count group (neutrophil count ≤ 5200 mm[-3]), and 48.8% for the high-neutrophil-count group (neutrophil count > 5200 mm[-3]). As for the lymphocyte count, the maximum log-rank statistical value was 7.275 (P = 0.007) when the cut-off value was 1700 mm[-3]. The overall 5-year survival rates were 65.5% for the low-lymphocyte-count group (lymphocyte count ≤ 1700 mm[-3]) and 75.4% for the high-lymphocyte-count group (lymphocyte count > 1700 mm[-3]). High neutrophil count was significantly associated with tumor size, pleural invasion, sex, smoking index, lactate dehydrogenase, and C-reactive protein. On the other hand, low lymphocyte count was related to tumor size, vascular invasion, and age. Cox proportional hazards model showed that neutrophil count and lymphocyte count were independent prognostic factors. The hazard ratio of neutrophil count was 1.880 (P = 0.022), and that of lymphocyte count was 1.645 (P = 0.036). Other significant factors were tumor size (hazard ratio: 2.418, P = 0.001) and lymphatic invasion (hazard ratio: 1.829, P = 0.035). Pleural invasion, nodal status, and vascular invasion were not significant.

Conclusion
Preoperative neutrophil count and lymphocyte count were independent prognostic factors in completely resected NSCLC. High neutrophil count was associated with tumor size and pleural invasion, and low lymphocyte count was associated with tumor size and vascular invasion.

Background
Aim: Mediastinal lymph node metastases are frequent in non small cell carcinomas (NSCLC). We aimed to investigate the diagnostic accuracy of PET-CT for different mediastinal lymph nodes in operable NSCLC patients by comparing PET-CT results with cervical mediastinoscopy and thoracotomy findings.

Methods
Methods: Medical records 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 negative in 64 of 124 patients. Thirty-four of the patients underwent cervical mediastinoscopy, 4 underwent anterior mediastinotomy, 3 underwent thoracotomy and the remaining 83 were operated without any prior invasive procedure. PET/CT uptake of different stations were explored, sensitivity, specifity, negative (NPV) and positive predictive (PPV) values and accuracy rates were calculated

Results
Results: Sensitivity, specifity, PPV, NPV and accuracy rates for N1 and N2 lymph nodes are shown in the table. Accuracy rates were low for 4th, 7th and 10th numbered lymph nodes. However any significant correlation was not observed between pathology and PET-CT for nodal stations 3 and 10.

%	Sensitivity	Specifity	PPV	NPV	Accuracy
N1	8	94	21	82	78
N2	57	93	49	95	89

Conclusion
Conclusion: The lower rates of PET-CT sensitivity and PPV for N1 lymph nodes than N2 lymph nodes reflect the poor success rates of N1 determination with PET-CT. The lower accuracy rates of 4, 7 and 10 station lymph nodes with PET-CT as well as the pathology and PET-CT uncorrelation for 3 and 10 lymph nodes might be explained by the close localization of these stations to N1 lymph nodes and the restriction of the PET-CT in discrimination of N2 lymph nodes from N1 in this area.

Background
Asian ethnicity is associated with distinct molecular etiology, treatment response, and survival among patients with non-small cell lung cancer (NSCLC). This study examines the survival impact of platinum-based adjuvant chemotherapy for Asian patients with stage I-IIIA NSCLC.

Methods
This study recruited patients ³ 18 years old with histologically proven stage IA-IIIA NSCLC registered in the Taiwan Cancer Registry Database between January 2004 and December 2007. Platinum-containing adjuvant chemotherapy should be started within 90 days of the primary surgery. Kaplan-Meier survival curves, log-rank tests, and the Cox proportional hazards regression model were used to assess the influence of various risk factors on survival time.

Results
This study included 2,231 patients with stage IA to IIIA NSCLC who underwent primary surgery with a clear surgical margin. The percentages of all causes of death were significantly lower for the chemotherapy group in stage II and stage IIIA patients. Multivariate analysis identified platinum-based adjuvant chemotherapy as an independent prognostic factor for the overall survival of stage II (HR 0.61, 95% CI 0.39-0.94, p = 0.024) and IIIA (HR 0.71, 95% CI 0.52-0.96, p = 0.029) patients. Among these patients, those who received adjuvant chemotherapy demonstrated superior overall survival in both genders and in the subgroups of patients aged ³ 70 years and those with adenocarcinoma.

Conclusion
Platinum-based adjuvant chemotherapy should be considered in the treatment plan for Asian patients with resected stage II and stage IIIA NSCLC.

Background
The standard operation for patients with stage I lung adenocarcinoma is considered as a lobectomy. Recently, some researchers have reported that patients with tumors tend to show less aggressive nature which it could be candidates for thoracoscopic limited resection. In regard to mediastinal nodal metastasis, however, the precise criteria as an index for planning limited resection are obscure. Therefore, we have attempted to determine low-risk or high-risk populations for mediastinal nodal metastasis in patients with clinical stage I adenocarcinoma of the lung.

Methods
A retrospective analysis was made of 617 patients who underwent curative pulmonary resection with mediastinal lymph node dissection by video-assisted thoracoscopic surgery (VATS) between Jan 2006 and Nov 2012 for clinical stage I adenocarcinoma of the lung. Preoperative computed tomography (CT) and positron emission tomography (PET) were performed in all patients. Additionally, endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) was performed in 12 patients, mediastinoscopic lymph node biopsy in one patient, and endoscopic ultrasound (EUS) was performed in one patient. The patients had received the treatment with wedge resection or the patients who had other malignancies were excluded in this study.

Results
Among 617 patients, mediastinal nodal metastasis was found in 47 patients (7.6%), consisted of N1 disease in 24 patients (3.9%), N2 disease in 23 patients (3.7%), and skipped N2 disease in 6 patients (0.9%). Five year survival rate of the patients with N0 disease, N1 disease, and N2 disease was 90.3%, 55.6%, 54.8%, respectively (p<0.001). A univariate analysis identified the following four variables as significant predictors for mediastinal nodal metastasis: tumor size (p=0.003), consolidation/tumor ratio (p<0.001), maximal standardized uptake value (SUVmax) of tumor (p=0.002), and differentiation of tumor (p < 0.001). The optimal cutoff points of continuous variables were determined as: 1.7cm for the tumor size, 84.0% for consolidation/tumor ratio, and 3.3 for SUVmax. A multivariate analysis revealed that following three significant predictors for mediastinal nodal metastasis as shown in the next statement: the consolidation/tumor ratio of 84% or more (OR: 4.097, p=0.001), maximal SUV of 3.3 and more (OR: 3.662, p=0.002), moderate or poorly differentiation of histology (OR: 3.794, p=0.016). The prevalence of nodal metastasis was 0% in patients who had none of these three predictors. 2.1% in patients with one of the three predictors, 10.8% in patients with two of the three predictors, and 21.0% in patients with all of the three predictors (p<0.001).

Conclusion
Among the patients with clinical stage I adenocarcinoma of the lung, low-risk population for mediastinal nodal metastasis could be predicted by following the three predictors (84% of consolidation/tumor ratio, 3.3 of SUVmax, ‘moderate’ and ‘poorly’ differentiation of tumor). These predictive parameters may provide detailed criteria for thoracoscopic limited resection in regard to mediastinal nodal metastasis.

Background
The objective of this study was to identify the risk factors for early (within 2 years after surgery) recurrence in patients with completely resected pathological stage I (p-stage I) non-small cell lung cancer (NSCLC).

Methods
We reviewed retrospectively 864 consecutive patients with p-stage I NSCLC who underwent complete resection between 1992 and 2012 at our institution. The correlation between clinicopathologic factors (sex, age, preoperative CEA level, tumor laterality, primary lobe, smoking history, histological type, histological differentiation, p-T status, lymphatic permeation, vascular invasion, pleural invasion) and early recurrence was evaluated using chi-square test and multivariate analysis.

Results
There were 498 men and 366 women, with an average age of 67 years. (range: 33-87). The median follow up period was 78 months. Histologically, 659 patients had adenocarcinomas, 189 squamous cell carcinomas, and 16 other types. T status was 1a in 230 patients, 1b in 274, and 2a in 360. Vascular invasion was observed in 326 patients, and lymphatic permeation in 169. Recurrence developed in 208 patients (24.1%), and 64 (7.4%) of them developed within 2 years after surgery. By multivariate analysis, vascular invasion (hazard ratio 3.441, 95% confidence interval 1.892-6.428) and moderate to poor differentiation (hazard ratio 3.252, 95% confidence interval 1.242-8.512) were shown to be independently significant risk factors for early recurrence. In patients with vascular invasion, distant failure occurred significantly more frequently than locoregional recurrence. The early recurrences were distant failure in 46 patients (72%). Of the 18 patients with locoregional recurrence only, 13 had malignant pleural effusion or pleural dissemination.

Conclusion
Moderate to poor differentiation and vascular invasion were the significant predictors of early recurrence within 2 years after complete resection of p-stage I NSCLC. More than 90% of the early recurrences were disseminated diseases. Therefore, adjuvant chemotherapy after complete resection may be beneficial for p-stage I NSCLC patients with vascular invasion or moderately to poorly differentiated tumors.

Background
Brain metastasis is rare in pathological stage I non-small cell lung cancer (NSCLC). Brain magnetic resonance imaging (MR) should discover more synchronous asymptomatic brain metastasis than computed tomography (CT), but the efficacy of brain MR in pathological stage I NSCLC is not yet determined. This study aimed to investigate the effect of different strategies for preoperative brain imaging survey of pathological stage I NSCLC underwent complete resection.

Methods
The clinicopathological characteristics of 870 patients underwent complete resection of stage I NSCLC at Taipei Veterans General Hospital between Jan. 2002 and Dec. 2011 were retrospectively reviewed. The patients were divided into three groups according to pre-operative brain survey strategy (no imaging study, CT, or MR). Multivariate analysis for survival was done.

Results
In total 870 patients, 446 patients with no brain imaging study, 304 had brain CT and 120 had brain MR. Median age was 65±11.36. Average tumor size was 2.2±1.07, 2.8±1.16 and 2.4±1.01 centimeters in the three groups, respectively. 238, 103 and 544 patients were pathological T1a, T1b and T2a, respectively. Adenocarcinoma was identified in 716(82.3%) patients, while 94(10.8%) had squamous cell carcinoma. With median follow up time of 42.3 months, 21 (2.4%) brain metastases in 870 patients after complete resection were identified, with 7(1.5%), 10(3.3%) and 4(3.3%) patients in each group, respectively (p = 0.027). Within the first year and the second year follow-up, 2 and 11 brain metastases were noted, respectively. In subgroup analysis, 3 patients with brain metastases had pathological T1a, 1 had T1b, and 17 had T2a. The overall 5-year survivals were 76.9%, 72.0% and 85.4% in non-imaging, CT and MR group, respectively (p = 0.014). Disease free survival of each group were 84.1%, 84.0% and 83.4% (p = 0.167). Under multivariate analysis adjusted with age, gender, T stage, pathohistological grading, pleural invasion status and whether patient receiving whole body PET/CT, there were 3 factors associated with poorer survival: age, male sex and T stage. Brain survey strategy did not affect survival in multivariate analysis. Figure 1

Conclusion
Preoperative brain MR survey did not have a less frequent rate of brain metastasis comparing with non-imaging and brain CT strategy, nor a better survival in pathological stage I NSCLC patients. Use brain MR in preoperative staging routinely in clinical stage I patients should be reconsidered, especially in NSCLC with smaller tumor size.

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. Also tolerance of carboplatin (CBDCA) in better than tolerance of cisplatin (CDDP). Randomized studies in adjuvant chemotherapy (ACT) settings are missing.

Methods
This prospective multicenter study evaluates the tolerance and survival parameters of the ACT based on CDDP (75mg/m[2]) or CBDCA (AUC 5) with vinorelbine (25 mg/m[2] D1 i.v. and 35 mg/m2 D8 given orally). After radical resection, ACT (4 cycles of 21 day, out-patient regimen) was applied to patients with stage IB, II, and IIIA of NSCLC. Selection of CDDP or CBDCA was based on individual center preference. During the follow-up period of 42.2 months (m) survival was evaluated according to gender, smoking, age, tumor histology, stage and grading, surgical procedure, CDDP or CBDCA treatment.

Results
ACT was applied to 154 eligible patients (110 men, 44 women, median of age 63 years). Surgically determined stages were IB in 46 pts, II in 46 pts, and IIIA in 52 pts. CBDCA was given to 77 patients and CDDP to 77 patients,11 of whom switched to CBDCA due to toxicity. Mean age was 63.6 years in CBDCA group and 61.7 years in CDDP group. Altogether 586 cycles were administered, 82.6% of patients finished four cycles of planned ACT. Mean number of cycles was 3.79 per patient (3.76 in CDDP and 3.83 in CBDCA). The most frequent WHO grade 3/4 of toxicity were neutropenia in 16.8%, leucopenia in 7.9%, anemia in 1.2%, thrombocytopenia in 0.5%, alopecia in 2.9%, vomiting in 2.3%, neurotoxicity, diarrhoea and mucositis in 0.2% of cycles. Neutropenia, nausea and vomiting were more frequent in CDDP group. Relative dose intensity (RDI) was 94 % for vinorelbine i.v. and 88.6 % for vinorelbine p.o. In CBDCA RDI was significantly higher than CDDP (94 % vs 90 %, p 0.009). Three years overall survival (OS) was 68.2%, 5-year OS was 55.0% and 79 pts still live, 66 live without progression of the disease. OS was significantly longer in stage IB and II than in stage IIIA (p 0.007) and in CBDCA than CDDP treatment (p 0.01). Disease free survival (DFS) was 41.6 m, it was longer in men (p 0.049), in stage IB and II (p 0.041) and in DBDCA treatment (p 0.021).

Conclusion
Both applied regimen were tolerable. Survival was influenced by stage of the tumor. Patients treated with CBDCA experienced less toxicity, obtained higher RDI of planned treatment and lived longer than those treated with CDDP. Study showed that both CBDCA and CDDP can be used in combination with oral vinorelbine in ACT of NSCLC. This study was supported by Grant NT-13569 and NS-9959-3 of the Czech Ministry of Health

Background
Clinicians play an important role helping patients make decisions about ACT, but their views about trade-offs between the benefits and harms of ACT may differ from those of their patients. We sought to determine the minimum survival benefits that lung cancer clinicians judged sufficient to make ACT in NSCLC worthwhile, the factors associated with these judgements, and comparisons with the preferences of their patients.

Methods
82 lung cancer clinicians (medical oncologists & thoracic surgeons) completed a self-administered questionnaire. The time trade-off method was used to determine the minimum survival benefits judged sufficient to make ACT worthwhile in 4 hypothetical scenarios. Baseline survival times were 3 years and 5 years and baseline survival rates (at 5 years) were 50% and 65%. Patients’ preferences were those of 122 patients considering ACT for NSCLC elicited in a related study using similar methods. Differences between groups were assessed by 2-sample non-parametric tests. Determinants of preferences were assessed by univariable comparison after normal score transformation. Variance was assessed with the Ansari-Bradley rank test.

Results
Most clinicians were male (75%) with a median age of 43 years (range 28-65), had 5 or more years of professional experience (69%), were married (92%), and had dependent children (72%). More were medical oncologists (63%) than thoracic surgeons (31%). The median benefit judged sufficient (by 50% of clinicians) was an extra 9 months (IQR 6-12 months) beyond survival times of both 3 years and 5 years, and an extra 5% (IQR 5-10%) beyond 5-year survival rates of both 50% and 65%. Medical oncologists, compared with thoracic surgeons, judged smaller benefits sufficient to make ACT worthwhile (median benefit 8 months v 12 months, p=0.03). Clinicians’ preferences, compared with patients’ preferences, had the same median benefit (9 months survival time, 5% survival rate) but varied over a smaller range (IQR, 6-12 months v 1-12 months, p<0.001; 5%-10% v 0.1-10% p<0.001).

Conclusion
Lung cancer clinicians judged moderate survival benefits sufficient to make ACT in NSCLC worthwhile, but preferences differed according to specialty. Clinicians’ preferences were similar to patients’ preferences, but varied less. Lung cancer clinicians should be mindful of their own preferences and how they may influence discussions and decisions about ACT in NSCLC.

Background
ACT for NSCLC improves overall survival, but the benefits are modest and must be weighed against the harms and inconvenience of the treatment. The aim of this study was to determine the survival benefits judged necessary to make ACT worthwhile for patients with resected early NSCLC, and the factors associated with their judgments.

Methods
122 patients considering ACT completed a self-administered questionnaire at baseline (before ACT, if they were having it) and 6 months later (after ACT, if they had it). The time trade-off method was used to determine the minimum survival benefits judged sufficient to make ACT worthwhile in 4 hypothetical scenarios. Baseline survival times were 3 and 5 years and baseline survival rates (at 5 years) were 50% and 65%. All tests were 2-sided and non-parametric. Determinants of preferences were assessed by (rank test) comparison of preferences in groups defined by each factor.

Results
Most patients were male (57%) with a median age of 63 years (range, 43-79 years), married (72%) and previous smokers (81%). The majority had had a lobectomy (84%), adenocarcinoma histology (60%), and half had stage II disease (50%). 106 patients decided to have ACT (87%), 16 declined ACT (13%); female sex and age over 65 years were associated with declining. ACT was most commonly 4 cycles (68%) of cisplatin/ vinorelbine (73%). At baseline, the median benefit judged sufficient (by 50% of patients) was 9 months (IQR 1-12 months) beyond life expectancies of 3 years and 5 years, and 5% (IQR 0.1-10%) beyond 5-year survival rates of 50% and 65%. Preferences varied across the entire range of possible benefits (from 0 days and 0% to an extra 15 years and 50%). At baseline, deciding to have ACT (p=0.01) was the only factor that predicted judging smaller benefits sufficient to make ACT worthwhile. At 6 months (n=91), the median benefits judged sufficient were the same as at baseline (9 months & 5%), but preferences varied over a greater range (IQR’s 0-18 months & 0-15%). At 6 months, deciding to have ACT (p=0.02) and better physical (p=0.02), emotional (p=0.004), and overall well-being (p=0.004) during adjuvant chemotherapy were associated with judging smaller benefits sufficient to make ACT worthwhile. Fatigue, nausea, sleeplessness and reduced appetite were the side effects of ACT that patients were most concerned about experiencing (at baseline) and were rated the most troublesome (at 6 months).

Conclusion
Most patients judged moderate survival benefits sufficient to make ACT worthwhile, but preferences varied widely and were not predicted by baseline characteristics. Preferences were stable over time. Patients with NSCLC judged larger benefits necessary for ACT than patients with breast and colon cancer in our previous studies. Clinicians should elicit the preferences of individual patients when discussing and making decisions about ACT.

Background
Patients with lung cancer should be treated differently based on their histologic subtypes because of the disparities in tumor aggressiveness and treatment response. In addition to epidermal growth factor receptor tyrosine kinase inhibitor, recent chemotherapeutic agents such as pemetrexed and bevacizumab have dissimilar activities between adenocarcinoma (AD) and squamous cell carcinoma (SQ). Therefore, it would be important to reevaluate the clinicopathologic features of the two major subtypes, both of which were classified as non-small cell lung cancer.

Methods
Between 1995 through 2012, 2412 patients with primary lung cancer underwent pulmonary resection in Nagoya University and Aichi Cancer Center Hospital. For the present study, a total of 2057 patients with AD and SQ who underwent complete resection were extracted, and their clinicopathological features and outcomes were evaluated.

Results
The cohort consists of 1585 ADs (77%) and 472 SQs (23%). Female sex, no history of smoking and smaller size of the tumor were distinct characteristics of AD patients, and higher age was that of SQ patients (p < 0.0001). Pathological stage I disease was found in 70% of AD patients and 41% of SQ patients. Significant difference was observed for overall survival with the 5-year survival rate of 78% in AD patients and 63% in SQ patients. Limited to stage I disease, SQ patients also showed significant worse outcomes (p < 0.0001). Since no survival difference was observed between pN0 and pN1 patients with SQ (p = 0.39), we tried to regard the pN0 patients as pN1 and restage them according to the newly defined N status. Thirty-seven stage IA and 42 stage IB patients were upstaged to stage IIA, 36 stage IB patients to stage IIB, and 47 stage IIB patients to stage IIIA. As a result, comparable survival curves were obtained between AD and SQ patients in stage II and IIIA.

Conclusion
We identified some significant differences between patients with AD and SQ in the large-scale Japanese cohort. Especially, patients with stage I SQ showed a significantly worse outcome. Newly defined stage grouping applied for SQ patients provided comparable outcomes with those of AD patients. Therefore, stage I disease of SQ may not be there.

Background
In recent years, Limited resection for ground glass opacity lesions is not inferior to lobectomy. However, the effect of limited resection on solid type early lung cancer is controversial. The aim of this study was to compare clinical outcomes of patients with solid type early stage non small cell lung cancer undergoing limited resection or lobectomy.

Methods
This is a retrospective study between March 2000 and September 2010. the patients with ground glass opacity lesion were excluded. Medical records of 164 patients with clinical stage IA were reviewed. 31 patients underwent limited resection and 133 patients underwent Lobectomy Disease free survival and overall survival were estimated by Kaplan Meier methods Prognostic factors associated with disease free survival and overall survival were analyzed by the Cox proportional hazards model.

Results
Limited resection group had medical comobidities significantly including old age (p<0.001), cardiovascular disease (p=0.001) and lower diffusing capacity of the lung for carbon monoide (p<0.001). The lobectomy was associated with longer disease free survival and overall survival (p=0.001) By multivariate analysis, Sublobar resection (p=0.011), lymphatic vessel invasion (p=0.006), and number of positive lymph nodes (p=0.028) were predictors for survival. Sublobar resection (p<0.001), visceral pleural invasion (p=0.002), and lymphatic vessel invasion (p<0.001) were predictors for disease-free interval.

Conclusion
Solid-type lung cancers demonstrated aggressive behavior and there were numerous significant pathologic prognostic factors in clinical stage IA NSCLC from our study. Lymph node metastasis was not rare in clinical stage IA NSCLC with a solid component. Lobectomy with lymph node dissection remains the standard surgical procedure for patients with solid-type clinical stage IA NSCLC.

Background
The aim of this paper was to evaluate survival according to tumor size, and the extent of mediastinal lymphadenectomy. Besides, we analyzed if a more extensive lymphadenectomy, based on the number of lymph nodes (LN) obtained, improves survival in early stages.

Methods
Retrospective review of 620 consecutive early stage NSCLC patients operated between 1995 and 2008. None of the patients underwent neoadyuvant treatment. T1 and T2 patients were divided in two subgroups, according to the number of LN resected (0-5, 6-10, ³11).

Results
We analyzed a total of 8.484 LN resected and an average of 13.68 (0-48). The majority of patients were male (86%) with a mean age of 65 (33-84). Mean follow-up was 52.6 months. Mean time to relapse was 28.6 months. SCC was the commonest histology (47.4%). Lobectomy was the commonest resection (81.6%) and 56.3% of the patients were staged as T2N0. 5-year overall survival was 53%. Mean survival according to size was 9.9 and 5.6 years (T1 and T2 respectively). In-hospital mortality was 2.7%. Mean survival according to N factor was 6.3 and 4.1 years (N0 and N1 respectively). 67% of the patients had mediastinal recurrence. The number of positive LN increased with the number of LN removed (26.4% vs 9.3% and 10.5%;p <0.001). The analysis showed that patients with more LN resected tend to have better survival (7.5 years, 7.8 years and 8 years; p=0.21). Data were similar if when analyzing LN resected from N2 stations. Survival was significantly worse in the group with positive LN (8.1 vs 2 years). The group with more N2 LN resected had significantly less mediastinal recurrence (16.3%, 9.2% vs 5.9%; p<0.002).

	MEDIASTINAL	RECURRENCE
RESECTED LYMPH NODES	NO	YES
0-5 (N= 458)	190 (83,7%)	37 (16,3%)
6-10 (N = 152)	187 (90,8%)	19 (9,2%)
³11 (N=174)	176 (94,1%)	11 (5,9%)

Conclusion
The probability of finding some positive mediastinal lymph node increases with a more extensive lymphadenectomy. A complete mediastinal lymphadenectomy provides a better staging and decreases mediastinal recurrence. A complete lymphadenectomy should be performed in all lung cancer patients to achieve a correct staging and a better survival, even in those with an early stage.

Background
The purpose of this study was to investigate the relationship between the amounts of tobacco smoking and the clinicopathological features of non-small cell lung cancer (NSCLC) patients.

Methods
We retrospectively reviewed the clinical records of 1825 consecutive NSCLC patients who underwent surgery in our department. Among them, the data sets of 363 squamous cell carcinoma (Sq) patients and 720 adenocarcinoma (Ad) patients who received lobectomy or more extensive resection were available. The definitions of smokers used in the study were: light smoker had a smoking history of 30 pack-years (PY) or less, heavy smokers had a history of more than 30 to 60 PY and super-heavy smokers had a history of more than 60 PY. The survival curves were estimated according to the Kaplan-Meier method and were assessed by the log-rank test. A multivariate survival analysis was performed using the Cox proportional hazards model. Differences were considered to be statistically significant for values of P < 0.05.

Results
There were more male patients, more aggressive operations (bi-lobectomy or pneumonectomy) and heavier smokers in the Sq patients than Ad patients (p< 0.0001, p=0.012 and p<0.0001). In Ad patients, the never-smokers (n=309) were more likely to be female, to have less advanced stage tumors and had a significantly better prognosis than ever-smokers (n= 441) (five-year OS: never-smokers, 67.9%; smokers, 53.7%, p<0.0001). In Sq patients, the never-smokers (n=15) were more likely to be female than the ever-smokers (n=348). There was no significant prognostic difference between never-smokers and ever-smokers in the Sq patients (five-year OS: never-smokers, 28.6%; ever-smokers, 46.7%, p=0.36). Among ever-smokers, the light-smokers (n=56) had more female patients, more advanced stage tumors and a significantly worse prognosis than heavy smokers (n=292) (p = 0.0003). The multivariate survival analysis showed that light smoking was related to a worse prognosis compared to heavy smoking (HR=2.06, 96%CI 1.43-2.98, p=0.0001).

Conclusion
The never-smokers had a better prognosis than ever-smokers in Ad patients, whereas the light-smokers (PY ≤ 30) had a significantly worse prognosis than heavier smokers (PY > 30) in Sq patients. There might be other factors than tobacco carcinogens that influence the development of squamous cell carcinoma in light smokers.

Background
Correlation between clinicopathologic features and prognostic implications of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) has been intensively studied. Thailand is one of the high prevalence of NSCLC, therefore the Northern Thailand Thoracic Oncology Group (NT-TOG) would like to identify the incidence of ALK rearrangement which might be different from Western and predictive or prognostic factors for ALK positive in resectable NSCLC in northern Thailand.

Methods
From January 2008 to December 2012, 266 completely resected NSCLC patients in Chiang Mai University Hospital were enrolled in this study. General characteristics, histo-pathologic results and clinical outcomes were retrospectively reviewed from the computerized medical records. Anatomical resection (lobectomy or pneumonectomy) with systematic mediastinal lymphadenectomy was performed in all cases. Immunohistochemistry (IHC) method with mouse monoclonal, clone 5A4, Ventana D5F3 antibody using a Ventana automated immunostainer (Ventana Medical Sustems, Tucson, AS) by optiview detection system was used to evaluate ALK rearrangement in all pathological specimens. The positive stained cancer cells were collected. Multivariable logistic regression analysis was used to identify the clinico-pathological correlation with positive results of IHC.

Results
Twenty-two (8.2 %) of 267 specimens were ALK IHC-positive with intense cytoplasmic staining. Age less than 55 years (Diagnostic odds ratio (DOR) of 7.3, 95 % confidence interval (CI) of 2.0-26.4, p-value of 0.002) and simultaneous multiple sites of tumor recurrence (DOR of 5.3, 95 % CI of 2.9-9.8, p-value of < 0.001) were identified as predictive factors of ALK positive from IHC. Female seem to be predictive factor for ALK positive but there is no statistically significant difference. There were no statistically significant differences in term of histology, tumor grading, stages of disease, tumor recurrence, intratumoral lymphovascular invasion, ERCC1 and RRM1 expression, EGFR mutation and overall survival between ALK positive and ALK negative. Table1 Multivariable logistic regression analysis of predictive factors of ALK positive

Covariates	Diagnostic Odd Ratio (DOR)	95% Confidence Interval	P-value
Age < 55 years	7.3	2.0-26.4	0.002
Female	2.0	0.9-5.0	0.123
Visceral pleural invasion	3.9	0.9-16.2	0.061
Intratumoral lymphatic invasion	4.0	0.4-37.1	0.222
Multiple site of recurrence	5.3	2.9-9.8	<0.001

Conclusion
The incidence of ALK positive in completely resected NSCLC in northern Thailand is 8.2 % by IHC method. Age less than 55 years and simultaneous multiple sites of tumor recurrence are predictive factors of ALK positive. Other clinicopathologic factors are neither predictive factors nor prognostic factors for ALK positive. Validation of IHC positive cases with fluorescence in situ hybridization (FISH) is being conducted.

Background
We conducted this ‘window- of-opportunity’ study to characterize the biologic activity of everolimus, an allosteric inhibitor of mTOR pathway, in patients with surgically resectable NSCLC.

Methods
Patients with surgically resectable NSCLC (Stage I-III) underwent baseline tumor biopsy and FDG PET/CT scan followed by treatment with everolimus (5 or 10mg daily for up to 28 days). A repeat PET/CT scan was obtained 24 hours prior to surgery. Blood samples for pharmacokinetic (PK) assay for drug levels were collected at 0.5, 1, 2, 5, 8 and 24 hours post drug ingestion on Days 1, 8 and 21. Control patients not treated with everolimus also had paired FDG PET/CT scans prior to surgery. Pharmacodynamic (PD) effect of everolimus was assessed in vivo by PET and ex vivo by immunohistochemical detection of total and phosphorylated mTOR, Akt, S6, eIF4e and 4EBP1 in pretreatment and posttreatment tissue samples. Alterations in common driver mutations in NSCLC were assessed using SnapShot multiplex minisequencing technique. Statistical comparisons by T-Test, ANOVA, Wilcoxon signed rank test or Kruskal-Wallis test were performed as appropriate using SAS statistical package V9.3. The significance level was set at 0.05 for all tests.

Results
We enrolled 33 patients; 23 on everolimus and 10 on the control arm. Median age: 64 yrs (range 36-77), gender: (14/19 -M/F), stage (I - 14; II - 13; IIIA - 6); histology (adenocarcinoma - 22; squamous - 7; others - 4). Treatment was tolerated well with mostly grade 1/2 anticipated toxicities (hyperglycemia, hypertriglyceridemia, stomatitis, anemia and fatigue) and 32 of 33 patients proceeded with surgery on schedule. Compared to controls, there was significant reduction in SUVmax and median anatomic tumor size in a dose-dependent manner in everolimus-treated patients (15.38 vs. -21.74 vs. -23.23; p=0.012 and 4.39 vs. 0 vs.-13.33; p=0.039 in the control, 5mg and 10mg cohorts respectively). There was a similar trend in reduced metabolic activity in Ras mutant tumors treated with 10mg everolimus compared to control (88% vs. -28%). Comparison of baseline biopsy samples and resected tumor specimens in control and everolimus-treated patients showed reduction of S6 (-27.38 vs. 0 vs. -78.95; p=0.0536), pS6 (-20 vs. -29.17 vs. -57.14 ; p=0.0233) and p4EBP1 (-45.83 vs. 0 vs. -75; p=0.057) with greatest reduction observed in patients treated with higher dose of everolimus.

Conclusion
Everolimus exerts a measurable, dose-dependent biologic activity in NSCLC. ‘Window of opportunity’ studies in early stage NSCLC can provide strong mechanistic insights to guide optimal development of novel targeted agents.

Background
Although the carcinogenic effects of cigarette smoking are important in the pathogenesis of lung carcinoma, the impact of quantitative smoking history on survival in resectable tumours has not been well described. Using a comprehensive database in which smoking was quantitatively documented, we analysed the impact of increasing number of pack years of smoking on stage, histology, mutation status and overall survival in an Australian population. We focused on patients without nodal involvement (N0) as they were less likely to have received neoadjuvant or adjuvant therapy.

Methods
Data was extracted from a large single institution database containing information on patients who underwent curative resection of non-small cell lung cancer from 1992 to 2012. Cigarette smoking history was documented in pack years. DNA was isolated and analysed using Sequenom’s LungCarta panel which interrogates 214 mutations in 26 genes. Statistical analysis was performed using Chi-square tests and the Kaplan Meier method for survival.

Results
Information on pack year smoking status was available for 470 patients, 70% of whom were male. This included 311 (66%) pathological N0 (pN0), 64 (14%) pN1 and 95 (20%) pN2. Smoking history ranged between 0 (never smokers N=32, 7%) and 180 pack years, with a median of 45 and mean of 48. Patients were divided into quartiles based on their smoking history: never- and < 10 pack year smokers (N=43; 9%), 11-25 pack years (N=74; 16%), 26-50 pack years (N=180; 38%) and >50 pack years (N=173; 37%). Adequate DNA was isolated in 425 samples. Frequencies of mutations were as follows: KRAS 21%, TP53 10%, EGFR 5%, PIK3CA 4%; other mutations occurred at lower frequencies. In 44% no mutation was found. Increased pack year history of smoking was not associated with overall survival. In the pN0 wild type population, no association with smoking and survival was seen. In the pN0 mutation group (Figure 1) those with a <25 pack year history had significantly better overall survival than heavier smokers (HR 0.61, 95% CI 0.40-0.92). Figure 1: Overall Survival by smoking status in pN0 tumours with a mutationFigure 1

Conclusion
Smoking status was not associated with overall survival across the entire cohort. In patients whose tumour harboured a mutation, increased smoking was associated with a less favourable mutation profile including in KRAS, TP53 and PIK3CA. In patients with pN0 disease a significant difference in overall survival was observed favouring light smokers. The presence of mutations in association with heavy smoking negatively impacts overall survival.

Background
The female patients with Non-small cell lung cancer in China have higher mortality than in the most of other countries. And the main pathological type is adenocarcinoma. Even though after complete resection, these patients still have an unsatisfactory prognosis. We retrospectively analyzed prognostic factors of 106 female patients with completely resected lung adenocarcinoma in Shaanxi province to find patients with unfavorable factors for proper management.

Methods
Clinical data of 106 female patients with complete resection of lung adenocarcinoma at Shaanxi Provincial People’s Hospital between January 2003 and December 2010 were reviewed retrospectively and analyzed the effect of factors about age, with symptoms or not, operation types, the maximum-diameter of tumor, postoperational pathological stage, dissected lymph nodes, the adjuvant therapy and the recurrence or metastasis on 5-year overall survival(OS). Cumulative survival was analyzed by the Kaplan-Meier method and compared by log-rank test. Prognosis was analyzed by the Cox proportional hazards model.

Results
The overall 5-year survival rates were 57.0%. 38(35.8%) of the 106 patients had recurrence or metastasis. A univariate analysis demonstrated that age(>54 years), postoperational pathological stage, the total number of removed lymph nodes(>12), the total number of removed N1 lymph nodes(>7), the total number of removed N2 lymph nodes(>7), the number of involved N2 lymph nodes(>2), removed N2 stations(>2), the adjuvant therapy and the recurrence or metastasis were significant prognostic factors for 5-year OS. In the multivariate analysis, the total number of removed N2 lymph nodes(>7) and the recurrence or metastasis were independent prognostic factors for 5-year OS.

Conclusion
For female patients with completely resectable lung adenocarcinoma in Shaanxi province, it is very important to give systematic mediastinal lymphadenectomy，7 and more N2 lymph nodes should be removed during surgical resection. The individual adjuvant therapy and the intensive follow-up should be given to the patients with the high risk for the recurrence or metastasis. Total number of removed N2 lymph nodes ＞7 was the favorable prognostic factor and the recurrence or metastasis was the adverse one.

Background
To improve the understanding of current attitudes of the thoracic community to video-assisted thoracoscopic surgery (VATS) lobectomy, the Collaborative Research Group conducted the Cross-sectional Survey On Lobectomy Approach (X-SOLA) study. The aim was three-fold: to assess the practice of lobectomy in the current clinical setting, to identify potential reasons that may inhibit the popularization of the VATS lobectomy technique, and to hypothesize potential strategies that can advance this field in the future.

Methods
Participants included thoracic surgeons identified through an index search from the Web of Science and the cardiothoracic surgery network. A confidential questionnaire was emailed in June, 2012. Non-responders were given two reminder emails at monthly intervals.

Results
838 thoracic surgeons completed the questionnaire within a three-month period, including 416 surgeons who only performed lobectomy through open thoracotomy and 422 surgeons who performed VATS or robotic-VATS. Two sets of standardized questionnaires were completed by these two groups. Ninety-five percent of VATS surgeons agreed with the definition of ‘true’ VATS lobectomy according to the CALGB trial. Ninety-two percent of surgeons who did not perform VATS lobectomy were prepared to learn this technique, but were hindered by limited resources, exposure and mentoring. Both groups believed VATS lobectomy should be incorporated into thoracic surgical training and for more standardized workshops to be made available. Figure 1 Figure 1. Survey responses for surgeons who performed video-assisted thoracoscopic surgery lobectomy (n=422) Figure 2

Conclusion
The X-SOLA study represents the largest cross-sectional report within the thoracic community to date, demonstrating the current status of clinical practice of lobectomy approach for NSCLC worldwide and identifying areas in need of further development.

Background
The true incidence of occult N2 lymph node metastasis in patients with clinical stageⅠnon-small cell lung cancer (NSCLC) remains controversial. Estimation of the probability of N2 lymph node metastasis can assist physicians when making diagnosis and treatment decisions.

Methods
We reviewed the medical records of 739 patients with computed tomography–defined N0 NSCLC that had an exact Tumor-Node-Metastasis stage after surgery. A random subset of three fourths of the patients (n=554) were selected to develope the prediction model. Logistic regression analysis of the clinical characteristics was used to estimate the independent predictors of N2 lymph node metastasis. A prediction model was then built and internally validated by using cross validation and externally validated by the remaining one fourth(n=185) patients which made up the validation data set. The model was also compared to 2 previously described models.

Results
We identified 4 independent predictors of N2 disease: a younger age, larger tumor size, central tumor location, and adenocarcinoma or adenosquamous carcinoma pathology. The model showed good calibration (Hosmer–Lemeshow test: P = .92) with an area under the receiver operating characteristic curve (AUC) of 0.748 (95% confidence interval, 0.687-0.809). The AUC of our model was better than those of the other two models when validated with independent data.

Table 1 . Multivariate Logistic Regression Analysis

Variable	Regression Coefficient	P	OR	95%CI Lower	95%CI Upper
Age	-0.032	0.007	0.969	0.957	0.981
Tumor Size	0.456	<0.001	1.577	1.449	1.705
Central	1.753	<0.001	5.771	5.453	6.089
Adenocarcinoma /mixed	1.787	<0.001	5.970	5.546	6.394
Constant	-2.983	0.001	0.051

Figure 1 Figure 1. The ROC curves of our model, the VA model and the Fudan model for all patients of group B. The AUC of our model was 0.786 (95% CI, 0.690-0.881); the VA model was 0.673 (95% CI, 0.554-0.792); the Fudan model was 0.757 (95% CI, 0.659-0.885).

Conclusion
Our prediction model estimated the pretest probability of N2 disease in computed tomography–defined stageⅠNSCLC and was more accurate than the existing models. Use of our model can be of assistance when making clinical decisions about invasive or expensive mediastinal staging procedures.

Background
In lung adenocarcinoma, prognostic importance of maximum standardized uptake (SUV max) value on positron emission tomography (PET) has been well observed. Different subtypes had different 18F-fluorodeoxyglucose (FDG) uptake, and it was also related with tumor size. The ratio of SUV max and tumor size was supposed to be different depending on the subtypes of lung adenocarcinoma.

Methods
Medical records of the lung adenocarcinoma patients who underwent surgery in Seoul National University Bundang Hospital between 2003 and 2012 were reviewed. Ratio of SUV max and invasive tumor sizes was calculated and categorized into two groups. Group 1 included patients of ratio < 1.5, and Group 2 included the rest. The subtypes of lung adenocarcinoma were categorized into 4 groups; solid, acinar, lepidic, papillary according to their pathologic reports. Overall survival and disease-free survival rates of Group 1 and 2 were compared in each predominant subtype patients.

Results
Total number of patients was 680. The average ratio of SUV max/invasive size was 1.63. The ratio of SUV max/invasive size of solid subtype was 2.48 and it was significantly higher than acinar and lepidic subtypes. (p<0.000) Overall survival (OS) and disease-free (DF) survival of lepidic subtype were 39.3 months and 41.4 months each, and were significantly higher than solid and acinar subtypes. OS and DF of Group 1 were 36.4 and 32.8 each. Those of Group 2 were 29.8 and 21.6 months. Group 1 had significantly longer OS and DF than Group 2. (p<0.000, and p=0.001 each) In solid subtype, OS and DF of Group 1 were 32.8 and 27.7 months and those of Group 2 were 22.7 and 17.6. But there were no significant differences. (p=0.117 and p=0.123 each) In acinar subtype, OS and DF of Group 1 were 38.2 and 34.4 months, those of Group 2 were 32.9 and 24.3 months. The differences were statistically significant. (p<0.000, p=0.023, each) Three-year overall survival rates and 3-year disease-free survival of Group 1 were 45.2% and 39.1%. Those survival rates of Group 2 were 32.2% and 19.2% respectively. Recurrence hazard ratio of Group 2 was 1.68. (p<0.000, 95% confidence interval 1.379-2.061) In acinar subtype, recurrence hazard ratio of Group 2 was 1.83 and there was significant difference. (95% confidence interval: 1.410-2.381, p< 0.000) In other subtypes, recurrence hazard ratio showed no significant differences.

Conclusion
Ratio of SUV max and invasive tumor size had limited prognostic value in subtypes of lung adenocarcinoma. It could be used as a prognostic factor for recurrence in acinar predominant subtype category.

Background
The new International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification has been proposed in 2011. The aim of the study is to demonstrate the prognostic factors and pattern of recurrence in lepidic predominant lung adenocarcinoma.

Methods
We retrospectively reviewed 545 patients undergoing surgical resection for lung adenocarcinoma in Taipei Veterans General Hospital between 2006 and 2010. Fifty-two patients with lepidic predominant lung adenocarcinoma were identified. The predictive factors and pattern of recurrence of these patients were investigated.

Results
The 5-year overall survival and recurrence-free rates were 84.0% and 83.0%, respectively. During follow-up, 7 (13.5%) patients developed recurrence. The median time to recurrence was 28.7 months (range, 10.6 to 57.8 months). The percentage of T2-4 (P = 0.003), N1-2 (P < 0.001), TNM stage II-III (P < 0.001), and visceral pleural invasion (P = 0.049) was significant higher in patients with recurrence. N status (N1-2 vs. N0) (P < 0.001), TNM stage (II-III vs. I) (P < 0.001) were significant prognostic factors of freedom from recurrence in univariate analysis. Visceral pleural invasion (P = 0.093) and presence of solid pattern (P = 0.089) tended to be significant prognostic factors of freedom from recurrence in univariate analysis. TNM stage (II-III vs. I) (P = 0.005) was still a significant predictive factor of freedom from recurrence in multivariate analysis. Figure 1

Conclusion
The overall survival and freedom from recurrence rates were good in lepidic predominant adenocarcinoma. TNM stage (II-III vs. I) was a significant predictive factor of freedom from recurrence in these patients.

Background
PM01183 is an inhibitor of transactivated transcription and also acts on the tumor microenvironment. It lacks cross-resistance with platinum (Pt) agents whereas strong synergism with DOX has been observed preclinically. Single agent PM01183 clinical evaluation in non-small cell lung cancer (NSCLC), pancreatic, ovarian and breast cancer patients (pts) is ongoing. Reversible myelosuppression and high emetogenic potential are common side effects.

Methods
Consenting adults with selected solid tumors, including SCLC, and ≤ 75 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, adequate organ function and up to 2 prior chemotherapy-containing (CT) lines were included in successive cohorts aiming to primarily define the recommended dose (RD) of PM01183 and DOX (50 mg/m[2], fixed dose) combination every three weeks (q3wk). No prior DOX was allowed in the metastatic setting. DOX had to be discontinued once a maximal cumulative dose of 450 mg/m[2] during treatment was reached. Available results in the SCLC population are presented here.

Results
Recruitment was closed in December 2012; 13 of 43 enrolled/treated pts (30%) had SCLC diagnosis. Of these, 8 (62%) were males. Median age was 58 years (r: 48-73). Ten (77%) and 2 pts (15%) were chemo-refractory or had known central nervous system (CNS) involvement, respectively. Five of 12 pts evaluable for efficacy [Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1] were responders, for an overall response rate (ORR) of 42% [95% confidence interval (CI): 15-72]. No responses occurred in pts with >1 prior CT lines (n=5). In evaluable pts with 1 prior CT line (n=7), the ORR reached 71% (95%CI: 29-96). All chemosensitive pts (n=3) responded to treatment. Severe myelosuppression, G3/4 neutropenia or thrombocytopenia, was observed in 89/22% of pts, respectively. Other toxicities, in ≥ 10% of pts, were generally mild and included transaminase increases, fatigue, alopecia, mucositis, nausea/vomiting, diarrhea, anorexia and constipation. No cardiac toxicity was observed. Febrile neutropenia (FN) occurred in 11% of pts. Overall, 2 pts discontinued treatment due to toxicity (pneumonia; and repetitive myelosuppression despite successive dose adjustments, respectively). No treatment-related deaths occurred. The RD was defined as PM01183 4.0 mg and DOX 50 mg/m[2] q3wk.

Conclusion
PM01183 and DOX resulted in relevant activity in SCLC patients with less than 2 prior CT-lines. Toxicity with this combination seems both manageable and predictable. Despite the high level of myelosuppression, FN was relatively uncommon and colony-stimulating factors (CSFs) are not currently indicated. The novel mechanism of action, and particularly the lack of Pt cross-resistance, is of interest in this patient population. These results warrant further study of the potential role of this regimen in relapsed SCLC pts.

Background
There is some evidence that the standard uptake value (SUV) measured using 18F- fluorodeoxyglucose positron emission tomography ([18]FDG-PET) in patients with non-small cell lung cancer (NSCLC) may be prognostic for survival. Small cell lung cancer (SCLC) clinically differs from NSCLC by its rapid proliferation and is staged as either limited disease (LD) defined as disease confined to one hemithorax and the regional lymph nodes or extensive disease (ED) which is disease that has spread beyond this. There is much less information available on the potential prognostic value of the SUV obtained during [18]FDG-PET scanning in SCLC. This study thus aims to explore whether SUV can be effective in the prognostic stratification of SCLC patients with LD and ED.

Methods
Retrospective study of patients diagnosed with SCLC who underwent a pre-treatment 18FDG-PET scan between 1999 – 2008 at the Peter MacCallum Cancer Centre and 2004 -2011 at the Austin Hospital. Patients with LD were treated with radical concomitant chemo-radiotherapy and those with ED treated with chemotherapy alone. Maximum and mean SUVs were retrieved, and survival of patients measured. The correlation between SUV and other patients’ clinicopathological factors, including age, sex, performance status, weight loss and tumour stage (TNM) were also explored.

Results
Thirty-six eligible patients were identified, with a median follow-up of 14 months (range, 3-103 months). There were 23 males and 13 females. The median age was 69 years (55-84 years). Twenty patients had LD and 16 had ED. Thirteen patients had stage IV disease and 10 patients each had stage IIIA and IIIB disease (3 patients were unable to be staged according to TNM classification system). Higher TNM stage was associated with higher SUVmax (r~s~=0.37, p=0.036) but not with SUVmean (r~s~=0.30, p=0.086). There was no evidence of a significant association between clinicopathological factors with SUVmax in patients with LD and ED, except for age in patients with ED. Increasing age was associated with higher SUVmax (r~s~=0.72, p=0.002) and higher SUVmean in patients with ED (r~s~=0.81, p<0.001). SUVmax and SUVmean were not significantly associated with OS in patients with LD or ED or in the whole sample.

Conclusion
In patients with SCLC there was an association between higher SUVmax and higher TNM stage, as observed in patients with NSCLC. However, in this small patient cohort, we were unable to find evidence of an independent prognostic effect of SUVmax on overall survival.

Background
Serum lactate dehydrogenase (sLDH) is a prognostic factor in small cell lung cancer (SCLC). The aim of this study was to evaluate the impact of pre-treatment levels on survival in a contemporary patient population with limited disease (LD) and extensive disease (ED).

Methods
SCLC patients were identified by searching the hospital cancer registry from 1999 to 2009. Patient characteristics, sLDH, management and outcomes were collated by reviewing clinical records. A sLDH result < 230 was designated normal and a result >230 was designated elevated in line with our institutional reference range. Survival analysis was performed using stata software using cox regression.

Results
168 patients were diagnosed with SCLC, 103 males and 65 females. Median patient age was 71 years. Pre-treatment sLDH was available for 128 patients. An elevated sLDH was associated with worse survival with Hazard Ratio (HR) 2.17 (95% CI 1.46-3.20, p-value <0.001). Elevated sLDH remained a significant independent poor prognostic factor in a multivariate model when adjusted for age, sex, treatment and stage. In LD patients 52.6% had an elevated sLDH and median overall survival (MOS) was significantly worse in patients with elevated sLDH compared with normal sLDH, 7.97 months versus 16.50 months (HR 2.1, 95% CI 1.07-4.32, p-value = 0.032). In ED patients 69.4% had an elevated sLDH and MOS was also significantly worse in patients with elevated sLDH compared with normal sLDH, 5.22 months versus 8.23 months (HR 1.8, 95% CI 1.1-2.9, p-value = 0.019). Figure 1Figure 2

Conclusion
This study confirms the prognostic significance of sLDH. LD patients with an elevated sLDH had a MOS which was similar to ED patients with a normal sLDH. Further studies to determine the biology of this subgroup of poor prognostic patients will be important to tailor therapeutic strategies.

Background
According to 2004 WHO classification there are four pulmonary neuroendocrine (NE) histopathologic entities, ranging from low- to high-grade (HG) neoplasms. LCNEC belongs to the latter group. There are different opinions regarding whether LCNEC and small-cell lung cancer (SCLC), both HG, are essentially indistinct and thus deserve the same therapy, or not. LCNEC consists only about 3% of all lung cancer patients. We aimed to examine biologic characteristics of LCNEC patients and their implications on therapy choice and outcome.

Methods
A retrospective observational study of 21 consecutive patients seen at the thoracic oncology unit, division of oncology, Sheba Medical Center during the years 2008-2012. Histopathology was studied in a dedicated thoracic pathology unit and was based on 2004 WHO classification. Ki67 index evaluation was performed. Staging followed the 2009 TNM classification. Patients were examined for tumor somatostain receptors (SSTR): by In-111 Octreoscan or by Ga68 DOTANOC/DOTATATE PET/CT scans. We studied circulating proGRP as NE tumor marker.

Results
21 Patient fulfilled the LCNEC diagnostic criteria, 14 M, 7 F. 8/21 were diagnosed at an operable stage, 7/8 had received post operative adjuvant chemotherapy and 5/7 of this subgroup are still alive. At a 17-month median follow-up time, of the entire series 7/21 are alive. The Ki67 score ranged 20-100%, median 72.5%. The score was less than 70% in 7 cases. Two cases were defined HG, without Ki67 score. Five Stage IV patients were SSTR-positive and received octreotide depot therapy, which in 2/5 was given 1[st]-line (their Ki67 index was 20-25%). One of the latter received also peptide-related radionuclide therapy ( PRRT). An additional patient had received octreotide as 2[nd]-line therapy, and achieved durable (> 3-years) stabilization. Of note is metastatic brain disease in six patients: synchronous with initial diagnosis in two cases and metachronous in the others. Also, six patients have had non cerebral, non synchronous 2nd primary tumors. Additional histological elements were found in 6 patients: SCLC in 3, basaloid- 2 and adenocarcinoma-1. Circulating proGRP in LCNEC was elevated less frequently, and showed lower titers, as compared with SCLC patients data.

Conclusion
LCNEC is an uncommon entity within the pulmonary NE neoplasms spectrum. Despite its similarity to SCLC it is distinct in several senses: biologically, an aggressivity profile is not always seen, as reflected by the broader Ki67 range. A related feature is the higher rate of LCNEC operable patients, compared with exceptional primary surgery in SCLC. A substantial fraction of patients are SSTR positive and can benefit from corresponding targeted therapy. Due to LCNEC heterogeneity it is important to characterize it adequately prior to 1[st] line therapy so that the therapeutic options are delineated on time, thus optimizing patients benefit and quality of life. Due to the limited patient number in a given institution, collaborative studies are warranted.

Background
Patients with Small Cell Lung Cancer (SCLC) whose disease progresses during or shortly after treatment with platinum, have a poor prognosis. Paclitaxel (P) and irinotecan(I) have demonstrated activity both as monotherapy as in combination regimen for this neoplasm. We present preliminary data from our experience in patients with SCLC refractory or resistant to platinum.

Methods
We included patients with measurable disease that had progressed during or within six months of first-line chemotherapy based on platinum, with an Eastern Cooperative Oncology Group (ECOG) performance status <2, adequate liver, renal and bone marrow function. They were treated with (P): 75 mg/m2 and (I): 50 mg/m2, both drugs administered on days 1 and 8 of a 21 day cycle. Treatment was maintained until disease progression and/or unacceptable toxicity.

Results
We included 24 patients with a mean age of 59.5 years (43-79) and with metastases in two or more locations in 21 of them (87.5%). A median of 4 cycles of treatment was administered and eight patients (33.3%) received six or more cycles. The main reason for discontinuation of chemotherapy was disease progression, observed in 20 patients (83.3%). Partial response was documented in 16 patients (66.6%), stable disease in three (12.5%) and disease progression in five (20.8%). The median survival time was 24,9 weeks and the 1-year survival time was 22%. There have been no treatment-related deaths. The clinical and hematologic toxicities most frequently observed were grade 1 and 2: nausea (n:7; 29,2%), asthenia (n:7; 29,2%), anorexia (n:6; 25%), diarrhea (n:4; 16,6%), anemia (n:16; 66,6%) and neutropenia (n:12; 50%). There was one (4,1%) grade 4 and two (8,3%) grade 3 neutropenia. There were no cases of grade 4 clinical toxicity and there were eight (33,3%) grade 3 : three of diarrhea (12,5%), two hepatic (8,3%) and three of asthenia (12,5%).

Conclusion
This (P) and (I) regimen is an effective and well tolerated option for this subgroup of poor prognosis patients with SCLC. We still continue including patients in this protocol, which ensures future communications of the same.

Background
Standard therapy for extensive stage small cell lung cancer (ES-SCLC) with etoposide (VP16) plus cisplatin or carboplatin (Carbo) results in median time to progression (TTP) of 4 months with overall survival (OS) of 9 months. Bendamustine (B) induced DNA damage is repaired by excision repair and irinotecan (I), a topoisomerase-1 inhibitor (Top-1), leads to increases in topoisomerase-2 (Top-2), the target of VP16. Therefore, the sequence B+I → VP16+Carbo was hypothesized to increase TTP by exploiting mitotic catastrophe, with subjects with low ERCC-1 expression and high Top-1 or Top-2 expression having longer TTP and OS compared to those with high ERCC-1 expression

Methods
This is an open label trial enrolling patients (pts) with evaluable ES-SCLC. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of B+I; the phase IIa primary endpoint was TTP after B+I→E+C. Secondary endpoints were objective response rate (ORR) and OS. In the phase I (N=15), pts received I (150 mg/m[2], d 1) with B at 80, 100, or 120 mg/m[2]/day (d 1,2) every 3 weeks for 3 cycles. Phase IIa pts were treated at the selected phase II dose of B+I for 3 cycles, followed by E (100 mg/m[2], d 1-3) + Carbo (AUC 6, d 1) for 3 cycles. Restaging was performed after 3 cycles of each regimen. The phase IIa was powered to detect a 30% increase in TTP from 4 to 5.2 m with a of 0.1. The Kaplan-Meier method was used to calculate TTP and OS. Toxicities were evaluated using the NCI CTCAE.

Results
The MTD of B was not reached and a dose of 100 mg/m[2 ]was selected as the phase IIa dose, with dose-escalation allowed in subsequent cycles of therapy for ≤ grade 2 toxicity. Dose limiting toxicities were diarrhea, nausea, and vomiting. Two treatment-related deaths, from metabolic encephalopathy and from neutropenic sepsis, occurred in the Phase IIa portion. The commonest grade 3/4 hematologic toxicity was neutropenia. Fatigue, nausea, vomiting, and diarrhea were common non-hematologic toxicities. Efficacy Parameters (N=28): Median TTP 6.0 m (95% CI 4.8-7.2); Median OS 10.0 m (95% CI 8.4-11.6); ORR 83% (4% CR); Median tumor reduction after B+I 65%; Median tumor reduction after E+C 73%. Statistically significant prognostic factors for TTP were sex, LDH, Top-1 and Top-2 and for OS were Top-2 and LDH. The predictive significance of Top-1 for TTP is confounded by insufficient samples with no expression of Top-1 and failure to demonstrate correlation with ERCC1 levels may have been related to antibody selection – reanalysis in in progress.

Conclusion
B+I is an active regimen in ES-SCLC and the treatment sequence B+I→E+C seems to improve the TTP and OS in ES-SCLC compared to historic results for E+C. Toxicities were increased compared to historic results for E+C, but were manageable. Correlative studies with pre-treatment assessment of tumor ERCC-1 and Top-2 as predictors of response are ongoing.

Background
The aim of this study was to investigate the clinical significance of sum of the maximum standardized uptake value on pretreatment positron emission tomography/computed tomography ([18]F-FDG-PET/CT) in patients with newly diagnosed small cell lung cancer (SCLC) treated with front-line platinum-based chemotherapy.

Methods
We retrospectively analyzed 93 SCLC patients from March 2005 to May 2013 who underwent pretreatment [18]F-FDG-PET/CT. The sum of the maximum standardized uptake value (sumSUV~max~) was measured in all malignant lesions up to a maximum of five lesions and a maximum of two lesions per organ according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Results
Patients were divided into two groups according to the median value of sumSUV~max~ (46 patients, < 21.8; 47 patients, ≥ 21.8). Although no significant difference was found between low and high sumSUV~max~ group (low versus high sumSUV~max, ~87.9% versus 76.9%; p = 0.186) in response rate (RR) following front-line platinum based chemotherapy, the group with low sumSUV~max~ showed significantly better overall survival (OS) [low versus high sumSUV~max~, 18.9 months (95% CI, 15.3-22.6) versus 10.8 months (95% CI, 7.6-14.1); p = 0.002] as well as better progression free survival (PFS) [low versus high sumSUV~max~, 8.3 months (95% CI, 6.9-9.7) versus 6.2 months (95% CI, 5.8-6.6); p = 0.005], compared with the group with high sumSUV~max~. Moreover, multuvariate analysis revealed that high sumSUV~max ~alone was an independent poor prognostic factor for OS (HR 1.95, 95% CI 1.12-3.39; p = 0.018).

Conclusion
This study showed that the sumSUV~max~ in pretreatment [18]F-FDG PET/CT was significantly correlated with the OS and PFS in patients with SCLC treated with front-line platinum based chemotherapy.

Background
Thoracic radiation target volume for limited-stage small cell lung cancer (SCLC) has long been a controversial topic. This study prospectively compares the local/regional failure pattern and overall survival (OS) between limited-stage SCLC patients who received different target volumes of thoracic radiotherapy (TRT) after induction chemotherapy.

Methods
Patients diagnosed as limited-stage (AJCC/UICC T1-4N0-3M0) SCLC received 2 cycles of etoposide and cisplatin (EP) and were randomly assigned to receive TRT to either the post-induction tumor extent (study arm) or pre-induction chemotherapy tumor extent (control arm). Elective nodal irradiation was omitted in both arms i.e. clinical target volume-nodal included only initially involved nodal regions. TRT dosage of forty-five Gy/30Fx/19d was administered concurrently with the third cycle of EP regimen. Then, additional 3 cycles of EP consolidation were administered. Prophylactic cranial irradiation was administered to patients who achieved complete or partial remission.

Results
Seventy-nine and 91 patients were randomly assigned to study arm and control arm. Five patients in study arm and 1 patient in control arm developed distant metastasis before TRT and received palliative treatment. One patient in study arm developed spontaneous pneumothorax and did not receive TRT. These patients were not included in the analysis of local/regional failure. However, they were included in the analysis of OS. Median follow up time for the whole group was 15.6 months (1.1 months- 129.3 months). The local recurrence rates were 30.1% (22/73) and 33.3% (30/90) respectively (P = .73). The isolated nodal failure (INF) rates were 2.7% (2/73) and 5.6% (5/90) respectively (P = .46). All INF were developed in supraclavicular regions except for one patient developed contralateral hilum lymph node recurrence. The estimated 1 and 2-year local/regional progression free survival time were 88.6%, 82.1% and 77.3%, 63.5% respectively in study arm and control arm (P = .56). The median OS time were 23.5 months (95% CI: 15.5-31.4 months) and 25.4 months (95% CI: 19.6-31.1 months) respectively in study arm and control arm. One, three and 5-year OS rates were 79.4%, 33.6%, 22.5% and 84.0%, 34.3%, 29.1% respectively (P = .74).Figure 1

Conclusion
The results indicate that irradiation to the post-chemotherapy tumor extent and initially involved positive nodal regions did not increase local/regional failure. However, the sample number in this analysis did not meet the design requirements. Enrollment of patients is still in progress.

Background
Quantifying the burden of malignant pleural mesothelioma (MPM) is an important yet challenging task. Little is understood about the societal and economic costs following a diagnosis of MPM. We investigated survival, years of life lost, and direct medical costs associated with MPM using data from Australia and Taiwan.

Methods
159 and 136 MPM patients from New South Wales (NSW) Disease Dust Board data and Taiwanese Cancer Registry (TCR) data respectively were included in: (i) survival function analyses and (ii) analyses to estimate the years of life lost associated with a MPM diagnosis. Further, data on 428 patients from the Taiwanese National Health Insurance Research Database, and the NSW data linked to Medicare data, were also used to (iii) estimate lifetime healthcare expenditure following a MPM diagnosis.

Results
(i) The mean age at MPM diagnosis in NSW was 71 and 60 in Taiwan. Median survival in months for NSW MPM patients was 11.7 (95% CI 9.3, 13.5) and 6.0 (95% CI 5.1, 7.8) for TCR patients. Four and eight percent of patients in NSW and Taiwan respectively were estimated to survive up to five years following a MPM diagnosis. (ii) The lifetime survival difference between the MPM patient cohort and a comparable population free of the disease was estimated to be 13.6 (95% CI 13.4, 13.8) years in the NSW cohort and 18.8 (95% CI 18.5, 19.1) years in the TCR cohort. (iii) Using national health insurance data in Taiwan, we estimated that the direct heath care costs following a MPM diagnosis to be USD$18,812. In NSW, this cost was estimated to be USD$20,573.

Conclusion
We analysed MPM cohort data from Taiwan and Australia to estimate survival and expected life years lost, with possible differences in the age at diagnosis and median survival. We also analysed Taiwan and Australian data to estimate direct medical costs following a MPM diagnosis. The impact of selection bias in this study cannot be ruled out as there is likely under-ascertainment of MPM cases in the Taiwanese Cancer Registry and the NSW data is a subset of all MPM cases diagnosed in NSW. However, these estimates provide useful data to contribute to evidence-based clinical and policy decision-making in the area of MPM prevention and care services.

Background
After initial therapy with pemetrexed/platinum, second-line therapy options are not well established. Gemcitabine and vinorelbine are often used based on small trials and first-line data. To augment the existing data, we examined our institutional experience using vinorelbine and gemcitabine in patients with previously treated MPM.

Methods
We reviewed the records of all patients treated with vinorelbine and/or gemcitabine as second- or third-line therapy for MPM between 2003 and 2010. Vinorelbine was administered at a dose of 25 mg/m[2] days 1 and 8 in a 3-week cycle and gemcitabine was given at 1000 mg/m[2] days 1, 8, and 15 in 28 day cycles. CT scans were generally performed after every two cycles. Imaging studies were reviewed with a radiologist according to the modified RECIST criteria.

Results
60 patients were identified: 33 treated with vinorelbine, 15 with gemcitabine, and 12 with both. Patient characteristics are as follows: 78% men: median age 67 (range 41-85); 63% epithelioid, 19% mixed histology, and 18% sarcomatoid; 83% received first-line pemetrexed-platinum therapy and 10% gemcitabine-platinum therapy. One partial radiographic response was identified among the 56 patients with follow up imaging available for review (Figure 1) giving a response rate of 2% (95% CI 0-5%). With gemcitabine, 10 patients (37%) had radiographic progression, 6 (22%) had clinical progression, 6 (22%) had radiographic stable disease, 4 (15%) had clinically stable disease, and 1 (4%) had radiographic partial response. With vinorelbine, 20 patients (43%) had radiographic progression, 2 (4%) had clinical progression, 19 (42%) had radiographic stable disease, 4 (8%) had clinically stable disease, and there were no responses. 53% experienced at least one episode of grade 3-4 toxicity, most commonly anemia, neutropenia, fatigue, and neutropenic fever. 24 patients received more than 2 cycles. Median progression free survival was 1.6 months and median overall survival was 5 months. Figure 1

Conclusion
Response to second-line therapy with gemcitabine or vinorelbine is rare. The rate of stable disease suggests some level of activity of these agents. Therefore, it remains a reasonable standard therapeutic option. However, survival was comparable to the placebo arm in the phase III vorinostat trial (Krug, ECCO/ESMO, 2011). This lack of efficacy supports the use of placebo control arms in randomized second-line MPM trials. Novel therapies are desperately needed for this patient population.

Background
Background: Malignant pleural mesothelioma (MPM) is a relatively rare, but aggressive tumor that causes high mortality. The major risk factor involved in the etiology is environmental and occupational exposure to asbestos. The optimal modality of therapy is controversial.

Methods
Methods: The present study retrospectively evaluated the 141 patients from the database.

Results
Results: There were 80 males and 61 females with a mean age of 56 ± 1.07 years. The median survival in patients who were administered front-line chemotherapy was 17 months (95% CI: 13.19-20.81). 106 patients were administered pemetrexed-platinum combination and 35 patients were administered gemcitabine-platinum combination as front-line chemotherapy. For the patients who received pemetrexed-platinum regimen, a median of 6 cycles of chemotherapy was administered and 50 patients (47.2%) were able to receive all 6 cycles as planned. For the patients who received gemcitabine-platinum regimen, a median of 6 cycles of chemotherapy was administered and 19 patients (54.3%) were able to receive all 6 cycles. Median survival was found 16 months in the pemetrexed-platinum regimen and 26 months in the gemcitabine- platinum regimen. There was no statistically significant difference between the patients who received pemetrexed-platinum and gemcitabine-platinum regimens in terms of the median overall survival (p = 0.15).

Conclusion
Conclusions: Results of our study suggest that chemotherapy prolongs overall survival. Survival rates in patients who received combining platinum analogues with pemetrexed or gemcitabine as front-line chemotherapy were found to be similar.

Background
Survival after recurrence following surgical management with curative intent for malignant pleural mesothelioma is typically measured in months. In this study, we compare survival after recurrence in patients progression free less than or greater than one year after radical pleurectomy.

Methods
67 consecutive patients with malignant pleural mesothelioma, epithelial subtype, who underwent radical pleurectomy and intraoperative photodynamic therapy were assessed in this IRB-approved study. Four patients who experienced perioperative mortality were excluded from this analysis. Local recurrence was defined as recurrent disease in the ipsilateral hemithorax. Early vs. late recurrence was defined as recurrence before versus after the median recurrence time, respectively. STAT3 expression was quantified in tissue microarrays using computer-based quantification of immunohistochemical staining.

Results
Among the 63 evaluable patients, 78% (n=49) were male, the median age of patients was 64 years, and the overwhelming majority (87.5%) had locally advanced (AJCC stage3/4) disease. 49 patients (78%) had lymph node metastases (N1/N2). 60 patients (95%) received neoadjuvant or adjuvant pemetrexed-based chemotherapy. With a median follow-up of 31 months, 42 patients demonstrated disease recurrence. Of these recurrences, 18 were isolated local recurrences and 24 were combined local + distant. The median time to recurrence was 11.6 months and patients who experienced an early recurrence (<11.6 mo) demonstrated significantly decreased survival as compared to patients experiencing a late recurrence (p < 0.0001, Figure 1). The median survival after recurrence was significantly decreased for patients who experienced an early vs late recurrence (54.7 mo [46.0-63.4 mo 95% CI] vs 10.8 mo [8.5-22.7 mo 95 % CI], respectively). We and others have previously shown that STAT3 expression can make mesothelioma more resistant to cytotoxic agents such as chemotherapy or photodynamic therapy. Preliminary analysis of TMA staining indicates that patients who experience an early disease recurrence in our series exhibit significantly higher STAT3 expression. Figure 1

Conclusion
This study is among the largest to describe the survival after initial recurrence for malignant pleural mesothelioma in patients undergoing definitive surgical management. Patients recurring prior to the median of 11.6 months experienced an aggressive tumor recurrence phenotype with a median 10.3 months from recurrence to death. Patients recurring after the median of 11.6 months experienced a relatively indolent disease course with a median survival of 37 months after recurrence. Further evaluation and additional studies are necessary to confirm if elevated STAT3 expression could be a poor prognostic factor for patients undergoing radical pleurectomy, photodynamic therapy and chemotherapy.

Background
Malignant pleural mesothelioma (MPM) remains an almost universally fatal disease. Preclinical models indicate that the oncolytic modified vaccine strain measles virus (MV) carrying the gene for the human sodium-iodine symporter (NIS) - MV-NIS preferentially targets MPM tumors cell. In patients with refractory ovarian cancer the intraperitonial administration of MV-NIS was recently found to be safe and induced an anti-tumor immune response.

Methods
Phase I dose escalation study (3+3 design). MV-NIS is administered intrapleurally. Starting dose level was 10[8] TICID 50 (Level 1) and the current dose level is 3 x 10[8] TICID 50 (Level 2). In the absence of dose limiting toxicity and disease progression patients continue MV-NIS therapy for up to six 28-day cycles. MV-NIS infection and replication is monitored by Iodine[123] SPECT/CT and RT-PCR and anti-tumor and anti-viral immunity are monitored in correlative studies. Patients are followed clinically using modified RECIST criteria.

Results
Up to now 4 patients have received MV-NIS therapy. Three patients were treated at Level 1 and the fourth patient at Level 2. No dose limiting adverse events occurred. The best therapeutic response was stable disease, observed in patient #1 for 6 months and patient #2 for 2 months. The remaining two patients progressed radiologically after one treatment cycle. I[123] SPECT-CT imaging did not demonstrate changes in iodine uptake compared to baseline in any of these patients. However, we detected MV RNA by QRT-PCR within the pleural cells 24-48 hours after the intrapleural administration of MV-NIS in 3/4 patients. In patient #4, treated with 3x10[8] TCID 50, MV replication was detectable within the pleural space by plaque assay 24 hours after MV-NIS administration. Following MV-NIS therapy a profound influx of neutrophils into the pleural space occurred in 3/4 patients and pleural fluid cytokine concentrations changed significantly. In addition, a humoral anti-tumor immune response emerged in patients #2.

Patient #	Age	Disease Stage	Histology	Line therapy
1	75	II (T2N0M0)	Epitheloid	First
2	53	IV (T4N0M0)	Epitheloid	Second
3	84	IV (T4N0M0)	Epitheloid	First
4	73	IV (T2N3M0)	Mixed	First

Conclusion
Thus far the intrapleural administration of MV-NIS appears to be safe and well tolerated in MPM. Our study will continue to enroll patients.