Virtual Library

Background
Non small cell lung cancer with brain metastases are usually associated with poor outcomes and survival and about 40-50% of all patients with lung cancer develop brain metastases during the course. The poor outcomes and relapses following WBRT alone indicate a need for new therapeutic options. As some patients with NSCLC have mutations in the EGFR and treating with WBRT with the anti-EGFR agent erlotinib in patients of NSCLC with brain metastases may benefit the patients in terms of disease regression and possible improvement in quality of life. Temozolomide has been already used alone or in combination with radiotherapy in the treatment of primary brain tumors and there are few studies showing its benefits in metastatic brain with WBRT. In this study we test the feasibility and efficacy of both of the drugs with WBRT.

Methods
A total of 12 elderly patients of biopsy proven adenocarcinoma lung with brain metastases (on MRI) were analyzed from July 2010 to March 2012. All the patients were planned for palliative radiation of 30 Gy/10#/2 weeks to local disease with WBRT of 20 Gy/5#/1 week with concurrent Temozolomide@ 75mg/m[2] followed by assessment for further therapy after 3 weeks of radiation. All the patients were evaluated 3 weekly for assessment of symptom relief and improvement or progression. After 3 weeks all the patients were started on Erlotinib@ 150 mg, daily and Temozolamide@ 150-200 mg/m[2], D1-5, 4 weekly.

Results
The patient's age ranged from 58 to 75 years. All the patients completed the scheduled radiation with oral steroids. Five patients progressed and died between 3 and 10 months. One patient defaulted during the radiation therapy and another after completion of 6 cycles of oral chemotherapy. Only 5 patients could complete the 12 cycles of oral chemotherapy with Temozolamide and Erlotinib, 4 weekly. Only two patient needed dose reduction of Erlotinib to 100 mg due to grade III rashes in 3rd cycle. The patients who improved after local and brain RT have shown to tolerate the further oral chemotherapy. These patients are still alive with the metastatic disease.

Conclusion
The combination of Erlotinib with temozolomide appears to be a promising therapy for treating brain metastases in NSCLC in terms of tolerability and efficacy. Further studies need to be done in our set up of patients.

Background
Half of Non-small cell lung cancers are diagnosed in locally advanced stage (LA-NSCLC) and warrant multidisciplinary treatments including chemotherapy, radiation, and surgery (S) in a not well-defined combination and sequence. We compared tolerance and effectiveness of different combos of inductive chemo (iCT) or chemoradiotherapy (iCRT) followed by S or consolidative radiation (RT)

Methods
We retrospectively reviewed 108 consecutive LA-NSCLC diagnosed in our center between October-2004 and June-2012 and treated with: 1) iCRT+S (N= 24); 2) iCT+S (N= 31); 3) iCRT+RT (N= 36); 4) iCT+RT (N= 17). Their tolerance, response, and outcome were statistically compared. Survival of five patients that progressed during inductive therapy was not analyzed

Results
Mean age of the patients was 66.2 years-old, 92% were male, and 85.1% ECOG-0. Histology was squamous carcinoma in 71.3%, non-specified NSCLC in 15.7%, and adenocarcinoma in 12%. iCT included platin-doublets with taxanes, vinorelbine, and gemcitabine. CBDCA-combinations were commonly used in elderly patients (15.6% vs. 31.8%, p= 0.001). Grade 3-4 toxicity was observed in 14.8% of inductive therapies, without significant differences between iCT and iCRT arms (p= 0.976). No patient interrupted therapies due to toxicity. Progression rate was higher with iCT than iCRT (8.3% vs. 0; p= 0.023). S was performed in 51 patients (pneumonectomy 30%, bi/lobectomy 56%). Severe S complications appeared in 13.7% of cases. Three patients in the iCRT+S arm died due to early postoperative complications. Complete pathologic responses were higher with iCRT than iCT (25% vs. 11.5%, p= 0.049). Resected patients presented better disease free (DFS) and overall survivals (OS) than those definitively radiated (27.9 vs. 12 months, p= 0.000; and 37.8 vs. 25.9 months, p= 0.009). Higher DFS and OS was found among patients of the iCRT+S arm (p= 0.000 and p= 0.049, respectively)

Conclusion
Those LA-NSCLC that achieved S after inductive therapy presented a better outcome that those non-resected. iCRT+S was tolerable, feasible, and obtained the higher response and survival rate of our series, although these results are biased by the better prognosis of resectable patients. Anyway, prospective trials are warranted to confirm the benefits of triple multidisciplinary approach. Figure 1. DFS and OS Kaplan-Meier curves of patients according to the treatment arm. Figure 1

Background
Nimotuzumab, a humanized IgG~1~ monoclonal anti-EGFR antibody, is approved and widely used in patients (pts) with head and neck cancer or malignant glioma in combination with radiotherapy (RT) in several countries. In previous clinical studies, nimotuzumab has demonstrated a very mild and low incidence of skin toxicity compared to other anti-EGFR antibodies. On in-vitro and in-vivo experiments using NSCLC cell lines, nimotuzumab showed a radio-sensitizing effect.

Methods
This open-label, multicenter phase II study evaluated the tolerability and efficacy of nimotuzumab in combination with concurrent CRT in pts with unresectable locally advanced NSCLC. All eligible pts received concurrent thoracic RT (60 Gy, 2 Gy/day, 6 weeks from day 1) and 4 cycles of chemotherapy (cisplatin 80 mg/m[2] on day 1, vinorelbine 20 mg/m[2] on days 1 and 8) once every 4 weeks as scheduled. Nimotuzumab (200 mg) was administrated once a week from cycle 1 to 4. The primary endpoint was tolerability in combination with concurrent CRT, which was measured by the percentage of pts who completed 60 Gy of RT within 8 weeks, completed 2 cycles of chemotherapy and received more than 75% of nimotuzumab.

Results
Between June 2009 and May 2010, 40 pts were enrolled from 7 institutions in Japan, and 39 eligible pts received the study treatment. The pts characteristics (n = 39) were as follows: 62 years (median); male/female, 34/5; stage IIIA/B, 21/18; PS0/1, 25/14. Thirty-four pts (87%) met the criteria for treatment tolerability, and 38 pts (97%) completed 60 Gy of RT within 8 weeks. Infusion reaction, >grade 3 skin rash, >grade 3 radiation pneumonitis, or >grade 4 nonhematological toxicity were not observed. The 2-year overall survival rate for the 39 pts was 76% (95% CI; 59-87%). The median PFS was 16.7 months; and 30 pts were alive at the cutoff date (Nov 2011). The 1-year PFS rate for pts with squamous cell carcinoma (Sq; n = 16) was 75%, while that for pts with non-squamous cell carcinoma (non-Sq; n = 23) was 41%. In terms of the first relapse site, in-field relapse rates were low for both Sq (3/16; 19%) and non-Sq (3/23; 13%). However, the distant relapse rate was significantly higher for non-Sq (15/23; 65%) than that for Sq (2/16; 13%) (p<0.01, chi-square test with Yates correction).

Conclusion
Addition of nimotuzumab to the concurrent CRT in this setting was well tolerated with clinical benefit to the patients. The low in field relapse rates may be attributed to the radio-sensitizing effect of nimotuzumab. These findings warrant further clinical evaluation of nimotuzumab/cisplatin/vinorelbine/RT in a phase III trial.

Background
Series on aggressive local treatment in selected patients with oligometastatic non-small cell lung cancer (NSCLC) are mostly retrospective, and prospective data are scarce (De Ruysscher et al, JTO 7:1547-1555, 2012). Although a precise definition is lacking, ‘oligometastatic NSCLC’ is considered an intermediate biologic state of restricted metastatic capacity with a limited number of metastases. The turning point between oligometastatic and polymetastatic is merely based on personal opinion and situated somewhere between 1 and 5 distant metastases. In the absence of clear definitions or clinical practice recommendations, a treatment decision is mainly driven by the opinion of each local multidisciplinary tumor board (MDTB).

Methods
As the consideration of and the treatment modality for oligometastatic NSCLC is a controversial area in respiratory oncology, in preparation of a recent dedicated workshop, we simulated a MDTB with international experts in the field. Multiple disciplines from 7 different centers participated in the MDTB, including pathology (1), nuclear medicine physician (1), thoracic surgery (3), radiation oncology (3), and respiratory oncology (3). Participants were asked to assess an electronic file describing 10 clinical ‘oligometastatic NSCLC’ cases, with 2 simple questions per case: 1. Do you consider this case ‘oligometastatic’ (Yes/No) and 2. What is your preferred treatment proposal.

Results
A full response was returned by all 11 specialists taking part in the simulated MDTB. Only 1 case was considered ‘oligometastatic NSCLC’ by all MDTB members. The presented cases were considered by a median of 78% (range 36-100%) of responders as true oligometastatic disease. Despite the fact that each responder gave only one treatment proposal, a median of 4 different treatment proposals (range 2-6) was made per case. Except for brain metastases, most team members would treat the locoregional thoracic disease before the distant metastases. No preference towards neo-adjuvant or adjuvant chemotherapy could be found. The option for surgery or radiation therapy as part of a combined modality treatment was mainly driven by the physicians’ preference.

Conclusion
Our simulated MDTB shows that oligometastatic NSCLC is an entity with many unanswered questions, and thus a major challenge for clinicians. Patients with oligometastatic NSCLC are in the need of 1. discussion at an experienced multidisciplinary tumor board to select patients for a radical combined modality approach; 2. multidisciplinary prospective research protocols to set better definitions of oligometastic NSCLC, evaluate the validity of a radical approach, and to optimize therapeutic modalities.

Background
Neoadjuvant chemotherapy followed by surgical resection is uniquely permits assessment of the in vivo response to therapy in patients with IIIA non-small cell lung cancer. Studies of neoadjuvant chemotherapy often focus only on those who are ultimately resected. We describe an “intention-to-treat” analysis of sequential patients with stage IIIA adenocarcinomas receiving neoadjuvant chemotherapy with intent of surgical resection.

Methods
Using natural language processing software, we searched the electronic medical record at Memorial-Sloan Kettering Cancer Center for “neoadjuvant,” “preoperative,” or “induction” in physicians’ notes. Cases were limited to those with stage IIIA lung adenocarcinoma deemed resectable by a thoracic surgeon and treated with neoadjuvant chemotherapy (without radiation), including those enrolled in prospective clinical trials. Event-free survival (date of diagnosis to recurrence, relapse or death) and overall survival (date of diagnosis to death) were assessed using Kaplan-Meier methods.

Results
From 2007 until 08/2012, 129 patients were identified. Median follow up is 25 months (range 1-76). The patient details are described. 94/129 (73%) were treated with cisplatin-based therapy.Figure 1 The CONSORT diagram below describes the treatment patients ultimately received. Figure 2 The median EFS and OS were 16 (95% CI 13-22) and 44 (95% CI 36-NA) months. OS at 1, 2 and 3-years were 77%, 55%, and 32%. EFS plateaued at 23%, estimating the rate of cure. Overall survival strongly favored surgical resection over salvage radiation (HR=0.5, 95% CI 0.16-1.05).

Conclusion
These data provide unique perspective on the outcomes of patients with IIIA adenocarcinoma treated with neoadjuvant chemotherapy with intent of surgical resection. EFS and OS compare favorably to historical outcomes in this stage of disease, demonstrating the value of the neoadjuvant approach. The inferior survival in patients treated with radiation as a “salvage” approach emphasizes the recommendation for definitive concurrent chemoradiation in those unlikely to be resectable.

Background
Concurrent chemoradiation (C-CRT) is standard therapy for fit patients with unresectable, LA-NSCLC. We evaluated outcomes of patients treated with curative intent at our centre for quality assurance, and to compare outcomes between elderly (≥75) and younger patients.

Methods
Patients with stages IIIA/ IIIB NSCLC from 2002 to 2008 were identified, and those planned for curative-intent radiation (minimum 50Gy) included, irrespective if therapy was actually completed. Charts were reviewed for patient demographics, baseline prognostic factors, treatments planned and administered, hospitalizations and outcomes. Multivariable analyses were performed to determine factors associated with survival.

Results
329 patients were included: median age 66 (range 40-89), 60% male, 15% ECOG 2+, 60% IIIB, 35% weight loss >5%. 20% (66/329) were ≥75. C-CRT, sequential CRT and radiation alone were delivered in 85%, 5%, and 10% of cases, respectively; the elderly were less likely to receive C-CRT (61% vs. 91%). Median survival (all patients) was 18.4 months; for < and ≥75 cohorts, MS were 20.8 and 16.4 months (p=0.0533). 3 and 5 year OS (all patients) were 29% and 17%; for the < and ≥75 cohorts values were 31/21% and 19/8%. Elderly patients had lower treatment-related hospitalization (6% vs. 20%) and death (2% vs. 5%). Radiation compliance was equivalent however chemotherapy completion was higher in younger patients (78% vs. 45%). In multivariate analysis, age ≥75 (HR=1.68, 95% CI 1.03-2.75, p=0.038), female gender (HR=0.60, 95% CI 0.41-0.87, p=0.008), and completion of radiation therapy (HR=0.39, 95% CI 0.25-0.62, p<0.0001) were independent predictors of outcome. Figure 1

Conclusion
Outcomes of patients with LA-NSCLC offered curative therapy at the Ottawa Hospital Cancer Centre are comparable to those obtained in clinical trials of C-CRT, despite a more unselected population with a higher proportion of poor prognostic features. Those ≥75 were less likely to be offered C-CRT and were less likely to complete planned chemotherapy. However fit patients ≥75 offered radical therapy still have reasonable MS and 3-year OS.

Background
We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.

Methods
　cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with　CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Additional analysis are being performed to assess ERCC1 isoform expression with an isoform-specific TaqMan probe (Applied Biosystems, CA). The expression of each gene was dichotomized according to its median value.

Results
Molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). We quantitated ERCC1 by isotype (202 and 204 cannot be distinguished). There was a trend in patients with high 201 or 202/204, CDDP/S-1 was worse than S-1.

Conclusion
Quantitation of ERCC1 by isotype may define a patient subset that would benefit from postoperative platinum therapy.

Background
To retrospectively investigate the prognosis of locally advanced non-small cell lung cancer (LA-NSCLC) patients initially presenting with superior vena cava syndrome (SVCS) following partially accelerated definitive concurrent chemoradiotherapy (C-CRT).

Methods
Forty-seven LA-NSCLC patients presented with SVCS between June 2007 and December 2011 were included. All patients received an initial daily 4 Gy radiotherapy (RT) followed by weekly cisplatin-based chemotherapy given concurrently with 2 Gy daily RT for additional 26 fractions, which corresponds to a biologically equivalent dose (BED10) of 79.2 Gy. Primary endpoint was overall survival (OS).

Results
Median follow-up time was 20.3 months for whole cohort, and 37.4 months for surviving patients. Median age was 63 years. Squamous cell- and adenocarcinoma rates were 54 and 46%, respectively. Stage distribution was 29.8% stage IIIA and 70.2% stage IIIB. Treatment was relatively well tolerated. All patients were able to receive planned RT, and 39 (83%) received 4 or 5 courses of prescribed chemotherapy. There were no treatment related deaths at acute phase while 8 (17%) grade 4 hematologic toxicity was reported, with no grade 4 non-hematologic toxicity. At long term 2 patients died of tracheoesophageal fistula and caval rupture. Median, 2-, and 3-year OS were 19.4 months, 36.2%, and 25.5%, respectively. On univariate analyses; cause of SCVS (nodal vs. primary tumor; p<0.001), status of SVC (infiltrated vs. compressed; p<0.001), and tumor stage (IIIA vs. B; p<0.03) were the factors significantly associated with prognosis. Of these, cause of SCVS (p<0.001) and status of SVC (p<0.001) retained their significance on multivariate analyses.

Conclusion
Partially accelerated C-CRT regimen utilized here is reasonably safe and efficient in LA-NSCLC patients initially presenting with SVCS. Present survival rates, which are almost equivalent to those reported for similarly staged patients without SVCS suggest treatment of such patients with aggressive C-CRT protocols.

Background
Purpose of this study was to assess clinical outcomes of concurrent chemoradiotherapy (CRT) in Stage IIIB non-small cell lung cancer (LA-NSCLC) patients younger than 45 treated with concurrent chemoradiotherapy (CRT).

Methods
Medical records of 145 ≤45 years old patients out of 942 LA-NSCLC patients, who had been treated with definitive CRT [60-66 Gy thoracic radiotherapy (TRT) concurrently with 1-3 cycle cisplatin-based doublet (vinorelbine/docetaxel/etoposite/gemcitabine) chemotherapy] at our department between dates 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
At the time of analyses, 58 (40%) patients were alive, and median follow-up for these patients was 30.5±11.2 months. For whole study group, median, 3- and 4-year OS, LRPFS and PFS were 24.8 months, 38% and 24%, 15.7 months, 26.3% and %18.9, and 12 months, 18.2% and 11.2%. On univariate analyses, CRT duration (≤50 vs. >50 days; p<0.001), pretreatment anemia (Hb<12 g/dl vs. ≥12; p<0.001) were significantly associated with survival while there was a statistical trend for nodal stage (N2 vs N3; p=0.09). On multivariate analyses, longer CRT duration and pretreatment anemia retained their prognostic significance.

Conclusion
Median OS of 24.8 months for younger stage IIIB NSCLC patient treated with CRT is promising, and superior OS in patients with no pretreatment anemia and in patients completing their CRT earlier than 50 days suggest that pretreatment anemia should be corrected and all preventive measures should be performed to complete CRT at planned period of time.

Background
Aim of this study is to investigate the relationship between the treatment duration on prognosis in stage IIIB non-small cell lung cancer (NSCLC) patients treated with definitive concurrent chemoradiotherapy (CRT).

Methods
Medical records of 824 18-70 years old stage IIIB NSCLC patients treated at our department between dates January 2007 and December 2011 were retrospectively evaluated. Patients received 60-66 Gy thoracic radiotherapy concurrently with at least 1 cycle cisplatin-vinorelbine/docetaxel (q21) regimen chemotherapy. 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 locoreginal PFS (LRPFS).

Results
At a median follow-up of 22.8 months (range 17.4-25.2), Median OS, PFS and LRPFS for whole group were 21.2 (%95 CI: 20.2-22.2), 9.9 (%95 CI: 9.4-10.3) and 13.7 months (%95 CI: 13.1-14.3), respectively. The most significant cut off point for CRT duration defined in ROC (receiver operating characteristic) curve analysis was 50.5 days, and patients were dichotomized into two groups; namely Group 1: ≤50 (n=420) and Group 2: ≥ 50 (n=404). On comparative survival analyses, patients completing their CRT in shorter period of time revealed superior OS (26.6 vs.15.5 months; p<0.001), PFS (12.8 vs.7.7 months; p<0.001), and LRPFS (16.4 vs.10.2 months; p<0.001) than the others. Duration of CRT retained its significant association with OS, PFS, and LRPFS on multivariate analyses (p<0.001).

Conclusion
Results of this study has demonstrated that completion of CRT in longer than 50 days was associated with significantly shorter survival. Therefore, treatment delays due to religious or official holidays should be avoided, and all comprehensive palliative measures should be performed in order to minimize treatment-related toxicities that might potentially prevent shorter delivery of CRT.

Background
Concurrent chemoradiation is the standard of care for majority of medically fit patients with locally advanced (IIIA and IIIB) NSCLC. Whilst the optimal radiation dose and schedule is well established (66Gy in 30#) the optimal chemotherapy regimen is less certain due to a paucity of phase III chemotherapy trials in this context. Phase II studies have demonstrated high disease response rates with acceptable toxicities when weekly cisplatin and docetaxel were administered concurrently with radiotherapy.SWOG chemoradiotherapy regimen with cisplatin and etoposide which is commonly used has not been compared to modern cisplatin doublet in phase III setting. Furthermore, in our experience the SWOG regimen is associated with significant toxicity. In 2004 we adopted a local chemoradiation protocol using weekly low dose cisplatin and docetaxel.

Methods
We searched oncology pharmacy dispensing records to identify community based patients treated with weekly cisplatin (20mg/m[2]) and docetaxel (20mg/m[2]) doublet regimen between 2004 and 2011. This data was cross referenced with radiation oncology database to identify a cohort of patients with locally advanced NSCLC who received concurrent radical radiation.Disease stage was recorded as documented in medical records. Toxicity data was collected and graded according to the NCI criteria. Progression free survival(PFS) was calculated from commencement of treatment until radiologically confirmed recurrence.Overall survival(OS) was calculated from commencement of treatment until death from any cause.

Results
Sixty eligible patients were identified. Median age was 63 yrs. 75% patients were male. Predominant histologies were squamous (43%) and adenocarcinoma (35%).The majority of patients were current or ex smokers (57% and 37% respectively) and were ECOG 1 at start of treatment (72%). 58% patients had stage IIIA disease and 40% stage IIIB. In addition to concurrent chemoradiation, 42% received either induction or consolidation chemotherapy. Grade 3/4 non haematological toxicities included oesophagitis (36%) and pneumonitis (1 patient).Significant haematological toxicities were rare with grade 3/4 anaemia,neutropenia and thrombocytopenia seen in 1, 2 and 1 patient respectively.Grade 3 /4 esophagitis seen in 36% cases. Treatment compliance was good with 73% of patients completing planned 6 weeks of chemotherapy. Chemotherapy delay due to toxicity occurred in 20 % patients.At least one hospital admission was seen in 36% patients. One treatment related death occurred. Median PFS was 10 months. Median OS was 20 months. In patients who relapsed ,chest was the most common site (n=15) followed by brain (n=13). As on February 2013,17 patients remain alive whilst an additional 8 patients have been lost on followup.

Conclusion
Low dose cisplatin and docetaxel when given concurrently with definitive radiotherapy for locally advanced NSCLC is a feasible regimen with negligible haematological toxicity. The incidence of esophagitis whilst relatively high is main non haematological toxicity seen and is comparable to that of other published data using this chemoradiation regimen. Furthermore this toxicity had minimal impact on treatment compliance and was without longterm sequelae. We believe our regimen is an acceptable alternative to the SWOG regimen.

Background
There are many clinical trials reporting good outcomes of patients treated with curative RT. However, clinical trials populations are highly selected and there are limited data on whether these outcomes are seen in community practice in the Australian setting. The aim of the study was to evaluate the outcomes and toxicity of patients treated with curative RT +/- chemotherapy for NSCLC.

Methods
Electronic medical records at Liverpool and Macarthur Cancer Therapy Centres, NSW, Australia were queried to retrieve data on patients with Stage I-III NSCLC who were treated with curative RT (minimum dose 60Gy) between 1/1/2000-31/12/2010. Patient death records were available up until 16/1/2013 with a minimum follow up time for patients of 2 years. Patient demographic data, tumour, and treatment details were retrieved. The records were retrospectively reviewed to collect data on patient comorbidities and treatment toxicities. The Simplified Comorbidities Score (SCS) was used to score comorbidity. The median follow up time was 22 months. For Cancer Specific Survival (CSS), patients were censored if they had died from another cause or survived until the last date of follow up, and for Overall Survival (OS), patients were censored if they survived until the end of the study. Univariate and multivariate Cox proportional hazards models were used to assess predictors of CSS and OS.

Results
One hundred and sixty patients were treated with curative RT over this period. The median age was 69 years (range 36-89). Seventy-six patients received RT alone, 59 received concurrent chemo-radiation, and 25 received sequential chemo-radiation. Twenty-nine patients had stage I disease, 28 had stage II, and 103 had stage III. Median overall survival was 29 months for patients with stage I NSCLC, 26 months for stage II, and 18 months for stage III. For stage II and III patients treated with concurrent chemo-radiation, median survivals were 29 and 18 months and 2-year OS were 64 and 42% respectively. On multivariate analysis, stage II or III and weight loss ≥5% were predictive of cancer specific survival with hazard ratio 4.47 (95% CI: 10.8-18.55, p=0.039) and 2.23 (95% CI: 1.13-4.39, p=0.021). Toxicity was acceptable with 2% grade ≥3 radiation pneumonitis, 6% grade ≥3 oesophagitis, and 2% grade ≥3 febrile neutropenia. There was no treatment-related death. Performance status, age, SCS, respiratory function, pathology, and grade were not predictive of survival.

Conclusion
Curative intent RT +/- chemotherapy is well tolerated and effective treatment for inoperable or locally advanced NSCLC. Tumour outcomes and toxicities were comparable to those reported in clinical trials. Higher SCS was not correlated with worse survival in this cohort.

Background
This study assessed the impact of imaging, surgical, histopathologic and patient-related factors on the risks of local and distant recurrence and overall survival for patients with stage III-N2 non small cell lung carcinoma (NSCLC) undergoing definitive resection after neoadjuvant concurrent chemoradiation (neoCCRT).

Methods
We retrospectively examined 129 consecutive patients with stage III-N2 NSCLC received neoCCRT followed by curative surgery between 2008 and 2011. We reviewed clinical data and operation method. We also analyzed histopathologic factors such as subtype, pathologic invasive tumor characteristics, differentiation, residual tumor size, or the number of residual LNs as well as imaging characteristics on chest CT and PET/CT. Disease free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and predictive factors for recurrence and survival were identified by univariate and multivariate Cox-proportional analyses.

Results
112 (87%) patients were pathologically staged for N2-positive status (82 patients by mediastinoscopic biopsy and 30 patients by EBUS). The 5-year recurrence rate was 28.3 %, and the 5-year survival rate was 43.4 %. Five-year OS for patients with recurrence compared with those without was 29.5 versus 59.1 % (P = 0.028). Based on the multivariate Cox-proportional analysis and log-rank test, history of adjuvant therapy was the only significant prognostic predictor for prolonged OS (HR 0.134, 95 % CI 0.039–0.455, P = 0.001). As for recurrence, less size decrease on CT (HR 1.030, 95 % CI 1.005–1.056, P = 0.017), higher T stage (HR 2.450, 95 % CI 1.322–4.540, P = 0.004), larger residual tumor size on the pathologic specimen (HR 1.124, 95 % CI 1.010–1.252, P = 0.016), and presence of lymphovascular invasion (HR 4.180, 95 % CI 1.093–15.984, P = 0.037) were the significant predictors in both the multivariate Cox-proportional analysis and the log-rank test. Figure 1

Conclusion
Recurrence remains high in resected stage III-N2 NSCLC patients after neoCCRT and nodal downstaging, and patients who received adjuvant therapy had longer overall survival rate than patients who did not. Size decrease on CT, T stage, residual tumor size on the pathologic specimen, and presence of lymphovascular invasion would be predictive for higher recurrence and may necessitate more aggressive adjuvant treatment.

Background
Investigators from the Hoosier Oncology Group reported that there was no survival advantage but significant toxicity from the addition of docetaxel consolidation to immediate radiation and concurrent cisplatin (P)–etoposide (E) for treatment in patients with unresectable stage III non-small-cell lung carcinoma (NSCLC). Concurrent chemoradiotherapy alone is standard treatment for fit patients in this group. The aim of this prospective study is to investigate the survival rates of standard treatment for these patients in a real-life.

Methods
Eligible patients had unresectable stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, less than 5% weight loss and adequate organ function. Patients received P 50 mg/m2 intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m2 IV on days 1-5 and 29-33 concurrently with chest XRT to 63.00 Gy (1.8 Gy per fraction and 5 fractions per week).

Results
From January 2008 until December 2010, 59 patients were entered into the trial, 57 were evaluated. Patient characteristics were as follows: 94,7% male; median age, 56 years; 40,3% stage IIIA; and 59,7% stage IIIB; 64,9% squamous cell carcinoma, 17,5% adenocarcinoma. Objective response rate was 61,4% (complete response 19,3%). Grade 4 neutropenia was the most common toxicity (35,1%). 19,3% of patients experienced grade 2-3 pulmonary- late toxicity. 44 patients have died. 12,2% of patients had febrile neutropenia. One patient died due to renal toxicity. With a median follow-up time of 18 months, median progression-free survival (PFS) was 10,5 months, median overall survival (OS) was 18 months (11,7 to 24,2, 95% confidence interval), and two-, 3- and 4-year OS rates were 36,1%, 23,2%, and 16,9%, respectively. Two-, 3- and 4-year PFS rates were 17,4%, 13,2%, and 9,9%, respectively.

Conclusion
The survival rates in real-life studies as the current study can be expected to be mildly shorter than those in controlled clinical trials.

Background
The optimal management of locally advanced N2 positive non-small cell lung cancer (NSCLC) is still controversial. Some studies have shown promising results of neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgical resection in terms of survival benefit without increasing morbidity and mortality. However, the role of adjuvant treatment after completion of neoadjuvant CCRT followed by surgery in N2 positive NSCLC patients has not defined yet.

Methods
From March 2006 to December 2011, 249 N2 positive NSCLC patients received neoadjuvant CCRT (weekly docetaxel/cisplatin with 45Gy/25Fx of thoracic radiotherapy) followed by curative surgery. Patients who died with post-operative complications within a month after surgery (n=5) were excluded to minimize selection bias.

Results
Among 244 patients, 80 patients (32.8%) receieved adjuvant radiotherapy alone, 26 patients (10.7%) received adjuvant chemotherapy alone, 57 patients (23.4%) received both of adjuvant radiotherapy/chemotherapy, and 80 patients (32.8%) did not receive adjuvant treatment. Survival was compared according to adjuvant treatment (any kind of adjuvant treatment [n=164, 67.2%] vs. no adjuvant treatment [n=80, 32.8%]). There was no significant differences between two groups in age over 60 years, ECOG performance, initial T stage, initial multistation N2 disease, completion of neoadjuvant CCRT, R0 resection, and pathologic down staging of N2 disease. In the univariate analysis, median overall survival (OS) and progression-free survival (PFS) were 54.1 months vs. 37.9 months (P=0.016) and 23.4 months vs. 17.7 months (P=0.239) in adjuvant treatment group and no adjuvant treatment group, respectively. In subgroup analysis, adjuvant treatment group showed significantly better OS than no adjuvant treatment group in patients who achieved N2 down staging by neoadjuvant CCRT (n=146, 59.8%) (78.1 months vs. 44.7 months, P=0.027) but not in patients who did not achieve pathologic N2 down staging (n=98, 40.2%) (32.3 months vs. 21.6 months, P=0.125).

Conclusion
This results suggest that adjuvant treatment may contribute survival benefit even after completion of neoadjuvant CCRT following curative surgery in N2 positive NSCLC. The role of adjuvant treatment should be seeked further in carefully selected patients who benefit most, such as CCRT sensitive patients who achieved pathologic N2 down staging.

Background
It has been shown an improvement in survival with concurrent chemoradiation versus the sequential administration of both treatment modalities. In patients with unresectable stage III disease, chemotherapy may best be started soon after the diagnosis of unresectable NSCLC has been made. Cisplatin (CDDP) plus oral vinorelbine (OV) as induction and concomitant regimen with radiotherapy (RT) has shown good efficacy outcomes and safety profile (Vokes, Fournel, Krzakowski). The objective of this study was to evaluate the effectiveness and toxicities of the combination of CDDP and OV given at full doses concomitantly with RT in locally advanced (LA) non-small-cell lung cancer (NSCLC).

Methods
Between February 2010 and December 2011, 48 chemo-naïve patients (p) with histologically confirmed unresectable stage IIIA/IIIB LA NSCLC were treated. Treatment consisted of 4 cycles (cy) of OV 60 mg/m[2] on days 1 and 8 and CDDP 80 mg/m[2] every 3 weeks plus RT 66 Gy starting on day 1, cy 2. The primary objective is the overall response rate (ORR) using RECIST 1.0. A standard Fleming two stage design was used. The sample size calculated with a type 1 error of 0.05 and type 2 error of 0.01, taking P~0~ 20% and P~1~ 40%. The study was approved by the local Ethical Committees of the participating institutions.

Results
Patient’s characteristics were: Median age 61 years (range 34-72); ≥ 65y 42%; males 89.6%; PS0 42% / PS1 58%; smokers 52%; adenocarcinoma 30% / squamous 64%; stage IIIA 46% / IIIB 54%. Median of days between initial diagnosis and study start was 28 days. 75% p completed the treatment as per protocol. Relative dose intensities of OV and CDDP were 97%/98%, respectively. 14.7% of cy were delayed, 11.8% due to toxicity. Dose of day 8 OV was canceled or delayed in 8.2% of cy. Hematological toxicities (% p): grade (g) 3/4 neutropenia 33.3%; g3 anemia 12.5%; g3/4 thrombocytopenia 16.6%; febrile neutropenia concomitant during CT-RT 14.6%. Non-hematological toxicities (% p): g3 esophagitis 12.5%; g3 dyspnea 4.2%, g3 vomiting 4.2%, g3-4 infection 4.2%. 2 treatment-related deaths were reported, both during cycle 1. 42 p (87.5%) received RT, 7.1% under 60 Gy, 23.8% with RT delays or interruptions due to adverse events. 44 p were evaluable for response. ORR 77.3% [CI 95%, 62.2-88.5], DCR 88.6% [CR 2 p (4.5%), PR 32 p (72.7%), SD 5 p (11.4%)]. Median follow-up was 19 months (m) (range 0.47-39.4). Median progression free survival (PFS), 12 m [CI 95%, 7.3-16.6]; 1-year PFS, 48.3% [CI 95%, 33.6-63], 2-year PFS, 30% [CI 95%, 15.8-44.2]. Median time to progression (TTP), 13.3 m [CI 95%, 9.7-16.9]; 1-year TTP, 51.7% [CI 95%, 36.9-66.6], 2-year TTP, 33.3% [18.5-48.1]. Median overall survival was not reached; 1-year and 2-year survival rates were, 72.3% [CI 95%, 59.6-85.1] and 49.4% [CI 95%, 33.8-64.9], respectively.

Conclusion
This prospective phase II trial shows that the schedule of cisplatin plus oral vinorelbine concomitant with radiotherapy from 2[nd] cycle obtains a good efficacy with an acceptable safety profile. Clinical trial information: EudraCT Number: 2009-010436-17

Background
ConCRT is considered to be the standard of care in LA NSCLC. We adopted ConCRT as our standard of care for appropriately selected patients since 2005. This is an analysis of a register of all patients consecutively assigned ConCRT since 2005 (in an intent to treat analysis).

Methods
From Feb 2005 to Feb 2013 we assigned ConCRT for 56 consecutive patients with LA NSCLC, who were deemed unresectable; this included T4/N3/ “bulky” N2 disease or locally recurrent disease after initial surgery. Patients had ECOG performance status (PS) 0-2 and were treated with Cisplatin 75mg/m2 d1 and Vinorelbine 30mg/m2 d1-8, 3-weekly during the induction chemotherapy phase (i.e. full doses for the first 1-2 cycles) whilst with the addition of radical RT delivered concurrently with subsequent chemotherapy cycles, Vinorelbine was reduced to 12.5mg/m2 d1-8. After ensuring acceptable toxicity with the first 11 patients treated, subsequent patients received Vinorelbine at 15mg/m2 d1-8 during ConCRT and the number of treatment cycles was escalated to a maximum of 6. Patients received definitive CRT (59.4-64.8 Gy) unless surgery was planned, in which case restaging evaluation for potentially resectable patients was performed at 45-50.4 Gy. PET staging was only available in a minority of these patients, since 2011.

Results
56 patients: 51 men and 5 women. Median age was 63 (43-81); PS 0-1 n=47, PS 2 n=9. Radiological stage IIIB n=34 (61%), IIIA n=16 (29%), IIB n=6 (11%). Histology, squamous n=31, adenocarcinoma n=13, unspecified/other NSCLC n=12. Treatment delivered: median 4 cycles of chemotherapy (range 1-6) delivered. 50 patients (89%) completed ConCRT. Radiological response rates: Objective responses n=34 (29 partial, 5 complete) yielding a response rate of 61%; stable disease (SD) n=7; progressive disease (PD) n=7; of the remaining 8 non-evaluable patients, 6 patients did not complete ConCRT, either due to toxicity/death or disease progression. 7/50 patients who received ConCRT underwent surgery (5 lobectomies, 2 pneumonectomies). 6 of these 7 patients had a complete pathologic response (pCR) and 1 a near pCR. Kaplan Meier survival figures: median progression-free survival (PFS) 12.2 months (95% C.I. 8.8-15.6) and median overall survival (OS) 17.2 months (95% C.I. 11.8-22.6). There were 2 toxic deaths from neutropenic sepsis. The incidence of grade 3-4 oesophagitis or pneumonitis was < 10% and manageable. Detailed toxicity data will be presented in the full publication.

Conclusion
This regimen has produced encouraging results in a patient cohort with predominantly IIIB disease and with a significant minority of poor PS=2 patients, with close to 90% being able to complete the treatment. The 17.2 month median OS achieved in this cohort is similar to that reported previously from larger randomized phase III studies of ConCRT. Finally 11% of patients had pathological pCR, whist it appears that about 35% patients treated with this regime can achieve long-term survival.

Background
Cisplatin-based chemotherapy and concurrent radiotherapy are the standard treatments for locally advanced unresectable NSCLC. New therapeutic combinations using molecular targeted drugs are needed. IFCT-0803 Trial is a phase II study evaluating the benefit of adding cetuximab to a combination of concomitant radio-chemotherapy with cisplatin and pemetrexed in patients with stage III, non-squamous NSCLC. Data on safety and tolerance during the first 16 weeks of treatment, available after the inclusion of the first 62 eligible patients, are presented.

Methods
Based on a two-stage Simon approach, 106 patients will be included in IFCT-0803 trial. An interim analysis of the first 34 patients authorized the continuation of the study. Eligible patients receive conformal thoracic radiation with no elective nodal irradiation (66 Gy in 33 fractions, ICRU) along with cisplatin (75 mg/m[2]) and pemetrexed (500 mg/m[2]) on day 1 administered intravenously every 21 days for four cycles; weekly cetuximab (400 mg/m[2] for the first week, then 250 mg/m[2]) is added from the first week of therapy for a total of 12 doses. The primary objective is to assess the disease control rate at the 16[th] week, one month after treatment completion

Results
62 patients were included (37 male, 56 years mean age), PS 0 = 39 and PS 1 = 23, ever smoker = 57, stage IIIA = 31 and IIIB = 31, adenocarcinoma = 50. Compliance for the first 62 patients included was as follows: Day 1 chemotherapy was administered to 100% of patients on cycles 1 and 2, to 98.4% on cycle 3 and to 96.6% on cycle 4. Radiotherapy protocol was respected: median was 33 for number of fractions, 66 Gy for total dose, 46 days for duration of treatment, 39 patients had a maximal toxicity of grade 3 and 6 of grade 4. Table 1 lists the number of patients for the main categories of toxicity.

n=62	grade 1/2	grade 3	grade 4
anemia	32	4	0
neutropenia	24	20	5
thrombocytopenia	30	4	2*
general toxicity	42	13	0
skin toxicity	51	9	0
digestive toxicity (nausea and vomiting)	42	6	0
esophageal toxicity	43	10	0
febrile neutropenia	-	5	0
renal toxicity	4	3	0
neurologic toxicity	11	0	0

* :One patient died consecutively to a subdural hematoma caused by a fall, he had a grade 4 thrombocytopenia

Conclusion
IFCT-0803 trial is ongoing, the end of the inclusions is scheduled for October 2013. This combination therapy is feasible without any unexpected side effects.

Background
Transglutaminase 2 (TG2), a cross-linking enzyme, is involved in drug resistance and the constitutive activation of NF-κB, a pro-inflammatory transcription factor. We investigated the association of the EGFR-TKI or cytotoxic chemotherapy clinical efficacy with transglutaminase 2 and NF-ĸB expression in non-small cell lung cancer (NSCLC).

Methods
TG2 and NF-ĸB expression was immunohistochemically studied in 120 patients with NSCLC who received an operation. Kaplan-Meier survival analysis and Cox regression analysis were used to estimate the effect of TG2 and NF-ĸB expression on chemotherapy clinical efficacy.

Results
Median age of patients was 64 years (41–82). There were 102 (85%) cases of adenocarcinoma and 18 patients (15%) had other histologies. Eight patients received adjuvant chemotherapy, 29 received platinum-based doublet chemotherapy and another 29 patients received EGFR-TKI. Smoking status was as follows: 25 current, 16 former and 79 never. There were 55 patients with an EGFR mutation. TG2 median value was 50 (0 to 300) and NF-kB median value was 20 (0 to 240). Response to platinum-based doublet was as follows: Overall response rate (ORR) was 13.8% and disease control rate (DCR) was 69% (Complete response (CR) 0%, partial response (PR) 13.8%, stable disease (SD) 55.2% and progressive disease (PD) 24.1%). Responses to EGFR-TKI was as follows: ORR was 24.1% and DCR was 58.6% (CR 3.4%, PR 20.7%, SD 34.5% and PD 34.5%). Among the 88 patients who received adjuvant chemotherapy, disease-free survival (DFS) did not differ between the low and high TG2 groups. Among patients (n=29) who received palliative platinum-based doublet chemotherapy, progression free survival (PFS) was significantly longer in the low TG2 group when compared with the high TG2 group (34.0 versus 15.0 months, p = 0.003). Among those who received EGFR-TKI (n=29) (first line 7, second line 18, third line 3, fourth line 1), PFS was significantly longer in the low TG2 group when compared with high TG 2 group (11.0 versus 2.0 months, p = 0.013). In patients with EGFR wild-type mutations treated with EGFR-TKI, progression free survival was longer in patients with low TG2 expression (9.0 vs 2.0 months, p=0.013).

Conclusion
This study suggests that TG2 expression can be predictive of success of cytotoxic chemotherapy and EGFR-TKI for patients with non-small cell lung cancer, particularly in patients with EGFR wild-type mutations.

Background
FRAME was a non-interventional, prospective observational study of advanced or metastatic non-small cell lung cancer (NSCLC) patients initiating first-line treatment (FLT) with platinum-based therapies in a routine practice setting across 11 European countries.

Methods
Patient enrollment occurred between April 2009 and February 2011. Consenting adults with Stage IIIB or IV NSCLC receiving platinum-based doublet chemotherapy with or without an additional targeted agent as FLT were eligible for this study. Patients were under routine treatment for NSCLC by their doctors and treatment choice and resource use were at the discretion of the treating physician. Secondary objectives of the study included determining resource use during FLT. Hospitalizations, outpatient visits, concomitant therapy use, transfusions and the use of colony stimulating factors (CSFs) are reported here. Cohorts were not adjusted for multivariate parameters prohibiting statistical comparisons.

Results
Evaluable patients (n=1564) were categorized into 4 main cohorts based on their FLTs: pemetrexed + platinum (n=569), gemcitabine + platinum (n=360), taxanes + platinum (n=295) or vinorelbine + platinum (n=300). Forty of the evaluable patients received other platinum-doublet treatments and were excluded from the analyses presented here.Across the four main cohorts, 55% of patients were hospitalized.A majority (61%) of hospitalizations were preplanned (71% in the pemetrexed cohort, 45% in the gemcitabine cohort, 67% in the taxanes cohort and 53% in the vinorelbine cohort). Among the unplanned hospitalizations, 54% were related to an adverse event (54% in the pemetrexed cohort, 54% in the gemcitabine cohort, 55% in the taxanes cohort, and 55% in the vinorelbine cohort). The mean (95%-confidence interval) duration of hospitalizations was 13 days (11.6 to 14.6) for pemetrexed (median=9 days), 11 days (9.4 to 12.8) for gemcitabine (median=7 days),17 days (14.0 to 19.7) for taxanes (median=12 days), and 13 days (11.3 to 15.0) for vinorelbine (median=9 days). Nearly half of patients (47%) were seen in an outpatient setting with most outpatient visits (82%)planned for scheduled treatments. Nineteen percent of patients received ≥1 transfusion (16% in the pemetrexed cohort, 24% in the gemcitabine cohort, 15% in the taxanes cohort and 24% in the vinorelbine cohort). Nearly all (94%) of these patients received packed red blood cells. Nineteen percent of patients received ≥1 colony stimulating factor (CSF), which included G-CSF (69%), or erythropoietin (39%). During therapy, 82% of patients used antiemetics and antinauseants, 58% used steroids, 40% used analgesics, and 24% used antibiotics. Twenty-eight percent of patients received radiation during FLT and most often radiation was delivered concurrently with chemotherapy (66% overall, 66% in the pemetrexed cohort, 54% in the gemcitabine cohort, 68% in the taxanes cohort, and 73% in the vinorelbine cohort).

Conclusion
The FRAME study provides unique, real-life data reflecting prospectively collected information on resource use not accessible in a clinical trial setting. This study revealed several important findings regarding real-world resource use during NSCLC therapy including data on hospitalizations, outpatient visits, transfusions, concomitant treatments, and radiation.

Background
G has been established as a standard first-line therapy in patients with advanced NSCLC harboring activating EGFR mutations. Results from preclinical and clinical studies have shown synergistic cytotoxic effects of EGFR tyrosine kinase inhibitors and P, and that P is a key cytotoxic agent for NS NSCLC. Therefore, combination of P and G may offer benefits that exceed the inhibition of tumor progression with G monotherapy in patients with NS NSCLC harboring activating EGFR mutations.

Methods
This randomized, multicenter, open-label, parallel-arm, Phase 2 East-Asian study has been initiated to test the hypothesis that G + P will prolong progression-free survival (PFS) compared to G in patients with NS NSCLC with EGFR mutation. Eligible patients must have stage IV NS NSCLC, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 and an activating EGFR mutation. Approximately 188 patients will be randomized in a 2:1 ratio (G+P:G) stratified by gender, ECOG PS and prior neo-/adjuvant treatment. Study treatment will continue until progression, unacceptable toxicity or another discontinuation criterion is met. Patients in the G + P arm are required to take prophylactic folic acid and vitamin B~12~ supplementation as stated on the P label. With a one-sided significance level of 0.2, 145 events (objective disease progression/death) will provide 70% power, assuming a true hazard ratio of 0.79 (about 26% prolongation in PFS time). It is expected that 145 events will be observed if 188 pts are enrolled within an accrual period of 12 months and followed-up over 18 months. The primary endpoint of PFS will be analyzed after 145 events have been observed by using a multivariate Cox model. Secondary endpoints include time to progressive disease, overall survival (OS), overall response rate, disease control rate, duration of response, biomarkers and treatment-emergent adverse events. To ensure mature OS data, the criteria to end the study will be the earlier of 130 OS events or 30 months from the last patient entered treatment milestone. Enrollment started in early 2012. The trial is sponsored by Eli Lilly and Company (NCT01469000).

Results
Not Applicable.

Conclusion
Not Applicable.

Background
Lung cancer patients may develop oral complications related to conventional chemotherapy or targeted and antiresorptive agents. Early diagnosis of those complications, within a multidisciplinary team, can lead to effective treatment and the maintenance of patient’s quality of life. The aim of the current study is to present our 4-year experience (2009-2012) in the treatment and prevention of oral complications in lung cancer patients.

Methods
Forty three patients (21 women, 22 men, mean age 62.6 years) were included in the analysis. Thirty patients received active chemotherapy treatment; 9/30 (30%) received conventional chemotherapy in combination with targeted therapy, 11/30 (36.7%) targeted therapy and 10/30 (33.3%) conventional chemotherapy. Twenty-one patients received i.v. bisphosphonates (zoledronate 76.2%). Eleven patients received bishosphonates combined with bevacizumab; 4 of them had interrupted bevacizumab at the time of referral. Oral clinical and radiographic evaluation, using periapical and panoramic x-rays were performed. Dental scan was performed in 2 patients. Oral hygiene instructions were introduced and patients were educated about the importance of the maintenance of optimal oral health.

Results
Thirty three patients were referred by their medical oncologist (25 patients, 58.1%, by the SOTIRIA Hospital), 1 was referred by his dentist and 10 were self referred. Twelve patients (27.9%) presented with jaw osteonecrosis (Stage 0: 6, 50%, Stage I: 4, 33.3%, Stage II: 2, 16.7%); of those 4 received bevacizumab concurrently with zoledronic acid, 2 received the same combination in the past, 5 received zoledronate alone and 1 received zoledronate followed by denosumab. Six patients were diagnosed with oral candidiasis, 4 with herpes infection, and 2 with necrotizing ulcerative gingivitis. Nine patients had dental problems, while 5 patients were introduced to the Unit for preventive measures. Jaw osteonecrosis was treated with long term antibiotics, while local ozone oil was applied in 3 patients. Three dental extractions were performed in one patient with osteonecrosis stage 0. Today, 6 patients with osteonecrosis remain in partial remission, 3 are in complete remission, 2 were lost of follow up and 1 worsened. Of the 3 dental extractions, 2 healed and one led to osteonecrosis stage I. Patients with dental problems were further referred to their family dentists.

Conclusion
Osteonecrosis of the jaw, in the present series, was the most common oral complication. The dental oncology expert within in the multidisciplinary team contributed to the diagnosis of oral pathoses and of the osteonecrosis at the early Stage 0.

Background
Amrubicin and cisplatin are active in the treatment of small cell lung cancer (SCLC), and carboplatin is an analogue of cisplatin with less nonh ematological toxicity. To determine the efficacy and toxicity of amrubicin and carboplatin for previously untreated patients with extensive-disease (ED) SCLC.

Methods
Patients and methods: Thirty-five patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naive, good performance status (PS 0-1), age < 76, extensive-disease, and adequate organ function. Based on the phase I study (J Thorac Oncol 4:741, 2009), the patients received amrubicin35mg/m[2] i.v. on days 1,2 and 3, and carboplatin AUC 5 i.v. on day 1. Four cycles of chemotherapy were repeated every 3 weeks.

Results
Results: Thirty-five patients we re eligible and 34 patients were assessable for response, toxicity and surviva l. Patients’ characteristics were as follows: male/female=27/8; PS 0/1=4/31; median age(range)=64(41-75); stage IV=35. The overall response was 81% (CR5, P R21, SD4, PD2, NE3). Grade 4 leukopenia, neutropenia, and thrombocytopenia occ urred in 11%, 60%, and 11%, respectively. There were no treatment-related deat h and pneumonitis. Three patients experienced hypotension for amrubicin infusi on reaction and two were terminated the study. The median overall survival tim e, and the 1-, 2- and 3-year survival rates were 15.6 months, 63%, 33% and 8%, respectively. The median progression-free survival time was 6.5 months.

Conclusion
Amrubicin and carboplatin was effective in untreated extensive-disease small cell lung cancer.

Background
Non-small cell lung cancer (NSCLC) patients harboring the epidermal growth factor receptor (EGFR) mutation show a survival benefit on treatment with EGFR-tyrosine kinase inhibitor (EGFR-TKI); however, few studies report on post-progression tumor behavior after treatment with EGFR-TKI. We investigated the post-progression clinical course after treatment with EGFR-TKI in NSCLC patients harboring the EGFR mutation. We also evaluated the correlation between the site of relapse after EGFR-TKI treatment and prognosis.

Methods
We retrospectively reviewed clinical data of stage IV or recurrent NSCLC patients harboring the EGFR mutation, who received EGFR-TKI as first-line treatment in our institute from 2009 to 2011.

Results
Thirty-six patients received EGFR-TKI as first-line therapy. Thirty of these patients with recurrent NSCLC were enrolled in this study. The median age of the patients was76 years (range, 38–97), and the male/female ratio was 4/26. The median progression-free survival (PFS) after EGFR-TKI treatment was 8.2months and the median overall survival (OS) was 20.4months. Sites of relapse in patients with progressive disease (PD) were the brain, pleural effusion, bone, and lung (n=5, 13, 6, and 8, respectively). Twenty-one patients received sequential therapy: 11 patients received continued EGFR-TKI treatment beyond PD and 10 patients received second-line therapy. Second-line therapies were platinum-based doublet therapy, monotherapy, and another cycle of EGFR-TKI (n = 6, 2, and 2 patients, respectively). Post-progression survival (PPS) of all the patients after treatment with EGFR-TKI was 9.2 months, whereas that of patients who received second-line therapy was 14 months. Subgroup analysis according to the site of relapse showed that after first-line EGFR-TKI treatment, PFS tended to be higher for patients with a relapse in the brain (11.6 months) than for patients with sites of relapse other than the brain (8.2 months).

Conclusion
PPS of all the patients after treatment with EGFR-TKI was 9.2 months, whereas that of patients who received second-line therapy was 14 months. Subgroup analysis showed that patients with a relapse in the brain might survive longer.

Background
A nested case control (NCC) study was conducted to assess the incidence of hemoptysis (Grade 2 cases that used an injectable hemostatic or Grade 3+ cases) and to explore risk factors for hemoptysis in patients receiving Avastin[®] (bevacizumab) in real-life-practice in Japan.

Methods
From November 2009 to August 2011 patients intending to use bevacizumab were pre-enrolled, and we calculated incidence of hemoptysis in the 6774 patients actually receiving bevacizumab. Excluding one patient of unspecified age, we selected a control group from the 6773 patients by matching each patient who developed hemoptysis (cases) to four patients who did not (controls) by sex and age. We selected 92 controls for the 23 cases and performed conditional logistic regression analysis of a total 113 patients (23 cases and 90 controls) to investigate risk factors for hemoptysis. A third party including radiologists performed blind assessment of imaging characteristics for the 104 patients with evaluable baseline computerized tomography images.

Results
In the 6774 patients receiving bevacizumab, incidence of hemoptysis was 0.33%. To perform conditional logistic regression analysis of the 113 patients in the case control study, we included the following factors in the model: smoking history, stage (7th ed.), PS (baseline), present metastasis, previous lung disease, concurrent lung disease, previous thoracic radiotherapy, concomitant drugs (anticoagulant, aspirin preparation, non-steroidal anti-inflammatory drug, antiplatelet drug), concomitant thoracic radiotherapy, treatment line, macrovascular (arterial) invasion, and central airway tumor exposure extending to segmental bronchus. Analysis using the stepwise method identified presence of previous thoracic radiotherapy (odds ratio [OR], 2.76; 95% confidence interval [CI], 0.61–12.43), concomitant thoracic radiotherapy (OR, 6.19; 95% CI, 0.63–60.47), and central airway tumor exposure extending to segmental bronchus (OR, 5.29; 95% CI, 1.22–22.89).

Conclusion
At 0.33%, the incidence of hemoptysis in this study was low, and three risk factors were identified. Because this was a case control study in patients receiving Avastin, these risks cannot necessarily be attributed to Avastin treatment, and further study of safety risks is needed.

Background
Despite the high disease control rate in EGFR-mutated patients, gefitinib treatment is not curative and eventually there is disease progression. Recent studies report that discontinuation of EGFR-TKIs result in rapid disease progression in NSCLC patients who had developed acquired resistance. These findings suggest that patients with acquired resistance could have sensitive and resistant tumor clones to EGFR-TKIs. We designed a phase I trial to assess the safety and efficacy of docetaxel combined with gefitinib in NSCLC patients who acquired resistance.

Methods
Patients with metastatic NSCLC who had responded to gefitinib treatment and then developed progressive disease were treated with docetaxel in combination with the continuation of gefitinib. Docetaxel was administered on day 1 of 21-day cycle and escalated from 50 to 70 mg/m[2]. Gefitinib was given at a fixed dose of 250mg/day. Dose limiting toxicities (DLT) were assessed after the first cycle, and doses were escalated in 3 to 6 patient cohorts.

Results
Fourteen patients were treated at doses of 50 (n=4), 60 (n=5) and 70 mg/m[2] (n=5). All 14 patients were evaluable for safety and efficacy. At a docetaxel dose of 60 mg/m[2], 1 patient experienced a DLT (grade 4 neutropenia for 4 days), and at a dose of 70 mg/m[2] 1 patient experienced a DLT (grade 4 neutropenia for 4 days and febrile neutropenia). Because all 5 patients treated at a docetaxel dose of 70 mg/m[2] had grade 4 neutropenia, this dose level was determined to be the maximum-tolerated dose. The overall response rate was 43%, median progression free survival was 183 days (95% CI, 157 to 215 days), and median overall survival was 575 days (95% CI, 220 to 816 days). At the recommended dose of 60 mg/m[2], the overall response rate was 40%.

Conclusion
Recommended dose of docetaxel is 60 mg/m[2] in combination with gefitinib. This combination was well tolerated and demonstrated activity in NSCLC patients with acquired resistance to gefitinib.

Background
Vascular endothelial growth factor (VEGF) plays an important role in non small cell lung cancer (NSCLC) with malignant pleural effusion (MPE), but there are little evidence regarding the efficacy of bevacizumab (Bev) with carboplatin-paclitaxel (CP) for treatment of NSCLC with MPE. Therefore, we prospectively evaluated the efficacy and safety of Bev and CP in non-squamous (SQ) NSCLC patients with MPE.Vascular endothelial growth factor (VEGF) plays an important role in non small cell lung cancer (NSCLC) with malignant pleural effusion (MPE), but there are little evidence regarding the efficacy of bevacizumab (Bev) with carboplatin-paclitaxel (CP) for treatment of NSCLC with MPE. Therefore, we prospectively evaluated the efficacy and safety of Bev and CP in non-squamous (SQ) NSCLC patients with MPE.

Methods
Chemotherapy-naive non-SQ NSCLC patients with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. In the first cycle, the treated patients received only CP to prevent Bev-induced wound healing delayed after chest drainage. Subsequently, they received 2–6 cycles of CP with Bev. Patients who completed more than 4 cycles of CP and Bev without disease progression or severe toxicities continued to receive Bev alone as a maintenance therapy. The primary endpoint was overall response, although an increase in MPE was allowed in the first cycle. The VEGF levels in plasma and MPE were measured at baseline and the VEGF levels in plasma were measured after 3 cycles of chemotherapy.

Results
Between September 2010 and June 2012, 23 patients were enrolled. The overall response rate was 60.8%, the disease control rate was 87.0%, and one patient was not evaluated response because of sudden death after 1 cycle treatment. Sixteen patients received maintenance therapy, following a median of 3 cycles. The median progression-free survival and the median overall survival were 7.1 months (95% CI, 5.6 - 9.4 months) and 11.7 months (95% CI, 7.4 – 16.6 months). Almost all patients experienced severe hematological toxicities, including ≥ grade 3 neutropenia. And there was no patient who experienced severe bleeding events. The median baseline VEGF levels in MPE was 1798.6 (range; 223.4 - 35,633.4) pg/mL. The VEGF levels in plasma showed a significant decrease after 3 chemotherapy cycles (baseline; 513.6 ± 326.4 pg/mL, post chemotherapy; 25.1 ± 14.1 pg/mL, p < 0.01), regardless of efficacy of CP with Bev.

Conclusion
The combination of CP with Bev was confirmed to be effective and tolerable in chemotherapy-naïve non-SQ NSCLC patients with MPE.

Background
Pemetrexed (Alimta) plasma clearance positively correlated with glomerular filtration rate (GFR), resulting in increased drug exposures in patients with impaired renal function. In US Food and drug administration guidances, pemetrexed is not recommended for patients with a creatinine clearance (CrCl) less than 45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance < 45 mL/min to give a dose recommendation. Here, we investigated the toxicity and effectiveness of pemetrexed in patients with impaired renal function.

Methods
Patients with nonsquamous non-small cell lung cancer who received chemotherapy with pemetrexed as a single-agent, were divided into two groups of CrCl<45 mL/min and ≥45 mL/min, and were analyzed retrospectively, between May 2009 and May 2012. Patients received a 10-minute infusion of 375 to 500mg/m[2] of pemetrexed every 3 weeks. Estimated CrCl was calculated using Cockcroft-Gault formula.

Results
Twenty-seven patients were ascessed in this study, 10 patients with a CrCl < 45 mL/min and 17 patients with a CrCl ≥ 45 mL/min. The rate of grade 3/4 neutropenia was higher in patients with a CrCl < 45 mL/min than ≥ 45 mL/min. There were no febrile neutropenia and treatment related death. Nonhematologic toxicities included fatigue, diarrhea, and nausea, did not correlate with renal function. Stable disease was observed in 6 patients (60%) in CrCl < 45 mL/min group, and in 12 (70%) in CrCl ≥ 45 mL/min group.

Conclusion
Although the risk of grade 3/4 neutropenia was higher in patients with impaired renal function (CrCl < 45mL/min) than maintained renal function (CrCl ≥ 45 mL/min), treatment with pemetrexed should be considered dose reduction in patients with impaired renal function.

Background
Treatment decision-making is associated with potential decisional conflict of patients. Aim of this study was to determine the preferences of advanced NSCLC patients for EGFR-TKI or chemotherapy as first-line therapy if they were in the situation of having a lung cancer harboring EGFR mutation, and to investigate the variables considered important to that preference.

Methods
Three vignettes were designed to assess the patients’, the physicians’ or medical staff members’ preferences for treatment decision-making and the reasons classified into five category such as “evidence level”, “type of drug administration”, “therapeutic efficacy”, “adverse events”, and “influence to ordinary life” behind the decision. HADS, FACT-L and characteristics of participants including gender, age, and performance status (PS) are also investigated in this analysis.

Results
Total 377 individuals containing 100 patients, 100 physicians, and 177 medical staff members were analyzed in this study, and 322 participants (85.4%) preferred to EGFR-TKI than chemotherapy as a first-line therapy. Preference rate of EGFR-TKI in patients was statistically significantly lower than those in physicians and medical staffs, 73%, 88% and 91%, respectively. Among the reasons we investigated, “therapeutic efficacy” was the only marginal significant reason for preference in patients (odds ratio: 3.88, p=0.06). In addition to “therapeutic efficacy”, “type of drug administration” and “influence to ordinary life” was the significant reasons for their preference in physicians (odds ratio: 11.57, 22.57 and 20.5, respectively). In pre-planned analysis, we found the difference of value between the patients and the physicians in “influence to ordinary life”.

Conclusion
If the patients have an advanced lung cancer with EGFR mutation, they may prefer EGFR-TKI as a first-line therapy to chemotherapy as well as physicians and medical staff members. However the reasons of those preferences among them may be different. We should consider continuation of patients’ ordinary life when we discuss about treatment decision-making with patients.

Background
A series of Japanese trials indicate docetaxel (DTX) monotherapy is a standard of care in elderly patients with advanced non-small cell lung cancer (NSCLC), and that the addition of platinum does not significantly improve the outcomes. Bevacizumab (BEV) has been shown to be beneficial when added to standard platinum-doublet chemotherapy in good-risk NSCLC patients. BEV toxicity is a major concern for elderly patients.

Methods
Patients with chemotherapy-naïve advanced non-squamous NSCLC who were >70 year old with performance status (PS) 0/1 and adequate organ function were enrolled. Eligible patients received DTX 60 (Level 0) or 50 (Level -1) mg/m2 and BEV 15 mg/kg on day 1, every 3 weeks. Toxicity was the primary endpoint and secondary endpoints were response rate, progression free survival (PFS), overall survival (OS), and completion rate of the 3 cycles of treatment. The planned sample size was 12 to 24, with at least 6 subjects treated at each level.

Results
Between December 2010 and September 2012, 21 elderly patients (9 in level 0 and 12 in level -1) were enrolled in the study (median age, 75 years; 43% male; 90% adenocarcinoma; 67% PS 1). Two of the 9 patients in level 0 had a dose limiting toxicities (DLTs). After 9 patients enrolled on level 0, two severe adverse events were reported. One patient had grade 4 sepsis in cycle 4 and another patient had grade 4 sepsis in cycle 5. We decided to stop enrollment to level 0 and reduce dose to level -1. Two of 12 patients in dose level -1 experienced DLTs. Grade 3 or 4 of toxicities among all patients were neutropenia (86%), anemia (5%), hypertension (19%), anorexia (10%), and increased aminotransferase levels (10%). Three out of 9 patients in level 0 achieved partial response (PR) and 3 out of 11 assessable patients in level -1 obtained PR. Completion rates of the 3 cycles of treatment were 78% (7/9) in level 0 and 67 % (8/12) in level -1. The median PFS and OS were 5.4 and 11.1 months, respectively.

Conclusion
The recommended dose for this combination in future study is docetaxel 50 mg/m2 and bevacizumab 15mg/kg.

Background
Aim of the study: to evaluate efficacy (CR, PR) of the two formulations with CDDP in advanced NSCLC. Secondary objectives were progression-free survival (PFS), overall survival (OS) and safety.

Methods
NVBo, 60 mg/m² (Arm A) and NVBiv, 25 mg/m² (Arm B) were delivered on D1, D8, repeated every 3 weeks. Doses were increased at cycle 2 (NVBo 80 mg/m[2], NVBiv 30 mg/m[2]) according to hematological tolerance. CDDP doses were 80 mg/m[2] D1 every 3 weeks in both arms. Pts received a maximum of 4 cycles in absence of progression.

Results
Between 1/2008 and 6/2009, 132 pts were randomized at 6 investigational centres (cut-off date for final analysis: August, 31[st] 2012 - Arm A 67 pts, Arm B 65 pts). One patient in Arm A was not treated. Among the 131 pts analyzed by an independent panel review, PR was 25.8% (95% CI [15.8-38.0]) in Arm A and 23.1% (95% CI [13.5-35.2]) in Arm B, and disease control (PR+SD) 72.7% (95% CI [60.4-83.0]) in Arm A and 72.3% (95% CI [59.8-82.8]) in Arm B. PFS (months) was 6.2 [3.8-7.7] for Arm A and 6.2 [4.9-7.8] for Arm B. One Year Survival was 59% and 61.6 in Arm A and Arm B, respectively, Two Years Survival: 39% Arm A, 38.7% Arm B, and 30 months Survival 29.2% Arm A, 26.9% Arm B. Median dose intensity (DI): NVBo 44.7 mg/m²/week, NVBiv 15.6 mg/m²/week. Relative dose intensity (RDI): NVBo 89.3%, NVBiv 81.5%. The CDDP median DI was 24.6 mg/m[2]/week in Arm A and 24.5 mg/m[2]/week in Arm B, with a RDI of 92.1% and 91.6% respectively. Grade 3/4 neutropenia: 29 pts and 43 cycles Arm A, 56 pts and 106 cycles Arm B. Febrile neutropenia : 4 (6.1%) pts Arm A, 6 (9.2%) pts Arm B. Grade 3 anaemia : 6 (9.1%) pts and 10 cycles Arm A, 13 pts (20%) and 18 cycles Arm B, with grade 4 anaemia in 3 (4.6%) pts and 5 cycles only in arm B. The most frequent non hematological disorders were nausea (8 pts Grade 3 - 12.1% Arm A; 6 pts Grade 3 - 9.2% Arm B) and vomiting (10 pts Grade 3 - 15.2%, 1 pt Grade 4 - 1.5% Arm A; 9 pts Grade 3 - 13.8%, 1 pt Grade 4 - 1.5% Arm B). Diarrhea was reported in 15 (22.7%) and 9 (13.8%) pts in Arm A and Arm B, respectively.

Conclusion
Both arms testing NVBo and NVBiv with CDDP reported similar efficacy results in term of Response Rate, PFS and OS, coupled with an optimal safety profile. NVBo is a step forward in the treatment of NSCLC since it optimises treatment convenience thanks to its oral formulation while maintaining a high level of efficacy.

Background
Platinum doublets are standard first-line treatment of stage IV non-small-cell lung cancer (NSCLC) without targetable driver mutations such as EGFR or ALK. Oxaliplatin is known to be more potent than cisplatin, requiring fewer DNA adducts to provide equivalent cytotoxicity. The objective of this study is to evaluate the efficacy and safety of oxaliplatin combined with docetaxel as a first line treatment of stage IV NSCLC.

Methods
This is prospective, single-center, phase II trial. Patients with chemotherapy-naive NSCLC received docetaxel 60mg/㎡ (day 1) and oxaliplatin 70mg/㎡ (day 2) every 3 weeks for up to 6 cycles. The primary endpoint was objective response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Treatment response was evaluated according to RECIST version 1.1.

Results
Thirty three patients were enrolled and response evaluation is available in 30 patients at the present time. There were 10 partial responses, 16 stable diseases. ORR was 33.3% and disease control rate was 86.7%. Median PFS was 127 days (95% confidence interval, 59~195) and median OS was 394 days (95% confidence interval, 264~524). Grade 3-4 toxicities occurred in 45% of patients, and the most common hematologic toxicity was neutropenia. There were two cases of hyperglycemia and sepsis.

Conclusion
This study suggests that the combination of oxaliplatin and docetaxel is effective in patients with NSCLC, with reasonable toxicities. (ClinicalTrials.gov Identifier: NCT01243775)

Background
This study was designed to determine the recommended dose of carboplatin plus pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer (NSCLC).Patients and methods: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for 4 cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed.

Methods
Patients received escalated doses of carboplatin area under the concentration–time curve (AUC) of 4 (cohort 0) or 5 (cohort 1) or 6 (cohort 2) and pemetrexed 500mg/m2 every 3 weeks for 4 cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed.

Results
In cohort 0, a dose-limiting toxicity (DLT) was not observed in three patients, and no DLTs were seen in the first three patients of cohort 1. In cohort 2, DLTs were observed in three of the seven patients: two of grade 4 thrombocytopenia and one of grade 3 febrile neutropenia. And in additional cohort 1, no DLTs were seen in the next four patients. Therefore, the combination of carboplatin at an area under the concentration–time curve (AUC) of 5, plus 500 mg/m[2 ]pemetrexed, was determined to be the recommended dose for elderly patients (≥75 years old) with advanced non-squamous NSCLC. Of a total of 17 patients, 10 received a median of 5 cycles of pemetrexed maintenance therapy without unexpected or cumulative toxicities. No complete responses and 8 partial responses were observed, and the study had an overall response rate of 47.1%. The median progression-free survival time was 5.5 monthes (95% confidence interval [CI], 2.4–8.9 monthes) and the median overall survival time was 12.6 monthes (95% CI, 7.4–17.9 monthes) in he final analysis of this study.

Conclusion
Figure 1 This combination was a tolerable and effective regimen, and recommended dose was carboplatin (AUC of 5) / pemetrexed (500 mg/m2) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced non-squamous NSCLC.

Background
In BR.21 Study, erlotinib was shown to significantly prolong OS, PFS and the time to progression of NSCLC-associated symptoms. The study reported that the RR was 7% for EGFR-wt cases but the MST was longer than placebo. S-1 is a fourth-generation oral fluoropyrimidine that contains tegafur, a prodrug of 5-fluorouracil (5-FU). The consecutive administration of S-1 at 80 mg/m[2]/day was well tolerated. The objective RR and MST were 22.0% and 10.2 months. Regarding the EGFR-TKI and 5-FU-based chemotherapy, EGFR-TKI has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported in basic study. Thus, we conducted a phase I study to find the maximum tolerated doses of erlotinib/ S-1 combination therapy, and a phase II study to evaluate the efficacy and toxicity of this combination strategy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC in the absence of EGFR gene mutations.

Methods
Eligibility criterias were as follows: 1) patients with histologically or cytologically diagnosed NSCLC, 2) patients at clinical stage IIIB or IV not indicated for radical radiotherapy/radical surgery or those with postoperative recurrence, 3) patients having received 2 or fewer prior regimens of chemotherapy (at least one regimen being platinum-based), 4) patients with no history of treatment with EGFR-TKI and drugs of the fluoropyridimine family. This combination chemotherapy consisted of two 3-week cycles of S-1 treatment and once daily erlotinib at a dose of 150 mg/body. In phase I study, the initial dose of S-1 was 60 mg/m[2]/day, and 3 patients were registered for each level of S-1 treatment. In phase II study, S-1 at recommended dose and erlotinib were administered similarly to the phase I study.

Results
In phase I study, seven patients (one man and 6 women) with a median age of 66 years (range: 52-70 years) were enrolled. All patients had ECOG PS of 0-1, six patients had adenocarcinomas, and one had large cell carcinoma. All patients were at clinical stage IV. No patient had grade 2 or more neutropenia, and each 1 had grade 2 leukocytepenia, anemia, mucositis, general fatigue, skin rash, and diarrhea; however, none experienced DLT. The RD for the phase II study was determined as 80 mg/m[2] S-1 and 150 mg/m[2] erlotinib. The phase II study was conducted in 10 patients, 9 men and 1 woman, with a median age of 60.5 years (range 42–75). PS was 0 in 2, 1 in 6, and 2 in 2 patients. The histological subtype was adenocarcinoma in 5 patients, squamous-cell carcinoma in 4, and others in 1. One patient had grade 3 diarrhea, grade 4 colitis, and grade 4 septic shock, and the other had grade 4 dehydration and acute respiratory failure which resulted in two treatment-related deaths. With these findings, the trial was closed to additional enrollment.

Conclusion
Erlotinib(150mg) and S-1(80 mg/m[2] for 14 days every 21 days) therapy seemed to be toxic for pretreated patients with EGFR-wt NSCLC patients.

Background
Pemetrexed plays an important role in the treatment of advanced non-small-cell lung cancer (NSCLC). The expression of thymidylate synthase in NSCLC has been reported to be a predictive marker for patients treated with pemetrexed; however, no practical marker has been established except for histopathological features. Thus we attempted to select a practical predictive marker for pemetrexed treatment from clinical characteristics.

Methods
We retrospectively reviewed the charts of patients with advanced non-squamous NSCLC treated with pemetrexed in our hospital from January 2009 to December 2012. We investigated clinical variables such as smoking history, gender, clinical stage, serum tumor marker levels at the diagnosis (CEA, CYFRA21-1, ICTP, and SLX), and epidermal growth factor receptor (EGFR) mutation status. The relationships between those variables and the patients survival or response to pemetrexed were evaluated.

Results
We identified 60 patients, 37 male, and the average age was 65 (range, 22-83) years. There were 59 patients with adenocarcinoma. The clinical stages were; IIIA/IIIB/IV = 3/3/54 (UICC TNM ver.7). Pemetrexed with platinum (cisplatin or carboplatin) was administered to 46 patients (bevacizumab was concurrently employed in 5 patients) and 14 patients underwent pemetrexed monotherapy. When the serum CYFRA21-1 cut-off level was set at 2.1 ng/ml, the patients with low serum levels had a significantly longer progression free survival (PFS) than those with high serum levels (130 versus 263 median days; p=0.038). There was no significant difference in overall response rate and overall survival between the two groups.

Conclusion
High serum levels of CYFRA21-1 might reflect the higher degree of biological characteristics of squamous cell carcinoma in a tissue; therefore they could be used to identify the individuals with short PFS among patients treated with pemetrexed. Serum levels of CYFRA21-1 may become a predictive marker for advanced NSCLC patients treated with pemetrexed.

Background
In the patients who had locally advanced or metastatic non-small-cell lung cancer with epidermal growth factor receptor (EGFR) mutation, progression-free survival (PFS) was prolonged by first line therapy of gefitinib than those of chemotherapy. However, overall survival (OS) was not prolonged due to the crossover administration of tyrosine kinase inhibitor. In such patients, the administration timing of gefitinib becomes a clinically interesting issue. Moreover, it is unknown whether effect of gefitinib was attenuated or not by alternate-day administration for the adverse effects such as exanthema, diarrhea, and liver function disorder. The suitable dosage of gefitinib to the patients with EGFR mutation is thought to be actually unidentified, because of the setting dosage before proving the EGFR mutation. Therefore, we retrospectively analyzed the population of patients receiving gefitinib at our hospital to solve these questions and examine the prognostic factors in the patients with EGFR mutations.

Methods
Eighty three patients (median age 66 years, 51 females), except ten patients with combined chemotherapy, have begun to be received gefitinib in our hospital between January 1, 2007 and December 31, 2012. These data were collected at May 31, 2013 and analyzed using Cox proportion hazard model with covariance which may influence OS and PFS of gefitinib therapy. These patients were composed of 3 negative, 34 unknown, and 46 positive patients with EGFR mutations. The median follow-up time was 7 months, ranging 1 to 141 months. The median OS was 34 months in all patients (n=83) and 43 months in the patients with EGFR mutation in exon19 or exon21 (n=44). The median PFS was 11 months in the former and 19 months in the latter.

Results
As previously reported, the factors such as female (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.26 to 0.81, P=0.007) or smoker (HR 2.55, 95%CI 1.46 to 4.47, P=0.001) influenced PFS in all patients. However, they did not in the patients with EGFR mutation. As for the administration timing of the gefitinib, the later starting date of its administration (HR 0.97, 95%CI 0.94 to 1.00, P=0.02) slightly improved the OS in all patients, which might be influenced by other factors, because the later therapy line (HR 1.55, 95%CI 1.17 to 2.05, P=0.002) worsened PFS. Its administration timing did not significantly influence OS or PFS in the patients with EGFR mutations. As for the dosage of gefitinb, the increase of body surface area significantly influenced PFS in the all patients (HR 7.12, 95%CI 1.05 to 49.1, P=0.045). Paradoxically, the prolonged administration intervals improved OS (HR 0.39, 95%CI 0.20 to 0.76, P=0.006) and PFS (HR 0.35, 95%CI 0.19 to 0.65, P=0.001) in all patients and PFS (HR 0.34, 95%CI 0.14 to 0.83, P=0.018) in the patients with EGFR mutations.

Conclusion
In summary, the administration timing did not influence OS or PFS in the patients with EGFR mutations. Moreover, the alternate-day administration might not decrease the effect on the patients with EGFR mutations. Given the adverse effects, the provision of appropriate dosage is required for these patients.

Background
The subset analysis of LETS study suggested that S-1 plus carboplatin was more beneficial than paclitaxel plus carboplatin in overall survival (OS) in squamous cell lung cancer. We previously showed the validity of tailored dose S-1 adjusted by BSA and Ccr. No maintenance study focusing on squamous cell lung cancer has been reported yet. Here, we conducted a phase II study to evaluate the efficacy and safety of tailored dose S-1 plus carboplatin followed by S-1 maintenance in chemonaïve patients with advanced and recurrent squamous cell lung cancer.

Methods
Patients receive carboplatin (AUC = 5, day1) plus S-1 (tailored dose b.i.d., days 1-14) every 21 days. Non-progressive patients after 4 cycles of induction continued to receive S-1 until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) with a threshold value of 15%. The secondary endpoints were progression-free survival (PFS) and OS from enrollment, PFS in maintenance phase, and safety.

Results
Between April 2011 and October 2012, 35 patients were enrolled. Thirty-three patients excluding 2 patients with protocol violations were analyzed. The median age was 72 years (range, 44-82), The ORR was 30.3% (95% CI: 15.6-48.7%) that met the primary endpoint. Disease control rate was 75.8%, and 10 patients (30.3%) received maintenance therapy. The median PFS was 3.7 months. The median OS and maintenance PFS are under follow-up. 10 patients received maintenance S-1 (median: 3 cycles, range: 1-9 cycles); median PFS from the beginning of induction treatment was 5.6 months. Grade 3/4 toxicities with the frequency more than 5% included 4 neutropenia (12.1%), 7 thrombocytopenia (21.2%), 2 anemia (6.1%), 4 appetite loss (12.1%), 2 nausea (6.1%) and 2 fatigue (6.1%). All of them were controllable and febrile neutropenia was not experienced.

Conclusion
This is the first trial of S-1 plus carboplatin followed by maintenance S-1 for chemo-naïve advanced and recurrent squamous cell lung cancer. This treatment strategy was effective and feasible.

Background
Standard second-line chemotherapy against advanced non-small-cell lung cancer (NSCLC) is a single agent such as docetaxel, pemetrexed, or erlotinib. The response rate of each agent as second-line setting are from 10% to 15% in Japanese NSCLC without EGFR mutation. Amrubicin, a totally synthetic 9-aminoanthracycline, is active as second-line chemotherapy for advanced NSCLC. The reported response rate to amrubicin as second-line treatment for advanced NSCLC is 11.5%. Erlotinib is an orally active reversible inhibitor of epidermal growth factor receptor tyrosine kinase activity (EGFR-TKI), which induces rapid tumor shrinkage if the tumor harbors EGFR activated mutation. Erlotinib is also effective for NSCLC without EGFR mutation, but the response rate is around 8%. We considered it worthwhile to explore if a doublet regimen consisting of amrubicin and erlotinib may provide therapeutic benefit and have a favorable toxicity profile. We performed the growth inhibition assay for NSCLC cell lines and made two-dimension isobolograms to estimate the synergy of the combination. The combination of amrubicin and erlotinib had significant synergistic effect on EGFR wild type NSCLC cell line A549, and additive effect on EGFR mutant cell line PC-9. We conducted a phase I trial of this combination. The aim was to determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs) and pharmacokinetics of this combination in patients with non-small cell lung cancer (NSCLC) who had previous chemotherapy.

Methods
Nine patients with stage IV disease were treated at 3-week intervals with erlotinib once daily on days 1-21 plus amrubicin 5-min intravenous injection on days 1-3.

Results
The dose levels evaluated were erlotinib (mg/day)/amrubicin (mg/m[2]): 100/30 (n = 3), 100/35 (n = 3) and 150/30 (n = 3). The MTD of erlotinib and amrubicin was 100 mg/day and 35 mg/m[2] since two of the three patients experienced DLTs during the first cycle of treatment at the third dose level of 150 mg/day and 30 mg/m[2]. Cessation of erlotinib administration for 8 days due to grade 3 leukopenia and grade 3 skin infection (erysipelas) were the DLTs. No drug-drug interactions between erlotinib and amrubicin were observed in this study. The overall response rate was 33%, including three partial responses, in the nine patients. The median progression-free survival for all patients was extraordinary long 11.3 months, and the median overall survival has not yet been reached.

Conclusion
Combined erlotinib plus amrubicin therapy seems to be highly effective, with acceptable toxicity, against NSCLC. The recommended dose for phase II studies was erlotinib 100 mg once daily on days 1-21, and amrubicin 35 mg/m[2] on days 1-3 administered every 21 days.

Background
Erlotinib is effective for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and also recommended in NCCN guidelines. However, there has been a few study done on second-line therapy in NSCLC with EGFR mutations in Japan. The aim of this phase II study was to evaluate the efficacy and safety of erlotinib therapy as second-line treatment in EGFR-mutated NSCLC who was previously treated with platinum doublet.

Methods
NSCLC patients with EGFR mutations (exon19 or 21) who were treated with platinum doublet previously as first-line therapy were treated with daily erlotinib (150mg/ day). The primary endpoint in this phase II study was response rate (RR), and the secondary endpoints were progression-free survival time (PFS), overall survival time (OS), and safety.

Results
From August 2009 to February 2012, 31 NSCLC patients were eligible in this phase II study. The patient’s demographics were a median age of 65 years (range 50-75 years), 21 men and 10 women, 30 adenocarcinomas and 1 other type of cancer, 9 never-smokers and 22 former smokers, PS (ECOG) were 0 in 15, 1 in 14, 2 in 2 patients, exon19 mutation in 15 and exon21 mutation in 16, respectively. Total RR of erlotinib treatment was 61.3%. The disease control rate was 93.5%. Median PFS was 308 days and OS was not reached. Toxicities such as acne, rush and diarrhea were less than Grade 2. Treatment-related death caused by pneumonitis in one patient.

Conclusion
Erlotinib therapy as second-line treatment in EGFR-mutated NSCLC patients who were treated with platinum doublet previously was effective with an acceptable toxicity profile.

Background
Bevacizumab (BEV) improves clinical response in patients with advanced NSCLC when it is used in combination with platinum-based chemotherapy. This study assesses the efficacy of bevacizumab as a maintenance therapy.

Methods
We retrospectively reviewed 67 patients with NS-NSCLC that were treated with bevacizumab (15mg/kg) in combination with any standard chemotherapy at Matsusaka Municipal Hospital (Japan) from November, 2009 through December, 2011. The therapy with bevacizumab was continued till the occurrence of disease progression or unacceptable toxicity; 45 patients received bevacizumab as a maintenance therapy. Survival was evaluated using the Kaplan-Meier curve.

Results
The median overall survival was 24.9 months, progression free survival was 7.0 months, and the overall response rate was 70.5%. No significant differences in overall survival or progression survival were found among regimens in which bevacizumab was used. As a maintenance therapy, the median progression survival was 6.0 months in the bevacizumab alone group and 9.9 months in the bevacizumab plus pemetrexed group (P=0.012). Grade 3/4 adverse events included neutropenia (44.8%), thrombopenia (9.0%), hypertension (14.9%), anorexia (4.5%), hepatopathy (4.5%), and nephropathy (3.0%). One patient had tracheoesophageal fistula.

Conclusion
The efficacy of regimens in which bevacizumab was included was similar. The combined therapy of bevacizumab plus pemetrexed as a maintenance therapy significantly improved the overall progression free survival compared to therapy with bevacizumab alone.

Background
In advanced non-squamous non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) status is important to determine the treatment. However, many previous studies of NSCLC were investigated regardless of EGFR mutation status. Therefore, we thought that the trial only for EGFR wild-type (WT) patients (pts) is required. We evaluated the efficacy and safety of combination therapy with pemetrexed (Pem) and carboplatin (Cb) for advanced non-squamous NSCLC EGFR-WT pts.

Methods
This study was multicenter, phase II trial. We recruited non-Sq NSCLC patients without EGFR mutation. Eligibility criteria were as follows; stage IIIB or IV, or recurrent disease after surgery (rec), no prior chemotherapy, age 20 to 74, ECOG PS: 0-1, and adequate organ function. We evaluated the efficacy and safety of Pem 500mg/m2 and Cb AUC 6 on day1, every 3 weeks, for 3 to 6 cycles. The primary endpoint was response rate (RR) and secondary endpoints were safety and disease control rate (DCR). We planned the sample size was 48 patients and recruited 54 pts. (Unique trial Number; UMIN000003393)

Results
From March 2009 to February 2012, 54 pts were enrolled from 18 centers. Of 53 evaluable for analysis, the median age was 65 years (range, 45–73); 41/12 males/females; 6/44/3 with IIIB/IV/rec; 47/3/3 with adenocarcinoma/large cell carcinoma/NSCLC. The median number of cycles was 4 (range, 1–6). There were 19 partial responses with an RR of 35.8% (95% CI, 23.6–51.0%). SD was observed in 20 pts and DCR was 73.6%. Median PFS was 5.2 months and median OS was 12.months. Major adverse event was grade 3–4 neutropenia in 19 pts (35.8%), anemia in 16 pts (30.2%), thrombocytopenia in 17 pts (32.1%). There was no treatment-related death.

Conclusion
Combination chemotherapy with Pem and Cb showed efficacious and well tolerated in advanced non-Sq NSCLC without EGFR mutation. This combination could include one of the options in standard regimen for 1[st] line therapy for advanced non-Sq NSCLC.

Background
In advanced non-squamous non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation (MT), EGFR-tyrosine kinase inhibitor (TKI) showed better response rate (RR) and longer progression free survival (PFS) than standard chemotherapy, but showed almost same overall survival (OS) in recent studies. Recently, chemotherapy with bevacizumab (Bev) showed higher RR, and maintenance therapy with Bev or pemetrexed (Pem) showed longer PFS (E4599, AVAiL, PARAMOUNT). But, there has been few report of chemotherapy with Pem and Bev including maintenance therapy in patients with EGFR-MT. According to the result of IPASS study, response to standard chemotherapy in patients with EGFR-MT is also better than patients without EGFR mutation. Therefore, we thought chemotherapy containing Pem and Bev may be more effective in EGFR-MT pts. This study is designed to evaluate the efficacy and safety of combination therapy with Pem, carboplatin (Cb) and Bev followed by Pem plus Bev maintenance therapy for non-squamous NSCLC patients with EGFR-MT.

Methods
This study was multicenter, phase II trial. Patients receive Pem 500mg/m2 day1 + Cb AUC6 day1 + Bev 15mg/kg day1, every 3 weeks, 4-6 cycles. Patients who achieved disease control receive Pem 500mg/m2 day1 + Bev 15mg/kg day1, every 3 weeks until disease progression. Key inclusion criteria are as follows; 1) histologically or cytologically proven non-squamous NSCLC, 2) patients with EGFR mutation (exon 19 deletion or L858R revealed by peptide nucleic acid-locked nucleic acid (PNA-LNA) PCR clamp assay), 3) patients with stage IIIB or IV, or recurrent disease after surgery and was not a candidate for curative radiotherapy, 4) no prior chemotherapy, 5) patient who has measurable lesion by RECIST, 6) age: 20-74, 7) ECOG PS: 0-1, 8) adequate organ function, 9) life expectancy more than 3 months,10) written informed consent. Key exclusion criteria are as follows; 1) brain metastasis, 2) hemoptysis (>=2.5ml), 3) active infection, 4) fever, 5) serious disease condition, 6) active double cancer, 7) cavity fluid retention difficult to control, 8) severe drug allergy, 9) receiving anticoagulant drug (except aspirin under 325mg/day), 10) active GI bleeding or inflammation in the abdominal cavity, 11) pregnancy or lactation, 12) patients whose participation in the trial is judged to be inappropriate by the attending doctor. Primary endpoint was RR. Secondary endpoint included safety, disease control rate, overall survival, PFS. (Unique trial Number; UMIN000003737)

Results
not applicable.

Conclusion
not applicable.

Background
Induction chemotherapy (IC) in locoregionally advanced non-small-cell lung cancer (LA-NSCLC) has shown survival benefit. This retrospective study aimed to assess clinical outcomes and to identify prognostic factors in the LA-NSCLC patients who received taxane-platinum IC (TP-IC).

Methods
We reviewed medical charts, imaging studies, and pathologic reports in 51 LA-NSCLC pts who were treated with TP-IC between January 2003 and June 2012 at Seoul St. Mary’s Hospital and St. Vincent’s Hospital.

Results
Mean age at diagnosis was 63.1 years (range, 43-77). Forty-two pts (82.4%) were male. ECOG performance status was 0 in 17 pts (33.3%) and 1 in 34 (66.7%). Histology was squamous cell in 30 pts (58.8%), adenocarcinoma in 20 (39.2%), and large cell in 1. Thirty-four pts (66.7%) had stage IIIA disease, 13 (25.5%) IIIB and 4 (7.8%) IIB. All pts were treated with docetaxel 75 mg/m[2] or paclitaxel 175 mg/m[2], and cisplatin 75 mg/m[2] or carboplatin AUC 5 on day 1 every 3 weeks. Forty-four pts (86.3%) received docetaxel-cisplatin IC, 4 (7.8%) docetaxel-carboplatin, and 3 (15.7%) paclitaxel-cisplatin. The median number of IC cycles was 3 (range, 2-4). Mean relative dose intensity was 90.4% (±10.8) and RDI ≥90% was achieved in 31 pts (60.8%). During TP-IC, asthenia (88.1%), anorexia (89.1%), neutropenia (84.4%), alopecia (80.4%), nausea (71.7%) and myalgia (57.1%) were frequent. Most common grade 3/4 toxicity was neutropenia (80%) and febrile neutropenia occurred in 3 pts (5.9%). All toxicities were manageable with supportive care with no treatment-related death. Tumor response was assessed according to the RECIST and PERCIST criteria. According to RECIST, 3 pts (5.9%) achieved complete responses (CR), 32 (62.7%) partial responses (PR), 14 (27.5%) stable diseases (SD), and 2 (3.9%) progressive disease (PD). In addition, response evaluation by PERCIST was available in 38 pts, 5 pts (13.2%) achieved CR, 26 (68.4%) PR, 5 (13.2%) SD, and 2 (5.3%) PD. Thirty-one pts (60.8%) underwent surgery, 12 (23.5%) concurrent chemo-radiation (CCRT), 2 (4.3%) radiotherapy alone, 5 (9.8%) 2[nd] line chemotherapy or best supportive care and 1 lost follow-up. In 31 pts undergone surgical resection, 27 (87.1%) achieved R0 resection while 30-day postoperative death was reported in 2 pts. Median relapse-free survival (RFS) and overall survival (OS) were 10.7 months (95% CI, 8.1-13.2 months) and 25.5 months (95% CI, 20.4-30.6 months), respectively. The pts. with MD histology and objective metabolic response (CR+PR) by PERCIST showed significant longer RFS with HR of 6.27 (P=.002) and 3.23 (P=.04), respectively.

Conclusion
The TP-IC in LA-NSCLC showed remarkable tumor regression activity, leading to high R0 resection rate. MD histology and tumor response (CR+PR) by PET (PERCIST) were significant prognostic factors for RFS. Further study is ongoing to identify molecular markers affecting clinical outcomes.

Background
Cisplatin-vinorelbine adjuvant chemotherapy significantly improves survival in resected NSCLC. We evaluated outcomes of patients receiving adjuvant chemotherapy in our institution between 2006-2011.

Methods
Outcomes of stage IB -IIIA NSCLC patients who received platinum-vinorelbine following radical lung surgery were collected and analysed to assess overall survival (OS), progression-free survival (PFS), and treatment intensity.

Results
53 patients were identified (23:30, M:F), mean age 62, and 35% were adenocarcinoma. Resected stage was 1B-3A, with one-third stage 3A. When tested, EGFR mutation prevalence was 33% (39% never smokers; 61% ever smokers). There was one death from chemotherapy toxicity. Median chemotherapy cycles given was 4. There was no difference in PFS or OS in patients having carboplatin compared with cisplatin. A significantly improved OS in patients that received ≥3 cycles of chemotherapy was observed (HR=0.25, 0.07-0.97, p=0.04). 60.4% patients had relapsed at last follow-up. Radically treatable disease on relapse was detected by surveillance imaging.

Conclusion
Our small dataset indicates that four cycles of adjuvant platinum-vinorelbine chemotherapy is deliverable in the real world setting, and that less than 3 chemotherapy cycles is associated with poorer outcomes.

Background
Gefitinib is the standard therapy for non-small cell lung cancer patients harboring activating EGFR mutation. However, there are some limitations; 1) we need sufficient tumor tissue to analyze EGFR mutation test; 2) we have to wait result of the test, causing delay of treatment; and 3) we can evaluate the response 4 weeks later but some of the patients do not respond to EGFR TKIs even though they have an activating EGFR mutation. Therefore, we investigated the role of FDG PET as a method overcoming the limitations to evaluate the response to EGFR TKIs.

Methods
Key eligibility is as follows; advanced/metastatic adenocarcinoma of the lung; never smoker; no prior chemotherapy; ECOG PS of 0-1; and main lesion > 2cm. The patients performed two times of FDG PET; before starting gefitinib and after 7 days of gefitinib 250mg/d therapy. If % decrease of peak standardized uptake value (pSUV) of main lesion was 20% or more, gefitinib was continued till progression (Group A). After 6 weeks of the treatment, conventional response evaluation using chest CT was done. But, if % decrease of pSUV less than 20% or increase, treatment changed from gefitinib to pemetrexed/cisplatin (Group B). Primary endpoint was to see the response rate of gefitinib in the patients of Group A. EGFR mutation test using direct sequencing method was also performed but the result was not available or unknown to investigators before the report of second PET result.

Results
Between Apr 2012 and Apr 2013, 50 patients participated. After 7 day-treatment of gefitinib, 28 out of 50 patients showed decrease of pSUV of main lesion ≥ 20 % (47.4±15.8%) (Group A). Out of the 28 patients in Group A, 27 patients were evaluable; PR in 24 (85.7%), SD in 2 and PD in 1 (Table). EGFR mutation was identified later in 24 patients (85.7%) and 4 patients showed wild type EGFR with 2 PRs, 1 PD and 1 NE. Twenty-two patients showed decrease of pSUV < 20 % or increase (-0.3±15.3%). Interestingly, 19 patients (86.4%) had wild type EGRF while two had an activating EGFR mutation. One patient who showed mutated EGFR in Group B was given gefitinib continuously as physician’s decision. But the patient did progressed after all.

	Group A (gefitinib, n=28)			Group B (pem/cis, n=22)
Response	EGFR mutation			EGFR mutation
	Postive (n=24)	Negative (n=4)	Total (n=28)	Postive (n=2)	Negative (n=19)	NE (n=1)	Total (n=22)
CR	-	-	0	-	-	-	0
PR	22	2	24 (85.7%)	1	13	-	14 (63.6%)
SD	2	-	2 (7.1%)	-	4	-	4 (18.2%)
PD	-	1	1 (3.6%)	-	1	-	1 (4.5%)
NE	-	1	1 (3.6%)	1	1	1	3 (13.6%)

Conclusion
The % decrease of pSUV of ≥ 20 % after 7 days of gefitinib treatment would be a good indicator to predict tumor response to EGFR TKI therapy in this clinical setting.

Background
EGFR TKI treatment is standard of care in patients with metastasized NSCLC carrying an activating EGFR mutation. However, induction concepts in locally advanced NSCLC with EGFR mutation including TKI have not been studied extensively. Recently new focus has been shed on intercalated regimens of chemotherapy and TKI, showing improved PFS as well as OS. This concept was used as induction regimen in a female patient with activating EGFR mutation as well as p53 mutation and stage IIIA 3 multilevel.

Methods
Patient was diagnosed and worked up according to standard imaging, histology and immunohistology methods. EGFR, KRAS, BRAF, ALK and P53 mutation analysis was performed as described by Halbfass et al. Remission induction was measured by RECIST 1.1, regression grading by Junker criteria.

Results
A female caucasian 62 y.o. never smoker was diagnosed with TTF1+ adenocarcinoma G3 of the upper lobe of the lung, c2T3 (extension to mediastinal pleura) c2N2 (LN 2R and 4R) c2M0, UICC7 IIIA4 (Robinson). Molecular analysis after microdissection revealed WT for ALK, KRAS and BRAF, but an activating EGFR mutation Exon19 (p.Leu747_Ala750delinsPro), as well as a TP53 mutation in exon 8 (p.Val272Met (c.814G>A) (Sanger Sequencing). Induction therapy was started with erlotinib 150 mg/die p.o. days -12 to -2 in order to prove responsiveness of the tumour to TKI. On day 0 partial response was achieved. Therapy was continued with 3 cycles of Docetaxel 75 mg/m2 d1 and Cisplatin 50 mg/m2 d 1 and 2 qd22 with intercalated Erlotinib 150 mg/die p.o on days 4-19. Almost complete radiologic remission was achieved after 2 cycles The patient underwent R0 resection (upper lobe resection and radical lymphadenectomy) 4 weeks after day 1 of the 3[rd] cycle of chemotherapy, pathologic examination revealed T0N0 (mic+) with only one insula of tumor cells in an N2 lymph node, demonstrating regression grade III in the primary tumor and Grade IIB in the lymph nodes, according to the Junker classification. Molecular analysis of residual tumor cell insula revealed the same EGFR and p53 mutations as the primary tumour. The patient underwent postoperative radiotherapy of the mediastinum. No additional therapy, including TKI was administered postoperatively.

Conclusion
Intercalated TKI treatment might be a promising treatment choice in patients with EGFR mutated locally advanced NSCLC. A phase II trial is currently being planned to expand knowledge in this challenging field.

Background
One of the strongest rationale for maintenance therapy in NSCLC is the fact that exposure to 2nd line therapy is only 40-60% in clinical trials in specialized treatment centers. Even with follow-up intervals of 6 weeks, the 2nd line treatment rate does not seem to increase in clinical trials. One of the main arguments for maintenance treatment not widely adopted in Germany is that 2nd line exposure in international clinical trials does not reflect the situation of treatment management in Germany. Therefore, we analyzed the exposure of patients with stage IV NSCLC in one German Cancer Society certified Lung Cancer Center since certification, as long term follow-up data are available.

Methods
All primary lung cancer cases stage IV in the lung cancer center were analyzed based on the documentation files between 2009 and 2013. Patients were followed between 1st and 2nd line therapy every 6-8 weeks according to S3 guidelines.

Results
203 patients were diagnosed with NSCLC IV (UICC7), or had systemic relapse of localized disease and were treated with 1st line therapy for metastatic disease. Of these, 130 (64 %) received 1st line combination therapy with Carboplatin, 44 (22%), 21 (10%) with TKI 1st line therapy and 8 (4%) with platin-free single agent therapy. 32 (16%) of all patients received maintenance therapy, most of them with bevacizumab. Of 203 patients, 168 progressed after 1st line therapy or 1st line and maintenance therapy. 111/163 (66%) pts. received 2nd line therapy. 57 pts (34%) did not receive 2nd line chemotherapy. Reasons for not receiving 2nd line therapy were mostly associated with intercurrent bone metastases that needed surgery and or radiotherapy and CNS metastases requiring radiation, as well as non-cancer related causes. Of 23 pts receiving maintenance therapy and requiring 2nd line therapy, 20 (87%) received 2nd line therapy.

Conclusion
In a certified lung cancer center and stringent follow-up every 6 to 8 weeks, about 1/3 of patients do not receive 2nd line therapy. The application of maintenance therapy raised the chances of receiving 2nd line therapy. Multiple metastases, especially bone and CNS, requiring radiation therapy, were associated with not receiving 2nd line therapy. These data suggest that maintenance therapy should be considered for pts after 1st line therapy and that radiation therapy for bone and CNS metastases should if possible be accompanied by systemic treatment.

Background
Previous studies investigating a combination of Pemetrexed (P)/Carboplatin (C) showed promising efficacy in the treatment of non-squamous (Sq) non-small cell lung cancer (NSCLC). However, there is no sufficient data of biomarkers. In the present study, we determined the efficacy and toxicity of 6 cycles of P/C for previously untreated patients with advanced non-Sq NSCLC. In addition, we investigated the correlation between the anti-tumor efficacy/toxicity and single nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate reductase (MTHFR).

Methods
Eligibility criteria were no prior chemotherapy, StageIIIB without any indications for radiotherapy or IV, non-Sq NSCLC patients, performance status (PS) 0-1, age <76 yrs, and adequate hematological, hepatic, and renal function. Patients received 6 cycles of P (500mg/m[2])/C (AUC6) on day 1, repeated every 3 weeks. Primary end-point was the assessment of tumor response rate measured by RECIST criteria. The SNPs of the MTHFR gene were analyzed from the genomic DNA extracted from the peripheral blood cells drawn prior to the chemotherapy.

Results
Thirty-nine patients (pts) were enrolled and all pts evaluable for toxicity and response. Male/Female: 30/9; PS 0/1: 11/28; median age 62(45-75); Path: adeno 37(95%), NSCLC unclassified 2(5%); EGFR mutation: positive 2(5%), negative 35(90%), unknown 2(5%). Evaluations of responses were 1CR, 17PR, 16SD, 5PD (response rate 46.2%). The median progression free survival time (PFS) was 6.8 months, and the median survival time (MST) was 18.1 months. Grade 3/4 toxicities in the first cycle included: leukopenia(3/1), anemia(1/1), thrombocytopenia(4/2), neutropenia(2/1), and AST/ALT elevation(2/0). SNPs of the MTHFR at codon 677 were examined in 28 pts. MTHFR genotypes were as follows: C677C; 8 cases, C677T; 14 cases and T677T; 6 cases. Response rates and disease control rates of MTHFR codon677 genotypes were as follows: C677C (50%/75%), C677T (36%/79%) and T677T (50%/100%). Median PFS and MST of MTHFR codon677 genotypes were as follows: C677C; 4.8/7.6 months, C677T; 6.4/20.6 months and T677T; 6.9/18.5 months. Although there were no significant differences of PFS and overall survival between MTHFR genotypes, those of C677C subjects were shorter as compared to the others.

Conclusion
In patients with previously untreated advanced non-Sq NSCLC, P/C appears to be well tolerated and demonstrates encouraging activity. PFS and overall survival of the MTHFR C677C subjects were shorter than those of the C677T or T677T subjects, while the disease control rate of the T677T subjects was higher than that of the C677C or C677T subjects.

Background
Belotecan (camtobell™) is a topoisomerase I inhibitor, and effective in small cell lung cancer (SCLC). The objective of this study is to compare the efficacy and safety of belotecan+cisplatin (BP) and etoposide+cisplatin (EP) in first line setting.

Methods
This is a multicenter, randomized, prospective controlled trial to prove non-inferiority of BP compared to standard EP regimen. The primary endpoint is overall response rate (ORR), and secondary endpoints are toxicity, overall survival (OS) and progression-free survival (PFS). BP was administrated by belotecan 0.5 mg/㎡ for 4 days combined with cisplatin 60 mg/㎡ only for first day. Treatment response was evaluated according to version 1.0 of Response Evaluation Criteria in Solid Tumors.

Results
A total of 147 (BP: 71, EP: 76) patients were randomly assigned and received study drug at least once. In BP arm, there were 1 complete response, 41 partial responses (PR), 17 stable diseases (SD), and there were 35 PR and 28 SD in EP arm. Non-inferiority of BP compared to the EP arm was confirmed by the ORR (BP: 59.2%, EP: 46.1%, 90% confidence interval -0.3 to 26.5, meeting the predefined non-inferiority criterion). Median OS (BP: 360, EP: 305 days, p=0.21) and PFS (BP: 190, EP: 172 days, p=0.37) were not significantly different. The mean relative dose intensity was significantly different (BP: 0.79, EP: 0.86, p<0.01). The frequency of grade ≥ 3 anemia (BP: 34.3%, EP: 13.0%, p<0.01) and thrombocytopenia (BP: 54.3%, EP: 16.9%, p=<0.01) were higher in BP arm.

Conclusion
In extensive stage SCLC, ORR of BP was not inferior to EP and there was no difference of survival. But anemia and thrombocytopenia were more frequent in BP arm. (ClinicalTrials.gov number, NCT00826644)

Background
Erlotinib is indicated in first line treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR positive mutation, then in maintenance treatment of patients with NSCLC, and in second line after failure of at least one chemotherapy regimen. Its efficiency is comparable with chemotherapy, but erlotinib has better adverse-event profile, it is better tolerated, with no haematological toxicity.

Methods
We evaluated data of 154 patients treated in 5 hospitals in Eastern Slovakia between January 01,2008, and October 31,2012. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) overall response and safety. Statistical analysis was performed using Kaplan Meier method and logrank test. The overall population had a median age of 63,6 years (range +-10,7 year).The group included higher percentage of: males (70,8%); patients with squamous-cell histology (52%); patients with stage IV disease 85,7% and patients with ECOG performance status O-1 53%. In total 62 % patients were treated in second-line and 38% in further lines of treatment.

Results
Median overall survival (OS) was 8,3 months. In multivariate analysis, significantly better OS was in group of patients with stage IIIB vs, IV (p =0.033), with PS 0-1 vs. 2 ( 0.011) and previous response on chemotherapy (p=0.011). There was no significant difference in multivariate analysis caused by histological subtype, smoking status and sex. Median of PFS was 4,96 months. Response rate (CR +PR) was observed in 24% of population (mainly PR), but clinical benefit was observed in 70% of patients. Most common toxicity of erlotinib treatment was skin rash (70%) but grade III and IV was only in 4 % of cases. Grade III and IV diarrhea was observed in 1,3 % of patients.

Conclusion
Erlotinib is acceptable treatment (with acceptable OS,PSF and toxicity profile) for patients either with unknown EGFR mutation status or patients unsuitable for chemotherapy.

Background
The brain is the most frequent site of distant metastases in patients with non-small cell lung cancer (NSCLC). In stages I-IIIA NSCLC, after complete resection of the primary tumor, brain metastases account for 9.4% to 36.8% of all recurrences. This study assessed the risk factors for brain metastasis and the prognostic factors for survival after brain recurrence in patients whose advanced NSCLC was resected.

Methods
A total of 101 patients with brain metastases occurring after resection of stage III NSCLC tumors at Tokyo Medical University Hospital between 1995 and 2010 were retrospectively reviewed.

Results
The median time to onset of brain metastasis was 11.2 months (1-72 months) and the median survival time from the diagnosis of brain metastasis was 18.5 months (1-60 months). Multivariate analysis revealed that the risk factors for brain metastasis in postoperative stage III NSCLC included the following parameters: adenocarcinoma,age <65 years at recurrence, N2-N3, incomplete resection, and vascular invasion. In addition, the significant favorable prognostic factors included the absence of neurologic signs and symptoms, single and small size of brain metastasis, age <65, and treatment with epidermal growth factor receptor tyrosine kinase inhibitors.

Conclusion
It was possible to identify patientsat high-risk for brain metastases after surgery. For these patients, careful follow-up is needed after surgery. It is important to detect brain recurrence in patients with NSCLC before neurologic signs or symptoms develop, as early detection improves prognosis.

Background
MGMT is a DNA repair protein which removes alkylating DNA adducts from the O[6] position of guanine. Expression of MGMT is often silenced by promoter methylation in human cancers. MGMT methylation is a predictive marker for prolonged survival in glioblastoma patients treated with an alkylating agent, temozolomide. As MGMT methylation has been found in lung cancers, there is an increasing interest on the clinical utility of temozomolide in the treatment of human cancers. However, it is essential to use appropriate quantitative or semi-quantitative method methods to definitively establish the methylation status of the tumour.

Methods
We critically assessed MGMT methylation status in 6 lung cancer cell lines and 56 lung tumours using three different methodologies. We first assessed the MGMT methylation pattern using methylation sensitive – high resolution melting (MS-HRM). The methylation status at each CpG dinucleotide was assessed bisulfite pyrosequencing of methylated clones. The level of MGMT methylation was quantified using quantitative methylation specific PCR.

Results
MGMT methylation was found in 3 lung cancer cell lines by MS-HRM. The melting profiles of all methylated samples were indicative of heterogeneous methylation pattern by melting curve analysis. To examine the methylation status at each CpG sites of individual template, two MGMT methylated lung cell lines (H1666 and H69) were further tested by limiting dilution analysis and bisulfite pyrosequencing. The number and site of methylated CpG dinucleotides greatly varied in each template, confirming the heterogeneous methylation pattern in both cell lines. In 56 lung tumours, heterogeneous MGMT methylation was detected in seven samples (13%) by MS-HRM. The level of MGMT methylation was then estimated. 17 lung tumours, including the 7 MS-HRM positives and 10 additional tumours, were positive. However, the methylated level in all of the methylated samples was low, ranging from below 1% (12 samples) and up to 12%.

Conclusion
The level of MGMT promoter in lung cancer is difficult to estimate. Ideally clonal analysis should be used to estimate the proportion of methylated alleles. Alternatively, methylation profiling using MS-HRM followed by pyrosequencing can be used to identify tumours showing significant levels of methylation. If MGMT methylation is found only in a small proportion of tumour cells, it is unlikely to be a useful target for therapy. Overcalling of MGMT methylated tumours may provide the explanation for the lack of survival benefit with temozolomide treatment in MGMT-methylated lung cancer patients in a recent phase II clinical trial (NCT00423150). This indicates that incorporation of immunohistochemistry for the MGMT protein should also be part of the assessment of the MGMT status of lung cancer.

Background
Diagnostic guidelines on CAP-IASLC-AMP recommend the use of the ALK fluorescence in situ hybridization (FISH) assay for selecting suitable patients for ALK-TKI therapy. However, based on some reports of the usefulness of immunohistochemistry (IHC) for the detection of ALK, it was considered that it may be possible to use IHC instead of FISH, which is more time-consuming and technically difficult, for the select suitable patients for ALK-TKI therapy in FFPE specimens. The purpose of this study was to investigate the usefulness of IHC as compared to FISH for the diagnosis of ALK-fusion gene-positive NSCLC in clinical practice.

Methods
A total of 52 patients with NSCLC who were examined for the ALK-fusion gene by both IHC (Envision Flex+, Dako) and FISH (break-apart probe) at the National Cancer Center Hospital East from March 2012 to March 2013 were included in this study. The reliability and usefulness of IHC as compared to those of FISH were examined for the diagnosis of ALK-fusion gene-positive NSCLC.

Results
There were 26 men and 26 women, with a median age 63 years (range, 25-78 years). The pathological diagnosis, based on the examination of 20 resected specimens and 32 biopsy specimens, was adenocarcinoma in 47 cases and poorly-differentiated NSCLC in the remaining 5 cases. ALK protein overexpression was detected by IHC in 11 patients, in contrast, ALK rearrangement was detected by FISH in 9 patients. When the results of the FISH assay were considered as true-positive, the sensitivity, specificity, accuracy, positive predictive value and negative predictive value of IHC were 78%, 100%, 74%, 64%, and 93%, respectively. There were 7 patients with discordant ALK status, consisting of 2 patients who were IHC-negative/ FISH-positive, 4 patients who were IHC-positive/ FISH-indeterminate and 1 patient who was IHC-negative/FISH-indeterminate. Of these patients with discordant ALK status, three received ALK-TKI (crizotinib) therapy. The best response rate according to assessment by the RECIST was SD in the patient who was IHC-negative/ FISH-positive, and PR in both the patients who were IHC-positive / FISH-indeterminate. Figure 1

Conclusion
Although the ALK-true positive result remained unclear, based on the responses to crizotinib, it might be judged that the result was true-positive in the patients who were IHC-positive/ FISH-indeterminate and true-negative in the patient who was IHC-negative/ FISH-positive. Thus, it appeared that FISH could not determine the ALK status in approximately 10% of the patients, and it can therefore not be considered an absolute diagnostic method.

Background
Backround and Rationale: The inhibition of the Epidermal Growth Factor Receptor (EGFR) is a treatment option in patients with non-small cell lung cancer (NSCLC). Afatinib is an inhibitor of EGFR as well as the other members of the ErbB family. This compassionate use program was initiated to offer a treatment option for patients after failure of platinum-based chemotherapy and reversible TKI.

Methods
Material and Methods: Patients with NSCLC who had had platinum-based chemotherapy and therapy with gefitinib or erlotinib for at least 6 months or who had an activating mutation in the EGFR-gene were eligible to enter this compassionate use program. Patients were given 50 mg (or 40 mg at the investigators´ decision) of afatinib daily until progression or intolerable adverse events. Here we report on our clinical experience at our institution.

Results
Results: 18 Patients were enrolled at our center. 6 had an activating mutation, 1 had proven wild type and 11 had an unknown EGFR-status. The median duration of therapy was 2.4 months (range 0.5 to > 19 months). Interestingly, one of the remissions was observed in a patient with proven EGFR wild-type. Most adverse events were EGFR-TKI class-specific and manageable by dose-adaption.

Conclusion
Conclusions: Afatinib is an appropriate treatment option for patients who benefitted from treatment with gefitinib or erlotinib.

Background
About 30–40% of all patients (pts) with non-small cell lung cancer (NSCLC) develop brain metastases (BM), leading to a poor prognosis and a median survival of <6 months after whole brain radiotherapy. There have not been standards of drug therapy for treatment for pts with BM. The main goal of this trial is to assess the efficacy of different schemes of drug therapy in pts with BM from NSCLC.

Methods
87 pts were included in this study. 56 pts with NSCLC were treated with gemcitabine (Gem) - 1000 mg/m[2] intravenous on days 1 and 8 + cisplatin (Cis) – 50 mg/m[2] intravenous on days 1 and 8, every 3-4 weeks. 10 pts with NSCLC (adenocarcinoma, without epidermal growth factor receptor (EGFR) mutations) were treated with paclitaxel (Pacl) -175 mg/m[2] intravenous on day 1 + Carboplatin (Carb) – AUC=6 intravenous on day 1, every 3 weeks. 21 pts with NSCLC (adenocarcinoma, with EGFR mutations – 12 pts; adenocarcinoma, without EGFR mutations – 9 pts) received treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib (Gef) - 250mg/day (15 pts) or erlotinib (Erl) - 150 mg/day (6 pts) until radiologically-verified progressive disease. The main aims of this study were objective response (OR) – complete response (CR) + partial response (PR) in the brain and in the extracranial sites (ES), median of survival (MoS), 1-year survival.

Results
Observations were as follows: in the Gem + Cis treated pts, 26 OR (46,4%) in 56 pts group in the brain and 22 OR (40,0%) in 55 pts group in ES. The MoS was 9.0 months, 1-year survival was 30,3%. In the Pacl + Carb treated pts, there were 3 OR (30,0%) in 10 pts group in the brain and 4 OR (40,0%) in 10 pts group in ES. The MoS was 7,5 months, 1-year survival was 30,0%. In the EGFR TKIs treated pts (with EGFR mutations), there were 9 OR (75,0%) in 12 pts group in the brain and 7 OR (70,0%) in 10 pts group in ES. The MoS was 14,5 months, 1-year survival was 66,6%. In the EGFR TKIs treated pts (without EGFR mutations), there were no OR in 9 pts group in the brain and in ES. The MoS was 4 months, 1-year survival was 11,1%.

Conclusion
Previous results of our study showed that efficacy of drug therapy in patients with BM from NSCLC depends on biology of tumor and scheme of treatment. The best results achieved in pts with EGFR mutations who received EGFR TKIs (Gef or Erl). Further investigation is to be expected.

Background
Patients with epidermal growth factor receptor(EGFR) mutation positive adenocarcinoma exhibited marked response to gefitinib. In most cases, the patients showed disease progression after EGFR-tyrosine kinase inhibitor treatment. We evaluated the efficacy and safety of pemetrexed after the failure of gefitinib in patients with adenocarcinoma with EGFR mutation.

Methods
Patients harvoring EGFR-mutant stage IV adenocarcinoma that progressed during gefitinb were administered pemetrexed after discontinuing of gefitinib treatment. We retrospectively analysed the efficacy of pemetrexed monotherapy.

Results
Retrospectively, we analysed the 41 patients in this study. All patients were treated with gefitinib as the first line and treated as the 2[nd] line with pemetrexed monotherapy. The median number of treatment cycles was 3.15±2.1 cycles. Overall response rate was 2.6% (95% confidence interval, 0%-7.9%) and disease control rate was 23.7% (95% confidence interval, 10.5%-39.4%). Grade 3/4 hematological toxicities were neutropenia (5.2%), leucopenia (5.2%), anemia (5.3%), and thrombocytopenia (2.6%). Grade 4 non-hematological toxicities and chemotherapy related death were not observed.

Conclusion
Pemetrexed shows unfavorable result to patients with acquired drug resistance after EGFR-tyrosine kinase inhibitor treatment. We will have to study the efficacy of pemetrexed after EGFR-TKI treatment prospectively.

Background
Lung cancer is the leading cause of cancer-related deaths over the world. Treatment in locally advanced non small cell lung cancer (NSCLC) is heterogeneous. The cure rate after complate surgical resections not good as expected. Additional treatment have come into question. Cisplatin based chemotherapy adjuvant or neoadjuvant increases overall survival in stage III NSCLC. The better understanding of the biology of NSCLC, may allow selection of appropriate treatment. Only a few research is made about prognostic value of xanthine oxidoreductase (XOR) and BRCA-1 in lung cancer.

Methods
In our study, stage IIIA and stage IIIB 35 patients who had been followed in Baskent Universty medical oncology and of thoracic surgery departments, operated in Baskent Ankara and Adana hospitals, and who received neoadjuvant chemotherapy were included. Clinical and histopatological parameters (age, gender, stage, smoking history, performans status, neoadjuvant chemotherapy) along with immunohistochemical BRCA1and XOR staining were examinated and corelated with survival.

Results
Median overall survival time was 38.5 months and 5 year survival rate was 33% Patients with ECOG PS 0 had better overall survival than the patients with ECOG PS 2 (p= 0.004) According to results of the analyses for overall survival BRCA1 positivity was significant P=0.047, XOR was 0.039. The only significant associated parameter with overall survival was ECOG PS. There was no significant relation between overall survival and XOR expression in our patients.

Conclusion
BRCA1 positivity was associated with shorter overall survival in stage III lung cancer in patients to whom neoadjuvant platinium based chemotherapy was given.

Background
Chemotherapy trials for stage IIIB/IV NSCLC have established that 3 cycles was better than 6. International guidelines stipulate 4-6 cycles but recent studies addressing maintenance or switch therapy suggest benefits with prolongation of treatment. Our regional protocol for chemotherapy in stage IIIB/IV NSCLC recommends platinum doublet chemotherapy first line to a total of four cycles with interim CT scan after two to assess response. This audit was undertaken to establish what additional benefit in response was achieved by cycles three and four. Our primary outcomes were response rate to chemotherapy after two cycles and change in response between interim imaging and end of treatment scan after four cycles.

Methods
During 2011/2012 all advanced non-small cell lung cancer patients referred for chemotherapy to our regional centre had treatment and outcomes recorded. We excluded from our audit any patients receiving non-first line chemotherapy, oral TKIs or clinical trial agents. We included patients who had received minimum two cycles, recording at baseline: age, gender, pathology, ECOG performance status and chemo regimen. Interim CT scans were classed as stable disease SD, partial response PR, mixed response MR( response at one site of disease with either stable or progressive disease at other sites) or progressive disease PD. CT following four cycles was compared to interim imaging and categorised as stable disease, increased response relative to interim scan, mixed response or progressive disease.

Results
188 patients fulfilled audit entry criteria: 96 men, 92 women: age range 36-83 years (median 67y). There were 107 adenocarcinoma (57%), 53 squamous carcinoma (28%) and 21 undifferentiated/ not otherwise specified (11%). ECOG: PS0-1 44%, PS2 6%, PS3 1% but 49% not recorded. Most common chemo regimens were cisplatin/pemetrexed (22%), carboplatin/pemetrexed (20%), gemcitabine/carboplatin (22%) and carboplatin/paclitaxel (14%). After 2 cycles chemotherapy 25 patients (13%) had progressive disease but 66(35%) PR, 72(38%) SD and 15(8%) MR. 25 patients stopped or changed therapy following 2 cycles with a further 25 stopping after 3 cycles. Of the 138 completing 4 cycles 26(19%) had PD on end of treatment scan. 62(45%) had stable disease compared to interim scan and 25(18%) had minor improvement relative to interim scan. Of those showing continuing response most (84%) had had initial PR.

Conclusion
Our response rates to chemotherapy after two cycles compare well with published series. Evaluation of interim and end of treatment scans has demonstrated that most of the radiological response to chemotherapy is achieved by the first two cycles. The number of patients responding after 2, if SD at 2, was low and the additional benefit in the minority of PR patients who did continue to respond was marginal. Our audit is limited by lack of quality of life data but if patients experience increased fatigue and toxicity with third and fourth cycles then our data would suggest that early stopping of platinum chemotherapy may not be detrimental to overall response rates. The optimal number of cycles of platinum based chemotherapy remains uncertain and worthy of further research.

Background
The impact of a systematic use of a Comprehensive Geriatric Assessment (CGA) on management strategies in elderly patients with no small cell lung cancer (NSCLC) is not well established. The objective of this study was to analyze if items of CGA may predict overall survival of elderly patients with NSCLC treated by chemotherapy or erlotinib in first or second lines setting.

Methods
Individuals data’s of GFPC 0504 study (population of fit elderly patients) and GFPC 0505 study (population of frail elderly patients) were pooled. The aim of these two prospective phase 2 trials were to compare a strategy using chemotherapy (doublet in fit patients, monotherapy in frail patients) in first line followed by erlotinib in second line to the reverse strategy (erlotinib in first line, followed by chemotherapy), in terms of progression-free survival (PFS) in second line period. Secondary outcomes were to compare first-line PFS, overall survival (OS), tolerance and costs. All patients had a complete comprehensive geriatric assessment, evaluating diverse areas as functional status, nutritional status, cognition, psychological functioning, and social support, at randomization. Predictive factors associated with OS were searched using Kaplan-Meier curves and logrank tests in the univariate analysis. A Cox model was used for the multivariate analysis.

Results
195 patients were included. Mean age was 77 years. 135 (70%) patients were males, 172 (89%) were stage IV and 109 (56%) were no or ex-smokers. At CGA assessment, 176 patients (70%) had an IADLD score of 3 or 4, 129 pts (66%) had a 0 or 1Charlson score, 167 pts (86%) had a simplified Charlson score < 8, 19 pts had a MMS score < 30, 146 pts (75%) had a situational score >10, 33 (17%) had a nutritional score <8. Factors predicting OS in the univariate analysis were 1-3 PS scores (1.5 [1.1 – 2.0], p=0.01); no or ex-smoker (0.70 [0.52–0.95], p = 0.02); 2-4 Charlson score (2.0 [1.4 – 2.7], p<0.0001, Simplified Charlson score ≥ 8 (1.50 [1.10–2.07],p=0.03), nutritional score>8 (0.60 [0.42 – 0.91], p= 0.01); 2 level mobility score (0.15 [0.04 – 0.62], p = 0.009). In the multivariate analysis, remained 1-3 PS (1.4 [1.02 – 1.9], p = 0.04), 2-4 Charlson score (1.46 [1.07 – 1.99], p=0.02), >8 nutritional score (0.69 [0.46 – 1.04], p= 0.07), level 2 mobility score level (0.25 [0.06 – 1.01], p = 0.06)

Conclusion
Comorbidities, nutritional and mobility scores, in this specific elderly population are predictive of OS. Prospective studies using large prospective cohort are needed to better select the more relevant management for elderly with advance NSCLC.

Background
Combined chemoradiotherapy (CRT) is the standard therapy for unresectable stage III non-small cell lung cancer (NSCLC). The most commonly used (~80%) chemotherapy regimens are platinum (cisplatin or carboplatin)-based. While carboplatin has been favored in older patients with comorbidities, there is very limited data regarding tolerability of these regimens in the elderly. In this study, we used population-based data to compare survival and toxicity of elderly stage III NSCLC patients treated with carboplatin vs. cisplatin-based chemotherapy in combination with radiotherapy.

Methods
Using the Surveillance, Epidemiology and End Results (SEER) database linked to Medicare records we identified 2,057 patients >65 years of age with histologically confirmed, unresected stage III NSCLC that received concurrent chemoradiotherapy between 2002 and 2009. We limited the cohort to patients treated with platinum-based regimens. We used logistic regression to fit a propensity score model predicting use of cisplatin-based therapy. Overall and lung-cancer specific survival of patients treated with cisplatin vs. carboplatin was compared after adjusting for propensity scores. We identified severe treatment-related toxicity requiring hospitalization and compared these rates among patients treated with cisplatin vs. carboplatin after controlling for propensity scores.

Results
Overall, 347 (16%) patients received cisplatin, most commonly (70%) in combination with taxanes. Patients treated with cisplatin were younger (p<0.001), more likely to be married (p=0.01), and had lower comorbidity burden (p=0.008). There were no significant differences in other sociodemographic characteristics, tumor location, and T or N status among patients treated with cisplatin vs. carboplatin (p >0.05 for all comparisons). Cox models adjusting for propensity scores showed that overall (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.86-1.11) and lung cancer-specific (HR: 1.01, 95% CI: 0.86-1.18) survival were similar for cisplatin compared with carboplatin-treated stage III patients. Adjusted analyses also showed that cisplatin-treated patients had increased risk of severe neutropenia (odds ratio [OR]: 2.70, 95% CI: 1.61-4.51), anemia (OR: 1.32, 95% CI: 1.01-1.73), and thrombocytopenia (OR: 1.62, 95% CI: 1.01-2.62). Rates of infection (OR: 1.10, 95% CI: 0.76-1.58), fever (OR: 1.07, 95% CI: 0.43-2.64), dehydration (OR: 1.11, 95% CI: 0.84-1.49), emesis/diarrhea (OR: 1.77, 95% CI: 0.98-3.20), and renal failure (OR: 1.58, 95% CI: 0.91-2.76) were not significantly different among groups.

Conclusion
Carboplatin, compared to cisplatin-based, chemotherapy is associated with similar long-term survival but lower rates of severe toxicity when used in combination with radiotherapy to treat elderly patients with stage III NSCLC. These data suggest that carboplatin may be the preferred therapy for elderly patients with locoregional NSCLC.

Background
In a phase III trial in first-line, advanced NSCLC, nab-paclitaxel + carboplatin (nab-P/C) significantly increased tumor response rates, with comparable overall survival (OS) vs solvent-based paclitaxel + carboplatin (sb-P/C). However, nab-P/C improved OS in prespecified, stratified subgroups of pts, including those aged ≥­ 70 y (19.9 vs 10.4 mo; P = 0.009) and in North American pts, (12.7 vs 9.8 mo; P = 0.008). Based on the data from this trial, nab-P/C was approved by the US Food and Drug Administration (FDA) as a first-line treatment in advanced NSCLC, a condition for which no drug has demonstrated a clinically meaningful survival advantage vs platinum doublets in an unselected population in FDA registration trials. Here, we report results of a cost-effectiveness analysis that was conducted from the US payer perspective, with resource use data collected during the trial.

Methods
Cost-of-care estimates were applied to patient-level data on chemotherapy, drug delivery, patient monitoring, supportive care drugs, and treatment of dose-limiting toxicity. Cost-effectiveness outcomes were presented as incremental cost per life year ($/LY) gained with nab-P.

Results
Use of colony stimulating factors and treatment discontinuations due to toxicity were comparable between experimental and control arms. Taxane dose intensity was higher with nab-P vs sb-P (79.6% vs 61.8%). For all pts, the nab-P/C group had a $25,868 higher cost compared with sb-P/C ($35,179 vs $9,310) and an incremental $/LY gained in excess of $100K, comparable with $/LY gained estimates published for other recently approved NSCLC agents. However, in the subsets of pts aged ≥ 70 y and those from North America, the cost differential was reduced to $18,244 and $19,941, respectively. $/LY gained was reduced to $23,000 and $83,000, respectively, which compares favorably with published incremental $/LY gained for other NSCLC agents based on their OS advantage in patient subpopulations. Similar results were observed in a post hoc analysis of the subgroup of pts aged ≥ 60 y.

Conclusion
Weekly nab-P/C can be considered a clinically and economically attractive treatment option for US payers for first-line advanced NSCLC, particularly in the North American and elderly subsets. Future clinical trials are needed to validate these findings.

Background
Docetaxel (75mg/m[2]) has been reported as first-line and maintenance treatment for Western population with advanced NSCLC. Different doses of docetaxel (60mg/m[2]) are currently delivered in Asian population. Pharmacogenomics alterations in taxanes disposition in different ethnic groups may explain this difference. TFINE study was to evaluate the efficacy, safety, and tolerability of Docetaxel in the maintenance setting, and to identify the preferable dose of docetaxel in Asian population. TFINE study demonstrated significant superiority in tolerability and similar efficacy for dose of 60mg/m2 of Docetaxel versus that of 75mg/m2 in first-line Chinese advanced NSCLC patients. And maintenance treatment with docetaxel significantly prolonged PFS compared with BSC. Here we report Overall Survival (OS) data from TFINE (ClinicalTrials.gov NCT01038661).

Methods
Previously untreated patients, aged between 18 and 75 years, histologically or cytologically confirmed advanced NSCLC with PS of 0-1 were included. Patients were initially randomized (R1, 1:1) to receive cisplatin (75mg/m2) plus docetaxel of 75 mg/m2 or 60mg/m2 for 4 cycles. Patients with disease control after the initial treatment were subsequently randomized (R2, 1:2) to best supportive care (BSC) or maintenance docetaxel of 60mg/m2 for up to 6 cycles. Genomic DNA was prospectively collected from all enrolled patients. The primary endpoint was PFS since R2, and the secondary endpoints included ORR, overall survival (OS), and toxicity. OS was defined as the time lasting from R2 to death of any cause. The subgroup analysis about OS included gender, historical category, smoking, ECOG PS. The maintenance treatments of every patient were recorded.

Results
This randomized study was undertaken in 15 centers in China. Between Dec 2009 and Aug 2011, a total of 382 patients were enrolled to R1 and 179 patients (46.8%) were enrolled to R2 (61 vs. 118). The median follow-up time for OS was 23.5 months (range 20.5, 28.1 months) for patients receiving BSC and 24.4 months (range 22.6, 25.3 months) for patients receiving maintenance docetaxel of 60mg/m2 for up to 6 cycles. Median OS of BSC group (13.7months, [95%CI:12.0, 15.7]) was not significantly different from that of docetaxel group(12.3months,[95%CI:11.2,14.1]) (p=0.77). No difference was found in the subgroup analysis. Post-discontinuation therapy was given at the discretion of the investigator. Numerically more patients in BSC group (n=35, 57.4%) received second-line treatments, including docetaxel, EGFR-TKI or pemetrexed, than those in maintenance group (n=56, 45.5%), although the difference is statistically insignificant (p=0.13). The failure observation of PFS gains translating into OS gains is partially related to post-progression therapy. Preliminary pharmacogenomics analysis demonstrated the CYP3A5*3C(6986 AG/GG) genotype associated with poor PFS and ABCB1:2677 GG genotype demonstrated less neutropenia in Chinese NSCLC patient treated with Docetaxel/DDP regiment, which did not correlated with OS.

Conclusion
Although there is no significant benefit in terms of OS with Docetaxel maintenance treatment, our finding for better tolerability suggest that Decetaxel maintenance treatment could be of some benefit to patients with advanced non-small cell lung cancer.

Background
Some clinical studies suggested a possible advantage of bevacizumab combined with taxanes. Although carboplatin is slightly inferior to cisplatin in terms of survival, addition of bevacizumab to carboplatin may overcome this disadvantage. The aim of this study was to clarify the efficacy and safety of combination chemotherapy consisting of bevacizumab, docetaxel and carboplatin in the 1st line chemotherapy for non-squamous non-small cell lung cancer.

Methods
Patients who are untreatable with thoracic curative radiotherapy, with stage IIIB/IV non-squamous non-small cell lung cancer, age ranging from 20 to 74 years, PS 0 or 1, adequate organ functions, measurable lesions, and written informed consents were eligible. Combination chemotherapy consisting of bevacizumab (15 mg/kg), docetaxel (60 mg/m2) and carboplatin (AUC=6) on day 1 was administered every 3 weeks up to 6 cycles (induction phase). Unless PD, bevacizumab maintenance therapy was performed until PD (maintenance phase). The primary endpoint was median PFS to prove its superiority to the previous standard combination chemotherapy consisting of docetaxel and cisplatin with its historical median PFS of 4.6 months. With =0.05 and =0.20, calculated minimum sample size was 37, and the final determined sample size was 40. This trial was registered to the clinical trial registration system with the ID of UMIN000004524.

Results
Forty patients enrolled and 39 patients were analyzed. They included women in 31%, patients with PS of 0 in 67%, stage IV in 92%, EGFR mutations in 13% and unknown EGFR status in 8%. The median age was 62 years. The induction phase was delivered for 4 cycles in median (range: 1-6), and 21 patients (54%) received maintenance phase with median 4 cycles (range: 2-24). Frequent toxicities ≥ grade 3 during the induction phase in completely analyzed patients (n=32) included neutropenia (50.0%), anemia (9.4%), thrombocytopenia (9.4%), febrile neutropenia (25.0%) and hypertension (37.5%). Other toxicities ≥ grade 3 were cholecystitis, increased ALP, hyperpotassemia, proteinuria, diarrhea, appetite loss, nausea, constipation, infection, stomatitis, and cancer pain in 3.1%, respectively. Interim external reviews of 35 pts revealed ORR of 74% (26/35) and median PFS of 6.4 months (95% CI: 4.8-9.9).

Conclusion
The primary endpoint was met because the lower end of the 95%CI exceeded the threshold of 4.6 months. This combination chemotherapy seems promising in terms of safety and effectiveness, warranting phase III studies.

Background
Efficacy of advanced non-small cell lung cancer treatment has been in platform. How to integrate the limited drugs and design the sequence of regimens is the key point in clinical practice.

Methods
Clinical data of 215 patients of pathologically confirmed advanced non-small cell lung cell from January 2010 to December 2012 was analyzed retrospectively. The clinical features, pathological diagnosis, numbers of treatment lines and the efficacy were analyzed. Efficacy and adverse events were evaluated according to the RECIST 1.1 Criteria, NCI Common Terminology Criteria v3.0, respectively.

Results
Among 215 patients treated in our cancer center, 135 were men and 84 were women. The squamous cell carcinoma and adenocarcinoma was 50 and 74 in man ; 8 and 70 in women, respectively. 111 cases had 1 line treatment, 53 had 2 lines, 31 had 3 lines, 10 had 4 lines and 9 had more than 4 lines. In all lines, patients with adenocarcinoma compared to the squamous cell carcinoma had more opportunities to receive more drugs(P<0.05). The therapy regimen was decided by the Chinese medical insurance. Combined with platinum, gemcitabine was 29.3% and Taxanes was 26.5%. Either of these two regimens was the preferred choice. Tyrosine kinase inhibitors(TKI) including those offered by clinical trail and pemetrexed which were paid at patients’ own expense were 14%, 22.8%, respectively. In patients received 1, 2 and multi-line therapy(more than 2 lines), the partial response rate was 14.4%, 3.8%, 0, respectively. The stable disease rate was 28.8%, 32.1%, 30%, respectively. OS of patients with multi-line therapy(more than 2 lines) was longer than those with 1 and 2 lines treatment but the data was not mature.

Conclusion
Patients with advanced non-small cell lung cancer had multi-line treatment had better disease control. Their regimens mainly covered the chemotherapy and TKIs. Limited of the Chinese medical insurance, the first choice was gemcitabine/taxanes combined with platinum. Tailored therapy may explore the rational therapy sequence to get much better efficacy.

Background
Two previous studies from our institution have shown that weight gain in the course of chemoradiotherapy for locally advanced or oligomestastatic NSCLC is associated with improved survival (Sher et al, 2013 and Gielda et al, 2010). This study aimed to determine the prognostic value of weight and serum albumin changes in patients with locally advanced and metastatic NSCLC receiving first-line platinum doublet chemotherapy.

Methods
Patients with newly-diagnosed locally advanced or metastatic NSCLC treated in the first-line setting with platinum doublet chemotherapy from June, 2011 to August, 2012 at RUMC were included for analysis. Weight and albumin values were recorded at baseline, 3, 6, and 12-week intervals from initiation of therapy. Their association with overall survival (OS) was assessed using Kaplan Meir methods and Cox proportional hazards regression.

Results
A total of 139 patients were included. Median age was 68 years (range 31-85). ECOG performance status (PS) was 0 in 29.5%, 1 in 46.7%, and 2 or greater in 16.5% of patients. Median baseline weight was 68.17 kg (range 40.1-123.4). Patients who experienced weight gain at 6 weeks had a significantly higher OS compared to those who lost weight, 20.4 months versus 13.6 months median survival respectively (log-rank p=0.025), Fig 1. In Cox regression analysis the hazard ratio (HR) for 1 kg of weight gain at 6 weeks was 0.84 (p <0.001). A marginal improvement in OS was seen for those who gained weight at 12 weeks, median survival not reached versus 15.5 months in those who lost weight (log-rank p=0.07). The HR for 1 kg weight gain by 12 weeks was 0.91 (p=0.002). Baseline albumin level was available for 97 patients. Median baseline albumin was 3.5 (range 1.5-4.7). A higher baseline albumin was found to be significantly associated with longer survival (HR 0.31, p<0.001). In a multivariate analysis, weight gain in 6 weeks was strongly associated (HR 0.81, p=0.003), and higher baseline albumin was associated (HR 0.49, p=0.03) with improved OS after adjusting for age, PS, and baseline weight. Figure 1: Figure 1

Conclusion
Higher baseline albumin and weight gain during first-line chemotherapy for locally advanced and metastatic NSCLC, appear to be associated with improved overall survival and may constitute important predictors of outcome. Study of molecular mechanisms involved in weight gain during anti-neoplastic treatment might provide ideas for novel therapeutic strategies.

Background
Chemotherapy improves overall survival in advanced non-small cell lung cancer (NSCLC). We sought to evaluate clinical effectiveness of chemotherapy in the general population by looking at referral patterns, and outcomes.

Methods
The British Columbia (BC) Cancer Agency is a publicly funded system that serves a population of over 4.5 million. All referred cases of stage IIIb/IV non-small cell lung cancer were identified using the BC Outcomes and Surveillance Integrated System and retrospectively reviewed. Patient demographics, tumour characteristics and treatments were extracted. Overall survival (OS) was estimated using the method of Kaplan-Meier. Cox Proportional Hazards (CPH) modeling was used to control for possible confounders. Multiple logistic regression (MLR) was used to compare characteristics between patients who were referred and not referred to a medical oncologist (MO).

Results
1384 patients were diagnosed with Stage IIIb/IV NSCLC between January 1 to December 31, 2009. Median age 70 years (29-96), male 53%, ECOG 0-1 38%, rural/urban 17%/83%, non-squamous/squamous/NOS 34%/21%/46%. 710 (51%) patients were assessed by a MO and of these, 382 (54%) received chemotherapy. 1225 (89%) were assessed by a radiation oncologist (RO), and 1025 (84%) received radiation. MLR showed that patients referred to MO were more likely to be younger, from an urban area, and have a better ECOG. Median OS for the entire cohort was 9.6 months (CI 8.5-10.7). There was a statistically significant improvement in OS in patients who received chemotherapy at 14.2 months (CI 12.5-15.9) in comparison to 7.6 months (CI 6.6-8.6) who did not receive chemotherapy (p<0.0001). This remained statistically significant in the CPH model, controlling for ECOG, sex, age, histology (HR 0.80, CI 0.65-0.92). In comparison, OS was 8.6 months (CI 7.4-9.8) for patients who received only radiotherapy, and 5 months (CI 3.1-6.8) for those treated with best supportive care.

Conclusion
Only half of the referred patients were assessed by a medical oncologist and only 54% of them received chemotherapy. This is despite the awareness that chemotherapy significantly improves OS. Strategies to improve upon this 51% referral rate should be evaluated, such that patients do not miss out on life-prolonging therapy.

Background
Autophagy (ATG) preserves tumor growth potential during cellular stresses, and may thus promote chemotherapy resistance. Hydroxychloroquine (HCQ) inhibits ATG in in-vitro and in-vivo models.

Methods
We thus initiated a phase II study of HCQ (200 mg/d p.o, twice daily) plus I.V. paclitaxel 200 mg/M2 and carboplatin AUC=6 every 21 days (group [GRP] 1) plus I.V. bevacizumab (GRP2; 15 mg/kg every. 21days as per Bev criteria).

Results
We entered 25 PS 0-1 patients (Pts), 14M/11F; 19 (5/4) in GRP1, 16 (9/7) GRP2. Median PS =1. Median age =70. Overall: 0 CRs; 13/25 (52%, 90% CI 40,64) Pts achieved PR (4/9 GRP1; 9/16 GRP2); 5/25 achieved SD (2/9 GRP1, 3/16 GRP2); 5/25 had PD, and 2/25 remain too early. Median F/U is 16 months, median TTP was 6+ months, and median OS was 10+ months. Pharmacokinetic analysis of CINJ phase I HCQ studies, showed results similar to studies in arthritis: HCQ was membrane bound at doses up to 800 mg/day, but free HCQ levels were seen at 1200 mg/day. In parallel laboratory studies, engineered murine k-ras -/- lung cancer models were dependent on ATG, and ATG inhibitors blocked tumor development and progression. K-ras data, available on 4/25 Pts showed 1/1 k-ras wt had PD. Among 3 Pts with k-ras-mutant tumors, 2 achieved PR and 1 SD

Conclusion
Further k-ras assessment on available tissue is in process. This study continues with HCQ at 1200 mg/day and required k-ras assessment.

Background
Platinum based combination chemotherapy is the mainstay of treatment in patients with small cell lung cancer (SCLC). However, changes of pulmonary function after the chemotherapy in these patients have not been well characterized.

Methods
We reviewed the data from patients with SCLC treated with platinum based chemotherapy as a first-line treatment at St. Paul’s Hospital, The Catholic University of Korea, retrospectively. The basal clinical features and the outlook of changes in pulmonary function test (PFT) values of the patients before and after 2 or 3 cycles of chemotherapy were analyzed. Also, we surveyed factors affecting such pulmonary function changes.

Results
Eighteen patients were enrolled in this study. Baseline PFT values were measured and forced expiratory volume in 1 second (FEV1, 80.4%), forced vital capacity (FVC, 87.4%), and FEV1/FVC ratio (62.5%) showed an obstructive pattern. After the chemotherapy, overall spirometric values and lung volumes were not significantly changed, but diffusing capacity of the lung for carbon monoxide (DLCO) was significantly decreased ( p = 0.023). In multivariate analysis, peripheral tumor location was the only significant factor associated with DLCO reduction (HR 21.00; 95% CI 1.504-293.253; p=0.024). Patients with limited disease had a declining tendency of DLCO (p = 0.058) compared to the patients with extensive disease.

Conclusion
Platinum based chemotherapy could reduce DLCO in patients with SCLC. Tumor location was the only independent factor associated with DLCO reduction.

Background
Chemotherapy is a mainstay of therapy for lung cancer, and lung is an organ that manifests adverse reactions of chemotherapy. Also, owing to association with smoking, lung cancer is often seen in cases with compromised lung functions. Nevertheless, the baseline pulmonary functions and the manifestations of pulmonary function change after chemotherapy in patients with lung cancer have largely been unknown.

Methods
This retrospective study analyzed the data from patients who had been diagnosed as having non-small cell lung cancer (NSCLC) and treated at St. Paul’s Hospital, The Catholic University of Korea. The basal clinical features and the outlook of pulmonary function change of the patients before and after chemotherapy were analyzed by dividing them into two groups: adenocarcinoma (ADC) and squamous cell carcinoma (SCC).

Results
Sixty-four patients with stage III and IV NSCLC were included for analysis. Thirty-nine out of 64 patients had SCC. The SCC patient group had more males (p = 0.001), higher pack-years in smoking history (p < 0.001), and a higher rate of chronic obstructive pulmonary disease (COPD) as the baseline disorder at cancer diagnosis (p = 0.005). With respect to the baseline pulmonary functions, the SCC group showed significantly lower spirometric values of forced vital capacity (FVC; 79.4% vs 90.2%, p = 0,031), forced expiratory volume in 1 sec. (FEV1; 69.4% vs 90.5%, p=0.002), FEV1/FVC (59.2% vs 70.3%, p <0.001) and maximum midexpiratory flow rate (MMFR; 38% vs 60.2%, p=0.002). Variables associated with lung volume, TLC showed no differences between the SCC and ADC groups. However, residual volume (RV; 107.6% vs 84.6%, p = 0.012) and RV/total lung capacity (RV/TLC; 43% vs 34.8%, p=0.009) were significantly higher in the SCC group. The baseline DLCO level was significantly lower in the SCC group (82.8% vs 100.8%, p=0.013). After chemotherapy, pulmonary functions related to spirometry significantly improved while DLCO reductions were not significant in patients with SCC (-0.22%, p = 0.972). The ADC group revealed no change in variables relating to spirometry, but DLCO was reduced significantly (-16.6%, p = 0.021).

Conclusion
The baseline pulmonary functions and the changing pattern of pulmonary function after chemotherapy were different between these two groups. The pathogenesis and biological behavior of these respective histologic types of lung cancer would be attributable to these pulmonary functional alterations.

Background
Lung cancers harboring epidermal growth factor receptor (EGFR) activating mutations are sensitive to EGFR tyrosine kinase inhibitor (TKI) therapy with tumor response rates of 70-80%. However, patients eventually develop resistance requiring the use of cytotoxic chemotherapy. Currently, the optimal chemotherapeutic agent in this molecular subtype is unknown. We have observed at our institution that EGFR mutation positive lung cancers are sensitive to subsequent taxane therapy. Here we present a single institutional experience of EGFR mutation positive lung cancer patients who have been treated with a taxane monotherapy after a prior TKI therapy.

Methods
This retrospective case series includes patients with advanced lung cancer with a documented EGFR mutation who have been treated with an EGFR TKI and who received subsequent taxane monotherapy between November 2006 and April 2013. The response rate was analyzed using RECIST 1.1. The overall disease control rate was evaluated at 8 weeks. Only the patients who received treatment for at least 4 weeks and who were evaluable for response were included in the analysis.

Results
Among the 19 patients identified, 17 patients were included in the analysis. Ten (59%) patients were found to have exon 19 deletion and five (29%) had exon 21 L858R point mutation. The median age of patients was 68 (range 46 – 78) and 65% were women. Sixteen (94%) patients received weekly paclitaxel 90mg/m2 d and one patient (6%) received docetaxel 60mg/m2 every 3 weeks. Patients had received a median of 3 previous lines of therapy (range 1-5) which included prior TKI therapy. Median duration of treatment was 4.0 months (range 1.0 – 9.6). Partial responses (PR) were observed in 4 (24%) patients with a median tumor reduction of 59.8% (range 37.7 – 76.4%) and the median duration of response was 6.9 months (range 6.5 - 7.0). Stable disease (SD) at 8 weeks was observed in 10 (59%) patients with a median tumor reduction of 18.7%. Median duration of stable disease was 4.0 months (range 3.3 - 9.6). The overall disease control rate (PR + SD) at 8 weeks was 82% (14/17). Figure 1

Conclusion
Patients with EGFR mutation positive lung cancers exhibit excellent disease control with taxane monotherapy in this case series, even in heavily pretreated patients. The role of taxane monotherapy in this patient population is currently being evaluated in a prospective phase II trial at our institution. Further investigation of the biological mechanism of this finding is warranted.

Background
Cabazitaxel-XRP6258 is a novel semisynthetic taxane derived from the European yew. In vitro, it has similar microtubules stabilization properties to docetaxel, even against resistant cell lines, due to its lower affinity for P-glycoprotein. Additionally, preclinical models indicated that cabazitaxel was able to cross the blood brain barrier. In addition to prostate cancer, data available from completed phase I, II and III trials showed activity in lung cancer. Based on these data we designed and conducted a phase II trial of Cabazitaxel in the second line treatment of NSCLC.

Methods
In this open-label, pilot Phase II trial, subjects with stage IV NSCLC [7[th] Edition of the TNM staging classification, 2009], who have failed first line chemotherapy (platinum doublet or non-platinum doublets, including previous taxane exposure) were randomly treated with either treatment Schedule A (20 mg/m2 every 3 weeks as a 1 hour IV infusion, f/b 25 mg/m2, if no DLTs) or B (8.4 mg/m2 as a 1 hour IV infusion on days 1, 8, 15, and 22 of a 5 week cycle, f/b 10mg/m2, if no DLTs). The primary endpoint was to assess the objective response rate (ORR) of Cabazitaxel-XRP6258. Secondary Objectives were to assess the time to progression (TTP), progression free survival (PFS), overall survival (OS) and safety.

Results
Overall the treatment was well tolerated. Among the so far 22 patients enrolled onto the trial, the most commonly found side effects to cabazitaxel were fatigue (18%), anemia (9%), hematuria (8%), neuropathy (6.5%), neutropenia (6%), nausea (6%), and dyspnea (6%), reported as a percentage of the total 141 censored events, compared with the previously most commonly described side effects to cabazitaxel of neutropenia, leukopenia, anemia, diarrhea, fatigue, and asthenia. Most side effects (76%) were grade 1/2 while 23% were grade 3/4; only one patient (4.5%) experienced grade 5 toxicity and succumb to sepsis. The most common adverse effects leading to treatment discontinuation were hematuria and sepsis. Often reported toxicities (over 10%) not found in this cohort includes diarrhea, vomiting, constipation, alopecia, arthralgia and mucosal inflammation. Inversely, the report of hematuria in almost one third of the patients (73% grade 1/2 and 27% grade 3/4) was significant, even more because contrary to the experience with prostate cancer (17% incidence) our population of patients lack the presence of blood in urine at baseline.

Conclusion
This Phase II study of cabazitaxel in second line advanced NSCLC showed good tolerance to the drug when administered in two different schedules. The observed side effects are in general consistent with prior reports but hematuria, developed upon exposure to the drug in almost one third of patients. We speculate that cabazitaxel may induce hematuria in cancer patients by direct injury of the urothelial mucosa.

Background
In the past 10 years, the standard of care in non small cell lung cancer has seen the adoption of several less toxic and better tolerated therapies, allowing a greater proportion of metastatic patients the opportunity to receive 2[nd] and even 3[rd] line treatment. We investigated whether this improvement in the number of available therapies for metastatic NSCLC had any bearing on overall patient survival, by retrospectively analyzing patients diagnosed in 1999/2000, 2004/2005 and 2009/2010 at our centre.

Methods
After ethical approval was obtained demographic details, clinical variables and outcome data were gathered retrospectively via chart review, on NSCLC patients diagnosed at the Tom Baker Cancer Centre (TBCC) in 1999/2000, 2004/2005 and 2009/2010 (Glans-Look Lung Cancer Database). All patients were restaged according to the new 7th Edition of the American Joint Committee on Cancer TNM system for NSCLC staging. Stage IV patients and early stage patients with subsequent metastatic recurrence were included in the analysis. Survival was analyzed using the Kaplan-Meier method and differences measured by a log rank test.

Results
1290 patients were included in the preliminary analysis (data only from 1999, 2004/2005 and 2009/2010), 1018 of which were stage IV at diagnosis, 272 who recurred with metastatic disease. The median overall survival (MOS) of patients increased slightly from 1999 to 2009/2010, from 4.5 months in 1999, to 5.7 months in 2004/2005 to 4.6 months in 2009/2010, as did the proportion of patients who received systemic treatment (21.3% in 1999, 28.9% in 2004/2005 and 28.1% in 2009/2010). However, the proportion of patients who received 2 or more lines of chemo doubled from 1999 to 2009/2010 (7.3% in 1999, 12.1% in 2004/2005 and 14.6% in 2009/2010)(p = 0.04). In addition, there was a trend towards increasing median overall survival (MOS) of systemically treated patients over 1999-2009, from 9.6 months (95% CI: 7.6-11.6) in 1999 to 12.7 months (95%CI: 11.0-14.4) in 2009/2010 (p=0.25).

Conclusion
Our analysis suggests that there are an increasing proportion of metastatic NSCLC patients being treated systemically at our centre, specifically, the proportion being treated with two or more lines of systemic therapy has significantly increased over the decade from 1999-2009/2010. This study also suggests a trend toward an increased MOS for systemically treated patients diagnosed in 2009/2010 compared to those diagnosed in 1999. However, the vast majority of patients (>3/4) are still not being treated with systemic therapy, despite the increase in available therapies now compared to a decade ago. The reasons for this are not clear but may include poor ECOG performance status, rapid decline, sub-optimal referral pathways and rural residence. Further analyses will be presented.

Background
Lung cancer is the leading cause of cancer death worldwide. Approximately 85% are of the non–small-cell lung cancers (NSCLC) histology and the majority have locally advanced or metastatic stage IV disease at diagnosis (85%). Cisplatin-based combination chemotherapy (CT) is the standard treatment in first line. Cisplatin plus paclitaxel (PT) it´s one of the most used combinations. Docetaxel (D) is approved for FDA in second line in NSCLC based in 3 phase III trials. Patients with breast cancer treated with paclitaxel (T) can respond to D. However, there is little information on lung cancer. We evaluate factors associated with response to D in patients previously treated with PT.

Methods
We analized consecutive patients treated in the thoracic tumors clinic of the Instituto Nacional de Cancerologia in Mexico between January 2007-december 2012 with NSCLC IV stage that previously were treated with PT and that at progression received D as second line (75mg/m2 each 3 weeks). We define as period free of Paclitaxel (PFT) the interval between the last cycle of PT and the progression of the disease, progression free survival (PFS) as interval since first cycle of CT and progression disease, and overall survival (OS) as the period from the diagnosis and death from any cause. The rate response (RR) was evaluated with RECIST criteria.

Results
Fifty-five patients were eligible for entry onto the study. Median age was 57.6 years (±15.1), female 54.5%, ECOG 0-1 (89.1%), cigarettes-smoking 45.5%, never smokers 54.5%; adenocarcinoma histology 74.5% and epidermoid 25.5%. The PFS to first-line was 6.7 months (IC 95% 5.8-7.6) and PFS to D was 4.3 months (IC 95% 2.8-5.9 months). The median period between last cycle of CT and progression disease was 2.99 months (IC 95% 2.1-3.9 months). The RR to D was 21.8% in all population. In patients with PFT >3 months compared with PFS <3months, the RR and PFS were 29% vs 14.3% (p 0.186) and 2.7 vs 6.7 months (p 0.021), respectively. We not found differences for type of response to first line CT neither histology subtype. The patients with partial response to D had were PFS prolonged in relation to patients with stable disease (5.3 versus 2.6 months, p 0.069).

Conclusion
Prior used of T not excluded for used D. Our results demonstrate that the PFT is the best predictive factor for response to D. Patients with PFT >3 months and response to D have better prognostic in relation with PFT <3months and with stable disease to D. This results must be validated in others prospective studies and Phase III trials that compared docetaxel with others therapies.

Background
Many randomized studies have shown that epidermal growth factor receptor (EGFR-) tyrosine kinase inhibitors (TKIs) are apparently advantageous over standard chemotherapy in non-small-cell lung cancer (NSCLC) patients with EGFR active mutation in front-line treatment. But the EGFR mutation status is not a compulsory guideline for second- or third-line treatment in clinical practice. which subgroup of advanced NSCLC could benefit from EGFR-TKIs in the second-or third-line setting remains elusive. To explore predictive factors of advanced NSCLC patients with the unknown status of EGFR mutation treated by gefitinib in the second-or third-line setting is warrant.

Methods
155 cases with advanced NSCLC who failed in previous platinum-based chemotherapy and received gefitinib as part of the Expanded Access Program (EAP) of the China Charity Federation were included in this study. Fifteen clinical variables were analyzed within the following general categories: demographic variables, smoking history, pathological and differentiation, involvement of specific metastasis sites, the number of comorbidities, and prior thoracic radiotherapy. Multivariate analysis of progression-free survival (PFS) was performed using recursive partitioning referred to as classification and regression tree (CART) analysis. This method uses recursive partitioning to assess the effect of specific variables on PFS, thereby ultimately generating groups of patients with similar clinical features on PFS.

Results
The median PFS in 155 patients with NSCLC who were treated with gefitinib after prior chemotherapy was 14 months (95% CI 13.4–18.6). CART was performed with an initial split on adenocarcinoma differentiation, followed by brain metastasis and prior thoracic radiotherapy. According to the analysis, four terminal subgroups were produced, and the median PFS was significantly different between the four terminal subgroups (P=0.011). The longest PFS subgroup was located in those patients with well-differentiated adenocarcinoma without brain metastasis, and received prior thoracic radiotherapy (mPFS 42 m). The poorest median PFS of 12 months was found in subgroup of patients with moderately and poorly-differentiated adenocarcinoma. The other two subgroup patients were well-differentiated adenocarcinoma without brain metastasis, and didn't receive prior thoracic radiotherapy (mPFS 18 m), and well-differentiated adenocarcinoma with brain metastasis (mPFS 13 m) respectively.

Conclusion
Adenocarcinoma differentiation, brain metastasis and prior thoracic radiotherapy are predictors of benefit of gefitinib in second- or third- line treatment after chemotherapy in advanced NSCLC. CART can be used to identify homogeneous patient populations in clinical practice and future clinical trials.

Background
mTOR pathway plays a key role in most of solid tumors. Its blockage has shown clinical and survival benefit in the context of advanced/metastatic breast, kidney and neutroendocrine cancer. Multiple preclinical and early clinical trials are ongoing to demonstrate mTOR inhibition role as monotherapy as in chemo combo in NSCLC.

Methods
Retrospective analysis of advanced and/or metastatic NSCLC patients treated in our Institution with mTOR monotherapy or combined chemotherapy and correlation between radiological cavitation pattern mTOR therapy induced as early response marker.

Results
Four patients with advanced/metastastic NSCLC in progression after more or equal 2 lines of standard chemotherapy were treated in our center during 2012 in the context of early clinical trials. Three patients had squamous NSCLC and one patient adenocarcinoma. All ones were evaluated at 6-8 weeks by CT scan: cavitation as early response marker was seen in all of them but measurement by RECIST 1.1 criteria only showed stable disease.

Conclusion
Preliminary data suggest that cavitation may be a marker of stable disease by RECIST and the therefore, a therapeutic benefit. Overinfection and haemoptysis are currently complications in this context. Careful patient assessment should be undertaken while the drug is being administered.

Background
The epidermal growth factor receptor (EGFR) oral tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, improve progression-free survival (PFS) compared to chemotherapy in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) with activating EGFR mutation. Previous trials of TKIs in unselected patients suggest that they may have some activity in EGFR wild-type (WT) patients, but the magnitude of benefit is unclear. We conducted a meta-analysis to determine the outcomes of EGFR WT patients with advanced NSCLC treated with gefitinib or erlotinib.

Methods
MEDLINE was searched for phase 2 and 3 clinical trials of gefitinib or erlotinib in advanced NSCLC published between January 2000 and May 2012. Trials using TKI as treatment arm (i.e. compared against placebo or chemotherapy), control arm or maintenance therapy were included. In addition, studies must have tested for EGFR mutation by polymerase chain reaction and analyzed EGFR WT patients. Random effects meta-analysis using the DerSimonian and Laird method was performed to pool survival estimates (hazard ratios (HR), risk ratios) and objective response rate (ORR). Placebo- and chemotherapy-controlled phase 3 trials were evaluated separately in a subgroup analysis.

Results
Six randomized controlled trials (RCTs) with a total of 1,180 EGFR WT patients (709 on TKI, 471 on control with placebo or chemotherapy) were available for meta-analysis. Pooled overall survival (OS) from 5 RCTs was not significantly different for patients in the TKI arm compared to control arm (HR 1.00; 95% CI 0.86-1.16). Subgroup analysis according to type of control showed that TKI offered no OS benefit compared to either placebo (HR 0.92, 95% CI 0.63-1.35) or chemotherapy (HR 1.02, 95% CI 0.86-1.22) (interaction p=0.63). Likewise, pooled PFS was similar between TKI and control in 4 RCTs (HR 1.35; 95% CI 0.79-2.31). However, the use of TKI significantly increased PFS compared to placebo (HR 0.78, 95% CI 0.63-0.97), but not compared to chemotherapy (HR 1.64, 95% CI 0.96-2.79) (interaction p=0.01). The rate of patients in the control arm who subsequently received TKI upon progression ranged from 3% to 52%. ORR estimated from 51 studies (1,872 EGFR WT patients) was 8.4% (95% CI 6.0-10.8), and was similar for gefitinib and erlotinib. Sensitivity analysis removing studies with estimated effect sizes did not affect these findings.

Conclusion
In this meta-analysis, gefitinib and erlotinib significantly increase PFS compared to best supportive care for advanced NSCLC with EGFR WT status. The lack of OS gain may be explained by significant crossover in these trials. TKIs may have a potential role in the management of EGFR WT patients who are not candidates for chemotherapy. There is a lack of studies on TKIs in EGFR WT patients, and more data with new generation TKIs are needed in this population.

Background
The use of liquid tissue, such as circulating cells or free DNA, to predict treatment response is attracting more attention.

Methods
Patients with stage IV adenocarcinoma of the lungs who were going to receive gefitinib or erlotinib treatment were included. Both tumor tissue and plasma specimens were prospectively collected before treatment and analyzed using the ARMS-Scorpions method for EGFR mutation status analysis. The numbers of circulating CD146+/CD3- cells (as circulating endothelial cells, CECs), CD34+/CD45- cells (as endothelial progenitor cells, EPCs), and CD133+ cells (as circulating cancer stem cells, CSCs) were measured with flow cytometry. From June 2010 to July 2012, 112 consecutive patients were enrolled.

Results
Eighty of the 112 patients had tissue EGFR (tEGFR) activating mutations. Plasma EGFR (pEGFR) activating mutations were detected in 24 of 80 patients with tEGFR activating mutations. There were lower CEC, EPC, and CSC counts in tEGFR mutated patients than in wild-type patients (p=0.001, 0.012, and 0.001, respectively). Progression-free survival (PFS) was best in those with only tEGFR mutations (n=56, median 16.8 months), followed by those with both tEGFR and pEGFR mutations (n=24, median 7.9 months), and worst in EGFR wild-type patients (n=32, median 2.1 months) (p<0.0001). PFS was significantly longer in patients with low CEC and low CSC counts than in those with high cell counts (p=0.0023 and 0.0053, respectively). Multivariate analysis showed that the presence of pEGFR was a poor prognostic factor, but not the presence of other markers.

Conclusion
The presence of pEGFR mutation is a poor prognostic factor for patients with tEGFR mutations when they receive EGFR-TKI treatment. EGFR wild-type patients had higher counts of CECs, EPCs, and CSCs. These circulating markers are useful in predicting EGFR-TKI treatment efficacy, but less useful than pEGFR detection.

Background
Some retrospective studies revealed that higher drug exposure of EGFR-TKIs was associated with better clinical outcome, especially in EGFR mutation-negative patients (pts). This randomized, open-label, multi-center study try to confirm whether dose-escalation of gefitinib would improve effect and survivals.

Methods
Key eligibility criteria of this study include: ECOG PS 0-2, stage IIIB/IV NSCLC all histologies, progression after previous platinum-based chemotherapy, SD after one-month treatment of standard dose gefitinib (250mg/d). Patients were randomized (1:1) to received either higher dose (500mg/d, H group) or continue standard dose (250mg/d, S group) of gefitinib untill progression or toxicities. The primary end-point was objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The sample size was determined based on the assumption that H group was superior to S group in ORR (15% vs 5%, a one-sided alpha of 0.1, 1 - beta = 0.8) and 50 pts per arm was needed. Paired plasma was collected for detection of gefitinib concentration with high-performance liquid chromatographic method with tandem mass spectrometric (LC–MS/MS) method in consented patients at baseline (randomization, D1) and first evaluation (D60). (NCT01017679)

Results
From May 2009 to Jan 2012, 466 pts treated with gefitinib were included in this study. Among these pts, 155 achieved SD after one-month gefitinib treatment and 96 pts were randomly assigned to H group (48 pts) or S group (48 pts), respectively. Baseline factors including age (55.5 vs 57.5 years), gender (M/F: 24/24 vs 19/29), histology (adenocarcinoma/others: 44/4 vs 41/7), smoking status (Y/N: 18/30 vs 15/33) and EGFR mutantion rate (20% vs 31%) were balanced between two arms. ORR were same (12.5%) in two groups (p=1.000); median PFS were 159 days (H group) vs 187 days (S group, p=0.077); and median OS were 411 days (H group) vs 743 days (S group, p=0.098), respectivedly. Significantly more grade 3/4 acne-like rash was seen in H group (14.6% vs 0%, p=0.012). PFS was significantly longer in EGFR mutation pts than wild type pts (344 d vs 135 d, p =0.001 ). Plasma gefitinib concentration increased significantly in the H group (n=12, D1 vs D60: 217.02 ng/ml vs 397.25 ng/ml, p=0.017) while it remained stable in S group (n=7, 312.59 ng/ml vs 310.33 ng/ml, p=0.972). However the gefitinib concentration increase did not translate to survival improvement.

Conclusion
Gefitinib 500mg/d did not confer a response or survival advantage over gefitinib 250mg/d in patients achieved SD with one-month gefitinib treatment. EGFR mutation remained predictive for PFS with gefitinib.

Background
Dovitinib (TKI 258) is an oral antiangiogenic agent that targets PDGFR, KIT, FLT3, VEGF, RET, and FGFR. Dovitinib induces CYP1A1/A2, CYP2C19, CYP2C9, and it inhibits CYP3A4. Dovitinib is metabolized mainly by FMO, CYP3A4, and CYP1A1/A2. Erlotinib is metabolized mostly by CYP3A4 (70%) but also by CYP3A5, CYP1A1, and CYP1A2.

Methods
This is a phase I 3+3 trial of E+D in patients with EGFR wild-type or mutated metastatic NSCLC who could have previously received E. Four cohorts were planned with E given daily and D given 5 days on/2 days off, starting after a 2-week lead-in of E alone. Only two cohorts enrolled due to dose limiting toxicity (DLT): cohort 1 [150 mg E +300 mg D] and cohort -1 [150 mg E+200 mg D]. Plasma concentrations of E and its metabolite OSI-420 were measured on day 14+/-4 (E alone; pre-dose, 2, 4, 6, 8, and 24 hours) and day 29 +/- 4 (D+E, at same time points). Pharmacokinetic (PK) samples were analyzed by a validated liquid chromatography-tandem mass spectrometry assay. PK parameters for E and OSI-420 were estimated from the plasma concentration data via noncompartmental analysis. Paired-t tests on log transformed PK parameters were used to detect a statistical difference (α < 0.05, 2-sided) between E alone versus E+D treatment days.

Results
Nine patients enrolled (3 in cohort 1 and 6 in cohort (-1)). The study was suspended due to excess of DLTs. Best response was evaluable in seven patients. Two unevaluable patients on follow-up scan were on E monotherapy for ~1 month. Four patients discontinued due to grade 3 AEs (syncope (n=1), fatigue (n=1), and pulmonary embolism (n=2)). Three patients had progressive disease and 4 had stable disease (duration: 6 cycles(C), 8 C, and 1-2 C for two patients who stopped due to AE). Two patients required a dose delay in D (one for grade 2 LFT elevation, the other for grade 3 fatigue) and one required dose reduction of E to 100 mg prior to initiation of D (dose-corrected for PK analysis). Six patients had data available for PK analysis. During E alone, erlotinib exposure (average C~max~ 2308 +/- 697 ng/ml and AUC~ 0-24 ~41.0 +/- 15.6 μg*h/ml) was similar to previous reports for multiple daily doses of 150 mg. During D co-administration, the concentrations of E were reduced. C~max~ on average decreased by 83% (p= 0.022) and AUC~0-24 ~by 94% (p= 0.0039). OSI-420 exposure was also reduced during D co-administration.

Conclusion
Our small study demonstrates a potential significant PK interaction with decrease of E and its metabolite in the presence of D. This decrease is higher than that reported in combination studies with other CYP1A1 or CYP3A4 inducers. Dovitinib PK data is pending. Given the toxicity and the potential PK interaction, further investigation with this drug combination will be challenging.

Background
Inhibition of the vascular endothelial growth factor receptor (VEGFR) pathway appears to be an effective treatment strategy for frontline non-small cell lung cancer (NSCLC), but small molecule VEGFR kinase inhibitors have failed to show survival benefit. Motesanib is an orally administrated small molecule antagonist of VEGFR 1, 2, and 3, platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (c-kit). In a subgroup analysis of Asian patients (n = 227) from the global phase 3 study (MONET-1), treatment of motesanib in combination with paclitaxel and carboplatin demonstrated significant improvements in overall survival (HR, 0.65; 95% CI, 0.46-0.91), progression free survival (HR, 0.59; 95% CI, 0.44-0.79), and overall response rate compared to placebo. To prospectively evaluate efficacy and safety of motesanib in Asian patients with NSCLC, this phase 3 study has initiated.

Methods
Stage IV/recurrent non-squamous NSCLC patients without prior chemotherapy receive oral motesanib (125 mg) or placebo once daily in combination with paclitaxel (200 mg/m[2]) and carboplatin (AUC = 6) every 3 weeks up to 6 cycles and continue motesanib or placebo until disease progression, consent withdrawal, or unmanageable adverse event. ECOG performance status 0 or 1 are eligible for this study regardless of epidermal growth factor receptor (EGFR) mutation status. Patients with untreated or symptomatic central nervous system metastases are excluded. Approximately 400 patients will be randomized in a double-blind 1:1 ratio to motesanib or placebo. Stratification factors include EGFR mutation status, weight loss of ≥ 5% in the previous 6 months, and region. This MONET-A trial will be assessed twice by the Independent Data Monitoring Committee (IDMC), at the time 50 and 150 patients complete their first cycle for unblinded safety data.

Results
This study initiated in July 2012 and is being conducted in Japan, Korea, Taiwan, and Hong Kong. The enrollment is ongoing. First evaluation by IDMC was performed using the data as of 26 December 2012. A total of 64 patients were enrolled and 63 patients (63 Japanese; median age, 64.5 years) received study treatment. All the blinded patients who received study treatment experienced adverse events (AEs); Grade 3 to 5 AEs were reported in 38 patients (60.3%). Common AEs included alopecia (63.5%), peripheral sensory neuropathy (57.1%), and decreased appetite (50.8%). 7 patients had 8 serious AEs (SAEs). SAEs considered to be related to blinded study drug were cholecystitis in 2 patients, gastric ulcer haemorrhage, nausea, and upper gastrointestinal haemorrhage in 1 patient. A treatment-related fatal AE (interstitial lung disease) was reported in one patient (blinded). AEs leading to permanent discontinuation of unblindedunblinded study drug (motesanib or placeco) were cholecystitis (Grade 2), liver injury (Grade 3), purpura (Grade 2), rash (Grade 3), eye haemorrhage (Grade 2), upper gastrointestinal haemorrhage (Grade 3), and gamma-glutamyltransferase increased (Grade 4).

Conclusion
The first IDMC recommended continuation of the study after the review of unblinded data of 63 patients. Updated safety data will be presented after the second IDMC (JapicCTI-121887).

Background
Platinum-based chemotherapy regimens using maximum-tolerated dosing schedules are the standard of first-line treatment for advanced non-small cell lung cancer (NSCLC) and are associated with a modest survival benefit and substantial toxicity. Targeting vascular endothelial growth factor (VEGF) has shown modest improvement in patients with advanced NS-NSCLC. Frequent administration of low dose chemotherapy agents (metronomic chemotherapy [MC]) is thought to target endothelial cells of the tumor vasculature as well as tumor cells. The hypothesis of this pilot phase 2 study is that the combination of bevacizumab and MC will result in enhanced antiangiogenic effect and clinical benefit in advanced NSCLC.

Methods
Untreated patients with stage 4 non-squamous NSCLC, PS 0-1 and measurable disease were treated with a 4-week cycle of paclitaxel (80 mg/m[2] D1, 8, 15), gemcitabine (200-300 mg/m[2] D1, 8, 15) and bevacizumab (10 mg/kg D1, 15) for 6 cycles. Patients without progressive disease received maintenance bevacizumab every 2 weeks. Primary endpoint: progression-free survival (PFS) with the goal to achieve a 30% improvement in the 6.4 months PFS observed in ECOG 4599. Secondary endpoints: objective response rate (ORR), overall survival (OS), safety, and the evaluation of potential biomarkers of angiogenesis. Blood samples for angiogenic and antiangiogenic biomarkers were collected at different intervals.

Results
33 evaluable patients were enrolled. Patient characteristics: median age 59 years; 61% female; 70% ≥5% weight loss; 24% never/light smoker; 48% genetic testing (mut EGFR-4 patients and 1 patient ALK+); and 9% brain metastases. Efficacy parameters are shown in the table below. Worst hematologic and non-hematologic toxicities: grade 3 neutropenia (15%); grade 3 fatigue (6%); grade 3 nausea (3%); grade 3/4 hypertension (30%); grade 3/4 proteinuria (18%); pneumonitis (3 patients); and ischemic events (2 patients). The following baseline biomarkers have shown significant correlation with response parameters: (VEGF2 (ORR); PLGF (OS); angiopoietin -2 (PFS, OS); endocan (ORR); IL-8 (ORR, PFS); TGFβ-1 (ORR); thrombospondin-1 (ORR); and angiopoietin-1(ORR).

Clinical Results
	Patients (N=33)
PFS (mo)
Median	9 (95% CI:7; 10)
OS (mo)
Median	30 (95% CI: 18; 37)
1-year survival rate	74%
2-year survival rate	55%
ORR	73% (95% CI:0.54; 0.87)
CR	N=1
PR	N=23
Stable Disease	N=6 (18%)
Progressive Disease	N=3 (9%)
Never or Light Smokers	N=8
Median PFS : 10m
Median OS : 37m

Conclusion
MC with a platinum doublet in combination with bevacizumab is a feasible, tolerable, and active regimen in advanced non-squamous NSCLC. Potential biomarkers were correlated with clinical outcome.

Background
We conducted a systematic review of data from patients reported in the TULUNG registry (data cut-off 18-Mar-13). The TULUNG registry prospectively collects data from all NSCLC patients treated by erlotinib in the Czech Republic.

Methods
Our analysis was performed on a subgroup of patients with non-squamous NSCLC (adenocarcinoma or large-cell carcinoma) with good performance status (PS 0-1), treated with erloninib in a second-line setting.

Results
521 of 2365 patients reported in the the TULUNG registry met the above-mentioned criteria. Of 521 patients analyzed, 51,2% were female; the median age at erlotinib treatment initiation was 64 years (range 29-88). The majority of patients were smokers and ex-smokers (34.4% and 34.0% respectively) and 93.1% of tumours were adenocarcinomas by histology. 86.1% patients were at the metastatic stage at the initiation of second-line erlotinib treatment, 12.8% of patients were in stage IIIb and only 1.1% of patients in stage IIIa. The majority of patients (87.7%) was in PS 1 at the initiation of second-line erlotinib treatment. From 521 of all analyzed patients, erlotinib therapy was terminated in 410 (78.7%) patients at data cut-off (the most frequent reasons for termination were disease progression, in 74.6% and death in 11.5% of patients) and treatment was ongoing in 111 (21.3%) patients. In 410 of patients with terminated treatment, the median duration of treatment was 3.0 months (95% CI 0.7 – 16.9), ORR assessment showed CR in 0.7%, PR in 8.3% and SD in 54.6% of patients. Median progression free survival was 4.0 months (95% CI 3.5 – 4.5), median overall survival 11.8 months (95% CI 9.6 – 14.0). 1-year survival from erlotinib treatment initiation was 49.4%. Adverse events were reported in 42.8% of patients, the most frequently reported adverse events (in >5% of patients) were skin toxicity (35.3%) and diarrhea (13.6%). Grade ≥3 adverse events were reported in 10.5% of patients, G≥3 skin toxicity 7.5% and G≥3 diarrhea in 1.3% of patients.

Conclusion
Erlotinib therapy of advanced metastatic adenocarcinoma or large cell carcinoma in a second-line setting was very well tolerated in eligible patients with PS 0-1; only 3.4% of patients had to discontinue erlotinib therapy due to adverse effects. In patients with completed erlotinib therapy 63.6% disease control rate was reached with a median survival of approximately 1 year from initiation of second-line erlotinib therapy.

Background
Although crizotinib which is a first-in-class oral ALK inhibitor shows dramatic response and prolonged PFS in patients with ALK(+) NSCLC, most of the patients relapsed within one year. However, patterns of relapse, prognosis, and outcome of further therapy after crizotinib failure have not been well examined.

Methods
We identified patients at our hospital with ALK(+) NSCLC who received and failed in crizotinib therapy.

Results
There were 20 patients (11 females and 9 males, with a median age 48 years). ALK fusion gene was confirmed by IHC and/or FISH (17 patients IHC+/FISH+, 3 patients FISH+). The median treatment duration of crizotonib was 4.5 months (range, 1.1-18.6 months) and the median overall survival (OS) after discontinued on crizotinib was 4.8 months; 13 patients died. At the time when crizotinib was discontinued, 2 patients (10%) had progressive disease (PD) at the primary site of disease (local recurrence), 18 patients (90%) had PD of distant metastasis and one patient had PD at both the primary site and distant metastasis. PD in CNS was observed in 9 patients. Re-biopsies after failure of criztotinib were performed in 3 patients. Two secondary mutation were identified in 2 of 3 pts (L1196M (n = 1) and G1269A (n = 1). Eleven of 20 patients received additional chemotherapy (7 cytotoxic chemotherapies and 4 ALK-inhibitor). Two of 7 patients who received cytotoxic chemotherapy (included docetaxel, S-1, cisplatin+pemetrexed+bevacizumab and carboplatin+pemetrexed) after crizotinib had PR (28.5%).

Conclusion
After crizotinib therapy failure, PD most commonly occurred at distant metastasis especially CNS in ALK+ NSCLC patients. Cytotoxic chemotherapy after crizotinib failure provide only minimum responses. A New effective therapeutic strategy after failure of crizotinib is necessary in ALK+ NSCLC patients.

Background
Ficlatuzumab is an anti-hepatocyte growth factor (HGF) monoclonal antibody (mAb) being tested in clinical trials for cancer. Hypoalbuminemia has been observed in these trials, as well as in trials with other HGF/c-Met inhibitory mAbs. The relationship between serum albumin (SA) and ficlatuzumab treatment is examined.

Methods
Ficlatuzumab was studied in P05538, a first-in-human dose escalation trial; in P05670, a dose ranging trial investigating the pharmacodynamic (PD) effect of ficlatuzumab; and in P06162, a phase II study in combination with gefitinib (FG arm) versus gefitinib alone (G arm) in NSCLC patients. Patient data from these studies were evaluated longitudinally for peripheral edema, changes in SA, serum Ca[2+] (Ca), liver function tests (LFTs), prothrombin time (PT) and proteinuria.

Results
In P05538, all 23 evaluable patients had SA decrease with median change to nadir of -29% (-46 to -11%) and median nadir SA level of 25 g/L (15 to 33 g/L). In P05670, all 19 evaluable patients had decreased SA, with median change to nadir of -20% (-49 to -7%) and median nadir SA level of 31 g/L (14 to 40 g/L). In P06162, 88 of 90 (98%) evaluable patients in FG arm experienced SA decrease, with a median nadir change of -27% (range -62 to 8%). No significant SA changes were observed in the G arm. LFTs and PT were not significantly changed in any of the trials. Peripheral edema was observed in 52%, 32%, 38%, and 4% of the patients in P05538, P05670, FG, and G arms of P06162, respectively. In P06162, low Ca laboratory findings (not corrected for albumin) were reported in 72% of patients, with median change to nadir of -11% (-24% to 5%). Changes in uncorrected Ca were secondary to changes in albumin (% changes Pearson correlation=0.68, P<0.0001). No difference in the rate of proteinuria was observed across FG and G arms of the 6162 trial.

Conclusion
Decrease in SA during ficlatuzumab treatment was seen in almost all patients and appears to be unrelated to hepatotoxicity. Decrease in SA resulting from ficlatuzumab treatment may be the cause of peripheral edema. Both hypoalbuminemia and peripheral edema were frequently observed with other HGF/c-Met inhibitors, suggesting they may be class adverse events. Decrease in SA could be explored as a PD marker for HGF/c-Met inhibition.

Background
Tyrosine Kinase inhibitors (TKIs) with gefitinib or erlotinib targeting the epidermal-growth factor receptor (EGFR) are a well-established therapy in the treatment of metastatic pulmonary adenocarcinoma, particularly in patients with activating EGFR mutations. EGFR mutations are rarely found in squamous cell carcinomas (SCC) of the lung. There is conflicting data supporting the efficacy of EGFR inhibitors in advanced SCC of the lung. In this analysis we examined the impact of EGFR TKIs on progression-free survival (PFS) and overall survival (OS) in unselected patients with SCC of the lung.

Methods
We searched for Randomised controlled trials (RCTs) comparing EGFR-TKIs alone with placebo (PL) in patients with metastatic non-small cell lung cancer. RCTs in the front-line, maintenance and subsequent therapies were included. The primary outcome was PFS in the SCC population. We used published hazard ratios (HRs), and when not available unpublished data was sought. Non-adenocarcinoma was used as a surrogate for SCC when analysis was available by specific histology. Pooled estimates of treatment effect on OS and PFS were calculated using the random-effects inverse variance weighted method.

Results
Eight eligible RCTs were included: 2 first line, 6 second-line or beyond, evaluating 1781 patients (EGFR TKI v PL). Data was available for analysis of OS in 4 studies (second-line; N = 1420) and for PFS in 4 studies (three second-line, one first-line; N = 788). EGFR TKIs significantly prolonged PFS, with a hazard ratio of 0.77 [95% CI 0.65 – 0.92]. OS was prolonged with a hazard ratio of 0.88 [95% confidence interval (CI) 0.78 – 1.00]. Efforts to obtain further missing data from the other studies to complement the analysis are on-going.

Conclusion
EGFR mutations are rare in SCC of the lung, yet EGFR TKIs have a significant PFS benefit and (less certain) OS benefit compared to placebo in unselected patients with advanced pulmonary SCC, and should be considered as a therapeutic option in patients with advanced SCC of the lung. EGFR mutation independent mechanisms may explain efficacy of EGFR inhibitors in this setting. An individual patient data meta-analysis is warranted to further characterize the OS benefit.

Background
Progression of disease (PD) in advanced NSCLC patients with an EGFR mutation (EGFR+) treated with tyrosine kinase inhibitors (TKI) is inevitable. Therapeutic options for these patients are lacking. Several patients with acquired TKI-resistance who were treated with high-dose, weekly erlotinib (‘pulsatile erlotinib’) for leptomeningeal metastases showed an evident thoracic response (1). We initiated this trial to evaluate the effect of pulsatile erlotinib on advanced, EGFR+ NSCLC patients with TKI-resistance.

Methods
This study was developed as a prospective, mono-center, open-label, single-arm phase II trial. Primary endpoint was objective response rate (ORR). Secondary endpoints were PFS, toxicity and safety. Eligibility criteria included histologically confirmed stage IV, non-squamous, EGFR+ NSCLC-patients who progressed on TKI (erlotinib or gefitinib) in standard dose. Biopsy was obtained before treatment initiation. Patients were treated with erlotinib 1500mg weekly. Response was assessed according to RECIST 1.1. Simon’s 2-stage optimal design was applied (2).

Results
Eleven patients were enrolled. Patient characteristics and pathological results are depicted in table 1. When 10 patients were assessed to have PD or stable disease, the trial was discontinued, according to predefined criteria. Objective response rate (ORR) was 9,1%. Median PFS was 1.6 months (95% CI, 0.9-2.0 months). One biopsy revealed KRAS mutation, whereas earlier biopsies had shown exon 18 + exon 20 mutation. A second primary tumour is not excluded in this case. Patients received pulsatile erlotinib as 3[rd] -6[th] treatment. At time of analysis, one patient remains on treatment. One patient had clinical benefit lasting for 3 months beyond PD. There were no deaths during the study. Toxicity was mainly grade 1-2.

Table 1: PATIENT CHARACTERISTICS		N = 11
		Median	Range
Age	(years)	57	(32-75)
		Frequency	(%)
Sex	female	11	(100%)
	male	0	(0%)
Smoking	Non-smoker	7	(63,6%)
	Previous smoker	3	(27,3%)
	Current smoker	1	(9,1%)
Performance score	PS 0	4	(36,4%)
	PS 1	5	(45,5%)
	PS 2	2	(18,2%)
Ethnicity	Caucasian	11	(100%)
Stage	IV - metastatic	11	(100%)
Histology	Adenocarcinoma	10	(90,9%)
		1	(9,1%)
Mutation	EGFR-exon 19	2	(18,2%)
	EGFR-exon 21	1	(9,1%)
	EGFR exon 19 + T790M	3	(27,3%)
	EGFR exon 21 + T790M	2	(18,2%)
	KRAS	1	(9,1%)
	No mutation	1	(9,1%)
	No biopsy	1	(9,1%)

Conclusion
Despite some individual successes with pulsatile erlotinib treatment of EGFR+ NSCLC patients, this trial failed to meet its primary endpoint and was discontinued prematurely. Pulsatile erlotinib was safe and toxicity was manageable. Further investigation of this treatment for this indication is not recommended.

Background
NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter highly expressed in non-small cell lung cancer (NSCLC) and ovarian cancer (OC). DNIB0600A is an antibody-drug conjugate consisting of a humanized anti-NaPi2b IgG1 monoclonal antibody and the anti-mitotic agent MMAE.

Methods
This study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to patients (pts) with non-squamous NSCLC or platinum-resistant, non-mucinous OC. A traditional 3+3 design was used for dose escalation followed by expansions in NSCLC and OC at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue by immunohistochemistry (IHC). Anti-tumor activity was evaluated per RECIST 1.1.

Results
As of 1 May 2013, 65 pts have enrolled (35 NSCLC; 30 OC), median age 62 (range 39-85), PS 0-1, median number of prior regimens 2 (1-8) in NSCLC pts, and 5 (1-12) in OC pts. Pts received a median of 4 (range 1-25) doses of DNIB0600A. One pt experienced a DLT (Grade 3 dyspnea) at 1.8 mg/kg; however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Two patients had Grade 1 and 2 infusion-related reactions. The most common related AEs (all grades) were fatigue (55%), nausea (35%), peripheral neuropathy (32%), decreased appetite (29%), vomiting (25%), alopecia (20%), and diarrhea, dysgeusia, headache, and pain (each 15%). The majority of these AEs were Grade 1 and Grade 2. Two patients had serious AEs (SAE) which led to discontinuation (dyspnea; dehydration and hyperglycemia). Four other related SAEs (nausea, upper respiratory tract infection, abdominal pain, and headache) were noted in 2 pts. Preliminary PK results support a q3w dosing regimen with no accumulation observed. Expansion at 2.4 mg/kg was selected based on cumulative safety data and a benefit/risk assessment performed at time of expansion. Exposures of analytes monitored were dose-proportional over all dose levels, and no PK difference was observed between NSCLC or OC pts. Approximately 60% of NSCLC and 90% of OC pts expressed high levels (IHC 2+/3+) of NaPi2b. Anti-tumor activity with DNIB0600A was associated with tumor NaPi2b expression for both NSCLC and OC. Of the 40 pts with NaPi2b IHC Score of 2+ or 3+, treated at dose levels 1.8-2.8 mg/kg, 10 pts had a confirmed partial response (PR); 2 of 18 NSCLC and 8 of 22 OC pts, respectively. Additionally, 3 NSCLC and 3 OC pts have unconfirmed PRs. No pt was enrolled with NaPi2b IHC Score of 1+; no pt responded among the 13 pts with NaPi2b IHC Score of 0, treated at dose levels 1.8-2.8 mg/kg

Conclusion
DNIB0600A administered q3w has an encouraging safety, tolerability, and PK profile and evidence of anti-tumor activity in NSCLC and OC pts whose tumors express NaPi2b detectable by IHC. This data supports further clinical evaluation of DNIB0600A in NSCLC and OC together with a companion diagnostic.

Background
A phase I, dose escalation study was conducted to evaluate the safety and antitumor activity of icotinib, an oral epidermal growth factor receptor inhibitor which was approved for treating advanced non-small-cell lung cancer (NSCLC) in China, and to explore its tolerable and effective dose range, and the maximum tolerated dose (MTD) in patients with advanced NSCLC.

Methods
Patients were enrolled into sequential dose-escalating cohorts to receive icotinib orally three times daily (tid) from 225 mg/day to 1875 mg/day for at least 28 days. Escalation of icotinib was based on toxicities observed in the preceding dose cohort. Tumor response was assessed every 4 weeks.

Results
103 patients were enrolled at 11 dose levels, including dose escalations and dose expansions. The most common drug-related adverse events were rash (51.5%, 53/103) and diarrhea (19.4%, 20/103), which were generally mild (grade 1/2) and revisable on symptomatic treatment. Two of six patients at 1875 mg/day experienced dose-limiting toxicity (grade 3 rash), and no further dose escalation occurred. Tumor responses were observed from 300 mg/day to 1875 mg/day. Out of 100 patients evaluable for tumor responses, the overall objective response rates and disease control rates were 27% and 76%, respectively, and the overall progression-free survival (PFS) was 5.0 months. Dose expansions were carried out in 300 mg/day, 375 mg/day and 450mg/day cohorts, and the median PFS for each cohort were 5.0 months, 5.6 months, and 4.0 months, respectively. Table 1: Safety profile of icotinib at various dose levels.

Dose (mg/tid)	N	Rash (N)		Diarrhea (N)		Overall adverse events (%)	Overall adverse reaction (%)
		Grade I/II	Grade III/IV	Grade I/II	Grade III/IV
75	7	5	-	1	-	85.7 (6/7)	85.7 (6/7)
100	27	6	1	7	-	70.4(19/27)	55.6(15/27)
125	24	13	1	4	-	75.0(18/24)	70.8(17/24)
150	13	6	-	1	-	69.2 (9/13)	69.2 (9/13)
200	3	1	-	1	-	100 (3/3)	100 (3/3)
250	8	4	-	1	-	75.0 (6/8)	62.5 (5/8)
300	3	2	-	-	-	100 (3/3)	100 (3/3)
350	3	1	-	1	-	100 (3/3)	100 (3/3)
400	3	3	-	-	-	100 (3/3)	100 (3/3)
500	6	5	1	1	-	100 (6/6)	100 (6/6)
625	6	3	2	2	-	100 (6/6)	100 (6/6)
Total	103	49	5	20	-	79.6(82/103)	73.8(76/103)

Table 2: Tumor response of icotinib at various dose levels.

Dose (mg/tid)	N	CR/PR	SD	PD	ORR (%)	DCR (%)
75	6	0/0	6	0	--	--
100	25	2/5	14	4	28 (7/25)	84 (21/25)
125	24	-/7	13	4	29.2 (7/24)	83.3 (20/24)
150	13	1/5	4	3	46.2 (6/13)	76.9 (10/13)
200	3	0/0	2	1	--	--
250	8	0/1	4	3	12.5 (1/8)	62.5 (5/8)
300	3	0/0	2	1	--	--
350	3	0/1	0	2	--	--
400	3	0/2	0	1	--	--
500	6	0/1	1	4	--	--
625	6	0/1	1	4	--	--
Total	100	3/24	49	26	27(27/100)	76(76/100)

Conclusion
Icotinib was well tolerated with manageable and revisable AEs at all dose levels. The MTD of icotinib was 1875 mg/day, and the tolerable and effective dose range was from 300 mg/day to 1875 mg/day. This study demonstrated that icotinib provided favorable safety profile and antitumor activity in advanced NSCLC patients.

Background
Single arm phase II studies have traditionally been conducted in oncology, but they rely completely on historical information to assess treatment benefits and are associated with high bias and false-positive error rates. This has contributed unsustainably high phase III clinical trial failure rates in oncology. On the other hand, conventional randomized controlled trials (RCT) involve more patients, higher cost and longer timelines. Thus, innovative statistical methods have been developed to try to address this challenge. An area of focus has been the use of statistical models to improve the design of phase II studies to better mimic what is intended for the phase III design, and therefore to predict its outcomes with greater precision.

Methods
Two statistical innovations have been applied to our phase II portfolio. Firstly, the Bayesian Augmented Control (BAC) design has been implemented to gain the benefits of using historical information (“borrowing”) as well as using randomization to a concurrent control arm. The BAC design utilizes models to summarize existing knowledge on the standard of care (SOC) in a defined patient population. For example, patients can be “borrowed” from a previous well-designed phase III RCT which established the SOC. The extent of “borrowing” depends on the similarity between the response in the new control patients and the historical patients, which is evaluated by pre-specified models. Secondly, Change in Tumour Size (CTS) from baseline to the end of Cycle 2 has been incorporated as an endpoint in our studies because this endpoint correlates strongly with progression-free survival (PFS) and overall survival (OS) in certain tumor types such as Non-Small Cell Lung Cancer (NSCLC). The approach consists in using tumor size measurements as a continuous variable, rather than a categorical endpoint based on Response Evaluation Criteria In Solid Tumors (RECIST), for assessing anti-tumor activity.

Results
The BAC design enables randomized controlled trials with smaller sample sizes, yet maintains statistical power. It also allows disproportionate enrollment to the experimental arm, which is often attractive to investigators and patients seeking access to novel therapies.

Conclusion
We believe that our phase II data package is now more informative whilst still meeting the logistical needs. It is hoped that this will facilitate a better Phase III prediction, which will increase our Phase III success rate. To date, insufficient phase III trials which were designed based on these improved phase II trials have yet been completed to be able to evaluate whether our phase III success rate has ultimately improved.

Background
The presence of mutations in the gene encoding the Epidermal Growth Factor Receptor (EGFR) predicts that P with aNSCLC may respond better to Tyrosine Kinase Inhibitors (TKIs). Recently, the Spanish REASON study has reported that the rate of EGFR mutations is 11.6% in Spain; however the mutation rate and the clinical management of aNSCLC carrying EGFR mutations in Galicia are still unknown.

Methods
All newly diagnosed aNSCLC P in 9 Galician centers were prospectively included for a 13-month period. P with M+ disease were followed for at least 9 months (m) in order to characterize their clinical management. Mutation testing was performed on available tumor and plasma samples, through a central laboratory using the EGFR RGQ PCR Kit™ (Qiagen). Pre-planned exploratory objectives included comparison of EGFR mutation status between matched baseline tumor and plasma samples.

Results
From February 2011 to March 2012, 198P were included in the study. Median age was 65.5 years (range 34-85). 76.3%P were men, 21.7% were never-smokers, 45.5% ex-smokers, and 32.8% current smokers. PS 0-1: 67.1%. 78.3% had non-squamous histology (68.7% adenocarcinoma, 8.1% large-cell carcinoma, 1% adenosquamous carcinoma, and 0.5% non-specified) and 21.7% p had squamous-cell carcinoma. Sample type provided included: 57.6% tissue, 42.4% cytology. Median turnaround time (TAT) was 8 days. Mutation rate in evaluable samples: 13.6% in tumor, tissue or cytology (25P) (11P had exon 19 deletion, 8P L858R mutation, 2P exon 20 insertions and 1P L861Q mutation); 5.9% in plasma. Tumor and plasma EGFR mutation status concordance rate was 90.8%.Plasma test sensitivity was 40%. Mutation rate did not vary by sample type (13.9% tissue, 13.2% cytology). A higher mutation rate was found in never smokers (42.5%), females (38.6%) and adenocarcinoma (19.8%). 23 out of 25 M+ P received first line treatment and 2P only best supportive care. 21P were treated with TKI (Gefitinib), 1P with chemotherapy (CT) (Cisplatin/docetaxel/bevacizumab) and 1P with CT+TKI (Carboplatin+Gefitinib). 20P were evaluated for response. 3P were lost for follow up. At data cut off (31/12/2012), with a median follow up of 9.8m, 14P had partial response (70%), 2 stable disease (10%) and 4P progressive disease (20%). Median progression free survival was 9.7m. 8 out of 20P (40%) received 2[nd] line treatment (7 CT and 1 TKI). 12 out of 25P had died, 3P were lost for follow up and 10P were still alive.

Conclusion
Mutation analysis is feasible in clinical practice for aNSCLC patients in Galicia and allows the customization of treatment based on molecular criteria. Despite of the relatively small number of patients in this study, EGFR testing in plasma has a low sensitivity and therefore should not substitute tissue testing although it could be an alternative for those patients without tissue samples.

Background
A number of lung cancer patients at different disease stages has availed of the autologous dendritic cell vaccination therapy since it was instituted as an adjunct therapy in 2009 at the Molecular Diagnostics and Cellular Therapeutics Laboratory of the Lung Center of the Philippines.

Methods
Following a protocol approved by the Institutional Ethics Review Board of the hospital and after a Safety Evaluation Trial involving 3 patients demonstrating patient tolerance to autologous DC with no adverse reaction, at least 19 lung cancer patients were treated. The protocol involves 1) consultation 2) signing of informed consent 3) extraction of blood for circulating tumor cells and blood tests 4) hematology clearance 5) growth factor administration 6) admission and central line insertion 7) leukapheresis (stem cell collection) 8) dendritic cell culture and maturation 9) vaccination and 10) IFN-gamma analysis. The compiled clinical responses include survival rate at different time points, PET/CT scan results, circulating tumor cell (CTC) gene expression profile, and plasma interferon gamma levels.

Results
Comparative survival rate at 9 months post-vaccination vs. average survival were the following: stage II, 100% vs. 75%; stage III, 85.71% vs. 60% and stage IV, 28.57% vs. 23%. The PET/CT Scan results showed a general pattern of remission and/or regression of the tumor, or stabilization of the disease process in 58% of the patients. The circulating tumor cell (CTC) gene expression profile using a panel of 14 Tumor Associated Genes (TAGs) showed at least two were positive in the patients' blood sample which could have upregulated expression. ERBB2 appeared as the most positive gene marker in all the samples (i.e. Rank 1). Livin showed the most elevated expression followed by ACTN4. KRT19 showed moderate expression while EGFR showed all downregulated expression. Post-vaccination monitoring showed a decline or complete abrogation of expression of the TAGs. The interferon gamma profile showed that majority (90%) of the patients had IFN gamma values above 10 pg/ml. A general trend of increasing IFN gamma is observed in the first 3 vaccinations, followed by a decline and subsequent increase in the fifth and sixth vaccination correlating with the introduction of new sets of antigens coming from the result of the follow-up CTC gene expression analysis. General observation indicated higher IFN gamma values correlate with better patient survival.

Conclusion
Thus, the clinical data of the patients who have undergone the DC vaccination therapy have indicated the positive effects of autologous DC as an alternative adjunct therapy for lung cancer specifically for stages II and III. This data also points to the importance of early diagnosis of lung cancer as well as the development of more aggressive immunotherapeutic interventions for stage IV cases (e.g. tumor-specific cytotoxic T-cells) which are the current directions of the Center.

Background
Screening for Epidermal Growth Factor Receptor (EGFR) mutation is a key molecular test for management of lung cancer. Patients who respond well to an EGFR inhibitor harbor certain mutations in the EGFR exons 18, 19 or 21. An additional mutation in EGFR exon 20 is known to be responsible for acquired resistance to this therapy.

Methods
We conducted an analysis of Galician advanced lung cancer patients who were tested positive for EGFR kinase domain mutations determination and were treated with gefitinib. Frequency and type of EGFR mutations and the clinical response in our area were explored. The aim is to analyse the pattern of response, toxicity, progression free survival and overall survival based on the type of EGFR mutation.

Results
Forty-six patients with EGFR mutations were collected, 36 women and 10 men. The median age was 67 years (43-86). Majority of the patients in the study had PS 0-1 (93%) and adenocarcinoma (96%) in the pathological study. The most frequent sites of metastasis were lymph nodes (59%), bones (33%), lung (33%) and pleura (33%). The median duration of treatment was 6 months. Progression disease was the most frequent reason of discontinuation of gefitinib; in 9 patients was discontinued because of toxicity. Ten patients were switched to cytotoxic chemotherapy and 10 patients continued with erlotinib. Twenty patients were detected to be positive for mutation in exon 19, 4 patients in exon 20 and 20 patients in exon 21. The L858R point mutation in exon 21 was observed in 14 patients and the L833F point mutation in the same exon was observed in 1 patient. Thirty-five patients were included in the response analysis. The response ratio to gefitinib was 57%. Depending on the type of mutation, the response in exon 19 mutation patients was 64%, in exon 20 patients was 0% and in exon 21 patients was 60%. Rash or acne was the most frequent toxicity (48%), only 2% was grade 3-4. Diarrhea and dysnea were the main toxicities grade 3-4 (9% both), without statistical differences based on type of mutation (p=0.78) . Progression free survival (PFS) of patients with EGFR mutations was 6 months. Patients with mutation in exon 19 had 9 months compared to 6.4 months for patients with exon 21 mutation, presenting a statistically significance difference (p=0.002). Overall survival (OS) was 17 months for EGFR mutations patients (19 months for exon 19 mutation patients and 14 months for exon 21 mutation patients; p=0.119)

Conclusion
Pacients in our area with exon 19 EGFR kinase domain mutations treated with gefitinib have higher PFS compare to exon 21 EGFR kinase domain mutations. Exon 20 mutation in our patients is responsible for resistance to gefitinib.

Background
Study NCT01203917 assessed the efficacy, and safety/tolerability of the EGFR tyrosine kinase inhibitor gefitinib in Caucasians with EGFR mutation-positive NSCLC, and compared mutation status in tumor-derived DNA and plasma-derived circulating-free DNA (cfDNA).

Methods
Patients: Caucasians; ≥18 yrs; PS 0-2; histologically confirmed Stage IIIA/B/IV EGFR mutation-positive NSCLC eligible for first-line treatment. Treatment: 250mg gefitinib once-daily until disease progression. Primary endpoint: objective response rate (ORR; investigator assessment). Secondary endpoints: disease control rate (DCR; complete/partial response or stable disease ≥6 wks), progression-free survival (PFS), overall survival (OS) and safety/tolerability. Pre-planned exploratory objectives: comparison of EGFR mutation status in tumor versus mandatory, duplicate plasma samples (all screened patients) collected at baseline (plasma1 and 2) and one optional plasma at progression.

Results
Of 1060 screened patients with NSCLC, 118 presented with activating, sensitizing EGFR tumor mutations, 106 of whom were enrolled and treated with gefitinib (Full Analysis Set; 71% female; 97% adenocarcinoma; 64% never-smoker). ORR (70%), DCR (90.6%), median PFS (9.7m), and median OS (19.2m) indicated gefitinib efficacy, with rash (45%), and diarrhea (31%) the most common adverse events (AEs; any grade; serious AEs: 19%) (previously reported at EMCTO 2013). Mutation rate for samples with known mutation status: 14% (118/859) in tumor, 10% (82/784) in plasma1. In 201 screened patients, tumor mutation status could not be detected due to technical reasons; however, 12 had a mutation in plasma1. Mutation status concordance in 652 matched tumor and plasma1: 94% (CI: 92-96; mutation subtype/frequencies in Table). Using tumor mutation status as reference, EGFR mutation test sensitivity in cfDNA was 66% (CI: 56-75), specificity was 100% (CI: 99-100); positive predictive value: 99% (CI: 92-100); negative predictive value: 94% (CI: 92-96). Mutation status concordance in 224 duplicate plasma samples: 97% (CI: 94-99) (subtype/frequencies in Table). ORR (post-hoc) for patients with both EGFR mutation-positive tumor and plasma1 or 2 (n=66): 77% (CI: 66-86); ORR for patients with EGFR mutation-positive tumor and EGFR mutation-negative plasma1 or 2 (n=37): 60% (CI: 44-74). Of 12 patients with baseline and progression plasma samples, 4 differences were observed: no mutations were detected at progression in 3 patients in which exon 19 deletions were detected at baseline; one patient with an exon 19 deletion at baseline acquired an additional mutation, T790M (75% concordance; CI: 43-95). Table

Baseline tumor EGFR mutation subtype results and corresponding plasma 1 results for 652 patients with matched tumor and plasma1 samples
		Plasma1,n				TOTAL
		Positive: Exon 19 deletions	Positive: L858R	Positive: L858R & T790M	Negative
Tumor, n	Positive: Exon 19 deletions	48	0	0	23	71
	Positive: L858R	0	21	0	12	33
	Positive: L858R & T790M	0	0	0	1	1
	Negative	0	1	0	546	547
TOTAL		48	22	0	582	652
Baseline plasma1 EGFR mutation subtype results and corresponding plasma2 results for 224 patients with duplicate plasma1 and 2 samples
			Plasma2, n			TOTAL
			Positive: Exon 19 deletions	Positive: L858R	Negative
Plasma1, n	Positive: Exon 19 deletions		43	0	4	47
	Positive: L858R		0	20	1	21
	Negative		1	1	154	156
TOTAL			44	21	159	224

Conclusion
First-line gefitinib was effective and well tolerated in Caucasian patients with EGFR mutation-positive NSCLC. EGFR mutation status assessment from plasma-derived cfDNA can be considered when tumor tissue is unavailable.

Background
B in combination with platinum doublets followed by continuation maintenance with B prolongs survival and delays progression in chemo-naïve pts with advanced nsNSCLC. In a phase II trial C, D and B (15 mg/kg) every 3 weeks followed by B showed a promising efficacy, in terms of progression free survival (PFS) and overall survival (OS), and an acceptable toxicity profile. In addition, a biweekly schedule of D and C in p with metastatic NSCLC as a front-line CT has demonstrated effective antitumor activity with a reduction in hematologic toxicity, comparable to the results of previous studies using 3-week schedule. Taken together, these data suggest that the addition of B to C/D administered every 2 weeks could increase the efficacy and reduce the toxicity associated with the other schedules.

Methods
GGCP 047-10 is a multicenter study in chemo- naïve p diagnosed with advanced nsNSCLC. Eligible p also have measurable disease according to RECIST criteria; age ≥18 years; ECOG PS ≤1; adequate hematological, renal and liver function; life expectancy of at least 2 months and signed informed consent. P receive C (50 mg/m2), D (50 mg/m2), and B (10 mg/kg) every 2 weeks for up to 6 cycles, followed by B alone every 2 weeks until disease progression or unacceptable toxicity. PFS is used as the primary efficacy endpoint. Secondary endpoints include safety profile, overall response rate (ORR), disease control rate (DCR) and OS.

Results
32 p were enrolled in the study. Median age was 60 years (range 44-72; 28.1% > 65 years); male/female (%): 81/19; ECOG 0/1/2 (%): 28/63/10; adenocarcinoma (%): 84. Median PFS in overall population was 6.4 months (95% CI, 4.2-8.7). Among the 22 p evaluable for response, the ORR was 63.6% and DCR was 95.4%. Most frequent grade 3/4 hematologic toxicity was neutropenia (40.6%) and grade 3/4 nonhematologic toxicities was asthenia (12.5%) followed by mucositis (6.2%) and diarrhea (3.1%). There were no grade 3/4 hemorrhagic events.

Conclusion
Treatment with B, C and D plus maintenance B every 2 weeks is effective as front-line treatment of p with advanced nsNSCLC with acceptable toxicity. These data provide further evidence that B may be used in combination with multiple standard, platinum-based doublets in this setting.

Background
Deep vein thrombosis (DVT) is the common complication found in malignancy. Currently, there were no current diagnosis guideline which could help to identify DVT in lung cancer. This study, is a pilot study to identify and see the magnitude at DVT proportion among lung cancer in our hospital. The objective of this study is to find proportion of deep vein thrombosis among lung cancer patients which is determined by clinical criteria such as Wells’ score in Persahabatan Hospital.

Methods
The study design is using a cross-sectional method. We examined 147 patients with pathological confirmed lung cancer who were hospitalized within September 2012 to February 2013. We excluded the lung cancer patients with infection comorbidity. The hemostatis function included PT, APTT, and D dimmer were conducted along with clinical Wells’ score criteria.

Results
Seventy eight of 147 sobjects were analyze in this study. They were mostly male (69,2%) with range of ages were 30 –79 years old with predominant age group of 51-60 years old (33,3%). Adenocarcinoma was found in 57,7%. This study found that deep vein thrombosis proportion is 23, 1% using Wells’ score. Clinical characteristics such as gender, age, smoking history, cancer cell type, stage of the diseases, performance status and homeostasis function did not have correlation with DVT whereas the D dimmer >500 have correlation with DVT.

Conclusion
The DVT proportion among lung cancer patients in Persahabatan Hospital is similar found in some studies in other countries which are approximately 21%. This study revealed that the simple and practical application of Wells’ score in determining DVT is still have valuable role in daily practice, especially in hospital with limited facility.

Background
Afatinib is an oral, irreversible ErbB Family Blocker which showed superior efficacy to standard first-line chemotherapy in two large randomized Phase III trials in global (LUX-Lung 3) and Asian (LUX-Lung 6) EGFR M+ patients. In both trials, median progression-free survival on afatinib was 11 months by independent review. This was also reflected in median treatment duration of 11–12 months in both trials. With long-term treatment duration, the safety profile of afatinib becomes particularly relevant to patients and physicians, and needs to be well characterized. Furthermore, differences in the pattern of some adverse events (AEs; notably interstitial lung disease [ILD]) have been previously described in Asian and non-Asian patients with reversible EGFR tyrosine kinase inhibitors. Here, we present a detailed review of afatinib’s safety profile in Asian and non-Asian patients.

Methods
229 (LUX-Lung 3) and 239 (LUX-Lung 6) EGFR M+ patients were treated with afatinib 40mg daily until progression or intolerable AEs. Afatinib dose could be escalated to 50mg daily or reduced to 30mg or 20mg based on predefined study criteria. Patients from both trials were grouped according to ethnicity: Asian vs. non-Asian. On-treatment AEs were summarized by preferred/grouped terms and graded using NCI-CTCAEv3.0.

Results
404 Asian (66% China/Taiwan; 16% Southeast Asia; 13% Japan; 5% Korea) and 64 non-Asian patients (95% Caucasian; 3% American-Indian; 2% African-American) received afatinib, with median exposure of 359 and 261 days, respectively. There was no difference in afatinib pharmacokinetic exposure in Asian vs. non-Asian patients. All patients reported at least one AE. Most common AEs were EGFR-mediated and are summarized in the table. Figure 1 Drug-related AEs leading to discontinuation were slightly higher in Asian patients, but at a rate lower than with chemotherapy (28%). Related ILD-like events occurred in four Asian patients (three Grade ≥3) and no non-Asian patients.

Conclusion
Most common drug-related AEs with afatinib were EGFR mediated and occurred at similar frequency in Asian and non-Asian patients. Treatment discontinuation due to EGFR-related AEs was low in both groups, indicating that afatinib has a manageable safety profile in both populations and is suitable for long-term treatment of EGFR M+ NSCLC patients.

Background
Approximately one third of all non-small cell lung cancer (NSCLC) patients will develop brain metastases. The majority of such patients are inoperable with a very poor prognosis, and for several decades the standard treatment has been a combination of steroids and whole brain radiotherapy (WBRT). However, little evidence exists to support this approach, and there is continuing debate over the use of WBRT. The diversity of clinical opinion and patient preference makes this a challenging question to address.

Methods
The multi-centre randomised QUARTZ trial assesses whether optimal supportive care including steroids (OSC) is a viable alternative to the current standard of OSC plus WBRT, in terms of duration and quality of life (QoL). The primary endpoint of Quality Adjusted Life Years (QALYs) reflects that both quality and duration of survival are important. Disease status, symptoms and QoL data are collected weekly. The impact of the disease and treatment on carers is also being assessed. A total of 534 patients is required to exclude a detriment in terms of QALYs of >1 week with OSC (from 5 weeks with OCS plus WBRT), and the aim was to recruit this number in three years.

Results
After four years, only 188 patients had been recruited and a decision was taken to present the interim results to participating clinicians. Interim data (from the first 151 QUARTZ patients)[1] provided no strong evidence that omitting WBRT was detrimental in terms of survival or QoL and there were no clear differences in steroid usage or toxicity. By June 2013 QUARTZ has recruited 438 patients (82%) and 336 carers from 78 UK and Australian centres. Data collection is excellent with 98% of forms returned.

Conclusion
Patients with brain metastases (and others approaching end of life) represent a difficult group to study, as they often have different priorities regarding treatment options, but it is vital that we obtain the highest quality evidence possible in order to best guide treatment. QUARTZ has demonstrated that good trial design (weekly phone assessments, using QALYs as the primary endpoint, releasing interim results, etc) makes it possible to conduct successful clinical trials in this challenging patient population in order to answer important clinical questions. The interim results have reassured QUARTZ Investigators that omitting WBRT does not appear to lead to any detrimental effect in terms of either length or QoL, and have proved very useful when discussing the trial with potential patients. Although molecular targeted agents can extend treatment options for some patients, QUARTZ remains an important trial, which will define the use of WBRT and may impact on practice worldwide. We estimate completing recruitment during Summer 2014. Recruitment rates remain constant with many centres demonstrating successful recruitment to QUARTZ. Acknowledgements Thank you to all the patients and their carers for participating in the trial and the recruiting centres for their hard work in recruiting patients and helping to achieve the high standard of data collection. QUARTZ is supported by Cancer Research UK (CRUK/07/001). References 1. Langley RE et al. Clin Oncol (R Coll Radiol) 2013;25(3):e23-30.

Background
KRAS mutations in NSCLC are supposed to indicate a poor prognosis and poor response to anticancer treatment. However, such evidence is only drawn from retrospective series giving controversial results. Aim of this study is to prospectively assess the prognostic and predictive value of KRAS mutations in NSCLC patients treated with either erlotinib or docetaxel. This is a planned ancillary study within the TAILOR trial (NCT00637910 ).

Methods
Main eligibility criteria were a diagnosis of metastatic NSCLC, prior platinum-based chemotherapy and mutational status of EGFR and KRAS centrally assessed by direct sequencing in two independent laboratories. Only patients with wild-type EGFR and KRAS status assessed were randomly allocated to receive erlotinib or docetaxel until disease progression. Overall survival was the primary endpoint. To detect a 33% reduction in mortality with an 80% power (2 sided a=0.05), 220 patients were randomized. A subgroup analysis aimed at detecting particular subgroups of patients, where the differential effect of treatment could be highlighted, was planned.

Results
Overall, median survival and progression free survival were superior in the docetaxel arm compared to the erlotinib arm. Fiftyone out of 220 patients were found to be mutated in KRAS. No interaction effect was found according to KRAS status. In mutated KRAS the HR for OS was 0.81 (95%CI: 0.45-1.47) in favour of chemotherapy, and in wild type KRAS the HR was 0.79 (95%CI: 0.57-1.10); p value for interaction effect: 0.82. Similar pattern was found for PFS. In mutated KRAS patients the HR for PFS was 0.89 (95%CI: 0.51-1.57), while in wild type KRAS the HR was 0.68 (95%CI: 0.50-0.93), p value for interaction effect: 0.33. No evidence of prognostic effect of KRAS could be found. For OS, the HR for associations of mutated KRAS status and mortality was 1.24 (95%CI: 0.87-1.77; p=0.23); for PFS the HR was 1.00 (95%CI: 0.71-1.41; p=0.98)

Conclusion
Although the study is not sufficiently powered to test interaction for KRAS mutations, TAILOR results show that KRAS can be considered neither a prognostic nor a predictive factor in second line treatment in advanced NSCLC.

Background
Cancer induced muscle wasting is a selective and progressive cancer related symptom that begins early in the course of malignancy. Greater than 50% of NSCLC patients have muscle wasting at diagnosis, increasing to >80% prior to death. Previous evidence suggests that a 1kg gain in lean body mass (LBM) is beneficial for increasing muscle strength. Enobosarm is a first-in-class nonsteroidal oral SARM. We report herein results for two Phase 3 enobosarm clinical trials, POWER1 (P1) and POWER2 (P2), for the prevention and treatment of muscle wasting in patients with advanced NSCLC.

Methods
Patients with Stage III or IV NSCLC were randomized into the trials at initiation of first-line chemotherapy based upon the chemotherapy regimen prescribed; platinum+taxane(P1, n=321) or platinum+non-taxane(P2, n=320). Patients (males and postmenopausal females ≥30y with ECOG ≤1) received either enobosarm 3mg or placebo for 5 months. LBM was measured by DXA and physical function was assessed by stair climb power (SCP) at days 84 (primary endpoint) and 147.

Results
Enobosarm had a significant effect on LBM at day 84 and 147 in both trials (P1:p=0.0003 and < 0.0001; P2: p=0.0227 and 0.0036 by continuous variable analyses). Additionally, a larger proportion of patients receiving enobosarm maintained or increased LBM at day 84 and 147 in both trials (P1:p=0.036 and 0.026; P2:p=0.113 and 0.013) as compared to placebo. Regardless of treatment, patients with ≥1kg increase in LBM were more likely to demonstrate ≥10% increase in SCP than patients that had lesser increases or had decreases in LBM (P1: 43.7% vs 29.3%, p=0.0250 and P2: 40.5% vs 26.5%, p=0.0321). The percentage improvement in SCP from baseline to day 84 differed significantly between patients with and without a ≥1kg increase in LBM: 9.1% vs -1.0% in P1(p=0.0022) and 7.7% vs -.0.6% in P2(p=0.0046). Importantly, patients with ≥1kg increases in LBM were more likely to demonstrate a ≥10% increase in SCP if they received enobosarm (P1: p=0.0698[trend] and P2: p=0.0335) than placebo (P1:p=0.3149 and P2:p=0.2852), suggesting that LBM increases in enobosarm-treated patients were more highly associated with SCP improvements in both trials (Figure). In general, patients that maintained or increased LBM had greater increases in SCP and survived longer (landmark analysis) regardless of treatment. The incidence of adverse events was similar between enobosarm and placebo in both trials. Figure 1

Conclusion
Overall, enobosarm was safe and well tolerated. Enobosarm had an unambiguous effect on muscle that may translate into improvement in physical function and survival in NSCLC patients.

Background
Polo-like kinases (Plks) are overexpressed in many cancers including NSCLC. Volasertib (BI 6727; an investigational drug) is a selective and potent Plk inhibitor, which induces mitotic arrest and apoptosis. This 3-arm trial compared the efficacy, safety and pharmacokinetics of volasertib monotherapy, volasertib combined with pemetrexed and single-agent pemetrexed as second-line therapy in patients with advanced/metastatic NSCLC (NCT00824408).

Methods
An initial run-in phase was conducted to determine the tolerability and dose of volasertib combined with pemetrexed 500mg/m[2]. Subsequent patients were randomised to one of three arms: (A) volasertib 300mg, (B) volasertib 300mg plus pemetrexed 500mg/m[2], or (C) pemetrexed 500mg/m[2]. Both drugs were administered on Day 1 every 21 days. Eligible patients had advanced/metastatic NSCLC, ECOG PS 0–2, adequate organ function and prior platinum-based chemotherapy. The primary endpoint was progression-free survival (PFS) evaluated using a stratified one-sided log-rank test (Arms B versus C); an exploratory analysis was performed for Arms A versus C. Secondary endpoints included objective response rate (ORR), overall survival (OS), safety and pharmacokinetics.

Results
Twelve patients were included in the run-in phase; the volasertib dose selected for the randomised phase was 300mg. 131 patients were then randomised to the three arms (A: n=37, B: n=47, C: n=47). Arm A recruitment was stopped early due to an increased rate of early progression. Demographic data were balanced between the arms. One patient per arm did not receive treatment. The median number (range) of treatment cycles in Arms A, B and C was 2 (1–49), 4 (1–36) and 5.5 (1–38), respectively. Median PFS (Arms A/B/C) was 1.4/3.3/5.3 months (HR B versus C =1.141 [95% CI: 0.735–1.771; p=0.2804]; HR A versus C =2.045 [95% CI: 1.271–3.292; two-sided p=0.0030]). ORR (Arms A/B/C) was 8%/21%/9%; no complete responses were observed. Disease control rates (Arms A/B/C) were 27%/66%/68%. Median OS (Arms A/B/C) was 22.9/17.1/17.4 months. Median relative dose intensity was 100% for both volasertib and pemetrexed in all arms with a range of 80.6–111.1% in Arm A and 83.3–100.0% in Arm B for volasertib, and 87.5–100% in Arm B and 81.3–100% in Arm C for pemetrexed. The most common all-grade adverse events (AEs) were (Arms A/B/C): fatigue (56%/74%/70%), nausea (14%/48%/54%), decreased appetite (8%/44%/41%), constipation (17%/37%/22%), dyspnoea (17%/28%/30%) and vomiting (19%/33%/24%). Most common grade 3/4 AEs (>5%) were (Arms A/B/C): fatigue (8%/13%/17%), neutropenia (14%/11%/4%) and dyspnoea (3%/9% /13%). Grade 3/4 febrile neutropenia was seen in 2 (4%) patients in Arm B and 1 (2%) patient in Arm C. One fatal AE of septic shock (Arm B) was considered drug-related; 22%/22%/26% of patients experienced a serious AE. Pharmacokinetic analysis of volasertib in Arms A and B, together with historical pharmacokinetic data for pemetrexed, did not reveal any evidence of pharmacokinetic interactions between volasertib and pemetrexed.

Conclusion
Volasertib and pemetrexed could be combined at full single-agent doses, with generally acceptable toxicities, and demonstrated modest antitumour activity. However, the addition of volasertib did not improve PFS compared to single-agent pemetrexed in patients with relapsed or refractory NSCLC after platinum-based first-line therapy.

Background
Selumetinib (AZD6244, ARRY-142886) is an orally available, potent and selective, non-ATP-competitive MEK1/2 inhibitor being investigated with docetaxel for treatment of KRAS mutation-positive advanced NSCLC. A randomised Phase II study of selumetinib 75 mg twice daily (bid) plus docetaxel 75 mg/m[2] q21d (SEL-DOC 75/75), with secondary granulocyte colony-stimulating factor (GCSF) prophylaxis if indicated, has shown promising efficacy in this setting but with more diarrhoea, neutropenic events, infections, hospitalisations and dose modifications than docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47; NCT00890825). Data from a small number of patients with advanced solid tumours in an open-label, Phase I study (NCT00600496) suggested that primary prophylactic (pp) GCSF reduces the incidence of neutropenic events associated with SEL-DOC 75/75 (Kim et al. Mol Cancer Ther 2011;10[Suppl 1:B225). We evaluated whether pp-GCSF could influence the incidence of hospitalisation or infection during treatment with SEL-DOC 75/75 using bias-reduced logistic regression modelling and medical review of data from NCT00890825.

Methods
Neutrophil counts and events of hospitalisation or infection from the safety analysis set of study NCT00890825 were used for modelling. This included 86 patients with KRAS mutation-positive advanced NSCLC randomised to receive second-line treatment with SEL-DOC 75/75 or placebo bid plus docetaxel. The relationship between maximum reduction in absolute neutrophil count (mr-ANC) and infection or hospitalisation events was explored using bias-reduced logistic regression (Firth. Biometrika 1993;80:27–38; Kosmidis. brglm, v0.5-6: www.ucl.ac.uk/~ucakiko/software.html). Starting models included terms for treatment group, mr-ANC, interaction between treatment group and mr-ANC, and baseline ANC. The final fitted models were used to predict the proportion of patients with events across the range of mr-ANC. Reported reasons for hospitalisation, dose modification and treatment discontinuation were medically reviewed in the context of expected pp-GCSF effect.

Results
The fitted logistic regression model showed some evidence of a relationship between hospitalisation events and mr-ANC for both treatment groups. A zero mr-ANC (assumed effect of pp-GCSF) predicted hospitalisation in 30% of patients (80% prediction interval 18–44%) in the SEL-DOC 75/75 group and 10% (5–18%) in the placebo plus docetaxel group. The observed incidence of hospitalisations in study NCT00890825 was 48% (80% confidence interval [CI] 37–58%) and 19% (11–29%) of patients, respectively. There was limited evidence of a relationship between events of infection and mr-ANC, suggesting other factors (eg immunosuppression and altered integrity of gastrointestinal wall) may influence the incidence of infection reported with this combination. Medical review indicated that use of pp-GCSF could reduce hospitalisation incidence during SEL-DOC 75/75 from observed 48% to a point estimate of 34% (80% CI 25–45%), and dose modification due to febrile neutropenia or infection from 23% to 5% (80% CI 1–12%). Permanent discontinuation of SEL-DOC 75/75 for reasons other than disease progression did not appear to be affected by pp-GCSF use.

Conclusion
Prevention of ANC reduction is predicted to lower the incidence of hospitalisation events in patients receiving treatment with selumetinib plus docetaxel for NSCLC. These findings support pp-GCSF use to reduce the incidence of hospitalisations previously reported with the SEL-DOC 75/75 regimen.

Background
KRAS mutations are the most common mutation type in patients with non-small cell lung cancer (NSCLC) with adenocarcinoma histology (Califano et al. Drugs 2012;72[Suppl 1:]28–36). The presence of the KRAS mutation has been associated with a poor prognosis (Mascaux et al. Br J Cancer 2005;92:131–139) and a therapy targeting Ras has yet to be proven in clinical trials. Selumetinib (AZD6244, ARRY-142886) is an orally available, potent and selective, non-ATP-competitive MEK1/2 inhibitor. MEK1/2 are proteins downstream of Ras in the Ras/Raf/MEK/ERK pathway. It is anticipated that inhibition of MEK activity should inhibit transduction of the mitogenic and survival signals via this pathway, resulting in an inhibition of tumour proliferation, differentiation and survival. A randomised Phase II study evaluating docetaxel plus selumetinib or placebo in pretreated patients with KRAS mutation-positive advanced NSCLC has previously demonstrated a significant improvement in terms of response rate, progression-free survival (PFS) and patient-reported outcomes (PROs) in favour of the combination arm (Jänne et al. Lancet Oncol 2013;14:38–47).

Methods
The SELECT-1 study is a randomised, double-blind, placebo-controlled Phase III study that will assess the efficacy and safety of selumetinib in combination with docetaxel in patients receiving second-line treatment for KRAS mutation-positive locally advanced or metastatic NSCLC (Stage IIIB–IV). Eligible patients will have centrally confirmed KRAS mutation-positive locally advanced or metastatic NSCLC, be suitable for second-line treatment and have had no prior treatment with docetaxel or a MEK inhibitor. Patients must have measurable disease, histologically or cytologically confirmed locally advanced or metastatic NSCLC and a WHO performance status (PS) of 0–1. Patients will be randomised in a ratio of 1:1 to receive selumetinib (75 mg, orally twice daily [BID]) or matching placebo BID in combination with docetaxel (intravenously 75 mg/m[2], on Day 1 of every 21-day cycle) until objective disease progression, intolerable toxicity or occurrence of another discontinuation criterion. Approximately 4000 patients will need to be screened from 220 centres globally to identify 634 KRAS mutation-positive patients for the study. Patients will be stratified at randomisation based on their WHO PS (1/0) and tumour histology (squamous/non-squamous). Following randomisation, patients will attend for visits on Day 8, 15, 22, 43 and every 3 weeks thereafter for as long as they are receiving study treatment. Tumour evaluation according to Response Evaluation Criteria in Solid Tumors version 1.1 guidelines will be performed at screening, Week 6, Week 12 and every 6 weeks thereafter, relative to the date of randomisation. The primary study endpoint is PFS; secondary endpoints include overall survival and objective response rate. Efficacy data will be analysed on an intent-to-treat basis using randomised treatment. Blood samples will be taken to assess the pharmacokinetics of selumetinib. The study will also evaluate PROs and safety for the selumetinib/docetaxel combination compared with placebo/docetaxel. In addition, outcome based on KRAS mutation type will be assessed.

Results
Not applicable.

Conclusion
This Phase III study will confirm the efficacy of selumetinib in combination with docetaxel in patients with NSCLCs that harbour mutations of KRAS and who are eligible for second-line treatment.

Background
Belinostat (PXD101), is a histone deacetylase (HDAC) inhibitor. HDAC inhibitors, including belinostat, have shown marked in vitro and in vivo activity against a number of solid tumors and hematological cancers. Belinostat is efficient as a single agent as well as in combination with other anticancer agents such as doxorubicin, paclitaxel, carboplatin, fluorouracil, bortezumib. Synergistic effect between HDAC inhibitors, incl. belinostat and EGFR inhibitors has been observed. Belinostat has been well tolerated at doses up to 2000 mg daily in patients. The main side effects are fatigue, nausea and vomiting. The trial was designed as an open, non-randomized phase I / II trial to assess the efficacy and safety of belinostat in combination with erlotinib in patients with advanced non-small cell lung cancer, who were eligible for treatment with erlotinib.

Methods
The primary endpoint of the phase I part was to establish the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib (150mg/d) in combination with increasing doses of belinostat. The study was designed as a 3+3 phase I trial. All patients began with 4 weeks of erlotinib 150 mg/d. If this was tolerated, patients started the combination erlotinib and belinostat. The belinostat dose steps were 500 mg, 1000 and 1500 mg, administered daily in 2 weeks on treatment, 1 week off treatment. When one patient was enrolled at one dose level, there would be no further dose escalation for that individual patient. Three patients were planned at each dose level. When the MTD was identified the trial was planned to expand to a phase II trial, and include 20 patients with non-small cell lung cancer.

Results
From October 2010 until June 2011 five patients were enrolled in the phase I part of the trial. Patient one and two started belinostat 500 mg after four weeks of erlotinib 150 mg/d.Both patients experienced grade 3 diarrhea in spite of supportive care with loperamid and antiemitics. The treatment was discontinued in both patients and the toxicity quickly resolved. In accordance with the trial protocol, patient three was started on belinostat 250 mg. Patient three experienced only grade 1 diarrhea and grade 1 nausea. The patient received 2 series of belinostat. Patient four experienced grade 2 diarrhea and grade 2 rash in the first series belinostat 250 mg. Patient five experienced, in the first series of belinostat, grade 3 diarrhea and was hospitalized despite intensive supportive care. All patients discontinued treatment and toxicity resolved.

Conclusion
The combination of the HDAC-inhibitor belinostat and the EGFR inhibitor erlotinib resulted in severe toxicity. The trial has been closed. NCT01188707

Background
Lung cancer remains the most leathal form of cancer. Overall five-year survival rate is poor but not without heterogeneity. The struggle to improve prognosis and treatment outcome is ongoing. Molecular pathways and “driver mutations” have been identified, some of which can be specifically targeted by new drugs. Mutations within the APT-binding domain of the EGFR gene constitute a predictive factor for the use of tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib. Our aim was to define the clinical importance of molecular pathological testing for activating EGFR-mutations in non-small lung cancer.

Methods
We have retrospectivly examined all histological and cytological sampling for molecular testing on NSCLC-patients in the two lung cancer centra in Stockholm, Sweden (Karolinska University Hostpital: sites of Solna and Huddinge) between 2009 and 2011. All samples with positive outcome were identified and clinical data from all patients in advanced stages of disease were collected.

Results
565 samples were collected for EGFR-mutation analysis. Mutations were identified in 66 cases (11,7%). Both cytological and histological material were analyzied (n=23 and 21 respectively). 42 tumors were adenocarcinomas, 1 was a large cell carcinoma and 1 was a squamous cell carcinoma. 29 presented deletion in exon 19 and 14 mutations in exon 21, whereof 21 and 12 respectively were women. 1 patient (male) presented a constitutive deletion in exon 20. 44 patients had metastatic disease. Clinical data from these patients were further analyzed. 21 were never smokers, 21 former smokers with 28 years in average since smoking cessation and 2 were current smokers. All patients recieved TKI-treatment, whereof 24 as 1[st] line, 14 as 2[nd] line and 6 as a later line. Partial remission was obtained in 77% of cases and stable disease in 11%. 2,2% of patients developed progressive disease according to RECIST-criteria during TKI-treatment. At time of data collection, 16 patients had died. The remaining 28 patients had ongoing TKI-treatment for 400 days on average and a median survival of 21 months.

Conclusion
A positive mutation test on either cytological or histological material carries a high predictive value for TKI-treatment. TKIs offer good and durable treatment results in patients with advanced NSCLC and activating EGFR-mutations. Thus, identifying this subset of patients offers new treatment options and realistically balanced hope in the severe setting of metastatic NSCLC.

Background
DRibbles are tumor-derived autophagosomes containing short-lived proteins (SLiPs) and defective ribosomal products (DRiPs). Vaccination with DRibbles produces tumor regression and provides cross-protection against syngeneic MCA sarcomas in preclinical models. Docetaxel can expose hidden tumor antigens and induces relative lymphopenia, potentially enhancing specific immune response. Sargramostim (GM-CSF) augments priming of tumor-specific T cells when administered at the site of DRibble vaccine in mice. This pilot study of autologous NSCLC DRibble vaccination with GM-CSF and docetaxel enrolled patients with advanced incurable NSCLC with malignant pleural effusion.

Methods
Pts had NSCLC with malignant pleural effusion, ECOG PS ≤ 2, and up to 2 prior chemotherapy regimens. Prior cancer-related vaccine therapy, active autoimmune disease, HIV, viral hepatitis, or chronic steroid use were not permitted. Pts with rapid clinical deterioration after enrollment were not eligible for vaccination. After informed consent, cells from malignant pleural fluid were cultured with bortezomib to block degradation of SLiPs and DRiPs and ammonium chloride to prevent lysosomal degradation of the autophagosome. DRibble vaccines were irradiated and passed sterility and endotoxin release criteria. Pts received docetaxel 75 mg/m[2] IV on day 1 and 29 for antitumor effect and to unmask tumor antigens and produce relative lymphopenia. Vaccination was scheduled for days 14, 43, 57, 71 and 85. GM-CSF (50 ug/d) was given via mini pump for 6d after each vaccination with immune monitoring pretreatment and at each vaccination.

Results
Six pts (3M, 3F, average age 65) with PS 1 and adenocarcinoma were enrolled. All received d1 docetaxel. Two did not receive further therapy due to clinical decline. Four pts were vaccinated (2-4 vaccines). One of 4 pts exhibited autologous tumor-specific immune response (IFN-γ, TNF-α, IL-5, IL-10) and 3 of 4 pts generated B cell responses (>5 fold specific antibody), with 1 patient not evaluable (Table 1). Figure 1

Conclusion
DRibble vaccine given with GM-CSF and chemotherapy is feasible. Small patient numbers preclude further conclusions. In order to translate this strategy to a larger number of pts in a more feasible population, we have developed an allogeneic DRibble vaccine from two NSCLC cell lines expressing at least 9 NCI-prioritized cancer antigens and including agonists for TLR 2, 3, 4, 7 & 9, HSPs and a dendritic cell-targeting molecule. A phase II trial of adjuvant DRibble vaccine alone or combined with GM-CSF or imiquimod is open in patients with definitively treated stage IIIA/B NSCLC. Support R21 CA123864-02 (WJU), R444 CA121612-01 (SA/TH) and Kuni Foundation (WJU).

Background
More than half of pulmonary adenocarcinoma patients present with locally advanced or metastatic disease. Most patients with brain metastases suffered from poor quality of life and poor survival time. Epidermal growth factor receptor (EGFR) mutations were most frequently found in patients with pulmonary adenocarcinoma and were associated with a better prognosis than patients with EGFR wild-type tumors. However, the association between tumor EGFR mutation and whether or not more frequent brain metastasis is still unclear.

Methods
We retrospectively reviewed the data of our pulmonary adenocarcinoma patients who have brain metastasis, and record the characteristics of brain metastasis. The association between tumor EGFR mutation and clinical characteristics of brain metastasis were analyzed.

Results
374 cases were reviewed. There are 239 patients with EGFR mutations, 69 patients with initial diagnosis of brain metastasis, and 82 patients with brain metastasis after treatment. Older patients (more than 70 years old) had fewer brain metastasis than younger (less than 70 years old) patients (25.8% v.s 48%, P<0.001). Patients with higher N stage of TNM staging system had higher proportion of brain metastasis (P=0.006). Patients with exon 19 deletion had more chance to suffer from brain metastasis than those with EGFR wild type (48.1% v.s. 34.1%, P=0.021). Patients with exon 19 deletion didn’t have significantly higher chance to have initial diagnosis of brain metastasis (P=0.216). However, patients with exon 19 deletion had higher chance to suffered from brain metastasis after treatment than those with EGFR wild type (35.6% v.s. 21.2%, P=0.019). Patients with exon 19 deletion survived longer than those with EGFR wild type (1-yr survival rate 95.8% vs. 78.7%, P=0.003). Thus, longer survival time may lead to higher proportion of brain metastasis occurrence in patients with exon 19 deletion than those with EGFR wild type.

Conclusion
There is no significant difference in frequency of initial brain metastases in patients with EGFR mutation or wild type. However, there are statistically significant association between brain metastasis and EGFR mutations in pulmonary adenocarcinoma patients in their disease process.

Background
CH5424802 is a novel tyrosine-kinase inhibitor that selectively inhibits ALK as well as secondary ALK mutations including L1196M. The preliminary results of the Phase I/II study (Lancet Oncol. 2013; 14: 590–8) showed that CH5424802 was active in the CNS and achieved a 93.5% objective response rate by RECIST in crizotinib-naïve NSCLC patients with a median follow-up of 7.6 months (range, 3.4–11.3). Here we report the 1-year follow-up results after the last patient enrolled in the Phase II analysis.

Methods
Patients with ALK-rearranged advanced NSCLC, who progressed after ≥1 prior chemotherapy regimens and who were naïve to any ALK inhibitors, received CH5424802 300 mg orally twice daily in the Phase II portion of the study. ALK fusion gene expression was confirmed by IHC and FISH or by RT-PCR at central laboratories. Tumor assessment was performed every cycle (21 days) until Cycle 4 and every 2 cycles thereafter with RECIST ver. 1.1.

Results
As of April 18, 2013, 46 patients had been treated with CH5424802 in the Phase II portion: median age, 48 years (range, 26–75); male/female, 22/24; ECOG PS 0/1, 20/26; never-smoker, 59%; ≥2 prior chemotherapy regimens, 52%. The objective response rate remains the same as previously reported, 93.5% (95% CI: 82.1% to 98.6%). At 1-year follow-up, a total of 7 patients (15%) had achieved a complete response. The median progression-free survival had not been achieved, and the 1-year progression-free rate (PFR) was 83% (95% CI: 68% to 92%). 34/46 patients were still on study treatment, and the median treatment duration had passed 14.8 months. CH5424802 also shows promising efficacy in the CNS: of 14 patients with baseline brain metastasis, 9 remained in the study without CNS or systemic progression for >12 months, with 6 of them exceeding 16 months. The other 5 patients with baseline CNS metastasis had no CNS progression during CH5424802 treatment. One of these patients discontinued the study due to AE, and the remaining 4 patients had systemic progression. The safety profile remains similar to that previously reported, with no patient requiring dose reduction.

Conclusion
CH5424802 demonstrated a high 1-year PFR of 83% and promising CNS activity. CH5424802 could be a novel therapeutic option for the treatment of ALK-rearranged NSCLC.

Background
Afatinib is a potent and selective, irreversible ErbB family blocker. Previous phase 3 trial demonstrated that afatinib prolonged progression-free survival compared with placebo in patients with advanced lung adenocarcinoma who progressed after 12 weeks of treatment with reversible EGFR tyrosine-kinase inhibitors (TKIs). The purpose of this Open Label Compassionate Use Programme is to provide afatinib to patients with advanced NSCLC with previous treatment failure on erlotinib or gefinitib and for whom no other approved treatment is available.

Methods
who have failed at least one line of platinum-based cytotoxic chemotherapy and following at least 6 months on erlotinib or gefinitib were eligible. Thestarting dose of afatinib was 50mg daily.

Results
Between Aug 2011 and Dec 2012, 107 patients were treated with afatinib. Most patients were females (60.7%) and never-smokers (69.2%) with a median age of 57 years. Of the 95 patients who had prior EGFR mutation results, 82 (86.3%) were positive. With afatinib treatment 25 (23.4%) of 107 patients had a partial response. Median progression-free survival was 4.6 months (95% CI 4.1-5.1). The most common adverse events were diarrhea (97 [90.7%] patients; 22 [20.6%] were grade 3) and rash or acne (72 [67.3%] patients; 11 [10.3%] were grade 3). No drug-related death was found. Sixty-four (59.8%) patients needed a dose reduction because of an adverse event.

Conclusion
Our results suggested that afatinib could be a feasible option to patients with advanced lung adenocarcinoma who have progressed after clinical benefit on previous EGFR TKIs.

Background
Gefitinib and Erlotinib are oral small-molecule kinase inhibitors that inhibit signaling via EGFR and both agents showed dramatic response rate and prolonged PFS in patients harboring activating EGFR mutation. We investigated the clinical outcomes between gefitinib- and erlotinib-treated patients with recurrent or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations.

Methods
A total 375 patients with recurrent or metastatic stage IIIB/IV NSCLC who had either an exon 19 deletion or L858R mutation on exon 21 and received gefitinib(n=228) or erlotinib(n=147) therapy between August 2007 and December 2011 were retrospectively reviewed. By using a matched-pair case-control study design, 121 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, smoking history, ECOG performance status, and types of EGFR mutation.

Results
The median age of all patients was 58 years(range, 30-84) and more than half of patients were never smokers(63.6%). Most patients had adenocarcinoma (98.3%) and good ECOG performance status (0, 1) (90.9%). The median number of cycles in TKI treatment was 12.7 in gefitinib group and 10.8 in erlotinib group. Of 242 patients, 64(26.4%) received an EGFR TKI as first line therapy. The overall response rates and disease control rates in the gefitinib-treated and erlotinib-treated groups were 85.5% versus 79.8 % (p=.375) and 94.0% versus 89.1%, respectively (p=.242). There was no statistically significant difference noted with regard to OS (median, 22.1 vs 25.2; p=.546) and PFS (median, 12.5 vs 9.9; p=.114) between the gefitinib-treated and erlotinib-treated groups. For a subgroup which patients were treated with TKI as first line therapy, the overall response rates were higher than those of patients who had progressed on prior chemotherapy (90.3% vs 79.9%; p=.063). However, there was no significant differences in PFS (median, 13.1 vs 10.1; p=.082) between subjects with first line TKI therapy and more than second line treatment. Regarding safety and dose adjustment of EGFR TKIs, patients with erlotinib more frequently had G3/4 toxicity than ones with gefitinib and required dose reduction(18.1% vs 1.65%).

Conclusion
Both gefitinib and erlotinib showed similar effective activity in selected population of NSCLC that harbored an EGFR mutation and further studies are needed to evaluate the efficacy of EGFR TKI as first line treatment.

Background
Previously we reported a phase II study of sorafenib, a multi tyrosine kinase inhibitor, in advanced NSCLC patients with a KRAS mutation [1]. While sorafenib was found active in this group of patients, progression free survival (PFS) and overall survival (OS) were disappointing. Concurrent inhibition of multiple pathways may improve treatment outcome. Metformin is a save and well known antidiabetic drug. It has been described that metformin has inhibitory effects against mTOR, downstream of PI3K. An in vitro study of our group has shown synergistic effects of sorafenib and metformin which provided the rationale for this study [2]. In a post hoc analysis of the previous study, metformin users appeared to be among the longest survivors.

Methods
Patients with advanced NSCLC with a KRAS mutation, pretreated with platinum containing chemotherapy were included. Other inclusion criteria were: ECOG performance score (PS) 0-1, adequate organ reserve, creatinine clearance >60 ml/min and provided written informed consent according to local IRB regulations. A tumor biopsy was mandatory to confirm the presence of a KRAS mutation, prior to start of treatment. Treatment consisted of sorafenib 400 mg BID and metformin 1000 mg BID until disease progression or unacceptable toxicity. Dose reductions and discontinuations were specified per protocol in the face of CTC toxicities grade 3 and 4. Primary endpoint: disease control rate (DCR) at 6 weeks according to RECIST version 1.1. Secondary endpoints: duration of response, progression free survival (PFS), overall survival and treatment related toxicities. A 2-stage design was implemented (Simon's optimal design; p0=50%, p1=70%, alpha=0.05, beta=0.20) for a total of 45 evaluable patients.

Results
Fifty-five patients were included between 1[st] of July 2012 and 1[st] of June 2013. Median age was 60 (range 34-77) years, 28 female (51 %), ECOG PS 0/1/2 16/32/1, all patients had stage IV disease. Of 47 patients disease evaluation after 6 weeks was available (Fig. 1). Two patients had a partial response, 23 stable disease and 22 patients had progressive disease. DCR was 53%. Results of secondary endpoints will be available at time of the conference.

Conclusion
This preliminary analysis suggests that the addition of metformin did not improve DCR, compared to previous reported results of sorafenib monotherapy in pretreated stage IV NSCLC patients with a KRAS mutation. [1] Dingemans AM et al. Clin Cancer Res. 2013 Feb 1;19(3):743-51 [2] Groenendijk FH et al. EJC. 2012 Nov; 48 (suppl. 6): p 48 Figure 1

Background
Wide screening for EGFR mutations in locally advanced or metastatic squamous NSCLC (SQLC) is not recommended by internationally accepted guidelines, mainly due to low prevalence. However, the COSMIC database shows the increasing incidence of EGFR mutations in SQLC, in 2008: 2,6% (upper limit of 95%CI: less than 3,6%), in 2012: 5%, and in April 2013: 6% (upper limit of 95%CI: 6,9%). In spite of this, there are only very limited data about the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in patients with SQLC containing activating EGFR mutations. The Purpose of this study was to assess the prevalence of EGFR mutations in SQLC in the Slovak Republic, and to assess the treatment results with TKIs in this group of patients.

Methods
A nationwide multicentre retrospective study was designed, and approved by the Ethical Committee of the National Cancer Institute, Bratislava, Slovakia. The databases of the participating institutions were searched for patients with locally advanced or metastatic SQLC tested for EGFR mutations between March 2010 and March 2013. The time limit reflects the fact, that the EGFR mutation testing has been available for all patients with locally advanced or metastatic NSCLC in the Slovak Republic since March 2010.

Results
Altogether 1502 patients with NSCLC were tested for EGFR mutations, among them 585 with SQLC. EGFR mutations were found in 26 SQLC cases, which give the prevalence 4.4%, 95%CI: 3.1 – 6.4%. Thirteen patients received treatment with EGFR TKIs, 10 with gefitinib, 3 with erlotinib. Patients’ characteristics: M/F: 10/3, age: median 65yrs (55 – 83), PS: 1/2/3: 1/10/2, all with stage IV SQLC, cytologically and histologically confirmed in 11 (85%), cytologically only in 2 (15%) patients. Treatment results: RR: PR: 7/11 (64%), SD: 2/11 (18%), PD: 2/11(18%), UNK: 2/13, PFS: median: 5.5 months (1 – 36+). PFS over 12 months was seen in 3 patients. There were no unexpected or treatment related SAEs.

Conclusion
EGFR mutations in SQLC as well as the treatment efficacy of EGFR TKIs in patients with SQLC containing EGFR mutations deserve further attention. EGFR mutation testing should be available also for patients with SQLC.

Background
Tecemotide (L-BLP25) is a mucin 1 (MUC1) antigen-specific cancer immunotherapy investigated in patients not progressing after primary chemo-radiotherapy for stage III non-small cell lung cancer (NSCLC) in the phase III START study. The objective of this analysis was to explore patients’ health status alongside the study.

Methods
From January 2007 to November 2011, 1513 patients with unresectable stage III NSCLC that did not progress after chemo-radiotherapy (platinum-based chemotherapy and ≥50 Gy) were randomized (2:1; double-blind) to tecemotide (806 μg lipopeptide) or placebo SC weekly x 8 then Q6 weeks until disease progression or withdrawal. The analysis population (n=1239) was defined prospectively to account for a clinical hold of the study. The impact on patient health status was assessed as an exploratory endpoint using the EuroQoL 5 Dimensions (EQ-5D), a widely used generic preference-based questionnaire covering 5 dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression). EQ-5D index score can be calculated for which perfect health is given a value of 1 and death a value of 0. EQ-5D was collected at baseline, weeks 2, 5 and 8 and then every 6 weeks until end of treatment (EOT) visit (i.e. at time of disease progression), the EOT visit and every 12 weeks afterwards. Analysis of covariance (ANCOVA) was carried out to explore the change of EQ-5D index score over time in the overall population for patients on treatment. The change of EQ-5D to EOT visit was also estimated. Change of EQ-5D index score was explored using all data (i.e. collected both before and after EOT visit) using a linear growth curve model, with random intercept and slope, considering time as a continuous variable.

Results
EQ-5D compliance rates (percentage of patients still in the study who completed the questionnaire) were consistently above 85% for all visits of the treatment period in both treatment arms. Mean baseline EQ-5D score was 0.79 (sd=0.19) for both tecemotide and placebo arms. The results from ANCOVA on the overall population did not show any significant difference between the two arms during the treatment phase. Change in the EQ-5D index score from baseline to EOT visit was –0.102 (95%CI: –0.134, –0.071) for tecemotide and –0.136 (95%CI: –0.177, –0.095) for placebo. The linear growth model including the EQ-5D assessments before and after EOT showed that the EQ-5D index score decreased significantly over time in both treatment arms, but that the decrease was slightly slower in the tecemotide than in the placebo arm: –0.0076 per month in tecemotide patients vs. –0.01 in placebo (p=0.0498).

Conclusion
During treatment, there was no statistical difference in health status with tecemotide vs. placebo. This supports the good tolerability profile of tecemotide, with a lack of significant toxicity as compared to placebo. Disease progression was associated with a notable deterioration of patient health status, regardless of the treatment. Considering data from both before and after disease progression, patients’ health status appeared to worsen slightly over time, at a slower rate for patients treated with tecemotide.

Background
Nintedanib is an oral, twice-daily angiokinase inhibitor targeting VEGFR-1–3, PDGFR-α/β and FGFR-1–3. LUME-Lung 1 is a placebo-controlled phase III trial investigating nintedanib plus docetaxel in advanced NSCLC patients after failure of first-line chemotherapy.

Methods
Stage IIIB/IV or recurrent NSCLC patients were randomised to receive nintedanib 200 mg bid plus docetaxel 75 mg/m[2] q21d (n=655), or placebo plus docetaxel (n=659). The primary endpoint was centrally reviewed progression-free survival (PFS) analysed after 714 events; the key secondary endpoint was overall survival (OS) analysed hierarchically after 1121 events, first in adenocarcinoma patients and then all patients. Quality of Life (QoL) was included as a secondary endpoint. Lung cancer symptoms and health-related QoL were assessed every 21 days until the first follow-up visit using the EORTC (QLQ-C30/LC13) and EQ-5D questionnaires. Changes of ≥10 points as compared with baseline were considered clinically significant. Analyses of cough, dyspnoea and pain symptoms were prespecified. Time to deterioration (TTD, first 10-point worsening from baseline) was analysed using a stratified log-rank test. An exploratory analysis of all subscales/items from the EORTC QLQ-C30/LC13 questionnaires estimated the respective hazard ratios for TTD using a Cox proportional hazards model.

Results
LUME-Lung 1 showed that nintedanib in combination with docetaxel significantly prolonged PFS for all patients regardless of histology (3.4 vs 2.7 months; HR 0.79, 95% CI: 0.68–0.92; p=0.0019), with a trend for improved median OS (10.1 vs 9.1 months; HR 0.94, 95% CI: 0.83–1.05; p=0.272) and significantly improved OS in patients with adenocarcinoma (HR: 0.83; p=0.0359; median 10.3 to 12.6 months). The most common AEs were diarrhoea and reversible ALT elevations. With respect to the QoL assessment, there was a high compliance rate of >80% until treatment course 25 for QLQ-LC13 and QLQ-C30 in both treatment arms. The addition of nintedanib to docetaxel did not influence TTD for cough (HR 0.90; 95% CI: 0.77–1.05; p=0.1858), dyspnoea (HR 1.05; 95% CI: 0.91–1.20; p=0.5203) or pain (HR 0.95; 95% CI: 0.82–1.09; p=0.4373), and maintained global health status/QoL (HR 0.952; 95% CI: 0.83–1.10). There was a significant deterioration in scores for nausea and vomiting, appetite loss and diarrhoea. The results were similar for adenocarcinoma patients with respect to cough (HR 0.97; 95% CI: 0.78–1.20; p=0.7744), dyspnoea (HR 1.04; 95% CI: 0.86–1.26; p=0.6813) and pain (HR 0.93; 95% CI: 0.76–1.13; p=0.4785); however, there was a trend for improved global health status/QoL (HR 0.86; 95% CI: 0.71–1.05). For squamous cell carcinoma patients, there was a trend for delayed TTD for cough (HR 0.84; 95% CI: 0.66–1.07; p=0.1561) and a maintained global health status/QoL (HR 0.975; 95% CI: 0.788–1.206). Further analyses are ongoing and will be presented at the congress.

Conclusion
In second-line NSCLC patients, docetaxel plus nintedanib did not result in any significant improvements in cough, dyspnoea or pain compared with placebo and docetaxel. However, PFS was improved in patients of all histologies receiving docetaxel and nintedanib, and OS was improved in patients with adenocarcinoma histology without adversely affecting self-reported QoL.

Background
Crizotinibis is a MET inhibitor, having also an activity on ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) pathways. The ALK translocation is described in 4% of NSCLC and these patients (pts) benefit from crizotinib therapy with a response rate (RR) ranging from 51 to 61%.The drug is already approved by FDA and EMA; in Italy crizotinib is available in first line within controlled clinical trials and, until April 2013, within expanded access program (EAP).

Methods
From June 2010 to February 2013, 155 pts with advanced NSCLC were analyzed for Alk translocation using fluorescence in situ hybridization (FISH) at our institution. The selection criteria were: adenocarcinoma histology, never or ex smoker, EGFR status WT. Main pts characteristics were: 59% males, median age 57,5 years (range 26-76), 77 former smoker (76 pts for more than 15 years). Tissue samples were available from primary tumor and metastases in 78 and 22%, respectively, having 73% of cases with cytological material. In 23,2% of the specimens Alk rearrangement was not evaluable due to poor quality and/or quantity issues.

Results
Among the 155 pts, 22 (14%) are ALK translocated: 19 were treated within PROFILE clinical trials and 3 patients in the EAP. 20 pts are currently evaluable for response and toxicity: 6 of them received crizotinib as first-line treatment, the others in subsequent lines. The response rate was equal to 70%. The total number of administered cycles is 235.The reduction of the dose (7% of cycles) was necessary in two pts: in 1 case due to bradicardia and fatigue G3 (in first line treatment) and in the other one due to neutropenia G3 (in second line).The observed toxicities were mostly grade 1-2 (fatigue 47%, bradycardia 5,8%, visual disorder 5,8%, anemia 29%, neutropenia 18% and nausea 12%); grade 3-4 was less common. The temporary cessation of treatment was required in 3 pts (range 4-15 days) for grade 3-4 toxicity (mostly neutropenia plus fatigue). No drug interruption for unacceptable toxicity was reported. The most common progression sites were brain (37%) and bone (27%).

Conclusion
The introduction of a selection criteria (such as negative EGFR status) leads on an increase of our cases of Alk traslocated pts compared to literature data; this selection is moreover recommended in diagnostic algorithm recently proposed by the Italian Expert Panel (Marchetti A et al, JTO 2013). Efficacy and tolerability profile are consistent with published data.

Background
Activating mutations (MT) in the epidermal growth factor receptor (EGFR) gene are found in approximately 10-20% of patients with NSCLC. Guidelines recommend therapy with EGFR tyrosine kinase inhibitors (TKI’s) in these patients, and in patients with EGFR Wild type (WT) tumours beyond second line. Clinical trials have focussed on optimising the management of patients with an actionable target. The real-world management of patients with EGFR MT’s and clinical trial recruitment has yet to be explored. This retrospective study investigated treatment patterns in an Irish cohort of patients with non-squamous NSCLC, stratified by EGFR-MT status.

Methods
Patients with EGFR-MT positive tumours were identified from a National Multi-Institutional database. Patients with EGFR-WT tumours matched for age, stage and gender were identified. Treatment data including receipt of chemotherapy, EGFR TKI, and clinical trial participation were collected. Fisher’s exact and Mann-Whitney tests were used to compare variables. Cox model was used to examine the influence of treatment variables on overall survival (OS.) To ascertain the milieu of clinical trials applicable to this cohort, www.clinicaltrials.gov was searched for all phase III interventional studies in NSCLC between 1/1/2010 and 31/5/2013. Trial characteristics were summarized.

Results
We identified 416 patients with NSCLC. Forty (10%) patients had tumours with EGFR MT’s, of which data were available on 35 (87%) patients. Twelve (34%) patients had resected disease, and 23 (66%) had metastatic disease. Nineteen (82%) EGFR-MT positive patients with metastatic disease received first line systemic therapy, 12 (63%) receiving EGFR TKI (p=0.52.) Fifteen (65%) patients with EGFR-WT tumours received first line chemotherapy. The median number of lines of treatment was 1 (range: 0 – 4; 30% >1 line) for patients with EGFR-MT’s and 1 (range: 0 – 3; 13% >1 line) for EGFR-WT (p<0.01.) Receipt of second, third and fourth line therapy was 26%, 13% and 4.3% for EGFR-MT positive patients respectively, and 8.6%, 4.3% and 0% respectively in EGFR-WT (p<0.01.) Six (24%) patients with an EGFR MT and 0 (0%) with EGFR-WT participated in clinical trials (p<0.01.) Significant benefits were seen for 1) receipt of 1 line of treatment vs. 0 (HR=0.2, 95% CI=0.08 – 0.18, p=0.03) or 2) >1 line of treatment vs. 0 (HR=0.10, 95% CI= 0.01- 0.46, p< 0.01) Twenty-four phase III trials in advanced NSCLC were identified over the study period. The most commonly investigated agents were TKI's - 10 (42%) and monoclonal antibodies – 6 (25%). Ten (42%) trials required the presence of a driver mutation for eligibility, and 13 (54%) trials were in second line or beyond.

Conclusion
In Irish patients with NSCLC the incidence of EGFR MT’s is comparable to other European populations. Our real-world experience demonstrates that patients with EGFR MT’s tend to receive more lines of therapy and have a higher rate of clinical trials participation, reflecting the portfolio of currently available clinical trials. While trials should strive to optimise treatment for EGFR-MT positive NSCLC, the thoracic oncology community should consider that biological heterogeneity can lead to inequalities in clinical trial development and subsequent treatment.

Background
Since approved use of Gefitinib in March 2005 in China, more patients with lung cancer, especially those with lung adenocarcinoma, have chosen it for treatment. It is of clinical significance to compare survival of lung adenocarcinoma patients who received Gefitinib treatment after March 2005 and that of those who did not receive it so as to provide clinical clues for selection of Gefitinib in Chinese lung adenocarcinoma patients.

Methods
Clinical data of 558 patients with advanced lung adenocarcinoma who received palliative chemotherapy from January 2002 throughout December 2010 were reviewed retrospectively. According to the matched-pair case-control study design, 255 patients who only received palliative chemotherapyand 255 patients who received Gefitinib treatment after approved use of Gefitinib were stringently matched by age, sex and smoking history and finally enrolled in this study. Clinical factors including age, sex, smoking history, Eastern Cooperative Oncology Group performance status (ECOG PS), tumor stage, organ metastasis and the number of prior cytotoxic chemotherapies were analyzed to determine their correlations with OS.

Results
The median survival time (MST) of the 510 enrolled patients with advanced lung adenocarcinoma was 22.8 months. MST of the patients who received Gefitinib treatment was significantly longer than that of the patients without (33.5 months vs. 14.1 months, p<0.001). OS in patients who received Gefitinib treatment was significantly longer than that in patients without receiving Gefitinib treatment in almost all clinical factor-based subgroups, including age, sex ,smoking history, ECOG PS 0-1, tumor stage, the presence or absence of lung, pleural, bone, brain, adrenal gland and liver metastasis, and the number of prior cytotoxic chemotherapies (all p<0.001), except in ECOG PS ≥2 subgroup.

Conclusion
Gefitinib treatment significantly improved the survival of patients with advanced lung adenocarcinoma in China.

Background
We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival (OS), as well as patterns of treatment in a population-based cohort of advanced EGFR mutation positive NSCLC patients.

Methods
From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutations. Patients with EGFR mutation positive samples were identified and tumour sample cellularity, mutation fraction (percent of tumour cells mutated), demographic, treatment and outcome data were collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour sample cellularity and sample type on clinical outcomes.

Results
Among 293 patients identified with EGFR mutation positive NSCLC, 253 received EGFR TKIs and are included in this analysis. Most are female (72%), never smokers (59%), have exon 19 deletions (53%; 47% exon21 L858R), and median age 65 years (range 26 to 96). Tumour specimens tested include resection (32%), cytology (30%), and core biopsies (38%). Median EGFR mutation fraction is 30% (range 0.4% to 96%); 24% had a low (≤10%) mutation fraction, and 13% had a mutation fraction ≤5%. Responses (any tumour reduction) were seen in 62%, mixed response or stable disease in 25%, and progression as the best response in 13%. Median TTF from the start of EGFR TKI therapy is 13.2 months (range 0-43.7 months). Median OS from TKI start is 22.3 months (95% CI: 19.5-28.2 months), with 1-, 2- and 3-year survival rates of 72%, 49% and 37%. In multivariable analysis, factors associated with TTF included female sex (HR 0.69, p=0.03) and sample type (resection HR 0.56, cytology HR 0.82, core biopsy as reference, p=0.01). Age at metastatic diagnosis (p=0.01), sample cellularity (p=0.01) and sample type were significantly associated with OS, (resection HR 0.51, cytology HR 0.70, core biopsy as reference, p=0.04). Proportional odds logistic regression identified that mutation frequency and age at metastatic diagnosis were significantly associated with the odds of response, (p=0.047, p=0.04 respectively). Responses were seen even in those with lower EGFR mutation fraction, 48% (24/50) at a mutation frequency of ≤10% and 33% (9/27) at a mutation frequency of ≤5%. The average cellularity in the high (>10%) mutation fraction group was 53% (95%CI 50– 56%), and 36% (95%CI 29 – 43%) in those with a low mutation fraction (p<.0001).

Conclusion
Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, and specimen tested. The clinical relevance of sample tumour cellularity and sample type tested remains unclear. In particular, initial stage and prognosis may be confounders in the association between resected specimens and favourable outcomes. Given that those with mutation fractions ≤5% may have significant response from EGFR TKI therapy, treatment should not be withheld on the basis of mutation frequency alone.

Background
Several retrospective studies have reported that continued treatment with EGFR-TKI after developing progressive disease (PD) by RECIST improved survival compared to TKI-free treatment in NSCLC patients with EGFR mutations. However, it is unclear which patients would benefit from EGFR-TKI after PD. We hypothesized that patients with CNS progression only, without systemic deterioration, would show a good prognosis with EGFR-TKI after PD.Several retrospective studies have reported that continued treatment with EGFR-TKI after developing progressive disease (PD) by RECIST improved survival compared to TKI-free treatment in NSCLC patients with EGFR mutations. However, it is unclear which patients would benefit from EGFR-TKI after PD. We hypothesized that patients with CNS progression only, without systemic deterioration, would show a good prognosis with EGFR-TKI after PD.

Methods
In order to clarify the survival benefits in patients treated by EGFR-TKI after developing PD, particularly patients with CNS metastasis alone, NSCLC patients with EGFR mutations who were treated with EGFR-TKI and showed progression were analyzed retrospectively. The patients were categorized into two groups: patients continuing with EGFR-TKI treatment after progression (continuation group) and patients switched to chemotherapy or BSC (discontinuation group). Patients were also classified into two groups by site of progression: patients who showed deterioration involving only CNS metastasis (CNS progression group) and patients who showed progression of the primary lesion, lymph nodes, bone, liver, adrenal glands, CNS, or other sites (systemic progression group). Differences in post-EGFR-TKI progression survival (PPS) and overall survival were compared between the groups.

Results
A total of 160 patients, including 107 women, 116 light or never smokers, 156 patients with adenocarcinomas, and 130 patients with good performance status, were analyzed. There were 78 patients with deletions in exon 19, 69 patients with L858R, and 13 with minor mutations. At the time of the analysis, 111 patients showed disease progression by RECIST. No significant difference in the PPS was observed between the CNS progression group (n=29) and systemic progression group (n=82) (10.6 m vs. 11.2 m, p=0.90). Although it was not significant, the continuation group (n=43) showed longer PPS than the discontinuation group (n=68) (13.0 m vs. 9.7 m, p=0.06). The analysis of Cox hazards model including five variables (sex, smoking status, PS, continuation of EGFR-TKI, CNS progression or systemic progression) showed that the continuation of EGFR TKI beyond PD was the factor associated with longer PPS (HR=0.55, 0.31-0.92).

Conclusion
In this retrospective analysis, continued treatment with EGFR-TKI after PD resulted in longer PPS. A prospective study of continuation EGFR-TKI beyond REIST PD is needed.

Background
Recent years have seen worldwide interest in the study of driver mutations in lung cancer, in particular epidermal growth factor receptor mutation (EGFR) and anaplastic lymphoma kinase gene rearrangement (ALK). ROS1 gene rearrangement is a recently identified driver mutation and potential therapeutic target for crizotinib and similar agents. However little is known of the natural history of patients with ROS1, and moreover the diagnostic value of immunohistochemistry (IHC) compared to fluorescent in-situ hybridization (FISH).

Methods
12 patients from a single Australian tertiary institution with advanced non-small cell lung cancer (NSCLC) were screened for ROS1 overexpression and gene rearrangement. Selection was based on negative testing for EGFR and ALK, and unusually long natural history.

Results
We report 2 patients with ROS1 overexpressed advanced NSCLC, their unique characteristics, long natural history and the use of IHC as a complementary method to FISH in identifying these patients. Mr GL was a 62 year-old Caucasian man and lifelong non-smoker who presented with an incidental 19mm subpleural left lower lobe lung nodule found on computed tomography (CT) when he was treated for pneumonia in 2008. He was monitored with CT for his pulmonary nodule and pre-existing interstitial lung disease. In 2011, CT and subsequent positron emission tomography (PET) showed new regional lymphadenopathy and widespread sclerotic bone disease with the pulmonary nodule unchanged in size but moderately glucose avid. Axillary and supraclavicular lymph node biopsies confirmed metastatic adenocarcinoma consistent with a lung primary. EGFR and ALK testing was negative. He received induction and maintenance chemotherapy until disease progression in 2013. His original biopsy tested negative for ROS1 rearrangement by FISH but stained strongly positive for ROS1 overexpression by IHC using the Epitomics rabbit monoclonal antibody (D4D6) with diffuse cytoplasmic positivity. He was commenced on crizotinib, achieving and maintaining stable disease after three months. Mrs MM was a 54 year-old Caucasian woman and lifelong non-smoker who presented with an incidental 26mm right lower lobe lung nodule found on CT when she presented with left sided chest pain in 2009. PET and endobronchial biopsy of mediastinal lymph nodes confirmed stage IIIA lung adenocarcinoma. EGFR and ALK testing was negative. She received neo-adjuvant chemotherapy, followed by right lower lobectomy and post-operative radiotherapy. In 2010 she developed right supraclavicular lymph node recurrence and achieved radiological complete response after radiotherapy. In 2011 she developed another isolated nodal recurrence in the right supraclavicular fossa, which was surgically resected and confirmed adenocarcinoma. It stained strongly positive for ROS1 overexpression by IHC and positive for ROS1 rearrangement by FISH. In 2013, PET found an isolated hepatic metastasis. She was commenced on crizotinib with plans for re-staging and consideration for liver directed therapy. Clinical progress of the patients will be updated and presented.

Conclusion
Our cases of ROS1 overexpressed NSCLC illustrate unique patient characteristics of never-smoking status, adenocarcinoma histology, negative testing for EGFR and ALK, and an unusually long natural history. Our cases highlight the need for greater understanding of the predictive value of ROS1 overexpression by IHC as opposed to FISH alone for targeted therapy.

Background
The brain is a common site of metastatic spread in non-small cell lung cancer that is often associated with morbidity and poorer survival. Previously, we have published that ALK, EGFR, or KRAS status alone was not associated with the presence of brain metastases at diagnosis. Additional methods are needed to predict which patients are at risk for presenting with brain metastasis at diagnosis. The purpose of our study was to develop a more detailed predictive model to identify patients at high risk of brain metastasis at diagnosis.

Methods
Patients with metastatic non-small cell lung cancer in whom molecular analysis was conducted in the Colorado Molecular Correlates Laboratory were identified. Data were collected through retrospective review of charts of 120 patients. Characteristics at the time of diagnosis were collected, including stage, tumor size, histology, age, ethnicity, molecular markers including the presence of EGFR, ALK, KRAS, or p53 mutation, and sites of metastatic disease, including brain, bone, liver, and adrenal metastasis. A logistic regression model was tested using backward elimination, with presence of brain metastasis at diagnosis as the outcome of interest.

Results
No statistically significant association was seen between the presence of brain metastasis and any of the above covariates. We examined the relationship between brain metastasis and KRAS mutation, even though this variable was not selected in the model selection procedure. The odds ratio for brain metastasis with KRAS mutation was 0.3714, indicating that patients with KRAS mutation have 63% lower odds of brain metastasis at diagnosis than patients without a KRAS mutation (95% exact confidence interval: 0.0825, 1.3321, p= 0.1184).

Conclusion
No significant association was observed between the presence of brain metastasis and various clinical presenting characteristics in patients with metastatic non-small cell lung cancer, including stage, tumor size, histology, age, ethnicity, molecular markers including the presence of EGFR, ALK, KRAS, or p53 mutation, and sites of metastatic disease, including brain, bone, liver, and adrenal metastasis.

Background
Crizotinib was approved in 2011 by the FDA in for treatment of patients with locally advanced or metastatic NSCLC that is ALK-positive as detected by an FDA-approved test. In order to better inform U.S. policymakers, this study aimed to assess the cost-effectiveness, from a payer perspective, of crizotinib compared to either pemetrexed or docetaxel.

Methods
We created a decision model using published data from the randomized phase 3 trial that led to its FDA approval, where patients with ALK+ NSCLC were randomized to receive one of the following: crizotinib (250 mg twice daily), pemetrexed (500 mg/m[2]), or docetaxel (mg/m[2]). Utilities were derived from available published literature. Costs, when available, were obtained from the Center for Medicare Services (CMS) drug payment table and physician fee schedule and were represented in 2012 U.S. dollars. Because, the price of crizotinib was not available from the most recent CMS drug payment table, we averaged three different published prices that were publically available. The quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER) were calculated. One way, two way, and probabilistic sensitivity analyses were performed.

Results
Since the phase 3 trial by Shaw et al. permitted cross-over to crizotinib at the time of progression, it is entirely likely that this confounded any apparent survival advantage for crizotinib. Therefore, we first evaluated our model with progression-free survival (PFS) rather than OS. Compared to docetaxel, crizotinib had an incremental benefit of 0.14 progression-free QALYs, which came at an overall cost of $102,420.04, and an incremental cost of $77,138.81, for an incremental cost effective ratio (ICER) of $535,956.19/PF-QALYs. The results of the model were robust in sensitivity analyses. The two primary drivers in this model were found to be: crizotinib cost and crizotinib median overall survival. For crizotinib to be cost effective, its monthly cost would have to be reduced from approximately $9,300 to $3,500. When we utilized OS in our model, as expected the ICER was even higher, at a cost of $1,197,005/QALY. This is expected, due to absence of a significant difference between chemotherapy and crizotinib arms in the phase 3 trial.

Conclusion
Crizotinib on our initial decision analytic model did not appear to be cost-effective compared to docetaxel at its current price of approximately $9,388 per month. Further analysis will be performed utilizing a Markov decision model.

Background
Afatinib is an oral, irreversible pan-EGFR inhibitor with demonstrated superiority over first-line chemotherapy in advanced EGFR mutation positive NSCLC. It is also active after failure of chemotherapy and reversible EGFR tyrosine kinase inhibitor (TKI) therapy, with higher response rate and better progression-free survival than placebo (LUX-Lung 1, Miller et al. Lancet Oncol. 2012). Through a national special access program (SAP), Canadian patients with advanced NSCLC, similar to those in the LUX-Lung 1 trial, may access afatinib after exhausting all other available therapies. We report our Canadian experience with afatinib at the two largest centres participating in the SAP.

Methods
Retrospective chart review of SAP participants was undertaken at 2 major Canadian cancer centres, the British Columbia Cancer Agency (Vancouver) and Princess Margaret Cancer Centre (Toronto). Demographic, disease and treatment data were abstracted, including toxicity, response (clinically documented tumour reduction), treatment duration and overall survival.

Results
From July 2010 to the present, 54 patients at the two sites were treated with afatinib through the SAP. Median age was 59.5 (range 37 to 88 years), 57% were female, 52% were never smokers (7% current, 35% former smokers), 67% had adenocarcinoma histology and 28% were East Asian. 26% had known EGFR mutations (7% wild type, 67% unknown), most commonly exon 19 deletions. Patients received a median of 3 previous therapies (range 2 to 5). All had received prior EGFR TKI therapy (81% erlotinib, 11% gefitinib, 6% both, 2% dacomitinib). Half (47%) had a response to prior EGFR TKI therapy, and 37% experienced grade ≥2 rash and 9% grade ≥2 diarrhea on prior EGFR TKI. The median time from metastatic diagnosis to starting afatinib was 23.1 months. The median treatment duration was 2 months (range 0 – 26). 21% of patients had a response (tumour reduction) to afatinib, 20% stable disease and 50% disease progression as their best response. Median survival from the time of afatinib start was 5 months (95% CI: 2-12 months). The average starting dose of afatinib was 40 mg (6% 50 mg, 94% 40 mg), with 11% requiring dose reduction. One third of patients (34%) stopped treatment for disease progression, 17% for toxicity, 30% for clinical deterioration and 19% for other or unknown reasons. The rate of grade ≥2 diarrhea, rash, paronychia, or stomatitis with afatinib was 17%, 20%, 9%, and 9% respectively (grade ≥3 in 10%, 11%, 5% and 5%). Response (non-RECIST) to afatinib was seen in EGFR wild type (2/4) and mutation positive (3/13) patients. Response to erlotinib or gefitinib was non-significantly associated with response to afatinib (OR 3.3, p=0.22). A similar non-significant association was seen with rash (OR 1.7, p=0.22), but not with diarrhea, (OR 0.37, p=0.45).

Conclusion
Afatinib demonstrates activity in clinical practice similar to that reported in LUX-Lung 1. While some required dose reduction, toxicity from afatinib appeared manageable for the majority. Although not significant, there was a propensity to experience response or rash on afatinib if seen with prior EGFR TKI, although this was not seen with diarrhea.

Background
RET-translocations have recently been identified as oncogenic drivers in a subset of non-small cell lung cancer (NSCLC). Up to now, there is limited information on the therapeutic value of RET-inhibitors in treating patients with RET-translocated NSCLC. Here we report on the clinical course of a patient with RET-translocated NSCLC treated with sunitinib, a multitarget tyrosinkinase-inhibitor with activity against RET.

Methods
A 65 year old woman with a non smoking history was diagnosed with adenocarcinoma of the left upper lobe in october 2009. Staging by CT and PET revealed stage II. Therefore the patient was referred to lobectomy plus lymphnode dissection. Pathologic work up in the following led to an upstaging to stage IIIA (pT1N2M0L1V0R0,GIII). The patient refused to get adjuvant chemotherapy but postoperative radiotherapy was applied. In may 2012 the patient developed left-sided pleural carcinomatosis and a thoracoscopic biopsy confirmed recurrence of the bronchial adenocarcinoma. Molecular workup of the available tissue showed EGFRwt and no evidence for ALK-translocation. As a platinum-based chemotherapy was not acceptable for the patient she was treated with pemetrexed monotherapy for 3 cycles leading to disease stabilization. At that timepoint the patient opted for a treatment holiday. In december 2012 CT-restaging showed progressive disease with increasing pleural tumor deposits. As the patient denied further cytostatic therapy, additional analyses for potential driver mutations were initiated and the existence of a KIF5B/RET-translocation was detected by FISH-analysis. As, at that timepoint, sunitinib was the only available RET-inhibitor at our site the patient was offered sunitinib treatment.

Results
Sunitinib was initiated in january 2013 (50mg qd, 4 weeks on/2 weeks off) with the patient at that timepoint not suffering from any symptoms (WHO 0). Due to severe toxicities (mucositis, fatigue, diarrhea) a dose reduction had to be performed allready during the first treatment cycle (37,5mg, 4/2 weeks). CT-restaging after 2 cycles showed stable disease. Treatment was continued, but, due to ongoing toxicities, the dose of sunitinib had to be further reduced (25mg qd, continously). In may 2013, with the patient free from tumor-associated symptoms, another CT-scan still revealed disease stabilization. At that timepoint the patient refused further treatment with sunitinib, due to subjectively inacceptable side effects (diarrhea, fatigue).

Conclusion
In this case of a patient with recurrent RET-translocated NSCLC treatment with sunitinib showed signs of clinical activity by inducing disease-stabilization for at least 4 months despite substantial dose reductions due to toxicities. As the patient withdrew further treatment, no further conclusions on the potential long term effects of such treatment can be drawn. Based on the preclinical evidence and the published case reports so far, testing of RET-inhibitors for the treatment of patients with RET-translocated NSCLC within prospective clinical trials is strongly recommended.

Background
Bevacizumab is reported to produce clinical benefit in advanced non-squamous non-small-cell lung cancer (NSCLC) patients when combined with chemotherapy. However, no biological markers have been identified for patient selection of bevacizumab treatment.

Methods
We describe an ongoing observational study in patients with advanced non-squamous NSCLC patients. Patients with metastatic disease will be recruited to receive chemotherapy plus bevacizumab 15 mg/kg for 4-6 cycles and radiotherapy when necessary. VEGF-A、VEGFR-1、VEGFR-2 levels in peripheral blood of patients will be tested before and after the bevacizumab treatments. Cycles are 3 weeks.The primary endpoint is progression-free survival (PFS) without grade 4 toxicity. The secondary endpoint is overall survival (OS). The study will enroll 40 patients approximately. The relationship between VEGF-A、VEGFR-1、VEGFR-2 levels and the effect of treatment will be evaluated.

Results
no

Conclusion
This study will provide results on biomarker options for patient selection of bevacizumab treatment. Correspondence to Li Liu, E-mail: [email protected]

Background
To improve outcomes of nsNSCLC, investigators have empirically combined targeted therapies with conventional platinum-based regimens. The potential for combining E with cytotoxic drugs was initially investigated in two randomized phase III trials. Data from this studies showed that simultaneous EGFR-TKI/platinum combination resulted in antagonism in NSCLC. First-line sequential administration of E with chemotherapy in several studies, particularly the FAST-ACT trial, has demonstrated promising results in patients with nsNSCLC. The aim of this study is to combine E with C/P + B as per a sequential schedule in order to avoid the potential cell cycle-based antagonism between E and chemotherapy. In this study B has been added to the chemotherapy regimen since the addition of B has demonstrated improvement in response and survival, and should be considered as the most efficacious treatment for patients with nsNSCLC.

Methods
AVAFAST is an ongoing, open-label, multicenter, phase II study in chemo-naïve pts diagnosed with unresectable advanced, metastatic or recurrent nsNSCLC. Elegible pts also have 1 unidimensionally measurable lesion according to RECIST; age ≥ 18 years; ECOG PS ≤ 1; adequate hematological, renal and liver function; treated brain metastasis and signed informed consent. Radiological evidence of tumor invasion of major blood vessels, EGFR-mutation-positive disease, hemoptysis grade ≥2, significant cardiovascular disease or uncontrolled hypertension are exclusion criteria. Pts receive sequential combination of C (6 AUC), P (175mg/m2), B (7,5 mg/kg) on day 1, and intermittent E (150 mg) from day 5 to18 up to 4 cycles of 21 days. Pts who had not progressed after 4 cycles continue to receive B (7,5mg/kg) on day 1 until progression of disease or unacceptable toxicity. Non Progression Rate (NPR) at 12 weeks is used as the primary efficacy endpoint. Secondary endpoints include ORR, DCR, NPR at 24 weeks, PFS, OS, Safety profile and Quality of Life. 35 of planned 64 patients have been enrolled.

Results
not applicable

Conclusion
not applicable

Background
Chemokines and chemokine receptors not only have the powerful ability in cancer metastasis and tumorigenesis, but also act as anti-tumorgenic ability. Lung Krueppel-like factor (LKLF, KLF2) is a member of the family of the Krueppel-like factors (KLFs).　KLF2 was initially described as a lung-specific transcription factor. KLF2 is reported to regulate some malignant cells. We examined and evaluated the effect of KLF2 on lung adenocarcinoma and the relationship of their mRNA expression with CCR7, EGFR and p53 genetical mutations in lung adenocarcinoma.

Methods
120 patients of stage I to IV with lung adenocarcinoma were included in this retrospective analysis. The expression of CCR7 and KLF2 mRNA expression in surgically resected lung adenocarcinoma specimens were examined and evaluated the relation to prognosis, the effect of EGFR and p53 genetical mutations. In addition the expression of CCR7 and KLF2 exprssion were analyzed with immunohistochemical analysis and measured their mRNA expression extracted from tissue sections of lung adenocarcinoma specimens by laser capture microdissection.

Results
High mRNA expression of KLF2 in lung cancer patients indicated significantly good prognosis than the groups of low expressions (p= 0.0066, HR= 2.008, 95% CI of ratio 1.215 to 3.319). The expression of KLF2 mRNA had relationships with CCR7, CCL21 and CCL19 mRNA expression in lung adenocarcinoma. Moreover the mRNA expression of KLF2 in lung adenocarcinoma specimens was influenced by the mutation of p53 mutation in lung cancer specimens. In addition the expression of KLF2 was confirmed with immunohistochemical analysis and was ditected mRNA expression extracted from tissue sections of lung adenocarcinoma specimens by laser capture microdissection.

Conclusion
We propose KLF2 as clinical good prognostic factors and that KLF2 has strong relation with CCR7, the ligands CCL19, CCL21 and p53 genetical mutation in lung adenocarcinoma.

Background
The non-small-cell lung cancer (NSCLC) staging system published in the 7th edition of the Union for International Cancer Control (UICC) and American Joint Commission on Cancer (AJCC) cancer staging manuals in 2009 did not include any changes to current N descriptors for NSCLC. However the prognostic significance of the extent of lymph node (LN) involvement, including the lymph node zones involved (hilar/interlobar or peripheral), cancer-involved lymph node ratios (LNR), and the number of involved lymph nodes remain unknown. The aim of this report is to evaluate the extent of lymph node involvement and other prognostic factors in predicting outcome after definitive surgery among Chinese stage II-N1 NSCLC patients.

Methods
We retrospectively reviewed the clinicopathological characteristics of 206 stage II (T1a-T2bN1M0) NSCLC patients who had undergone complete surgical resection at Shanghai Chest Hospital, Jiao Tong University from June 1999 to June 2009. Overall survival (OS) and disease-free survival (DFS) were compared using Kaplan-Meier statistical analysis. Stratified and Cox regression analyses were used to evaluate the relationship between the lymph node involvement and survival.

Results
Peripheral zone lymph node involvement, cancer-involved lymph node ratio(LNR), smaller tumor size, and squamous cell carcinoma were shown to be statistically significant indicators of higher OS and DFS by univariate analyses. Visceral pleural involvement was also shown to share a statistically significant relationship with DFS by univariate analyses. Multivariate analyses showed only tumor size and zone of lymph node involvement were to be significant predictors of OS.

Conclusion
Zone of N1 lymph node, LNR and tumor size were both found to provide independent prognostic information in patients with stage II NSCLC. This information may be used to stratify patients into groups by risk for recurrence.

Background
AIM: PET/CT has been widely used in the diagnosis and management of lung cancer patients. We aimed to investigate the progress of N2 positive NSCLC patients after PET-CT examinations.

Methods
METHODS: Clinical and pathological data of 124 operable NSCLC patients to whom PET-CT was applied for clinical staging between November 2009 and December 2011 were evaluated retrospectively.

Results
RESULTS: PET-CT was positive for N2 disease in 60 patients. Among them 24 were operated without any prior invasive procedure, while the remaining was investigated with different procedures for mediastinal lymph node involvement. Thirty of them had cervical mediastinoscopy, 4 had anterior mediastinotomy and 2 had thoracotomy. N2 positivity determined in nodal stations 5 and 7 was also corrected with thoracotomy. However, N2 involvement was not observed in one patient who underwent anterior mediastinotomy and 13 patients who underwent cervical mediastinoscopy, although they had positive PET/CT results. The overall true positivity within these patients who underwent preoperative diagnostic procedures for N2 lymph nodes was 22 out of 36 patients (61%). N2 lymph node involvement was observed in 6 of the 24 patients who were directly operated (25%).

Conclusion
CONCLUSION: Although PET/CT had an important contribution in the preoperative management of NSCLC patients, histopathological confirmation remains the golden standard for operable cases.

Background
Genotype-directed therapies are transforming the care of patients with advanced NSCLC, but these have not yet been incorporated into curative therapy for early stage disease. Because trials are in development which will study genotype-directed induction therapy for stage III NSCLC, we retrospectively examined practice patterns to identify strategies for maximizing the feasibility of this approach.

Methods
Patients with stage IIIA NSCLC who were treated at our institution with upfront concurrent chemoradiotherapy between 1/2004 and 5/2012 were identified from an institutional database. Management prior to start of definitive therapy was reviewed. For this analysis, biopsies were considered adequate for genotyping while cytology specimens were considered inadequate. To gauge the feasibility of genotyping, we compared the intervals between biopsy and treatment and between first oncologist appointment and treatment with a range of hypothetical turnaround times for genotyping (i.e. time between when test is ordered and when results are available).

Results
150 patients were identified in an initial query. 57 were excluded from the analysis: 46 due to treatment at an outside hospital, 5 due to upfront surgery, and 6 due to sequential chemotherapy and radiation. 89 patients were included in the study population with the following characteristics: median age at diagnosis 61 (range 33-86), 45% adenocarcinoma, 25% squamous, 2% neuroendocrine, and 28% NSCLC NOS. Clinical stage: 17% T1N2M0, 42% T2N2M0, 3% T3N1M0, 24% T3N2M0, 9% T4N0M0, 6% T4N1M0. Staging evaluation: 86% underwent bronchoscopy, 86% underwent mediastinoscopy; 100% underwent PET-CT, 100% underwent brain imaging. Best biopsy for genotyping: 51% surgical biopsy, 20% endobronchial biopsy, 7% CT-guided core biopsy, 22% cytology. The median time between best biopsy and treatment initiation was 34 days (IQR: 23-45). The median time between first oncologist appointment and treatment initiation was 18.5 days (IQR: 14-25). Simulating reflex genotyping versus oncologist-ordered genotyping for a range of hypothetical turnaround times (Figure), reflex genotyping may increase the number of patients genotyped in time for start of therapy when turnaround time exceeds 8 days. Figure 1

Conclusion
In this practice-based analysis of patients with stage IIIA NSCLC receiving definitive chemoradiotherapy, 78% of patients had a biopsy expected to be adequate for genotyping. To maximize the feasibility of genotype-directed induction therapy for NSCLC, reflex genotyping of staging biopsies may be needed, particularly when genotyping turnaround time exceeds 8 days.

Background
Surgical treatment is the most efficient therapy for early non-small cell lung cancer (NSCLC). For surgical treatment, oncological and physiological indications may be considered. For physiological indication, cardiopulmonary function evaluation, such as a general respiratory function test, arterial-blood-gas (ABG) analysis, an electrocardiogram, and echocardiogram are important to be determined. In ABG analysis, PaCO2>45 Torr and hypoxemia (< 90% of SaO2) have been reported as risk factors of complications after surgery. This study aimed to establish the clinical significance of preoperative ABG analysis in patients with stage I NSCLC in aspect of long-term risk.

Methods
The study involved 253 patients (154 male, 99 female; median age 68 years) who underwent lobectomy/bilobectomy with radical mediastinal lymph node dissection in patients with stage I NSCLC in our institution between January 1998 and December 2008. One hundred and seventy six patients had adenocarcinoma, 68 had squamous cell carcinoma, five had large cell carcinoma, and four had adenosquamous carcinoma. On pathologic staging, 129 patients were in stage IA, and 124 in stage IB. Predicted postoperative values of FEV~1~ and DLCO less than 40% is defined as high risk in pulmonary function tests. Concerning ABG parameters, the normal range for 1) PaO2 is over 75 Torr, 2) PaCO2 is 36-45 Torr and 3) pH is 7.36-7.45. The patients were divided into two groups according to ABG analysis: normal ABG group (n=167) and abnormal ABG group (n=86). The abnormal ABG group includes those whose 1)PaO2 is less than 75Torr (n=39, median 73, range, 63-74.9), 2)PaCO2 is less than 36 Torr (n=21, median 35.4, range, 32.7-35.9) or over 45 Torr (n=33, median 46.2, range, 45.0-50.6) and 3)PH is less than 7.36 (n=5, median 7.338, range, 7.332-7.356) or over 7.45 (n=8, median 7.454, range, 7.451-7.463).

Results
There were no significant differences in gender, performance status, Hugh-Jones classification, pathological stage, tumor histology, tumor location, surgical procedure, blood loss, operative time, and postoperative complications between the two groups. The age of patients in the normal ABG group (mean 68 years old) was significantly lower than those in the abnormal ABG group (mean 71 years old, p = 0.026). The mean follow-up period for the entire study population was 5.8 years (range 123-5201 days). No operative death occurred. The 3-, 5-, and 10-year survival rates in the normal and abnormal ABG groups were 87%, 76%, and 62%, and 78%, 64%, and 42%, respectively (p = 0.029). A log-rank test using physiological factors revealed that gender, age (>70 years old), performance status (0-1 vs 2), Hugh-Jones classification (1-2 vs 3), postoperative prediction pulmonary function test, and ABG were associated with a significant survival rate. By multivariate analysis, age, gender, and ABG (risk ratio, 4.03) were independent prognostic factors.

Conclusion
Preoperative ABG was a prognostic marker for stage I NSCLC. We should consider surgical strategies for patients with abnormal ABG analysis not only for immediate or short-term risk, which refers to perioperative morbidity and mortality, but also long-term survival risk.

Background
Ki67 and p53 were suggested to be associated poor survival in stage I-III patients. The aim of this study was to explore the association of Ki67 and p53 expression with prognosis in curatively resected non-small cell lung cancer (NSCLC) patients.

Methods
We retrospectively identified patients with stage I-III NSCLC who underwent curative surgery in Gachon University Gil Medical Center from January 2007 to December 2012. Ki67 and p53 expression levels were evaluated by immunohistochemistry. Clinicopathologic features and disease free survival (DFS) were retrospectively estimated.

Results
One hundred and eighteen consecutive patients with Ki67 or p53 results were identified. Median Ki-67 labeling index was 30%. P53 expression was positive in 88 (25%) patients. Higher Ki67 expression (>30%) was significantly frequent in male(53.0% vs 13.3% of female, p<0.001) and non-adenocarcinoma(64.3% vs. 20.3% of adenocarcinoma, p<0.001) patients. In univariate analysis, median DFS had a trend toward worse in patients with higher Ki67 (55.9 months vs. not reached in those with lower Ki67 expression, p=0.113) and with positive p53 (55.9 months vs. not reached in those with negative p53 expression, p=0.123). In Cox multivariate analysis, higher Ki-67 expression was an signitifant independent prognostic factor associated with poorer DFS (HR 3.083, 95% CI 1.342-7.084), along with histology and stage. Among 44 stage Ib patients, 14 patients received adjuvant chemotherapy. In stage IB patients with higher Ki67 expression, adjuvant chemotherapy administration had a trend toward higher 3-year DFS rate (100% vs. 72% in patients without adjuvant chemotherapy). In contrast, 3-year DFS rate with adjuvant chemotherapy was 69%, compared with 79% without adjuvant chemotherapy in stage IB patients with lower Ki67 expression. In patients with tumor size≥4cm, there was no differences in DFS according to adjuvant chemotherapy.

Conclusion
Higher Ki67 expression was independently associated with shorter DFS in resected NSCLC patients. In stage IB, higher Ki67 seemed to be associated benefit of adjuvant chemotherapy. The value of Ki67 as a predictive biomarker of advantage of adjuvant chemotherapy should be further studied in a prospective larger cohort.

Background
Intraoperative pleural lavage cytology (PLC) has been reported to be useful in detecting subclinical pleural dissemination. However, the result of this examination is not reflected on the current TNM staging system.

Methods
A total of 1038 patients with non-small cell lung cancer who underwent surgery were retrospectively reviewed and evaluated for the clinical relevance of intraoperative PLC. PLC was performed by washing the pleural cavity with 200ml of saline solution and 20ml of lavage was obtained for cytological examination immediately after thoracotomy (pre-resection PLC) and just before closing the pleural cavity (post-resection PLC).

Results
Thirty five (3.4%) patients were positive for PLC. Among them, 27 (2.6%) patients were positive for pre-resection PLC and 17 (1.6%) patients were positive for post-resection PLC. The pleural invasion score was pl0 in 4 (14.8%) patients, pl1 in 10 (37.0%) patients, pl2 in 9 (33.3%) patients and pl3 in 4 (14.8%) patients in positive pre-resection PLC group and pl0 in 4(24%), pl1 in 7(41%), pl2 in 5(29%) and pl3 in 1(6%) in positive post-resection PLC group. On the other hand, in the negative PLC group, pl0 in 695 (69.3%) patients, pl1 in 206 (20.5%) patients, pl2 in 47(4.7%) patients and pl3 in 55 (5.5%) patients. The distribution rate of pl0 was significantly higher in the negative PLC group than in the positive group both of pre- and post-resection PLC (p<0.001). The 5-year survival rate was 61.7% for the positive PLC group and 79.2% for the negative PLC group (p<0.01). In regard to the survival stratified according to the pleural invasion, the 5-year survival rates was 81.2% for the negative PLC with pl0 or pl1 group (pl0-1 group) and 61.2% for the negative PLC with pl2 or pl3 group (pl2-3 group)(p<0.01). The survival of the positive PLC group was a significantly worse than that of the pl0-1 group (p<0.01) whereas there was no significant difference in survival between the positive PLC and the pl2-3 group (p=0.4732). A multivariate prognostic analysis adjusted by age, sex, tumor size and pathologic nodal status confirmed the superiority of the pl0-1 group over the pl2-3 and the positive PLC group (HR 0.547,p<0.01 and HR 0.426,p<0.01, respectively) and the similarity between the pl2-3 and the positive PLC group in survival (HR 0.776, p=0.4082). A total of 267 patients had recurrent diseases. Regarding the initial site of recurrence, pleural dissemination occurred in four of 21 (19%) patients in the positive PLC group, 19 of 197 (9.6%) patients in the pl0-1 group and 10 of 49 (20.4%) patients in the pl2-3 group.

Conclusion
The present study demonstrates the clinical relevance of intraoperative PLC in non-small cell lung cancer. Positive intraoperative PLC is of predictive value for adverse survival and has a similar impact on survival with the pleural invasion score of more than pl2.

Background
Since 1997, lung cancer practice guidelines have been developed through Cancer Care Ontario’s Program in Evidence-based Care. A 2006 CCO guideline (EBS 7-1-2) recommends adjuvant chemotherapy (AC) in selected patients with resected lung cancer.

Methods
In 2008, CQCO began to measure concordance with guidelines and to publically report regional results through the Cancer System Quality Index (CSQI),a web-based public reporting tool released annually by the Cancer Quality Council of Ontario (CQCO). Guideline concordance is a measure within the Effective quality domain of CSQI and is used to track the consistency of cancer treatment services across Ontario. This measure links data within Cancer Care Ontario’s Activity Level Reporting Enterprise Data Warehouse and the Ontario Cancer Registry with information from the Canadian Institute for Health Information’s Discharge Abstract Data and National Ambulatory Care Reporting System. Two cohorts of patients who were diagnosed with Stage II or IIIa NSCLC between January and December 2008 to 2009 (cohort 1; n=685) and 2010 to 2011 (cohort 2; n=626) and resected within 270 days of diagnosis and who received cisplatin-based chemotherapy within 120 days of surgery are included in this analysis.

Results
In 2011, 60% of stage I, 64% of stage II and 15% of stage III NSCLC underwent surgical resection. On average, AC use increased in those resected from 54.3% in cohort 1 to 56.7% in cohort 2 but with significant variation amongst the 14 health service regions of the province (range 42.9 to 72.1%). 3 regions were moderately different from the Ontario rate based on Cohen’s d effect test at 95% CI, (d = 0.53-0.65). The variation between regions was greater in cohort 1 (31.4% to 66.9%; Δ 35.5%) than in cohort 2 (42.9% to 72.1%; Δ 29.2%) suggesting that public reporting may have driven some modest change. However, although the rate of use of AC increased for 10 regions, it actually decreased in 4. Men were significantly less likely to be treated with AC (38.2%) compared to women (52.7%) (95% CI, 44.6-60.8, p=.0001), as were patients over age 65 (65% < 65 yr vs. 34% % > 65 yr), (95% CI, 27.5-41.2; p=0001). Patients from areas with the highest tercile of immigrant population were also significantly less likely to be treated 14.3% (95% CI, p=.023) vs 46.0% for the middle; and 51.0% (p=.0001) for the lowest tercile. There were no differences based on quintiles (Q) of income (lowest Q 48.3% vs Q4, 48.3%; Q5, 40.8%) or rural versus urban residence.

Conclusion
Overall guideline uptake appears low for a therapy with the potential to improve long term survivorship and there is wide variance between regions only partially explained by factors such as age, gender and immigrant status. Further study is necessary to understand the factors driving this variation in practice and the best strategies to ensure that patients receive guideline recommended therapy.

Background
Randomised controlled trials have shown that adjuvant chemotherapy is the standard of care for patients with resected, stages II and IIIA NSCLC. The benefit in stage IB disease remains inconclusive. There are limited data regarding the patterns of care, benefits and toxicities of adjuvant chemotherapy in the non-clinical trial population. We reviewed patterns of care and survival outcomes in patients with resected NSCLC receiving adjuvant chemotherapy.

Methods
We retrospectively reviewed medical records for patients with resected, pathologic stages IB-IIIA NSCLC diagnosed between 1/1/2005 and 31/12/2012 in SWSLHD. Patients were identified using an institutional electronic database. Staging was according to the American Joint Commission on Cancer (AJCC) 6[th] edition tumour-node-metastasis (TNM) system. Information was extracted on baseline patient and tumour characteristics, treatment modalities, chemotherapy delivery, treatment-related toxicities and patient outcomes. Survival analysis was performed using Kaplan-Meier method.

Results
We identified 137 patients who underwent surgical resection, 63 (46%) received adjuvant chemotherapy and are presented in this analysis. The main reasons that patients did not receive adjuvant chemotherapy included stage IB disease (32%), advanced age/comorbidities (24%), patient preference (14%), prior neoadjuvant treatment (7%) and non referral (7%). The median age at diagnosis was 64 (range 45 - 77) with 57% male, 81% were ex- or current smokers and 80% had an ECOG performance status of 0 or 1. Adenocarcinoma and squamous cell carcinoma histology accounted for 54% and 27%, respectively. Forty one patients (65%) had lobectomy and 22 (35%) had pneumonectomy. Pathological stage was: 1B 5 patients (7.9%), IIA 11 (17.5%), IIB 13 (20.6%) and IIIA 34 (54%). Adjuvant chemotherapy commenced within 90 days of surgery in 94% with a median time to treatment of 60 days (range 25-110). Adjuvant radiotherapy was given to 18 patients (29%), with 52% of patients with N2 disease receiving radiotherapy. Platinum doublet chemotherapy was administered to 62 patients (98%) and cisplatin/vinorelbine was the most common regimen given to 41 patients (65%). The number of planned treatment cycles was completed by 40 patients (63%), and of these, 11 patients (17%) completed all chemotherapy on schedule without dose modification. Eighteen patients (29%) required hospitalisation during treatment. Febrile neutropaenia occurred in 10 (16%), with an additional 24 (38%) developing non-febrile neutropaenia, thrombocytopenia or anaemia. Other clinically significant non-haematological toxicities included: vomiting (11%); renal impairment (10%); ototoxicity (6%); peripheral neuropathy (16%); fatigue (6%); allergy (2%) or myalgias (3%). There were no toxic deaths. With a median follow-up of 18.6 months (range 3.4 to 96 months), 56% had developed recurrent disease with a median disease-free survival of 18.9 months. The majority (94%) developed recurrent disease within 3 years. The median overall survival was 25.6 months. A total of 34 (54%) had died, including 3 non-cancer related deaths.

Conclusion
The utilisation of adjuvant chemotherapy rate is moderate but is consistent with other reports. Our results demonstrated a higher rate of febrile neutropenia and shorter median overall survival than the clinical trial population. Therefore, careful selection of patients to undergo adjuvant chemotherapy is essential.

Background
In the 7th tumor, node, metastasis (TNM) classification or lung tumors, visceral pleural invasion (VPI) of lung cancers is defined as invasion beyond the elastic layer, including invasion to the visceral pleural surface, and T1 tumors with VPI are upgraded to T2a. Recently, we demonstrated that the microscopic invasion beyond elastic fibers of the visceral pleura but no penetration to the parietal pleura at tight adhesion sites (we term this p1-3) should be managed as a T2 disease in the 6th edition (Virchows Arch. 2005; 447: 984-9). Thus, this study investigated the prognostic value of p1-3 invasion in the current 7th TNM classification.

Methods
Between 2000 and 2012, 976 consecutive patients with non-small cell lung cancers (NSCLCs) underwent curative surgical resection at the Kitasato University Hospital. Staging definitions for T, N, and M components were according to the 7th International Staging System for Lung Cancer. Twenty two patients (2.3%) with p1–3 pleural invasion were included. These patients were studied clinically and pathologically in comparison with cases treated during the same period. To maximize the power of assessing prognostic potential, we set the significance level at 0.10, one-sided.

Results
The p1–3 condition sites of the 22 cases were the parietal pleura for all cases. The 5-year overall survival (OS) rate for these p1–3 patients was 62%. No significant differences were observed among p1–3, IB, IIA or IIB groups (p=0.185). However, the 5-year OS curve of p1-3 and N0 group (n=15) was similar to that of N0 and IIB disease.

Conclusion
Our results indicate that p1–3 patients can be managed as having a T3 (PL3) disease for the present classification, and that in such cases, complete tumor removal could improve the long-term survival. Because of the small number of patients available for this analysis, a large-scale and nationwide study is warranted for validation of p1–3 status as a T3 (PL3) disease for NSCLCs.

Background
The aim of this paper is to review the pulmonary resections for NSCLC and analyze its survival related to the tumor size (T1 and T2), lymph nodes (LN) removed and mediastinal relapse of the disease.

Methods
We made a retrospective review of mayor lung resections performed consecutively for T1 and T2 NSCLC at the Vall d'Hebron University Hospital, from October 1995 to December 2011. Mean follow-up was 50 months.

Results
We analyzed 755 patients, 646 men (85.5%) with a mean age of 64 years (r: 21-84). The most common histology was squamous cell carcinoma SCC (45%) followed by adenocarcinoma (35%). There were 595 lobectomies, 119 pneumonectomies and 41 bilobectomies. The number of LN removed was directly proportional to the number of positive nodes (p = <0.001). We found significantly more positive nodes in T2 patients (p<0.001). The stages were IA: 152 patients (20%), IB: 348 patients (46%), IIA: 24 patients (3%), IIB: 99 patients (13%), IIIA: 113 patients (15%) and IV: 18 patients (2%). 193 patients (25.6%) were classified as T1 and 562 patients (74.4%) as T2. In the last follow-up 377 patients (49.9%) were dead. In-hospital mortality was 2.9%. 73 patients (12.2%) had mediastinal LN recurrence. Mean time between surgery and relapse was 27 months. Mean overall survival was 7.6 years (1-year: 85%, 3-year: 65%, 5-year: 51%). Mean survival according to size was, T1: 9 years, T2: 7 years (p = 0.006), and to LN was N0: 8.3 years, N1: 6.9 years, N2: 4.9 years. Overall survival was 3.8 years for those who had a recurrence and 8.7 years for those who not (p<0.001).

Conclusion
In our series, SCC remains the most common type. The mean overall 5-year survival was 51%, significantly affected by the size of the tumor, mediastinal nodal involvement and the presence of recurrence.

Background
Rearrangements of oncogenic kinase proteins, anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), were discovered as key oncogenic molecular drivers of lung adenocarcinoma recently. The aim of this study is to evaluate the prevalence and survival outcomes of ALK and ROS fusion in never smoker patients with surgically resected lung adenocarcinoma.

Methods
We analyzed consecutive stage IB to IIIA never smoker lung adenocarcinoma patients who underwent curative surgery in our institution. All resected tumors underwent comprehensive molecular profiling including EGFR mutation, KRAS mutation test, and fluorescence in situ hybridization (FISH) assay for ALK rearrangement. ROS1 rearrangement was evaluated by FISH assay in all triple-negative tumors (negative for EGFR, KRAS, and ALK).

Results
Of 162 never-smoker patients with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) patients had ALK and ROS1 rearrangement, respectively. Proportion of ALK or ROS fusion-positive (fusion-positive) patients was 26.0% (15 out of 73) among patients who are negative for EGFR and KRAS mutation. Fusion-positive patients tend to have a shorter disease free survival (DFS) than fusion negative patients, but without statistical significance (p= 0.124). However, multivariate analysis showed significantly poorer DFS of fusion-positive patients than fusion-negative patients with adjustment for T stage and lymph node metastasis (Hazard ratio 2.26; 95% Confidence interval, 1.19-4.30; p = 0.013). The 3-year DFS rate was 47.0% in fusion-negative patients and 32.7% in fusion–positive patients. Fusion-positive patients also showed poorer DFS in stage IB to IIB subgroup. (n=123, p= 0.046) Overall survival of patients was not different according to ALK or ROS fusion status. (p= 0.535) More extrathoracic metastasis was noted in fusion-positive patients than fusion-negative patients at the first time of recurrence. (46.2% vs. 35.8%, p= 0.539) The median progression free survival on EGFR tyrosine kinase inhibitor treatment after recurrence was 0.9 months in fusion-positive patients, which was significantly shorter than 10.2 months in EGFR mutation positive and 6.4 months in wild type patients..

Conclusion
This study shows significantly poorer DFS of ALK or ROS fusion positive patients in Asian never smoker lung adenocarcinoma patients. Development of ALK or ROS targeted adjuvant therapies in this subset of patients is needed to improve their poor survival after curative surgery.

Background
In general, metastatic NSCLC has a poor prognosis and systemic therapy is the cornerstone of treatment. However, extended survival has been reported in some patients presenting with a limited number of metastases, termed oligometastatic disease. The goal of this study was to assess outcomes for patients presenting with NSCLC and synchronous oligometastases, treated with radical intent, and to determine predictors of long-term survival.

Methods
A retrospective chart review was undertaken at two cancer centres, on patients with NSCLC presenting with 1-3 metastasis, who received radical intent treatment (surgery and/or radiotherapy (RT) ± chemotherapy) to the primary lung tumor including the pathological regional nodes and all sites of metastatic disease. Overall survival (OS), progression-free survival (PFS) and survival after first progression (SAPF) were evaluated. Recursive partitioning analysis (RPA) was performed based on significant factors from univariable analysis to identify different risk groups.

Results
Between 1999 and 2012, 61 patients were treated with a total of 74 metastases. Median follow-up was 26 months. Patients had a median age of 62 years, a median performance status of 1 and intrathoracic disease that was predominately stage III (n=38). The majority of patients had a solitary metastasis (n=50). Common sites of metastases were brain (n=47 lesions), bone (n=11), adrenal (n=4), contralateral lung (n=4) and extrathoracic lymph nodes (n=4). Treatment of the primary tumor consisted of RT ± chemotherapy in 52 patients and surgery alone or in combination with other modalities in 9 patients. Metastases were treated with stereotactic or high-dose RT (n=39) or surgery (n=22). Median OS was 13.5 months, 2-year OS was 38%. Median PFS was 6.6 months and median SAFP was 4.9 months. Predictors of improved survival were surgery for the primary lung tumor (p<0.001), and intrathoracic PTV size in patients receiving RT (p<0.03). These factors were used for RPA (Figure 1). No significant differences in outcomes were observed between the two centers. Figure 1 Figure 1. RPA flowchart for OS showing characteristics of risk groups (A) with accompanying Kaplan-Meier curves of OS by RPA risk groups (B)

Conclusion
Radical treatment of selected NSCLC patients presenting with 1-3 synchronous metastases can result in favorable 2-year survival, although progression in the first year was common. Outcomes were strongly associated with intra-thoracic disease status: patients with small radiotherapy treatment volumes or resected disease had the best OS. Prospective clinical trials, ideally randomized, should evaluate the role of radical treatment strategies in patients with oligometastases.

Background
Lymphovascular invasion (LVI) has been reported to be an unfavorable prognostic factor in patients with non-small cell lung cancer (NSCLC). We investigated the prognostic impact of LVI according to the tumor size in patients with pN0 NSCLC to elucidate the candidates for adjuvant chemotherapy.

Methods
Records of a total of 274 patients with pN0 NSCLC who underwent lobectomy with hilar and mediastinal lymph-node dissection were reviewed. Patients were divided into 3 groups according to the tumor diameter; group A: smaller than 20 mm, group B: 21 to 30 mm, and group C: greater than 31 mm. The comparison between the groups (A, B, and C) and LVI status (positive/negative) was analyzed by chi-square test. Kaplan-Meier analyses and log-rank tests with 95 % confidence intervals were employed to evaluate the impact of LVI on overall survival (OS) and relapse-free survival (RFS) in each group. Cox proportional hazards models were applied to assess the independent risk factors.

Results
Group A, B, and C consisted of 99, 86, and 89 patients, respectively. The frequency of positive LVI was increased in larger tumors (group A: 19.2%, group B: 25.6%, and group C: 36.0%; P = 0.033). In both group A and B patients, positive LVI was a significant risk factor for poor prognosis of OS and RFS in univariate analysis. In multivariate analysis, positive LVI was an independent risk factor for OS in both group A and B patients (hazard ratio = 10.6 and 10.5, P = 0.005 and 0.006, respectively) and for RFS in group A patients (hazard ratio = 14.7, P = 0.001)．LVI status was not shown to be a prognostic factor for OS or RFS in group C patients.

Conclusion
The impact of positive LVI on prognosis was more significant in the smaller tumors, although the frequency of LVI was higher in the larger tumors. Adjuvant chemotherapy for patients with pN0 small-sized NSCLC and positive LVI should be considered.

Background
Erlotinib has demonstrated major activity in EGFR mutation positive NSCLC, but may also benefit those with wild type tumours. We conducted a single-arm trial of pre-operative erlotinib in early stage NSCLC to assess radiologic and functional response as well as correlation with known and investigational biomarkers.

Methods
Patients with clinical stage IA-IIB NSCLC received erlotinib 150 mg daily for 4 weeks followed by surgical resection. Tumor response was assessed using pre- and post-treatment CT and PET imaging. Tumor genotype was established using Sequenom MassARRAY analysis. EGFR, PTEN, cMET and AXL expression levels were determined by immunohistochemistry. Pre- and post-treatment circulating markers/ligands for EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR ECD) were measured by ELISA. Tumor MET copy number by FISH and VeriStrat® analysis of pre-treatment serum samples is ongoing. Secondary endpoints included pathological response, toxicity and progression-free survival.

Results
Twenty-five patients were enrolled; 22 received erlotinib treatment with a median follow up of 4.4 years (range 2.2 to 6.4 years). Histology was predominantly adenocarcinoma (15) with smaller numbers of squamous cell carcinoma (7). PET response (25% SUV reduction) was observed in 2 patients (9%), both with confirmed squamous carcinoma histology. All patients met criteria for stable disease by RECIST and several experienced minor radiographic regression with histologic findings of fibrosis/necrosis, including 2 with squamous histology. The presence of an EGFR activating mutation was detected in two adenocarcinoma cases; one patient experienced minor radiographic response to treatment (exon 19 deletion) and the other stable disease (L858R). High pre-treatment serum levels of TGF- α correlated with tumor growth or primary resistance to erlotinib therapy (p=0.04), whereas high post-treatment soluble EGFR levels correlated with tumor response (p=0.02). Expression of EGFR, PTEN, cMET and AXL did not correlate significantly with tumor response.

Conclusion
Erlotinib appears to demonstrate some activity in EGFR wild-type tumors including those with squamous histology. These findings support that certain EGFR wild-type patients may respond to EGFR TKIs. Further research is needed to characterize these patients and elucidate the predictive ability of potential biomarkers such as TGF- α, EGFR copy number and others.

Background
Routine mutation testing for potential targeted therapy is a challenge in the management of lung cancer. As part of a feasibility study on the implementation of molecular testing in the United Kingdom, Cancer Research UK (CRUK) set up a stratified medicine program testing EGFR, K-RAS, BRAF mutations and ALK translocation on lung cancer samples. We present the result from the first ten months from two hospitals feeding into one diagnostic molecular laboratory.

Methods
Mutations detection in EGFR and KRAS genes was undertaken using cobas®4800 (Roche) and single-strand conformation analysis for BRAF gene. ALK translocations were screened using Vysis ALK break apart rearrangement probe.

Results
A total of 94 resections all (but one) in stages I - IIIA were analysed, with mutations found entirely within adenocarcinomas (n=64), with a frequency of mutations/translocation identification of 30% (K-RAS) , 12.5% (EGFR), 1.5% (ALK) and 1.5% (BRAF) (Figure 1). Over the same period, 360 biopsies from patients with non-resectable/advanced disease, were analysed, the majority being stage 4, with a frequency of 24% (K-RAS), 10%.6 (EGFR), 4.3% and 1.9% (Figure 2). Figure 1 Figure 2

Conclusion
The data suggest that frequency of K-RAS, EGFR and BRAF mutations are similar in early and advanced non-small cell carcinoma, however ALK translocations were observed to be more frequent in patients with advanced disease. This may have implications when considering which patients should undergo FISH testing for ALK translocation and entry into clinical trials. This study was funded by Cancer Research UK, Astra Zenica and Pfizer.

Background
PET scans are generally believed to be more sensitive than are CT in detecting metastatic disease and thus are widely used in the pre-operative assessment of patients with early-stage lung cancer. Given the increased sensitivity afforded with PET, one would expect the PET-staged patients to be “more favorable” than their “CT-staged only” patients (i.e. “stage migration”). The PET-staged patients should theoretically have a lower rate of subsequent distant failure. Further, among those who fail, the PET-staged patients should theoretically fail at a later time post-operatively (compared to their CT-only-staged patients). We herein compare the clinical outcomes in a group of patients with early stage lung cancer staged pre-operatively with CT with or without PET scan.

Methods
The records of 335 patients undergoing curative surgery at UNC hospital between January 1996 through December 2006 were retrospectively reviewed, with extensive data extraction including staging, treatment, and outcome data. Univariate and multivariate analysis were performed to identify predictors for clinical outcome. Failure times in sub-groups were calculated with the Kaplan–Meier method and compared via log-rank test. The rate and pace of recurrence were considered. Independent factors adversely affecting failure were determined with Cox regression.

Results
Figure 1112/335 patients (33%) had pre-operative staging PET scans. For the overall group (n= 335), and for the N0 (n=256) and N1 (n=79) subgroups, there was no evidence that the use of a pre-operative PET scan was associated with a lesser rate of subsequent distant failure, or a slower rate of distant failure (p>0.05 on uni- and multi-variate analyses) (Figure-1). On multivariate analysis, the predictors of distant failure included lympho-vascular invasion (p=0.02, HR=1.3), T stage (T1-2 vs T3) (p=0.009, HR=1.4) and N stage (N0 vs N1) (p=0.007, HR=1.5). The predictors for recurrent disease included lympho-vascular invasion (p=0.004, HR=1.8), T stage (p=0.001, HR=1.3) and N stage (p=0.004, HR=1.7).

Conclusion
The use of a pre-operative PET scan did not significantly alter the rate, or the pace, of distant recurrence or relapse of any kind, in patients undergoing surgery for non-small cell lung cancer (compared to CT-only staged patients). The retrospective nature of this study limits its validity. However, the PET-scanned patients were treated more recently, and were therefore perhaps more favorable (with both shorter follow up and with access to more modern interventions).

Background
We suggested that vessel invasion may be an important recurrence factor of Stage I non small-cell lung cancer in the UICC-TNM 7th classification same as the previous classification in the 14th WCLC. On the basis of the result, we have performed postoperative adjuvant chemotherapy to the vessel invasion-positive patients who agreed to our informed consent as pilot study.

Methods
We reexamined the influence that vessel invasion gives prognosis of Stage I non small-cell lung cancer. We analyzed 279 Stage IA-IB cases to whom prognosis is clear and postoperative adjuvant therapy was not performed among 711 cases to whom radical operation was performed in Tokyo medical and Dental University Hospital in Nov.1993-Jun.2008. And we more weighed about prognosis 33 vessel invasion-positive Stage IA-IB cases to whom postoperative adjuvant therapy was performed in above Hospital and Musashino Red-Cross Hospital in May.2004 - April.2011 against 125 vessel invasion-positive cases (:no adjuvant group) among above 279 cases. We used Kaplan Meyer analysis for survival rate, the chi-square test for comparison of recurrence rate and Logistic regression analysis for multivariate analysis.

Results
In 279 cases, p-Stage IA and IB cases were 168 and 111. Five year survival rate was 93% and 72% in each stage (p<0.001). But in case vessel invasion is negative, there were not significant differences between p-Stage IA and IB (95% vs. 87%, p=0.16). On the other hand, in case vessel invasion is positive, there were significant differences (83% vs. 59%, p=0.01). Multivariate analysis of 279 cases showed that vessel invasion is the worst factor of death from recurrence (p<0.001) in tumor diameter, pleural invasion, differentiation, vessel invasion and lymphatic involvement. And it was revealed that the recurrence rate is high so that the degree of vessel invasion becomes higher (Recurrence rate: V0 6%, V1 14%, V2 33%; p<0.001. Five year survival: V0 93%, V1 68%, V2 66%; p<0.001). In 33 cases to whom adjuvant therapy was performed, an oral treatment of tegafur uracil was performed to 22 cases (:TU group), and platinum-based chemotherapy was performed to 11 cases (:PB group). Platinum-based chemotherapy was performed actively to the cases that the degree of vessel invasion is high (V2-3). In the cases the degree of vessel invasion is low (V1), four year survival rate and recurrence rate was 94% in TU group vs. 81% in no adjuvant group (p=0.09), and 4% vs. 20% (p=0.43). In the cases the degree of vessel invasion is high (V2-3), four year survival rate and recurrence rate was 91% in PB vs. 60% in TU vs. 64% in no adjuvant (p=0.13) and 10% vs. 40% vs. 36% (p=0.21).

Conclusion
It is supposed that vessel invasion may be an important prognostic factor of Stage I non small-cell lung cancer. Only the platinum-based chemotherapy may improve prognosis as adjuvant therapy for the Stage I cases in which the degree of vessel invasion is high though there were significant differences in this investigation because the number of the specimens was small. Therefore a large-scaled trial that will make this point clear should be planned.

Background
Oligo-Recurrence (< 5 metastatic lesions) of surgically resected Non-Small Cell Lung Cancer (NSCLC) patient was stage IV disease, but long term survival was expected. Radical local therapy may be able to cure a subset of these patients, but clinical data has been insufficient.The purpose of this study is to evaluate the efficacy and toxicity of local therapy (include surgery (OP) and radiation therapy (RT)) according to the recurrence site.

Methods
We retrospectively reviewed surgically resected patients of NSCLC at our institution between 1994 and 2009, and extracted patients who received local therapy after recurrence. Efficacy and toxicity were compared between OP and RT. Significant differences among treatment groups were compared using the X[2]-test and survival curves were constructed using the Kaplan-Meier method and log-rank test.

Results
Of the 1975 patients who underwent surgery during this period, and 421 cases were relapsed. Two hundred sixty patients were oligo-recurrence case and were received local therapy (OP: 48/ RT: 143). Primary lesion had been controlled in all cases. Recurrence sites were lung: 55 (21/ 34), Brain: 52 (3/49), Mediastinal and neck LN: 49 (7/38), Born: 33(3/30) and Adrenal gland: 7 (3/4). RT for brain metastasis was r-knife: 38 and Whole brain irradiation: 11. There were no serious adverse events in both treatments. Performance status was not spoiled in both treatment groups. Overall median survival time (MST) after recurrence was 17 months (mo.) (OP: 27/RT: 11), 3-year survival rate was 22% (29%/19%). Twenty patients (OP 6/RT 6) were survived over 5 years. MST according to the recurrence site was, lung: 23 mo. (27/11), Brain 18 mo. (16/18), mediastinal and neck LN 14 mo. (12/14), born 12 mo. (17/11) and adrenal gland 26 mo. (22/47). There was no statistically significant difference in survival for overall patients, according to the recurrence site, and also treatment modality.

Conclusion
Local therapy for oligo-recurrence NSCLC could be safety performed. Overall survival data was not extremely superior to other Stage IV disease in this data. However, according to the recurrence site, MST of lung and adrenal gland were over 20 months. There was no significant difference between treatment modality. To confirm the true efficacy of radical local therapy for these patients, prospective study must be needed.

Background
Background: We have reported that the definition of lung cancer with scattered consolidation (LCSC) was difficult to measure the size of ground glass opacity (GGO) on thin section computed tomography (Matsunaga T, Suzuki K, et al. Interact Cardiovasc Thorac Surg. 2013).To add to clinicopathological features, We investigate in LCSC in detail.

Methods
Methods: Between Jan.2009 and Oct.2012, 590 consecutive patients underwent pulmonary resection for lung cancer with clinical stage IA and are performed on thin section computed tomography for preoperative evaluation. Among them, 79 patients (13.4%) who had lung cancers in which it was difficult to measure the size of consolidation tumor ratio (CTR) were investigated in this study. LCSC was divided into three categories: tumor with discontinuous consolidation like islands (small islands type); tumors with reticulate consolidation (reticulation type); tumors with denser GGO (denser type). The medical record of each patient was examined for the frequency of pathological nodal status, lymphatic invasion, vascular invasion, and adenocarcinoma in situ (AIS).

Results
Results: All of LCSC patients are adenocarcinoma. No nodal involvement was observed in all cohort. Pathological lymphatic invasion were found in 5 (17.2%) out of 29 pts with island type, 2 (7.4%) out of 27 patients with reticular type, 1 (4.3%) out of 23 patients with denser type.. Vascular invasion was found in 3 (11.5%), 2 (7.4%), and 0 (0%), respectively. AIS were included in 3 (11.5%), 5 (13.5%), and 2 (8.6%), respectively. There were no statistically significant differences.

Conclusion
Conclusions: There were no significant differences in the three categories as to pathological invasive factors among LCSC. Vascular and lymphatic invasions were frequently seen in island or reticular type compared with denser type. On the other hand, AIS was frequently seen in denser type.

Background
The prognosis remains dismal for most lung cancer patients, even for early cases, suggesting the existence of sophisticated pathogenetic mechanisms that are not reflected by pathological stage. Although a number of studies have been carried out in relatively recent times [], our understanding of the role and clinical significance of inflammation and immunity in human lung cancer is still limited. We investigated in detail the diagnostic and prognostic role of two acute phase proteins, Pentraxin 3 (PTX3) and C-reactive protein (CRP), in high-risk subjects and lung cancer patients.

Methods
A cohort of high-risk, cancer-free subjects enrolled in a lung cancer early-detection trial with spiral CT, a group of screening-detected lung cancer patients, and two groups of consecutive non-small cell lung cancer patients admitted to our Thoracic Surgery Department between January 2009 to June 2010 were included. Serum CRP and PTX3 levels were determined in the high-risk, healthy cohort (N=1434) and in patients with non-small cell lung cancer. Pre-treatment blood samples were prospectively collected prior to surgical resection in lung cancer patients. PTX3 expression was determined by immunohistochemistry and scored using semiquantitatively. Survival curves were calculated by the method of Kaplan and Meyer. Prognostic factors were analyzed by multivariate Cox regression.

Results
No significant association was found between PTX3 or CRP serum levels and the risk of subsequently developing lung cancer or any malignancy in the high-risk-cohort. 119 patients harbouring 124 primary lung cancers were evaluable. Screening and clinically detected lung cancer patients were comparable as to age and comorbidity. There was a significantly higher rate of stage I disease among screening patients (p=0.01). Preoperative serum CRP and PTX3 levels in lung cancer patients were significantly higher than in the tumour-free, high-risk population, p<0.001). In the tumour stroma, PTX3 expression was low or moderate in 55% and intense in 10%. Tumour cells stained weakly positive in 24%. Staining for PTX3 was virtually absent in the normal lung interstice. Median follow-up was 27 months (0-140), Median 2-year disease-free survival was 71 % and median overall 2-year survival was 75% Preoperative serum levels of CRP and PTX3 did not correlate with survival. Instead, age (p=0.029), stage (p=0.001) and interstitial PTX3 expression (p<0.001) were independent prognostic factors

Conclusion
PTX3 and CRP levels are not linked to a higher risk of developing lung cancer or any cancer in a healthy high-risk population. Nonetheless, mean CRP and PTX3 concentrations in patients with lung cancer are significantly higher than in the blood of healthy high risk subjects, and a significant and independent correlation was found for interstitial PTX3 expression with lung cancer prognosis after surgery. Altogether this data suggests a connection between smoldering inflammation in the tumor bed and lung cancer progression that warrants further investigation.

Background
There is a significant risk of disease recurrence following surgery with curative intent for non-small cell lung cancer (NSCLC). However, limited data is available on the patterns of recurrence and best practice for follow up imaging after lung cancer surgery. Current practice in the United Kingdom (UK) is to perform interval chest x-ray for 5 year following surgery. We aimed to determine the incidence, anatomical site, modality of detection and percentage of patient requiring acute admission as a harbinger of disease recurrence post thoracotomy for NSCLC

Methods
Records of consecutive patients with NSCLC who underwent thoracotomy and resection of early stage lung cancer at 5 institutions situated in the South East of the UK between October 2007 and September 2012 were interrogated. Data collection was completed in Jan 2013.

Results
A total of 314 patients were included; 59 (18.8%) patients died from disease recurrence during the study period, the site of recurrence was lung, central nervous system, bone/ soft tissue, abdominal and lymph node respectively in 24 (40.7%), 17 (28.8%), 10 (16.9%), 4 (6.8%) and 4 (6.8%) cases. In 45 (76.2%) patients disease recurrence was detected during outpatient consultation, modality of detection for routine chest x-ray, CT and other modalities were respectively 7 (15.5% ), 28 (62.2%) and 10 (22.3%) in every case CT was prompted by change in symptoms, a clinically palpable mass lesion or clinical suspicion. Other modalities used were MRI, ultrasound and lymph node aspiration in 4, 3 and 3 cases respectively. Emergency admission accounted for 14 (23.8%) patients pathway to detection of recurrence, of these 9 (64.3%) were admitted with symptoms relating to cerebral metastases, 4 (28.6%) with symptomatic breathlessness and 1 (7.1%) with a pathological fracture.

Conclusion
Almost a quarter of patients with relapsed lung cancer following surgery present with acute symptoms requiring emergency admission. Standard chest x-ray follow-up detects very few recurrences with most cases being detected once reported symptoms direct further investigation. It is currently unknown whether earlier detection of recurrence may offer symptomatic or survival gains however avoidance of emergency admissions is likely to have a positive impact on quality of life. Further studies to investigate which patients are at highest risk of recurrence and the most appropriate post-surgical follow-up strategies are required.

Background
This is an ongoing phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy, based on thymidilate synthase (TS) and excision-repair cross-complementing-1 (ERCC1) gene expression versus standard adjuvant chemotherapy in completely resected Stage II-IIIA non-small cell lung cancer (EudraCT #: 2008-001764-36).

Methods
For all the registered patients (pts) the expression of ERCC1 and TS is assessed by qRT-PCR on paraffin-embedded tumor specimens in a central laboratory. Randomization is stratified by stage and smoking status. Trial was emended on Feb, 2011 with the 7th staging system. Primary end point is overall survival; secondary end points include recurrence-free survival, therapeutic compliance, toxicity profile and comparative evaluation of ERCC1 and TS mRNA versus protein expression. It is assumed that the 5-year survival rate in the control arm is 45% and the hazard reduction associated to the experimental treatment is 30%. With a power of 90% to detect the estimated effect with log-rank test, a significant level of 5% (2 tails), 336 events have to be observed; the expected total number of pts is 700. The final statistical analysis will compare all pts in the control arms versus all those treated in the tailored chemotherapies groups. Efficacy analysis will be done on an intent-to-treat basis. Cox proportional hazard model will be used for estimating hazard ratios after adjusting for relevant variables. Within 45 days post-surgery, pts in each genetic profile are randomized to receive either a standard chemotherapy selected by the investigator (cisplatin/vinorelbine, cisplatin/docetaxel or cisplatin/gemcitabine) or an experimental treatment (tailored arms) selected as follows: 1) high ERCC1 and high TS 4 cycles of single agent paclitaxel 2) high ERCC1 and low TS 4 cycles of single agent pemetrexed 3) low ERCC1 and high TS 4 cycles of cisplatin/gemcitabine 4) low ERCC1 and low TS 4 cycles of cisplatin/pemetrexed. All chemotherapy regimens are administered for a total of 4 cycles on a 3-weekly basis.

Results
Not applicable

Conclusion
Currently, 558 pts have been randomized from 26 institutions mainly located in Italy and Germany (average enrolment: 19 patients/month). This is one of the pharmacogenomic-driven trial in the adjuvant setting in the European scenario.

Background
Stage IIIA NSCLC constitutes 30% of all NSCLCs. The most powerful prognostic factors identified in this stage are mediastinal lymph node clearance and a pathologic complete response (pCR). A pCR is obtained in 5-15% of patients (pts) with significant prolongation of survival. The identification of molecular biomarkers, such as excision repair cross-complementation 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1) and thymidylate synthase (TS), may predict the response to CT. Similarly, EGFR mutations may predict the response to EGFR inhibitors.

Methods
CONTEST, a multicenter (19 Italian centers), randomized (2:1), 2-arm, phase II study, will recruit pts with resectable stage IIIA (N2) NSCLC. Pts will be randomized to receive before resection either standard CT with cisplatin (CDDP) 75 mg/m2 + docetaxel (Doc) 75 mg/m2 on day (d) 1 q 21 d for 3 cycles (cys) or customized therapy using predetermined values for ERCC1, RRM1, TS and EGFR mutations. Specimens will be sent to Response Genetics (Los Angeles, CA, USA) for the evaluation of ERCC1, RRM1 and TS using RT-PCR and EGFR using Sanger sequencing. The customized arms are as follows: -EGFR+: Gefitinib 250 mg/d for 8 weeks. -EGFR-/non-squamous (NS)/TS-/ERCC1-: CDDP 75 mg/m2 + pemetrexed 500 mg/m2 d 1 q 21 d for 3 cys. -EGFR-/squamous (S) or NS TS+/ERCC1-/RRM1+: CDDP 75 mg/m2 + Doc 75 mg/m2 d 1 q 21 d for 3 cys. -EGFR-/S or NS TS+/ERCC1-/RRM1-: CDDP 75 mg/m2 d 1+ gemcitabine (Gem) 1250 mg/m2 d 1, 8 q 21 d for 3 cys. -EGFR-/S or NS TS+/ERCC1+/RRM1+: Doc 75 mg/m2 d 1 + vinorelbine 20 mg/m2 d 1, 8 q 21 d for 3 cys. -EGFR-/S or NS TS+/ERCC1+/RRM1-: Doc 40 mg/m2 y 1, 8 + Gem 1200 mg/m2 d 1, 8 q 21 d for 3 cys. The primary end point is pCR, and all randomized pts will be compared by treatment arm. Because pCR is a surrogate endpoint and given the expected proportion of pCRs in the control group (pc= 5%), the minimal clinically worthwhile effect of this customized treatment is an increase to 20%. To detect such an effect at the 0.05 (1-sided) significance level with 80% power, a total of 168 pts (112 in the investigational arm and 56 in the standard arm) will be enrolled. The secondary endpoints are overall survival, disease-free survival, overall survival at 1, 2 and 5 years, overall response and safety. The major eligibility criteria are as follows: histologically confirmed NSCLC appropriate for surgery; ≥18 years old; ECOG performance status (PS) 0-1; sufficient tissue to perform marker analyses; medically fit for resection by lobectomy or pneumonectomy; stage IIIA (N2) patients with technically operable disease limited to T1a, b, T2a, b N2 M0; T3 (>7 cm) N2 M0 are eligible; stage IIIA pts limited to T3 N1 M0, T3 (invasion) N2 M0; T4 N0, N1 M0 are not eligible; NSCLC confirmed by mediastinoscopy; informed consent. This study is open for accrual; further details can be found at ClinicalTrials.gov (NCT01784549). Funded by the Italian Ministry of Health – RF 2009-1530324.

Results
N/A

Conclusion
N/A

Background
For patients older than 80 years old, surgical treatments for resectable lung cancer were usually to a limited extent, or even not considered. Few studies evaluated the true effect of surgery for these patients. The aim of this study is to compare the survival between the octogenarians and younger patients with pathological stage I non-small cell lung cncer (NSCLC) underwent complete resection using multivariate analysis.

Methods
The clinicopathological characteristics of 870 patients underwent complete resection of stage I NSCLC between Jan. 2002 and Dec. 2011 were retrospectively reviewed. The patients were categorized as octogenarians (aged 80~90) or younger (aged < 80). Survival under multivariate analysis was examined.

Results
76 (8.7%) octogenarians were indentified in the 870 patients, average age was 82.4±2.5 years old. The 794 younger patients had average age of 63.0±10.4. Pulomany function test including forced expiratory volume in one second (FEV~1~) and FEV~1~/ forced vital capacity (FVC) were 1.80±0.44 L and 70.5±11.7 % in the elder group, and were 2.23±0.59 L and 76.3±9.9% in the younger patients (p < 0.001). There were 44 (57.9%) lobectomies and 32(42.1%) sublobar resections performed for the octogenarians, while 689 (86.8%) lobectomies and 94(11.8%) wedge resections/segementectomies were done for the younger patients (p < 0.001). Average tumor size was 2.6±1.15 cm and 2.4±1.12 cm, respectively (p = 0.076). Five surgical mortalities were found, 2 (2.63%) were in the elder group and 3 (0.37%) were in the younger group. The overall 5-year survivals of the two groups were 64.9% and 76.9%, respectively (p = 0.015). Under multivariate analysis, male sex, extension of resecion, FEV~1~ and tumor T-status associated with poorer survival. Older than 80 years old didn’t associated with difference in survival (p = 0.911). Figure 1

Conclusion
Octogenarians with pathological stage I NSCLC underwent complete surgical resection had similar survival with their younger counterparts. Although they usually had poorer lung function, thus received more wedge resections or segmentectomies, aggressively performing surgical resectionon the elder ones would have similar benefits as on the younger ones.

Background
It is of great importance for treatment optimization to know before the initiation of treatment the different variables that may be used to help determine the result in the oncological diseases. It has been shown in preveious studies that have been performed that standard uptake values obtained in PET-CT carried out before the treatment in various cancer types enable us to make predictions regarding the tumor’s “aggressiveness”, response to treatment and survival. In this study, we researched the predictive role of pretreatment SU values of the patients with SCLC in determining the response to treatment and the survival.

Methods
Ninty patients were enrolled into this study, with whom we had follow-up in our center due to SCLC, and in whom pretreatment PET-CT was performed. The SU value of primary tumor was then determined. The relationship between these values and response to treatment is examined through ROC analysis and the cut-off value, effective and thus the determination to the response to treatment is identified. In the patient group, age, gender, stage, performance status, response to treatment, and effect of SU values upon response to treatment and survival are studied.

Results
Ninty patients were enrolled into the study. Median follow-up period is 11 (1-43) months, and the median age is 58 (39-83). Ninety percent of patients are male and the diseases in 37% of were noted to be of limited-stage. All patients received platinum+etoposide chemotherapy once every 21 days, as median amount of treatments to cure was 6 (3-7). When ROC analysis was carried out the SU value, suitable for determining the response, is found to be 10. The sensitivity of this value is found 85.7% (CI 95%; 63-96), the specificity was found to be 61.8% (CI 95%; 49-73) (AUC: 0.783; p: 0.0001). The overall response rate (complet response+partial response) is 59.1% in the other patients, while this rate is 93.3% in patients with involvement above the cut-off value(p:<0.0001). The response rates are higher in patients with age greater than or equal to 60 years old (p:0.047). No significant relationship is found between gender, stage and performance status, and the response to treatment. In the survival analyses carried out, median disease-free survival is found to be 9 months (SE:1; 95% CI: 8-10), and median general survival was determined to be 17 months (SE:3; 95% CI: 12-22). When single and multivariate analysis are carried out, the positive impact/effect of limited-stage disease and response to treatment upon the progression-free survival is determined (p<0.05). The fact that SU value is higher than cut-off value, affects the progression-free survival positively borderline (p:0.085). As a result, this is effective upon general survival, and studied using single and multivariate analysis. It is seen that only the response rates affect the general survival positively (p<0.05).

Conclusion
PET-CT is used in SCLC frequently for staging purposes. The data obtained in PET-CT may have a role in determining the prognostic characteristics of the disease as well as the response to treatment.

Background
Brain metastases are very common in patients with small-cell lung cancer (SCLC). Prophylactic cranial irradiation (PCI) has been shown to reduce the incidence of brain metastases and to improve overall survival in patients with limited-disease SCLC (LD-SCLC). However, brain metastases are often observed after PCI, and the optimal treatment for these brain metastases is still unclear. The present study investigated the recurrence of brain metastases after PCI in patients with LD-SCLC and the therapeutic efficacy of stereotactic radiosurgery for these metastases.

Methods
Between December 2000 and December 2012, 228 patients with LD-SCLC were treated and 98 of these patients with a complete response (CR) or a near CR to chemoradiotherapy underwent PCI at the National Cancer Center Hospital. We retrospectively reviewed the medical records and imaging data for these 98 patients.

Results
Twenty-four (24%) of the 98 patients developed brain metastases after PCI. The characteristics of the 24 patients were as follows: median age, 62 years (49-72 years), male/female, 21/3; performance status 0/1/2, 2/16/6. Twelve (50%) of the 24 patients had cranial recurrences only. Twelve patients had single brain metastases, and 12 patients had multiple lesions. Nine patients had neurological symptoms due to brain metastases. The median period after PCI until the appearance of the metastases was 9.9 months (1.1-34.9 months). Fifteen (63%) of the 24 patients underwent stereotactic radiosurgery (gamma knife radiosurgery [GKRS]), and one patient received whole brain radiotherapy. Six patients were treated with chemotherapy plus best supportive care (BSC), and two patients underwent BSC alone. The 15 patients who received GKRS had brain metastases with/without extracranial lesions (7 with, 8 without); three were symptomatic, and 12 were asymptomatic. The median number of brain metastases at the time of the first GKRS was one (range, 1-4). The local control rate of the lesions treated with GKRS was 86.7% (complete response in 3 patients, partial response in 7 patients, and stable disease in 3 patients). Five patients underwent further GKRS because of newly developing brain metastases (median: 4 times, range: 2-7 times). The median intracranial control time of the 15 patients was 6.8 months. The median survival time of the 15 patients was 29.3 months after the initial diagnosis, 13.7 months after the development of brain metastases, and 12.7 months after the treatment of GKRS. The median survival time of the patients without extracranial lesions was 20.2 months after the development of brain metastases and tended to be longer than that of the patients with extracranial lesions (12.6 months). Severe adverse events arising from GKRS were not observed in this series.

Conclusion
Stereotactic radiosurgery may be an effective option as a salvage therapy for brain metastases after PCI in patients with LD-SCLC.

Background
Small cell lung cancer (SCLC) is the most aggressive form of lung cancer. The prognosis for SCLC patients remains unsatisfactory, despite advances in chemotherapy. In this study, we sought to clarify the prognosis and treatment patterns of patients with SCLC.

Methods
A cohort comprising all patients diagnosed with SCLC between Jan. 2004 and Dec. 2006 was assembled from the Taiwan Cancer Database. Patients were followed up until December 31, 2009 to determine overall survival. Patient survival was estimated using the Kaplan-Meier method, and Cox’s proportional hazard model was used to determine the relationship between prognostic factors and median survival time.

Results
Among the 1684 patients diagnosed with SCLC, 1215 (72%) were diagnosed with extensive stage, and 469 (28%) with limited stage. Most of the patients were male (90%). The median survival time of patients with limited-stage (LS) and extensive-stage (ES) SCLC was 10.3 months and 5.6 months, respectively. For LS patients, surgery, chemotherapy, and combined chemotherapy and radiotherapy resulted in better survival than best supportive care (HR: 0.20, p<0.001; HR: 0.61, p<0.001; HR: 0.37, p<0.001 respectively). For ES patients, male gender was significantly associated with poor prognosis (HR:1.45, p<0.001) and chemotherapy was shown to improve overall survival more effectively than best supportive care (HR: 0.37, p<0.001).

Conclusion
For LS SCLC patients, surgery, chemotherapy, and combined chemotherapy and radiotherapy improved survival compared to best supportive care. ES SCLC patients benefited more from chemotherapy treatment than best supportive care.

Background
Belotecan is a new camptothecin analogue and a potent topoisomerase I inhibitor. The aim of this phase II study was to investigate the efficacy and toxicity of belotecan in previously untreated elderly patients with small cell lung cancer (SCLC).

Methods
A total of 26 patients, aged ≥65 years, with previously untreated, extensive-stage SCLC were enrolled in the study. Belotecan was administered by daily intravenous infusion at 0.5 mg/m[2]/day for 5 consecutive days every three weeks.

Results
The overall response rate and disease control rate of chemotherapy on an intention-to-treat basis were 35% and 54%, respectively. The median overall survival was 6.4 months, and the median time to progression was 2.8 months. The most common toxicity was hematologic. Grade 3 or 4 neutropenia occurred in 80.8% of patients, and grade 3 or 4 thrombocytopenia in 15.3%. Non-hematologic toxic effects of grade 3 or 4 were uncommon.

Conclusion
Belotecan had modest efficacy and well-tolerated toxicity in previously untreated, elderly SCLC patients. Single belotecan could be a promising treatment option, considering its lower toxicity in elderly patients who are unsuitable candidates for platinum plus etoposide chemotherapy.

Background
CONVERT is a multicentre, randomised, phase III trial open in Europe and Canada in limited-stage small cell lung cancer. Patients are randomised to twice (45 Gy in 30 fractions) or once-daily radiotherapy (66 Gy in 33 fractions) given concurrently with 4-6 cycles of chemotherapy. This study is funded by Cancer Research UK and involves centres from the UK NCRI, the ‘Groupe Francais de Pneumo-Cancerologie’, the Spanish Lung Cancer Group, the EORTC and NCIC CTG.

Methods
To identify and review the challenges in site set-up. To review time taken from site initiation to first patient randomised, number of centres opened that included 0-2 patients and number of centres that recruited the majority of all patients.

Results
In June 2013, 519/532 patients had been recruited in 9 countries; 299 from 32 UK centres, 100 from 17 French centres, 39 from 9 Canadian centres, 27 from 6 Spanish centres, 26 from 3 Belgian centres, 13 patients from 1 centre in Slovenia, 9 from 2 centres in The Netherlands and 6 patients from 1 centre in Poland. Figure 1 shows the number of centres open and patients recruited. 96 sites are currently open to recruitment (5 sites opened in 2008, 34 in 2009, 31 in 2010, 17 in 2011, 8 in 2012 & 3 in 2013, 2 sites subsequently closed early) of which 74 (77%) have randomised at least 1 patient. 24 sites (25%) recruited only 1 or 2 patients. 10 sites have recruited 49% of the total number of patients with a single site recruiting 18.5% of all patients randomised. Time taken from site initiation to 1[st] patient randomised ranged from 0–1029 days with a median of 144 days. Time taken to complete the QA exercise from initial information sent to site ranged from 14-1181 days with a median of 290.5 days. Figure 1

Conclusion
Recruitment to an academic trial in LS-SCLC is a challenge but accrual has improved considerably since 2008. This can be directly related to the increasing number of sites opened to recruitment. Duration of site set-up and completion of the QA exercise are factors explaining slower than anticipated accrual rates particularly between 2008 and 2010. We anticipate that the study will close to recruitment in July 2013. International participation has been a key factor to the success of the trial and the experience gained will be of value to the design of future radiotherapy studies to ensure target accrual.

Background
Patients with relapsing SCLC have a poor prognosis and options for treatment are limited. Paclitaxel in combination with platinum has demonstrated activity in first and second-line treatment. We conducted a phase II study to investigate the anti-tumor activity and safety profile of Docetaxel/Carboplatin (DC) in patients with refractory or relapsing SCLC.

Methods
SCLC patients who were refractory to or relapsed after first-line treatment and who did not receive platinum based chemotherapy within the 3 months before inclusion, were treated with Docetaxel (75 mg/m[2], day 1 iv) followed by Carboplatin (area under the curve 6, day 1 iv.) once every 3 weeks for 4-6 cycles. Primary endpoint was response rate (RR) and secondary endpoints were time to progression (TTP), overall survival (OS) and safety profile. Tumor response was measured according to RECIST version 1.1. Toxicity was evaluated according to Common Toxicity Criteria of the National Cancer Institute.

Results
50 patients (29 male and 21 female) were included with a median (range) age of 67 years (46-82). The majority of patients had an Eastern Cooperative Oncology Group performance status of 1; median time off first-line treatment was 12 weeks. Average number of treatment cycles was 4 (range 1-6). Evaluable for response and toxicity were 45 and 48 patients, respectively. A complete response was achieved in 1 patient, a partial response in 24 patients, stable disease in 16 patients, and progressive disease in 4 patients (RR 73.5%; 95% confidence interval, 59 to 88). Median time to progression was 133 days (range 89-177). Median overall survival was 198 days (range 77-322). One-year survival rate was 34%. Hematologic toxicity grade 3 and 4 was leukopenia 19% and 8%, thrombocytopenia 10% and 2%, and anemia 4% and 0%, respectively, in a total of 186 cycles. Nonhematologic toxicity was diarrhea grade 3-4 (15%), stomatitis grade 3 (4%) and hyponatriemia grade 3 and 4 in one patient each. Seven patients were hospitalized due to neutropenic fever; no toxic deaths occurred.

Conclusion
Second-line DC in refractory or relapsing SCLC patients yielded a high RR and toxicity was relatively mild in these poor-prognosis patients. NCT00686985

Background
Despite initial responses to chemotherapy, SCLC typically progresses within a few months. Targeting residual disease has the potential to improve outcomes. A number of tumor specific glycolipid antigens have been identified and are potential targets for immune therapies. In a series of phase I clinical trials, vaccination with each of these antigens individually was safe and induced antibody responses in the majority of patients. Preclinical data indicate that combining these antigens will expand the immunogenicity across a broader array of SCLC tumor cells. We conducted this pilot trial to determine the safety and immunogenicity of a vaccine combining five of these antigens.

Methods
Patients with limited or extensive stage SCLC who have completed initial chemotherapy +/- thoracic or cranial irradiation with a maintained response are eligible. Vaccinations must start within 3-8 weeks of the last chemotherapy, and at least 1 week after radiation. Patients receive KLH-conjugates of GD2L, GD3L, Globo H, fucosyl GM1, and N-propionylated polysialic acid (30mcg each) plus OPT-821 adjuvant (150mcg) subcutaneously on weeks 1, 2, 3, 9, 20, and 32. One cycle of etoposide/platinum chemotherapy was administered in week 6. A significant immune response is defined as an antibody titer of ≥ 1:80 by ELISA against a given antigen or a ≥ 8 fold increase over baseline for patients with a detectable baseline titer. The vaccine would be deemed worthy of further study if >5 patients had an immune response to 3 or more antigens.

Results
Ten patients were treated, including 9 with extensive stage, 4 women, 7 with prior brain radiation. The number of vaccinations administered was: 1 (1pt), 3 (2), 4 (3), 5 (2), and 6 (2). Toxicity was limited to mild skin reactions. One patient was taken off study after he developed aphasia the day after the first vaccination; MRI brain was unremarkable and symptoms resolved spontaneously. No patients met the predefined criteria for immune response. Six patients had increases in IgM titers to 1-2 antigens. The median time to progression was 4 months. The two patients with the strongest IgM responses to Globo H and fucosyl GM1, and also the only IgG responses to fucosyl GM1, had progression of disease 7 and 9 months after starting the vaccines, and both progressed initially in the brain only.

Conclusion
The polyvalent vaccine is safe, but fewer patients than expected had a significant immune response, Two patients with immune responses experienced a longer than expected time to progression. A second cohort of patients is now receiving the vaccinations over a shorter period of time and without the added cycle of chemotherapy. Five out of 10 of those patients have been enrolled, and preliminary data will be available on those patients for the meeting. Following completion of this pilot trial, a multicenter randomized trial is planned. Supported by MabVax Therapeutics’s NIH grant R41 CA128363 and a grant from FAMRI.

Background
The AJCC 7[th] TNM staging system is recommended for both non-small cell and small cell lung cancer (SCLC), although SCLC has traditionally been classified using the limited and extensive definition. We evaluated long-term survival of patients with SCLC according to the AJCC 6[th] and 7[th] TNM edition.

Methods
239 patients had been pathologically diagnosed with SCLC from January 2000 through December 2009 in our hospital. We included 187 patients who had initial CT scan of the thorax. We analyzed all available data for TNM staging using the AJCC 6[th] and 7[th] edition as well as the long-term survival rates.

Results
According to stages defined by the 6th TNM edition system, 5-year stage-specific survivals (5-YSR) were 43% for stage I and II, 36% for stage IIIA, 10% for stage IIIB, and 7% for stage IV. Applying the 7th edition system, 5-YSR were 46% for stage I and II, 24% for stage IIIA, 7% for stage IIIB, and 9% for stage IV. Using the 7[th] edition, 5-YSR of the stage IV was higher than that of stage IIIB. The number of changed stage from IIIB in the 6[th] edition to IV in the 7[th] edition was 22 and all were related to malignant pleural effusion.

Conclusion
Application of the TNM staging to SCLC stratifies survival more distinctly than limited and extensive definition by providing more substages. Slightly better survival of stage IV SCLC than that of stage IIIB in the 7[th] edition is related to malignant pleural effusion.

Background
Solitary Fibrous Tumors of the Pleura (SFTP) refer as to a heterogeneous group of mesenchymal malignancies with various anatomic and histologic features. Upfront surgical resection is the standard approach, but the outcome of patients is unpredictable. Recurrences may be aggressive and difficult to treat.The most widely accepted staging system has been proposed by De Perrot et al., and is based on the anatomy of the tumor implantation (sessile/pedunculated), and the presence of histologic signs of aggressiveness, including cellularity with crowding and overlapping of nuclei, cellular pleomorphism, high mitotic count, necrosis, or stromal/vascular invasion. Given the rarity of the tumor, limited evidence is available about the role and the modalities of perioperative and definite chemotherapy for SFTP.

Methods
Multicenter retrospective study of patients (pts) with histologically-proven SFTP with complete follow-up from surgical diagnostic to tumor recurrence and death.

Results
68 pts (28 males/40 females) were included. Median age at diagnosis was 62 year-old. Tumor stage according to the De Perrot system was 0/I for 29 pts, II for 23 pts, III for 7 pts, and IV for 4 pts. Adjuvant chemotherapy was given to 7 patients, mostly with stage III/IV SFTP, consisting of doxorubicin-based regimen. Recurrence rate and median time-to-progression (TTP) after surgery were 3%, 52%, 71%, and 75% (p<0.001), and 107, 70, 29, 11 months (p=0.006) for stage 0/I, II, III, and IV tumors, respectively. Besides tumor stage, predictors of shorter TTP were incomplete resection (p<0.001) and a higher number of histologic signs of malignancy (p=0.009). At time of tumor recurrence, 12 pts received chemotherapy. Highest disease control rates were observed with trabectedine (7/9 pts; Disease Control Rate (DCR): 78%; median TTP: 3,4 months), and gemcitabine-dacarbazine combination (2/3 pts, DCR: 66%; median TTP: 1,9 months). Median overall survival of the whole cohort was 56 months.

Conclusion
This study 1) confirms the prognostic value of the De Perrot staging system, 2) indicates a high recurrence rate in patients with stage II tumors, for which perioperative chemotherapy may be considered, and 3) suggests an interest for trabectedine in the setting of recurrent tumors. Besides clinical data, further molecular characterization, including recently identified specific gene fusions, may help to better predict the outcome of patients with SFTP.

Background
The number of patients with Malignant Mesothelioma is expected to increase over the next ten years from the number of 3.300 new cases that are reported annually nowadays. Most of the patients appear with advanced, surgically unresectable disease at the time of diagnosis and relapse is usual after the standard 1st line treatment with a platinum-pemetrexed doublet, due to intrinsic and acquired resistance to pemetrexed. This review focuses on the treatment options in Malignant Mesothelioma resistant to pemetrexed and is based on trials for possible 2nd line regimens tested the last ten years and ongoing trials of novel agents and studies exploring the basis of pemetrexed resistance.

Methods
We searched via PubMed/Medline, Clinicaltrials.gov and American Society of Clinical Oncology databases for articles and ongoing trials published until 1/2013 using the term: “mesothelioma”, in association with “2nd line chemotherapy”, “pemetrexed resistance”, “relapsed”, “pemetrexed-pretreated” and “biomarker”. Primary sources have been quoted.

Results
Data from forty eight conducted and ongoing trials, mainly phase II, single-armed, but also retrospective and phase III, are shown and discussed. Thirty different agents were tested in these trials as possible 2nd line drugs for Malignant Mesothelioma. Currently, no guidelines for 2nd line chemotherapy in Malignant Mesothelioma tumors resistant to pemetrexed are available.

Conclusion
In the absence of a “gold standard” as 2nd line treatment for Malignant Mesothelioma, results of ongoing trials are eagerly awaited and the research for novel agents remains critical. Furthermore, additional research should be done towards the understanding of the mechanisms that lead to pemetrexed resistance, the possible personalization of 1st and 2nd line treatment and the use of biomarkers that can be used as factors predicting the resistance itself. Finally, more patients should be convinced to enroll in clinical trials and more randomized trials have to be conducted.

Background
Early diagnosis of malignant pleural mesothelioma (MPM) can improve patients’ outcome but is hampered by non-specific symptoms and investigations, which delay diagnosis and result in advanced stage disease [van Meerbeeck JP, 2011]. An accurate non-invasive test allowing early stage diagnosis in asbestos-exposed persons is lacking. Breathomics aims at a non-invasive analysis of volatile organic compounds (VOCs) reflecting the cells’ metabolism. The breathogram obtained by the electronic nose does however, not allow identification of MPM-related VOCs [Chapman EA 2009, Dragonieri S 2011]. Ion mobility spectrometry (IMS) combines the advantages of online direct sampling with the possibility of VOC identification and linking to MPM pathogenesis [Baumbach JI 2009]. We investigated which VOCs could play a role in MPM pathogenesis in order to build a possible diagnostic MPM tool.

Methods
10 MPM patients and 10 healthy asbestos-exposed individuals (mean asbestos fiberyear count 14,6 (5,5) fibre.years/cc) were included after refraining from eating, drinking and smoking for at least 2 hours before sampling. They breathed tidally for 3 minutes through a mouthpiece connected to a bacteria filter. Ten ml alveolar air was sampled via a CO~2-~controlled ultrasonic sensor and analyzed using the BioScout Multicapillary Column/Ion Mobility Spectrometer (MCC/IMS, B&S Analytik, Dortmund, Germany) [Westhoff M 2009], by using N~2~ as a carrier gas. Per subject a background sample was taken. Peaks of interest were visually selected and their intensity (V) was analyzed and compared between background and breath samples via on-board VisualNow 3.2 software and SPSS v21 (IBM) using Mann-Whitney-U tests.

Results
Out of 41 peaks of interest, three show a significantly higher intensity in the exhaled breath of MPM patients than healthy controls [Table]. The high AUC~ROC~ of resp. P12 (0.877) and P24 (0.863) suggests a possible role of these associated VOCs in MPM pathogenesis and as a diagnostic marker in discriminating MPM patients from asbestos-exposed healthy controls. Figure 1

Conclusion
Several VOCs of interest were obtained in the breath of MPM patients. Two peaks were significantly discriminating between both populations. GC-MS analysis and further large cohort studies are ongoing in order to validate the accuracy of IMS as a diagnostic tool for MPM.

Background
Radiotherapy reduces local recurrence following extrapleural pneumonectomy (EPP), and forms part of a potentially curative, multimodality treatment of malignant pleural mesothelioma. Hemithoracic radiotherapy poses a significant dosimetric challenge. Conventional techniques have suffered with marked dose uncertainty, while modern IMRT techniques have been associated with increased pulmonary toxicity. We conducted a retrospective review of all patients referred to our institution for hemithoracic radiotherapy following EPP, with the aim of assessing treatment toxicity and outcomes. The present study is, to our knowledge, the largest Australian series of adjuvant radiotherapy for this disease.

Methods
53 patients were referred following EPP for malignant pleural mesothelioma, with or without neoadjuvant chemotherapy, between 2004 and 2012. 4 patients were excluded or did not commence radiotherapy due to poor performance (n = 3) or disease progression (n = 1). Radiotherapy involved a 3D conformal, mixed photon and electron technique, delivering 45-55 Gy in 25-28 fractions (2004-2009, n=31), and a 9-field IMRT technique, delivering 50.4-60 Gy in 28-30 fractions (2009-2012, n=18). We assessed toxicity, disease progression and survival in all patients who commenced radiotherapy (n = 49). Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0 and survival was calculated from the date of EPP using the Kaplan-Meier method.

Results
31 patients (59%) received neoadjuvant chemotherapy, with a combination of platinum agent and pemetrexed. 41 patients (84%) completed treatment as prescribed. 6 patients stopped prematurely due to toxicity, and 2 due to disease progression. Most patients discontinuing due to toxicity (n = 5) received over 90% of the prescribed dose. Low grade nausea, anorexia and fatigue were near universal, however severe (grade 3) skin toxicity, nausea and oesophagitis were 8%, 6% and 2%, respectively. One patient developed a grade 4 Pneumocystis carinii infection, however there were no cases of radiation pneumonitis. Late toxicities were rare, with the exception of a persistent elevation in the liver enzymes alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). Of the patients treated with right-sided disease (n = 26), 9 (35%) developed grade 2-3 elevations in ALP or GGT. Grade 2-3 liver toxicity was more common in patients treated with a conventional technique (53%) than with IMRT (11%). No patients developed clinical hepatitis. With a median follow up of 19 months (range 2-102 months), median progression-free survival and overall survival were 22 and 30 months, respectively. 2-year overall survival was 53.8%. 7 patients (14%) were alive beyond 5 years.

Conclusion
Hemithoracic radiotherapy can be safely delivered in selected patients following EPP. Although associated with significant early toxicity, most patients complete treatment and late toxicity is uncommon. Our outcomes compare favourably with recently-published international series.

Background
A brief review of the quality of life of one group of survivors and carers identified that after EPP the most common symptoms affecting quality of life were fatigue, dyspnoea, insomnia and pain. Survivors struggled to return to normal levels of social and role functioning. Interviews also identified the need to share stories with others survivors. In response to this information a well living programme was integrated into an EPP survivor support group. The aim being: to provide information and develop skills to empower survivors and carers to react and improve their quality of life; to optimize the physical, emotional, and social functioning of survivors; and, to assist carers to perform their role while remaining mindful of their own care need.

Methods
Four 1 day support / well living meetings were held during 2012. Each involved invited speakers, fitness assessments (6-minute walk test), and time allocated for networking over food and beverages. Topics included: optimizing living with one lung, physical and respiratory assessments, exploring survivor and carer experiences, mindfulness healing, exploring survivor and carer resilience, creating opportunities for self-attention and nurturing, relating science to the living experience, pain management, writing and music for healing, eating for wellbeing and a goal for 2013. Physiotherapy staff contributed regularly to the meetings.

Results
The average meeting attendance was 20 participants consisting, of 50% survivors and 50% carers. Patients responded positively to the physical challenges and set their 2013 goal as participation in a community 7 Km fun walk – The Sydney Bay Walk in August. In 2013, an exercise physiologist has worked individually with some group members, either face-to-face or via telephone. This encouraged increased aerobic and resistance training. A number of survivors report improvements in overall fitness, enjoyment of daily living and satisfaction with life.

Conclusion
There appears to be consistent changes in participant confidence, and attitude toward physical fitness leading to improved enjoyment of life. The support group is an important link between long term survivors, those currently being treated and a valuable resource for new patients deciding about EPP.

Background
To examine the evidence base for radiotherapy in the treatment of pain in malignant pleural mesothelioma.

Methods
A systematic search of the Medline (1946-2013), Embase (1974-2013) and Central (The Cochrane Library Issue 9, 2012) databases was performed looking for studies which evaluated the role of radiotherapy for pain relief in people with malignant pleural mesothelioma (MPM). Studies were included if MPM was radiologically or histologically diagnosed, radiotherapy was given with the intent of improving pain and response rates to radiotherapy were reported. Documentation of the dose and fractionation of radiotherapy that was given was required. Finally, the study must have explored the relationship between radiotherapy and pain response. Systematic reviews were ineligible.

Results
Nine studies were eligible. There was marked heterogeneity among studies so quantitative synthesis of results was not possible. The most recent study reported a clinical response rate of 54% two weeks after radiotherapy given at a dose of 36 Gray (Gy) in 12 fractions. This was targeted at the area of MPM that was felt to be causing the pain. However, this assessment was performed retrospectively. A radiological response of 43% measured via CT scanning two months after irradiation was also reported in this study. Another study reported a superior response rate (50%) for those treated with a 4 Gy fraction size compared with those treated with a fraction size of less than 4 Gy (39%). However, this was not randomised and reflected a change in policy to treat sites of symptomatic disease only rather than covering the entire volume of disease. A further study suggested a benefit to hemi-thoracic irradiation at a dose of 30 Gy in 10 fractions. However, Cobalt machines were used in this study. Another study suggested no benefit to hemi-thoracic irradiation at a dose of 40 Gy in 20 fractions. However, 27 of the 47 patients in this study had no pain at study baseline. The other studies in this review report varying response rates, primarily reported in a retrospective fashion.

Conclusion
There are no high quality data to support the use of radiotherapy for pain management in MPM. Studies focusing on clear pain endpoints, improving target delineation and delivering higher equivalent doses using modern day radiotherapy are needed. Biomarkers which may predict response in a proportion of patients should be sought.

Background
ACT using genetically modified T cells has shown great promise in different malignancies (eg melanoma, chronic lymphoid leukemia.) Our group has recently applied this technology by creating T cells that express a chimeric antibody receptor (CAR) that targets the highly expressed tumor antigen, mesothelin to treat malignant mesothelioma (MM), ovarian, and pancreatic cancer and has initiated a Phase I trial in MM patients using mRNA transfected CAR T cells against mesothelin (CART-meso cells) to test its feasibility and safety.

Methods
Three patients with progressive MPM with epithelial or biphasic MPM underwent apheresis for T cell isolation/electroporation/expansion. To mitigate concerns about potential off-target toxicity due to low levels of mesothelin expression in normal tissues we developed “biodegradable” mesothelin-specific CAR engineered T cells that transiently express CAR transcripts following mRNA electroporation. T cells were electroporated with the CAR mRNA and then frozen aliquots were thawed and administered to the patients. Serum/peripheral blood/marrow mononuclear cells were acquired from patients during the trial to detect/quantify abundance of transgene and CD3e transcripts, soluble cytokine factors, human anti-mouse antibody (HAMA), CAR T cell-induced humoral responses against tumor antigens.

Results
Adoptive transfer of mRNA engineered to express “biodegradable” CAR that target mesothelin was feasible. CARTmeso cells were detected in the blood and demonstrated the predicted transience of persistence in peripheral blood. Infusions were safe from the perspective of off target toxicity due to low level mesothelin expression in normal tissues. However, in one patient who received two courses of T cells, with the second course after a 6 week delay developed an anaphylactic reaction after T cell infusion, presumably due to IgE antibodies generated against the murine single chain antibody that is part of the CAR. We observed clinical activity in one patient who showed a 50% reduction in mediastinal tumor volume (Figure 1). This patient also developed antibodies against other proteins present in mesothelioma cell lines. Figure 1 Fig 1. Greater than 50% reduction in volume of mediastinal MPM tumor in one patient after infusion.

Conclusion
ACT of mRNA engineered CART-meso cells is feasible and safe from the perspective of off target toxicity due to low level mesothelin expression in normal tissues. mRNA engineered T cells can be used to evaluate potential issues of off-target CAR-mediated toxicity and support the development of CAR-based strategies to target mesothelin.

Background
Patients with malignant pleural mesothelioma (MPM) may be treated aggressively by a multimodality approach including radical resection with a curative intent. Yet, a large proportion of them fail locally. One of the measures to reduce local relapse is heated pleural chemoperfusion (HPCP) with platinum based compounds. We report the results of a combined treatment consisting of resection and HCPC in patients with epitheloid MPM (EMPM).

Methods
A single center retrospective study of 48 patients with EMPM scheduled for the combined approach over a 16 years period. Surgery consisted of extrapleural pneumonectomy (EPP), or lesser resections (LR), followed by HPCP with cisplatinum, 100mg/m[2] at >42[o]C for 60 min. Survival analysis was done with the Kaplan-Meier method and comparisons between groups with chi square analysis.

Results
Of the 48 pts only 42 had both resection and perfusion. Operative mortality was 6.2%; all fatalities occurring after EPP. There was no toxicity. EPP was performed in 72% of advanced stage (AJCCS III+IV) compared to 54% in early stage (AJCCS I+II) disease (p=0.238). Major and minor morbidity were 8(27%) and 9(32%) Vs. 2(16%) and 3(25%), for EPP and LR respectively. The Overall median survival was 14.6 (11.1-18.2, CI-95%); 13.4 months (3.4-23.5, CI-95%) and 28.3 (7.7-48.9, CI-95%) months for EPP and LR respectively (p=0.079). Patients undergoing EPP+HPCP for advanced stage EPMP (n=21) had a median survival of 21.6 months (2.0-43.0, CI-95%). Local control was achieved in 87.5% of the EPP group and 42% of the LR group (p<0.007). The common sites of relapse or progression were ipsilateral pleura (n=9), contralateral pleura (n= 7) and peritoneum (n=5). Early stage disease (I+II) had a survival not significantly better then late stage disease (III+IV).

Conclusion
In a center with low-volume surgery for mesothelioma, resection and HPCP can be performed with acceptable mortality and morbidity and no toxicity. In EMPM, HPCP does not reduce local relapse after resections lesser than EPP. In advanced stage EMPM, EPP coupled with HCPC seems to reduce the rate of local relapse, and may contribute to a relatively long survival. The role of HCPC in conjunction with surgery should be further investigated. Figure 1

Background
The legacy of occupational and environmental asbestos exposure in Piedmont, Italy, is a continuing epidemic of pleural malignant mesothelioma (MPM). MPM still entails a poor prognosis, but progresses in its medical and surgical treatment have occurred and guidelines started to appear. We aimed to assess: (i) the appropriateness of treatment for MPM cases recently diagnosed in the Piedmont population, taking into account patients’ general conditions and disease stage at diagnosis, (ii) the end results of treatment.

Methods
We exploited the Registry of Malignant Mesotheliomas (RMM) records to identify incident cases from 2008 to 2011. Patients diagnosed/treated in hospitals including a thoracic surgery unit and in the Casale Monferrato hospital were known to represent about 70% of all MPM incident cases and were included in this study, as for them not only clinical records on diagnostic procedures, but also on treatment and follow-up were completely retrieved by RMM. Vital status at 31/12/2012 was ascertained for all MPM cases. Current analyses were limited to incident cases 2008-2009, followed at least up to 3 years. Multinomial logistic regression was used to estimate the odds ratio (OR) of receiving a specific treatment (categories: cytoreductive surgery, CRS, chemo/immunotherapy, CIT, best supportive care, BSC), conditional on individual characteristics. Survival was assessed with univariate (Kaplan-Meier) and multivariate (Cox) methods.

Results
There were 297 MPM cases. Taking CIT as reference, the OR of receiving CRS was decreased by older age and low performance status (Table 1). That of receiving BSC alone was increased by older age and low performance status as well, and by non-epithelial histotype. Median survival was 13.6 months for patients receiving CIT and 18.3 for those undergoing CRS Figure 1

Conclusion
In participating centres, MPM are currently treated in agreement with available guidelines, and treatment outcomes are consistent with expectations.

Background
Single time-point unidimensional tumor thickness measurements define measurable disease for clinical trial inclusion and also constitute a field in the IASLC prospective mesothelioma staging database. The modified RECIST guidelines for mesothelioma did not alter the 10mm minimum tumor measurement recommendation. It is unclear at what minimum thickness interobserver variability exceeds 20% of tumor thickness and how morphology, and location affect interobserver variability in a single baseline measurement.

Methods
105 thoracic CT scans were collected retrospectively from 50 mesothelioma patients. Each scan was reviewed by a medical oncologist, who identified 170 discrete sites of mesothelioma tumor across all scans that represented a range of thickness. Lesion morphology (concave rind, convex rind, convex mass, fusiform mass), and anatomic location (chest wall, mediastinum, anterior angle, or posterior angle; craniocaudal location; bone/soft tissue) were categorized. Using a custom computer interface (Abras), reference tumor thickness measurements were obtained by creating a line segment that spanned the tumor from the parietal tumor margin along the chest wall or mediastinal structures to the inner tumor margin. Measurements were selected to capture a range of tumor thicknesses and morphologies, rather than the most clinically relevant measurement sites. An observer study was conducted in which each of five other physicians was presented with the individual CT sections and the same digitally fixed location of the outer tumor margin at each of the 170 pre-defined tumor measurement sites. Each observer then independently created a line segment to capture tumor thickness at all measurement sites. Relative differences among the tumor thickness measurements of observers were estimated using a random-effects analysis of variance model (ANOVA) to identify the smallest tumor thickness at which linear measurements could be made reliably. Comparisons were made with the RECIST tumor response criterion of 20% for progression.

Results
The median mean measurement across all sites was 9.68mm, reflecting the study’s aim to investigate measurement variability as a function of tumor thickness, given that the current standard minimum is set at 10mm. The mean range of observer measurements across all sites was 15.1% of the mean per-site measurement (SD 9.1%). Measurements acquired at tumor sites with reference thickness less than 7.5 mm demonstrated inter-observer variability (as defined by the difference between the maximum and minimum measurements of the observers at each site) with a 75th percentile that included 20% of the tumor thickness, while measurements acquired at sites with mean tumor thickness >7.5mm showed inter-observer variability with a 75[th] percentile <20% of tumor thickness. Inter-observer variability tended to be lower for convex mass lesions relative to that associated with the other three tumor morphologies.

Conclusion
The results of this study have implications for the definition of minimum measurable tumor adopted by clinical trial and staging protocols.