Virtual Library

Background
HSP90 is a promising anti-cancer target. Inhibition by the Hsp90 inhibitor ganetespib has shown promising activity with improved survival in patients with metastatic lung adenocarcinoma, and it is now being evaluated in malignant pleural mesothelioma. However, the mechanisms underlying resistance are currently unknown. The aims of this study were to establish the role for mitochondrial apoptosis in mediating the anti-cancer activity of ganetespib, and to also identify mechanisms of acquired resistance to support personalised therapy.

Methods
We conducted a functional genetic screen to determine the role of the proapoptotic BAX/BAK proteins using double knockout mouse embryonic fibroblasts (MEFs) shRNA and siRNA. Focused RNAi targeting BH3-only proteins, Caspase 8 and MCL1 was conducted in MSTO-211H, H460 and H23 cell lines. Apoptosis was measured by a Caspase3 activity assay and data were validated by western blot and SubG1 population analysis. Prosurvival Bcl2 family regulation was evaluated by western blot, and MCL1 transcriptional suppression monitored by real-time quantitative PCR and luciferase reporter assay. MCL1 amplification was quantified by genomic real-time PCR. Ganetespib resistant cells were generated by increasing drug exposure. Hsp90 ATP-binding site and Caspase8 were sequenced in both parental and resistant cell lines.

Results
Ganetespib required a functional mitochondrial pathway for induction of apoptosis. Interrogation of pro-apoptotic BH3-only proteins revealed a co-operation between BID, BIK and PUMA. Caspase8 activates BID and, when silenced, protected cells from ganetespib. MCL1 was transcriptionally suppressed by ganetespib, and when Mcl-1 downregulation was achieved by siRNA, it was sufficient to induce BID/BIK-dependent apoptosis in MCL1-dependent cells. We observed that MCL1 addicted cells were also more sensitive to ganetespib than non-addicted. In addition, amplification of MCL1 was detected only in ganetespib sensitive cell lines. Ectopic MCL1 was not sufficient to rescue from ganetespib-induced apoptosis. To better understand mechanisms of resistance, we established ganetespib-resistant cell lines. Resistant cells did not select for HSP90 mutations, and these cells conserved on-target suppression of PI3K/AKT, MAPK signalling, upregulation of HSP70, and MCL1 downregulation. However addiction to MCL1 was lost as was block of Caspase8 activation with consequent cross-resistance to TRAIL. PCR of Caspase8 cDNA revealed an acquired structural alteration in the 3’-untranslated region.

Conclusion
Here we show that HSP90 inhibition requires engagement of the mitochondrial apoptosis pathway, and involves cooperation of multiple BH3-only proteins with parallel suppression of MCL1. Interestingly, ganetespib may exploit tumour dependence on MCL1; this may be clinically relevant given that MCL1 (1q21.2) amplification correlates with dependence and its gene copy number alteration is one of the most frequent across cancers. Acquired resistance involves selection for loss of dependence on MCL1, and a block in Caspase8 signalling which lies upstream of BID. Failure of ectopic MCL1 overexpression to rescue is indicative of redundant death signalling by ganetespib. Clinical significance of core apoptosis gene expression will be explored and presented in a correlative analysis of the 9090-06 ganetespib monotherapy clinical trial in NSCLC.

Background
We report exploratory gene expression profiling data from a prospective single-arm Phase-II-study in patients with non-squamous non-small cell lung cancer (nsNSCLC) treated with pemetrexed. Main results indicated a significant association of low thymidylate-synthase (TS) expression with longer PFS and OS [1].

Methods
Treatment-naive nsNSCLC patients (Stage IIIB/IV) received 4 cycles of first-line pemetrexed/cisplatin; non-progressing patients continued on pemetrexed maintenance [1]. Diagnostic tissue samples were used to assess TS expression (nucleus/cytoplasm) by immunohistochemistry (IHC, H scores), and to extract total mRNA for expression-array profiling (expression of 1,030 genes summarized from 60,000 transcripts). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS, mRNA gene expression was used both as continuous and binary (cutpoint: median) variable. Unadjusted p-values (significance level =0.01) and false discovery rates (FDR) were calculated. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman rank test). Finally, unsupervised clustering was applied to all samples with mRNA expression (n=51) for all 1,030 selected array genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n=47) previously described [2].

Results
51/70 (72.9%) biopsies were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01). 8/9 genes were negatively correlated with nuclear TS expression; the test was statistically significant for 5/8 genes (unadjusted p<0.01, Table 1). None of these genes has a known relationship to folate metabolism. Cluster analysis of all 51 samples based on 1,030 genes revealed no clear trend regarding PFS/OS. Cluster-analysis of 47 ADC samples identified 3 groups (n=21, 11 and 15 patients, respectively) with median (95%CI) PFS and OS of 8.1 (6.9, not estimable [NE]) and 20.3 (17.5, N.E) months; 2.4 (1.2, NE) and 4.3 (1.4, NE) months; and 4.4 (1.2, NE) and 8.3 (3.9, NE) months, respectively. Figure 1

Conclusion
This exploratory analysis provides insights on key genes potentially linked to low TS expression. Nine genes were significantly associated with PFS/OS; however such association cannot be differentiated as prognostic or predictive since this study is single arm. Further research would be needed to understand the relationship of these markers with clinical outcomes. [1] Nicolson et al, J Thorac Oncol 2013, May 29 [Epub]. [2] Wilkerson et al, PLoS One 2012;7(5):e36530.

Background
The platinum-based doublet regimen was standard of care in advanced non-small cell lung cancer (NSCLC), but the biomarkers to predict the efficacy of first-line chemotherapy is still controversial.

Methods
We collected 239 tumor samples (83.0%) from a a randomized, controlled, multicenter clinical trial, which enrolled 288 treatment naïve nonsquamous NSCLC patients who were randomly assigned (1:1) to experimental group to receive cisplatin plus pemetrexed (PC) or the control group to receive gemcitabine plus cisplatin (GC) every 3 weeks for up to 6 cycles. We evaluated the EGFR mutation by Amplification Refractory Mutation System(ARMS) method and EML4-ALK fusion by real-time PCR. Meanwhile, the mRNA expression of excision repair cross complementation 1 (ERCC-1), thymidylate synthase (TS), ribonucleotide reductase M1(RRM-1), and folatereceptor 1(FR-1) was tested by real-time PCR. All of the EGFR mutation, ALK fusion and mRNA expression were analyzed for the correlation with progression free survival, the primary endpoint in the tiral.

Results
The EGFR mutation rate was 46.6%(110/236) in the overall population and the ALK fusion rate was 12.0%(29/233). The median PFS was similar between the EGFR mutated patients and wild-type patients(6.0m vs 5.7m,p=0.85), however, the patients of EGFR wild-type had better PFS in the PC group compared with GC group (5.7m vs 3.5m, p=0.03). There are no significant difference between groups in EGFR mutated patients(5.6m vs 6.1m, p=0.59). The patients with ALK fusion seem to have better PFS compared with fusion negative patients (7.7m vs 5.7m), but the difference is not significant(p=0.48). The mRNA expression level was available in 225 patients(94.1%) and we determined the median expression as the cutoff value. The TS expression is significantly correlated with ERCC-1(r=0.67,p<0.001) and negatively correlated with FR-1 expression(r=-0.21,p=0.002). EGFR mutation correlated with lower TS expression(p=0.034) and ALK fusion correlated with higher FR-1 expression(p=0.017). The differences of PFS between the high and low expression of ERCC-1, TS, RRM-1and FR-1 was not significant, in both PC group and GC group.

Conclusion
The expression level of ERCC-1, TS, RRM-1and FR-1 could not effectively predict the progression free survival of NSCLC patients receiving platinum-based doublet regimen. The pemetrexed plus cisplatin regimen should be the priority choice for EGFR wild type patients compared with gemcitabine plus cisplatin regimen.

Background
Upregulation of MET and more recently AXL have been described as potential mechanisms of resistance to EGFR tyrosine kinase inhibitors in NSCLC. We explored the impact of baseline MET and AXL tumour expression and circulating hepatocyte growth factor levels, (HGF), in advanced NSCLC patients receiving erlotinib plus foretinib, an oral multi-targeted kinase inhibitor of MET, RON, AXL, TIE-2 and VEGFR.

Methods
Advanced NSCLC patients that previously received one or two lines of chemotherapy were treated in IND.196, a phase I dose-finding trial with an initial two-week run-in of single agent erlotinib (100-150 mg daily). If erlotinib was well tolerated, foretinib was then added (30-45 mg daily). Submission of tumour samples (archival or fresh) was mandatory, and circulating HGF levels were determined at baseline and on treatment. Tumour samples were genotyped using Sequenom MassARRAY analysis. MET and AXL expression were determined by immunohistochemistry. For AXL, the human Axl affinity purified polyclonal goat IgG antibody (R&D systems, AF154, Minneapolis MN) was scored manually. For MET, the anti-total MET (SP-44) rabbit monoclonal antibody (Ventana Medical Systems, Tucson AZ) was scored using the Benchmark XT autostainer. Staining intensity (0-3+) and percent cells stained were used to calculate the H-score; H-scores >100 were deemed positive for AXL, and >200 positive for MET.

Results
Of 31 patients enrolled, 28 were evaluable for response to combination therapy, with a recommended phase II dose of erlotinib 150 mg daily for a 2-week run-in and then foretinib 30 mg daily added. The overall response rate in the intent to treat population (RECIST 1.1) was 16.1% (95% CI 5.5-33.7%), with partial responses (PR) seen in 5/31 patients and a median response duration of 17.9 months (range 3.6-17.9). Stable disease was seen in 42% (13/31), with a median duration of 4.8 months (95% CI 2.4-15.4). Tumour samples were submitted for 25 patients; 15 had sufficient tissue for genotyping, 17 for assessment of MET, and 16 for AXL expression. 2/5 responding patients had confirmed EGFR mutations, (1 wildtype, 2 unknown). Another 5 had KRAS mutations, one with >20% reduction in tumour size but SD by RECIST. Of 17 patients with MET IHC results, 71% (12/17) were positive. PR was seen in 3/12 patients with MET-positive tumours, (2 with EGFR mutations, 1 wildtype). No response was seen in those with MET-negative tumours. Of 16 samples with AXL IHC results, 9 were positive (56%). PR was seen in 2/9 with AXL-positive tumours and 2/6 with AXL-negative tumours. AXL expression was not seen in samples with EGFR mutations, but 3/5 KRAS mutant samples were AXL positive. Assessment of circulating HGF levels will be presented at the 2013 WCLC meeting.

Conclusion
Baseline MET expression, uncontrolled for EGFR status, may be associated with response to combination erlotinib/foretinib. No correlation between baseline AXL expression and response was seen although the sample size is small. Further study is needed to control for the impact of EGFR mutation status on response, and to assess whether combination erlotinib/foretinib can overcome resistance to EGFR TKI therapy mediated by MET and AXL.

Background
Heat shock proteins are a group of proteins termed stress proteins. The family of Hsp90 includes Hsp90α and Hsp90β, but only Hsp90α has been described to be extracellular, and the presence of Hsp90α on cell surface has been shown to correlate with malignancy in cancer patients, especially with the tumor metastasis. However, to the best of our knowledge, no large clinical samples have been reported to verify above standpoint. The aim of the present multicenter clinical study was to evaluate the expression level of Hsp90α in lung cancer patients and whether Hsp90α was monitor and predictor for response to therapy in lung cancer.

Methods
A total of 2284 lung cancer patients were enrolled in this study which was randomly assigned into two groups as static and dynamic groups. The static group (2036 samples) consisted of healthy subjects (592 samples), lung cancer (1046 samples), non-cancerous lesions of the lung patients(361 samples ) and other cancer patients(37 samples). Samples of peripheral blood from all subjects were collected in sterile EDTA-K2-coated vials. Whereas the dynamic group included lung cancer patients who received surgical treatment and underwent chemotherapy, with number of above mentioned parts 79 and 169, respectively. For surgical patients, plasma samples were collected at following time points: 3 days before surgery, 3-7 days after surgery and 3 days after clinical efficacy evaluation. Similarly, plasma samples of chemotherapy patients were also collected before treatment, after each chemotherapy cycle until the forth cycle. The concentrations of Hsp90α in plasma were measured by enzyme-linked immunosorbent assay.

Results
The concentration of Hsp90α in lung cancer patients was significantly higher than in other control groups (P <0.05). The cut-off value was 56.33 ng/mL for diagnosis, with high sensitivity and specificity (72.18% and 78.70%, respectively). Advanced lung cancer (stage III-Ⅳ) patients were with higher Hsp90α levels than the early patients(stage I-II) (251.38 ng/ml vs 111.50ng/ml, P<0.001), no significant relationship was found between non-small cell lung cancer（NSCLC,910 samples）patients and small cell lung cancer （SLCL, 136 samples）patients, and patients with adenocarcinoma(537 samples) and squamouscarcinoma (218 samples). Furthermore, a statistically significant association was observed between pre-operative and post-operative patients in surgical patients group (P<0.01). In chemotherapy patients group, Hsp90α level was correlated significantly with the effect of treatment [concentration of Hsp90α was higher in progressive disease(PD)group than in partial response(PR)/stable disease(SD) group].

Conclusion
This study firstly developed large clinical samples and elucidated the role of Hsp90α in the lung cancer patients. The cut-off value of 56.33 ng/mL was recommended to assess the expression level of Hsp90α in lung cancer patients. Hsp90α may be a potential biomarker for therapeutic monitor and prediction for lung cancer.

Abstract not provided

Background
MET signaling is correlated with a poor prognosis in multiple tumor types, including NSCLC. A randomized, controlled, phase II clinical trial demonstrated a PFS and OS benefit of inhibiting MET signaling with erlotinib + onartuzumab, a humanized monovalent antibody to the MET receptor, in patients whose NSCLC over-expressed MET by IHC (in press). A phase III trial (OAM4971g) is ongoing to confirm the benefit of onartuzumab when combined with erlotinib in patients with previously treated NSCLC whose tumors over-express MET by IHC (2+/3+ only). Here, we present the prevalence rates of MET expression and EGFR mutation status for patients whose tumor tissues were screened and for those enrolled in the phase III study.

Methods
Archival or fresh biopsy tumor specimens were submitted to a central laboratory for both MET IHC and EGFR mutation assessment. MET IHC status was determined using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems, Inc., Tucson, AZ). Patients were selected based on expression of MET by IHC, as defined by moderate or strong staining in at least 50% of tumor cells (clinical score 2+/3+). The cobas[®]EGFR mutation test was used to stratify enrollment.

Results
Between November 2011 and June 2013, 1605 tumor tissue samples were submitted for MET IHC and EGFR activating mutation analysis, from 188 clinical study centers. The majority of screened and enrolled patients were over 60 years of age, Caucasian, male, and had non-squamous NSCLC histology (see table). MET IHC results are available for 1474 (92%) of all submitted samples: IHC 0 (n=118, 8%), IHC 1+ (n=619, 42%), IHC 2+ (n=575, 39%), IHC 3+ (n=162, 11%). The incidence of MET IHC 2+/3+ in screened patient subgroups is as follows: non-squamous 52.5%; squamous 29.2%; non-Asian 45.9%; Asian 48%; EGFR wild type 50.3%; EGFR mutant 57.5%. Table: Patient characteristics for screened and enrolled patients in the OAM4971g study

Conclusion
In this large population, the prevalence of MET IHC 2+/3+ was 50% in screened samples, consistent with prior IHC results for MET prevalence. The prevalence of MET IHC 2+/3+ was higher in non-squamous vs squamous tissue samples, but equally distributed across ethnicity and EGFR mutation status. The ongoing OAM4971g study will prospectively confirm whether blocking MET signaling in patients with MET IHC 2+/3+ over-expressing NSCLC provides clinically meaningful benefit in all enrolled patients and in important clinical subpopulations.

Background
Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers. Treatment for SCLC has not changed in recent years and no targeted therapy has shown an increase in survival. We have previouly shown that Met phosphorylation is an adverse prognostic factor in this disease, suggesting a potential interest of Met targeted therapies in the treatment of SCLC patients. The aims of our study were to evaluate serum levels of the Met ligand, the hepatocyte growth factor (HGF) in patients with SCLC and to assess the correlations with other clinical variables and survival.

Methods
This is a prospective study conducted between 2009 and 2012. Serum samples were obtained from patients with SCLC at diagnosis, at first evaluation of response to standard chemotherapy by computerized tomography (CT) and at progression/relapse (first event). HGF levels were assessed by ELISA using the Quantikine commercial kit (R&D Systems, Minneapolis, MN). We evaluated the association between HGF levels and clinical-pathological variables by the Mann-Whitney tests and with survival in univariate (log-rank test) and multivariate analysis (Cox regression), assuming a statistical significance of p <0.05.

Results
Fifty-nine patients were included in this study. Median follow-up was 11 months. Patients’ characteristics are summarized in Table 1. The median serum HGF (range) at diagnosis, response and progression were 1750 pg/ml (651-9853), 1573 pg/ml (593-8518) and 1461 pg/ml (553-12956), respectively. In 72.5% of cases HGF levels decreased after 3 cycles of chemotherapy (platinum+etoposide). From the response time point to progression, 50% patients showed an increase in the HGF levels. The median overall survival (OS) for the entire population was 11,8 months(95% CI 6.4-14.8). The median OS for patients with high basal HGF (above 1750pg/ml) was 7,9 months vs 16,7 months for patients with basal HGF below the median. Patients whose HGF levels increased at progression presented a decreased survival (9,23 months) vs. those with a decrease (15,11 months) (p=0.032). In the multivariate analysis, PS> 1 (HR: 5.57, 95% CI 2.63-11.77 p < 0.001), stage IV (HR: 4.28, 95% CI 1.76-10.44 p = 0.001) and elevated HGF basal levels were independently associated with worse OS (HR: 3.32, 95% CI 1.57-7.03, p =0.002).

Conclusion
HGF serum levels at diagnosis and changes during treatment are predictors of survival in patients with SCLC treated with standard first-line chemotherapy.

Background
BIM deletion polymorphism was reported to be associated with poor outcome to epidermal growth factor receptor (EGFR) inhibitor in advanced non-small cell lung cancer (NSCLC) harboring mutant EGFR gene. Little is known whether BIM deletion polymorphism influences treatment outcome to chemotherapy in NSCLC.

Methods
We prospectively collect blood samples and clinical data from two independent cohorts of advanced NSCLC patients. The first cohort is composed of 52 patients who received first-line chemotherapies, and the second cohort is composed of 69 patients who received chemotherapy after front-line gefitinib. BIM deletion polymorphism was determined from blood using polymerase chain reaction. EGFR gene was studied in 94 tumors and were classified as wild type, common EGFR mutation (deletion 19 or L858R), or other mutations.

Results
The median progression-free survival (PFS) to the first cohort and second cohort were 4.6 and 5.7 months, respectively (p=0.94). The PFS for tumors carrying wild-type, common mutant, and other mutant EGFR genes were 5.8, 4.4, and 7.2 months, respectively (p=0.31). The BIM deletion polymorphism was detected in 19 samples (15.7%). The PFS of patients with normal BIM (solid line of the figure) and BIM deletion polymorphism (dashed line of the figure) were 5.6 and 3.5 months (p=0.03). BIM deletion was related to shorter PFS in tumors carrying mutant EGFR gene (p=0.006) but not those carrying wild-type or other mutant EGFR genes. A multivariate analysis suggested BIM deletion was an independent predictor for shorter PFS to chemotherapy (harzard ratio=2.71, p=0.003).

Conclusion
BIM deletion polymorphism is associated with shorter PFS to chemotherapy in advanced NSCLC.

Background
Drug resistance significantly weakens the effect of treatment. BIM deletion polymorphism has emerged as a potential drug resistant biomarker. This study aimed at assessing the correlation of BIM deletion with the outcome of Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs ) and chemotherapy in Chinese NSCLC patients

Methods
290 patients with advanced NSCLC who received EGFR-TKIs and chemotherapy were included in this retrospective study. BIM deletion polymorphism and EGFR mutations were detected by Polymerase Chain Reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) respectively.

Results
BIM deletion polymorphism occurs commonly in Chinese NSCLC patients (15.5%, 45/290). No associations were observed between BIM deletion polymorphism with clinicopathology characteristics including sex, smoking and EGFR mutation status. BIM deletion polymorphism predicts shorter PFS in Chinese patients with EGFR-mutant NSCLC received EGFR-TKIs (6.69 vs 8.47months, P=0.023). Meanwhile, we found that BIM deletion polymorphism is an effective predictor of short PFS in individuals with EGFR-mutant NSCLC treated with pemetrexed contained chemotherapy (3.32vs5.30, P=0.012) or with second-/beyond-line Taxanes contained chemotherapy (1.53 vs 2.61months, P=0.025) However, In the EGFR-wild type group, the difference is not significant for the former two groups. patients with this deletion are prone to suffering serious adverse event (SAE) (4.5% vs. 15.6%, P=0.018). BIM deletion lacks for correlation with OS. (21.87vs21.90months, P=0.627), even in the EGFR-mutant group.

Conclusion
BIM deletion polymorphism occurs in 15.5% Chinese NSCLC patients. BIM deletion polymorphism is a drug resistance biomarker for TKIs and chemotherapy in NSCLC. BIM deletion possibly affects OS, but not a decisive factor.

Background
The BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death (BIM) is a potent pro-apoptotic protein. Recent data suggest that pretreatment BIM level may predict responsiveness to EGFR-TKI in EGFR-mutant non-small cell lung cancer (NSCLC). In addition, a common BIM deletion polymorphism contributes to the heterogeneity of response to EGFR-TKI in EGFR-mutant NSCLC. We investigated whether BIM expression and BIM deletion polymorphism (BIM-DEL) are predictive for response rate (RR) and progression-free survival (PFS) to EGFR-TKI therapy in never-smoking lung adenocarcinoma (NSLA).

Methods
We analyzed EGFR mutation status by Sanger sequencing, BIM-DEL genotyping by polymerase-chain reaction and BIM expression by immunohistochemistry using archival tissues or blood from 203 patients who participated in the FIRST-SIGNAL trial (1[st] line gefitinib vs. Gemcitabine/cisplatin in advanced NSLA).

Results
EGFR mutation test, BIM-DEL genotyping and BIM-IHC analysis were available in 82, 126 and 60 patients, respectively. Forty-five (55%) patients had EGFR mutations, 22 (18%) showed BIM-DEL and 22 (37%) showed negative BIM expression. BIM expression was significantly associated with EGFR mutation status; more patients with EGFR-mutant NSCLC showed negative BIM expression (48% vs. 21%, P=0.030). BIM-DEL was not associated with EGFR mutation status or BIM expression. Among 181 patients who received EGFR-TKI as 1[st] or 2[nd]-line therapy, EGFR mutation, BIM-DEL and BIM expression data were available in 74, 11, 56 patients, respectively. EGFR mutation was predictive for higher RR (66% vs. 15%, P<.001) and longer PFS (4.5 vs. 1.9 months, P=.061) to EGFR-TKI therapy. Negative BIM expression also showed a trend toward higher RR (68% vs. 42%, P=.061) and longer PFS (6.9 vs. 2.3 months, P=.233) with EGFR-TKI. However, BIM-DEL was not predictive for RR (41% vs. 47%, P=.645) or PFS (3.5 vs. 3.7 months, P=.892) to EGFR-TKI.

Conclusion
Both BIM-DEL and BIM expression were not predictive for responsiveness to EGFR-TKI in NSLA. The trend between negative BIM expression and favorable response to EGFR-TKI may be resulted from higher frequency of EGFR mutation in these patients.

Abstract not provided

Background
Chemoradiation is the standard of care for the treatment of unresectable LA-NSCLC. Cisplatin plus either etoposide or vinorelbine are two of the chemotherapy (CT) regimens widely used for the disease concurrently with radiotherapy. Oral vinorelbine is a formulation which has achieved comparable results to the IV vinorelbine. The purpose of the study is to evaluate the efficacy and safety of cisplatin when combined with etoposide or oral vinorelbine with radical radiation for the management of stage III NSCLC.

Methods
Patients (pts) between 18 and 75 years, with histologically proven untreated and unresectable LA stage IIIA/IIIB NSCLC, adequate bone marrow, hepatic and renal function, ECOG PS 0-1, were randomized to: Arm OV-P: OV 60 mg/m[2] D1, D8 cycle 1 and 80 mg/m[2] cycle 2 (if no grade 3-4 toxicity) plus P 80 mg/m[2] D1 every 3 weeks for 2 cycles as induction; patients without progression received OV 40 mg/m[2] D1, D8, and P 80 mg/m[2] D1 every 3 weeks for 2 more cycles (4 cycles in total). Arm E-P: E 50 mg/m[2] intravenously D1 to D5 plus P 50 mg/m[2] D1, D8 every 4 weeks for 2 cycles. Both regimens administered with concurrent RT 66 Gy in 6.5 weeks. The primary endpoint was progression free survival using RECIST 1.1, and secondary endpoints were overall response rate, overall survival, and safety profile. To guarantee an overall type-1 α error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint of PFS, a sample size of 134 pts allocated in a 1:1 ratio is planned.

Results
Since August 2011 77 pts have been recruited. 46 pts have been included in the interim analysis, 23 pts have been randomly allocated to each treatment arm. Patient’s characteristics were: Male 91.3%; median age 64 (range 44-75); PS1 56.5%; smokers 46.8%; adenocarcinoma 40.4% / squamous 55.3%; stage IIIA 46.8% / IIIB 53.2%. Median of months between initial diagnosis and study start was 1 (range 0.3-15.7). Safety: 118 cycles (cy) were analysed, 79 in arm OV-P and 39 in arm E-P. Hematological toxicities arms OV-P/E-P (% cy): grade (g) 3/4 neutropenia 8.9%/13.1%; g3 thrombocytopenia 0%/5.3%; g3 anemia 0%/2.6%; febrile neutropenia 3 cases on OV-P arm (all during induction CT on cy 1) and 1 case on E-P arm (during concurrent chemoradiation). Non-hematological toxicities arms OV-P/E-P (% cy): g3 esophagitis/mucositis 1.3%/15.5%; g3 infection without neutropenia 1.3%/5.1%. No treatment-related deaths were reported. There was no remarkable difference in other toxicities between both arms. 39 pts completed the treatment as per protocol, 19 in arm OV-P and 20 in arm E-P. Overall response rates were 73.7% and 50% for the OV-P and the E-P arm, respectively.

Conclusion
This interim analysis shows that OV-P and E-P when administered concurrently with RT have a manageable safety profile with efficacy. Safety data is consistent with other studies reported for both chemoradiation regimens. Based on these positive results for safety, accrual is ongoing. Clinical trial information EudraCT 2010-022927-31.

Background
The Japan Clinical Oncology Group (JCOG) undertook 2 randomized phase III trials (JCOG9812 and JCOG0301) to assess whether daily low-dose carboplatin plus radiotherapy could improve survival in elderly patients with stage III non-small cell lung cancer (NSCLC) when compared to radiotherapy alone. Although JCOG9812 was prematurely terminated because of a high incidence of treatment-related deaths (TRDs) and instances of protocol violation, especially with regard to radiotherapy planning, the trial regimen was assumed promising. Therefore, JCOG0301 was conducted for the same subjects using the same protocol regimen with modified inclusion criteria regarding pulmonary function and radiotherapy quality control (RTQC) measures. We then carried out a preplanned pooled analysis of these 2 studies.

Methods
The eligibility criteria for both trials were age of ≥71 years and unresectable stage III NSCLC. Patients were randomized to receive radiotherapy alone (60 Gy, RT arm) or chemoradiotherapy (radiotherapy, 60 Gy plus concurrent carboplatin, 30 mg/m[2] per fraction up to the first 20 fractions, CRT arm). The primary endpoint for both studies was overall survival (OS). The pooled analysis included OS, progression-free survival (PFS), response rate, and toxicities.

Results
In JCOG9812, 46 patients (RT arm, n=23; CRT arm, n=23) were enrolled from November 1999 to August 2001. In JCOG0301, 200 patients (RT arm, n=100; CRT arm, n=100) were enrolled from September 2003 to May 2010, and in total, 246 patients were included in the pooled analysis. Patient characteristics for the RT (n=123) and CRT (n=123) arms were as follows: median age, 77 years (range, 71–93) and 77 years (range, 71–89); stage IIIA/IIIB, 65/58 patients and 63/60 patients; performance status (PS) 0/1/2, 44/74/5 patients and 50/69/4 patients; men/women, 103/20 patients and 96/27 patients, respectively. The median OS for the RT (n=121) and CRT (n=122) arms were 16.3 months (95% CI, 13.4–18.6) and 20.7 months (95% CI, 16.3–26.9), respectively (HR, 0.672; 95%CI, 0.502–0.898, stratified log-rank test one-sided p=0.0034). The pooled HR for PFS was 0.671 (95%CI, 0.514–0.875, stratified log-rank test one-sided p=0.0015). Response rates for the RT and CRT arms were 46.3% and 53.3%, respectively. The number of patients with grade 3/4 hematological toxicities was higher in the CRT arm than in the RT arm: leucopenia (62.2% vs 1.7%), neutropenia (54.6% vs none), and thrombocytopenia (30.3% vs 3.3%). The incidence of grade 3/4 pneumonitis decreased from 4.4% (JCOG9812; RT, 4.5% and CRT, 4.3%) to 2.1% (JCOG0301; RT, 3.1% and CRT, 1.0%), and that of late lung toxicity, from 14.0% (JCOG9812; RT, 10.0% and CRT, 17.4%) to 5.9% (JCOG0301; RT, 5.3% and CRT, 6.5%). The incidence of TRD also decreased from 8.9% (JCOG9812; RT, 1 patient and CRT, 3 patients) to 3.6% (JCOG0301; RT, 4 patients and CRT, 3 patients). As per subgroup analyses, ≤75 years, stage IIIA, male, PS 0, and smoking history were associated with statistically significant improvement in OS in the CRT arm.

Conclusion
This combination chemoradiotherapy for elderly patients with locally advanced NSCLC provides clinically significant benefits and RTQC measures are imperative to improve treatment outcome.

Background
This single-arm multicenter Phase II study investigated the efficacy and safety of PEM+CIS induction chemotherapy (CT) followed by full-dose PEM+CIS with concurrent radiotherapy (RT) in patients with LA NS-NSCLC. The 1-year progression-free survival (PFS) rate (primary endpoint) was 51.3% (ESMO 2013). Here, we report the safety data for induction CT and concurrent CT+RT.

Methods
Patients with unresectable Stage IIIA/IIIB NS-NSCLC (AJCC Version 6), ECOG-PS 0-1 and forced expiratory volume (FEV) >50% of predicted normal FEV received 2 cycles of PEM 500mg/m[2] + CIS 75mg/m[2] on Day 1, every 21 days. Patients who did not progress, with no residual neurological toxicity >Grade (G)2, ECOG-PS 0-1 and lung V20<35% were candidates to receive 2 cycles of the same full-dose PEM+CIS regimen with concurrent thoracic RT of 2Gy/fraction, 5d/week for 7wks (66Gy total). All patients received vitamin supplementation/dexamethasone prophylaxis as per PEM-label.

Results
90 patients were enrolled in 4 European countries, 75 (83.3%) completed induction CT and started concurrent CT+RT. Characteristics of 90/75 patients starting induction/concurrent therapy: median age 61/62yrs, male 57%/53%, ECOG-PS 0 66%/65%, mean(SD) FEV 2.3(0.62)/2.3(0.59)L, adenocarcinoma 90%/92%, Stage IIIA 36%/37%. 63 of 75 patients starting concurrent CT+RT (84.0%) received all 4 CT cycles and full dose RT. Median PEM+CIS dose intensities were 90-92% during induction and >97% during concurrent CT+RT, median RT dose was 66Gy (only 6 patients <60Gy). One patient died from study-drug-related toxicity (enteritis) during Cycle 4. Four patients discontinued due to non-fatal drug- or radiation-related adverse events (AEs), 1 on induction CT (renal failure), 3 on concurrent CT+RT (hypoacusis, 2 patients with radiation esophagitis). During induction/concurrent therapy, 8 of 90 patients (8.9%)/12 of 75 patients (16.0%) had ≥1 CT dose delay due to AEs, mainly neutropenia (n=5/6). 2/6 patients (2.2%/8.0%) required CT dose reductions. 13 of 75 patients (17.3%) experienced AEs requiring interruption of radiation, mainly radiation esophagitis (9.3%). Common G1-4 toxicities are presented in the table. 41.3% of patients reported ≥1 G3/4 toxicity during concurrent CT+RT, mainly esophagitis (12.0%), neutropenia (10.7%) and leukopenia (9.3%). G3 mucositis, G3 dysphagia and G3 acute pneumonitis were each reported by 1 patient (1.3%); 6 patients (8.0%) required blood-cell transfusions. Figure 1

Conclusion
PEM+CIS induction CT followed by full-dose PEM+CIS with concurrent thoracic RT was well tolerated in this study. Incidences of both G3/4 and low-grade toxicities were low, not only during PEM+CIS induction CT, but also during the subsequent 2 cycles of full-dose PEM+CIS CT with concurrent thoracic RT.

Background
To evaluate the effect and safety of concurrent thoracic radiotherapy (TRT) with Cisplatin/Etoposide (PE) compared with weekly Paclitaxol/Carboplatin (PC) regimens in patients with stage III non-small cell lung cancer (NSCLC).

Methods
Patients with stage III NSCLC were randomly assigned to receive PE regimen (PE arm) cisplatin 50mg/m[2] d1, 8, 29 and 36, etoposide 50mg/m[2] d1-5 and 29-33 concurrent with TRT 60Gy, or PC regimen (PC arm) carboplatin (AUC=2) and paclitaxol 45mg/m[2] concurrent with TRT 60Gy.

Results
156 patients were registered. Eventually, 149 were assigned to PE arm (73) and PC (76). The median follow-up time was 38 months. The median survival time (MST) was 20 months. The 2-year overall survival (OS) and 3-year OS were 39.8% and 32.9%. The 2-year progress free survival (PFS) and 3-year PFS were 24.8% and 22.4%. The MST of PE arm and PC arm were 22 months and 20 months, and the median progress free time were 13 months and 11months, respectively. The 2-year OS of PE arm and PC arm were 44.9% and 35%, the 3-year OS were 40% and 26.2% (p=0.323), respectively. The 2-year PFS of PE arm and PC arm were 27.7% and 22.1%, 3-year PFS were 24.5% and 20.5% (p=0.449), respectively. The incidence of Great 3/4 bone marrow depression of PE arm and PC arm were 34.2% and 23.7% (p=0.29). The incidence of Great 2 or greater radiation pneumonitis of PE arm and PC arm were 19.2% and 26.3% (p=0.059).

Conclusion
For stage III NSCLC, concurrent TRT with PE regimen has improved PFS and OS comparing with PC regimen without significant difference. Concurrent PE regimen has a lower incidence of Great 2 or greater radiation pneumonitis.

Abstract not provided

Background
Endostatin has been proved to be a potent endogenous angiogenic inhibitor. Recombinant human endostatin (Endostar) was reported to be efficient in blocking angiogenesis and suppressing tumor growth. Preclinical studies demonstrated that Endostar could normalize tumor vasculature, alleviate hypoxia and sensitize the function of radiation. This study was conducted to evaluate the efficacy and safety of Endostar combined with concurrent chemo-radiotherapy (CCRT) in patients with stage IIInon-small-cell lung cancer (NSCLC).

Methods
Patients with unresectable stage IIINSCLC were eligible. Patients received Endostar (7.5 mg/m[2]/d) through 7 days at weeks 1, 3, 5, and 7, and two cycles of docetaxel (65 mg/m[2]) and cisplatin (65 mg/m[2]) on days 8 and 36, with concurrent thoracic radiation at 60~66 Gy. Primary end points included the short-term efficacy and treatment-related toxicity of Endostar combined with CCRT.

Results
In all, 50 patients were enrolled onto the study, and 48 were assessable. Median follow-up was 32.1 months. Response rate was 77%. The estimated median progression-free survival (PFS) was 10.2 months and the estimated median overall survival (OS) was 22.6 months. The 1-year and 2-year PFS rates were 48% and 25%, respectively. The 1-year and 2-year OS rates were 81% and 47%, respectively (Figure 1).Nine patients (19%) experienced grade 3 or higher treatment-related nonhematologic adverse events (AEs). Predominant nonhematologic toxicities were grade 3 esophagitis (n = 4; 8%), and grade 3 to 5 pneumonitis (n = 6; 13%). The rates of observed grade 3 and 4 hematologic AEs were 77% (n = 37). The predominant hematologic toxicity was grade 3 to 4 lymphopenia (n = 32; 67%) and neutropenia (n = 23; 48%). Overall, the entire treatment regimen was well tolerated. Figure 1 Figure 1

Conclusion
The combination of Endostar with CCRT is feasible and shows promising activity. This regimen should be studied further in patients with locally advanced NSCLC.

Background
Increased treatment-associated esophagitis could be responsible for concurrent chemo-radiotherapy (CT-RT)-induced weight loss in patients with non-small cell lung cancer (NSCLC). However, based on clinical observations, we hypothesized that weight loss already starts early after initiation of concurrent CT-RT and might therefore be not solely dependent on decreased intake due to esophagitis symptoms.

Methods
In a retrospective cohort, the onset and frequency of weight changes and their association with esophagitis grade ≥2 were assessed in patients with NSCLC treated with concurrent (n=102) or sequential (n=92) CT-RT. The findings in the retrospective cohort were validated in a prospective study in which weight loss and esophagitis grade ≥2 was assessed over a longer time period and additional data on nutritional intake, muscle strength and quality of life was obtained of patients treated with concurrent CT-RT (n=9).

Results
In the retrospective cohort, both the number of patients with weight loss and the magnitude of weight loss was significantly higher in concurrent than sequential treated patients in week 2, 3 and 4 of (CT-)RT (p<0.05). Longitudinal data analysis showed no significant associations between weight loss and grade esophagitis ≥2 in patients treated with concurrent CT-RT (p=0.10). In the prospective cohort, a similar pattern of ‘early’ weight loss was observed in the first weeks of concurrent CT-RT (p<0.05). This early weight loss was not accompanied by significant decreases in nutritional intake but muscle strength did already decline in this early stage (p<0.05). In the following weeks of concurrent CT-RT, the weight further decreased and reached its minimum at the end of treatment (p<0.05), while the number of patients with grade esophagitis ≥2 increased during this time period. During the later part of concurrent CT-RT, dietary intake was significantly lower and patients became more reliant on supplemental nutrition (p<0.05). Although the weight increased again in the weeks after concurrent CT-RT, it had still not reached the baseline level after 4 weeks post treatment (p<0.05).

Conclusion
Weight loss is a common complication of concurrent CT-RT for locally advanced NSCLC, starts early after initiation of CT-RT and is not dependent of esophagitis. It is presumably caused by active catabolism as this ‘early’ weight loss is accompanied by decreased muscle strength, despite stable dietary intake. In the later weeks of treatment, concurrent CT-RT is characterized by a further decline in body weight, decreased dietary intake and higher reliance on nutritional support. In this phase the occurrence of radiation-induced esophagitis grade ≥2 increases. In the weeks following concurrent CT-RT, partial recovery of body weight takes place but this is still not complete after 4 weeks post CT-RT. The sustained weight loss during and following concurrent CT-RT might have major negative consequences as weight loss in patients with underlying malignant disease might has been associated with higher mortality, lower treatment responses and decreases in quality of life. Though the origin of weight loss during concurrent CT-RT seems to be different in the subsequent phases, more aggressive supportive nutritional support throughout the treatment course seems conceivable to prevent negative energy balances and optimize concurrent CT-RT management.

Background
In this study, impact of high pretreatment white blood cell count (WBCC) on survival outcomes in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with concurrent chemoradiotherapy (CRT) was investigated.

Methods
Medical records of LA-NSCLC patients treated with definitive CRT at our department between dates January 2007 and December 2011 were retrospectively evaluated. All patients received 60-66 Gy thoracic radiotherapy concurrently with 1-3 cycle cisplatin-vinorelbine/taxane (q21) regimen chemotherapy. Patients were divided into two groups according to pretreatment basal WBCC: Group1: normal (4.000-11.000) and Group 2: high (>11.000). These two groups are compared in terms of overall survival (OS), and progression-free survival (PFS).

Results
Pretreatment characteristics of 718 patients were given in Table 1. At a median follow-up of 23.2 months (range 8.8-44.6), median OS and PFS for whole group were 20.6 (%95 CI: 19.3-21.9) and 9.9 months (%95 CI: 9.4-10.1), respectively. On comparative survival analyses, patients with high pretreatment WBCC had inferior OS (22.8 vs.14.7 months; p<0.001) and PFS (10.4 vs. 7.0 months; p<0.001) than those with normal WBCC. On univariate analyses, T-stage (T1-2 vs. 3-4; p=0.035), N-stage (N2 vs. N3; p=0.002), and pretreatment WBCC (4.000-11.000 vs >11.000; p<0.001) were the significant prognostic factors. These factors also retained their significance on multivariate analyses as well (p<0.05 for each). Table. Pretreatment patients characteristics

Conclusion
Worse survival outcomes observed in patients with pretreatment WBCC above the reference limits suggest that pretreatment WBCC may be a potentially cheap and relevant independent prognostic factor that can be used besides other well-known factors to predict treatment outcomes in LA-NSCLC patients treated with definitive CRT.

Background
Perioperative chemotherapy improves overall survival in patients with resectable non-small cell lung cancers. In contrast to adjuvant chemotherapy, neoadjuvant chemotherapy enables radiographic assessment of chemotherapy effect and hence, the option to switch non-responding patients to a potentially more effective regimen. Responses to neoadjuvant chemotherapy assessed by PET imaging correlate better with clinical outcomes than does CT imaging. We have initiated a Phase II trial of PET response guided chemotherapy, where chemotherapy administration decisions are based on comparisons of baseline PET imaging, imaging after 2 cycles of platinum-based chemotherapy, and imaging after ‘switch’ chemotherapy in patients with an initial suboptimal response.

Methods
This Phase II trial (NCT01443078) is enrolling patients with clinical Stage IB-IIIA non-small cell lung cancers deemed operable by a thoracic surgeon. To be eligible, the primary lung mass must be >2 cm with a SUV ≥4.5. Patients with diabetes requiring insulin are excluded. Patients are initially treated with cisplatin (or carboplatin if cisplatin ineligible) + gemcitabine (squamous cell) or pemetrexed (non-squamous). After 2 cycles, if repeat PET imaging shows less than a 35% decrease in SUV of the primary tumor, patients are switched to vinorelbine + docetaxel every 2 weeks with pegylated filgrastim support (2 doses = 1 cycle). The primary endpoint of this study is partial metabolic response after 2 cycles of switch vinorelbine + docetaxel as assessed by PERCIST (SUV decrease of ≥30% using the pre-switch scan as the new baseline). We considered a >20% partial metabolic response rate in those who received vinorelbine + docetaxel worthy of further study. Therefore this study was powered to see at least 6 of 25 partial metabolic responses to vinorelbine + docetaxel, estimating a total patient accrual of 100 patients.

Results
27 patients have been enrolled. 5 are undergoing platinum-based chemotherapy and have not yet been reassessed. 22 patients have been reimaged after 2 cycles of platinum-based chemotherapy, 13 (59%) have had a > 35% decrease in SUV and continued on platinum-based chemotherapy. 9 (41%) patients have had a <35% decrease in SUV after platinum-based therapy and were assigned to switch chemotherapy. 7 received vinorelbine + docetaxel, and 5 (71%, 95% CI 29-96%) have had a PERCIST partial metabolic response after 2 cycles, 1 progressive disease and 1 is pending reassessment. 17 patients have been surgically explored with 13 (76%) R~0~ resections.

Conclusion
Preliminary results from this ongoing trial suggest that patients with resectable non-small cell lung cancers who have a suboptimal PET-assessed response to standard histology-selected, platinum-doublet neoadjuvant chemotherapy can be effectively treated with vinorelbine and docetaxel followed by surgery. This study is on-going. Assessment of pathologic response in resected patients and clinical follow-up in all patients will be available by the time of presentation.

Background
We hypothesized that individualized radiation treatment targeting to the FDG-avid tumor identified mid-treatment would improve local tumor control.

Methods
This is a phase II trial for patients with inoperable/unresectable NSCLC. Conformal radiotherapy (RT) was given in 30 daily fractions. RT dose was individualized to a fixed rate of grade >2 lung toxicity and adaptively escalated to the residual tumor on mid-tx FDG-PET upto a total dose of 86 Gy. Patients were given concurrent weekly followed by consolidation carboplatin/paclitaxel. The primary endpoint was local-regional tumor control (LRTC) and local-regional progression free survival (LRPFS) at 2 years.

Results
42 patients were enrolled: median age 63 years (range 45-83); 28 (67%) male; 39 (93%) smokers; 38 (92%) stage III; and 45% squamous cell. Median physical dose reached was 83 Gy (range 63-86 Gy), equivalent to 90 Gy in 2 Gy fractions (biological effective dose 107 Gy). Minimum and median follow-up were 9 and 27 months, respectively. The 2-year rates of in-field LRTC, overall LRTC, and LR-PFS were 84% (62-94%), 61% (39-77%), and 37% (22-52%), respectively. 15 patients progressed: 2 (13%) at primary tumor alone; 4 (27%) first at distant sites alone; 2 (13%) at nodal regions alone; 5 (33%) at both distant sites and nodal regions; 1 (7%) at both distant site and primary tumor; 1 (7%) at both nodal region and primary tumor. Median overall survival was 22 months (10-33 months) and 2-year overall survival rate was 49% (32-63%). These results compared favorably to stage-matched patients treated with standard-dose RT in our center 2-year overall survival 23% (8-41%) during the same time period.

Conclusion
Adapting RT by targeting high dose radiation to the FDG avid region detected mid-treatment provides outstanding 2-year local-regional tumor control. RTOG 1106 is currently testing this regimen in a randomized fashion.

Abstract not provided

Abstract
There has been an explosion of studies, reports and clinical experience with Stereotactic Ablative Body Radiotherapy (SABR) for lung lesions (both primary and metastatic). Most of the experience and published literature focuses on peripheral lesions; the published and used SBRT dose/fractions are safe, associated with virtually no acute toxitxity and very low rates of subacute and late RT toxicity and high rates of local control. There is an emerging experience in treating central lesions, previous described as a "no-fly zone" . There is also an emerging appreciation about the multitude of organs at risk -- the intiial focus was on bronchi and spinal cord, but clinicians and researchers need to be midful of esophagus, great vessels, heart and brachial plexus as well. The presentation will review the current state of knowledge and highlight the methodological challenges of interpreting the current literature, and emphasize the importance of careful followup of patients with more centrally located lesions, treated with SABR.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract
The past 15 years has seen dramatic developments in radiotherapy (RT) technology and techniques many of which are being applied to patients with lung cancer. The most important of these are PET imaging for RT planning, 3D conformal RT, Intensity Modulated RT, stereotactic body RT (SBR), Image Guided RT and techniques to compensate for respiratory movement such as gating. These are now in widespread use and becoming the ‘standard of care’ in developed countries. But significant questions remain about how fully they have been evaluated and whether or not they have actually led to improvements in clinical outcomes, let alone whether they are in fact cost effective innovations. In this presentation I will address the following questions: · Why are new RT technologies difficult to evaluate for anything beyond efficacy and safety? · Should they be subjected to the same rigorous evaluations as new pharmaceuticals through randomised controlled trials (RCTs) before entering wide clinical practice? · What strategies could be used to assess ‘value for money’ in the absence of high quality evidence? The model for assessing new technologies is derived from pharmaceutics where the new drug is first evaluated for safety and dosage (Phase I), then for efficacy (Phase II) and finally for clinical effectiveness compared to standard therapy (Phase III) before (in some health systems) being assessed for cost effectiveness. New non-pharmacological technologies are not subject to the same regulatory regime and, other than meeting routine requirements for radiation safety, RT technologies can be introduced into routine practice without evidence of clinical effectiveness – improving outcomes. Novel RT technologies are difficult to evaluate formally because: · They often develop incrementally over time with new refinements, especially in associated computer software. · There may be competing manufacturers with slightly different products. · There is often a ‘learning curve’ before they are used most effectively. · There are demonstrable improvements in planned dose distributions, imaging and accurate dose delivery which lead to a reasonable belief that clinical outcomes will be better. · There is always a need for capital investment, sometimes substantial, which means that only centres that already have the technology can participate in comparative clinical trials and those clinicians may be reluctant because they may already be convinced that their new technology is better. · The important clinical outcomes, local control, survival, late radiation toxicity take years to evaluate. · Funding for such research may be hard to find. Does this really matter? It can be argued that demonstration of better-looking computerised plans and apparently more accurate and consistent delivery of radiation dose is a good in itself and one should always try to use the best tools available. That is true – up to a point. But there are two important considerations. First does this apparent improved ‘accuracy’ give false reassurance and result in in unsafe margins and poorer local control? This problem can be partly addressed by careful and well planned prospective follow up studies. Secondly these innovations come with a real cost in capital investment, staff time and, often, longer individual treatment times and lower throughput. How much is that cost and could that money be used in another area to deliver more health benefit? In other words are these innovations cost effective? There are increasing concerns everywhere about the escalating costs of healthcare and whether the payer is the state, an insurance system, a health maintenance organisation or an individual, health professionals have a responsibility to deliver cost effective care. Given the difficulty of carrying out RCTs in this area, what can be done to help those deciding on the best use of resources? One option is to undertake modelling studies not only of dosimetric and clinical consequences but also of costs and consequences. It may then be possible to make to some high level decisions about whether the benefits are likely to large enough and the costs low enough to justify introduction into routine clinical practice, whether comparative research (ideally an RCT) is needed or whether further evaluation of efficacy and safety is needed in institutions experienced in such research. I would therefore argue for better coordinated efforts, preferably at an international level, to address this difficult problem and provide more information about how best to use these new and important resources.

Abstract not provided

Abstract
Resource Constraints is an important barrier to Lung Cancer Management. In order to understand this issue in Developing Nations, the questionnaires was set up and send to an experts in Asian countries to find out the fact about this issues. Data gather from the questionnaires will be present at the meeting. Specific information in the questionnaires are Drug lagging period, time to get new cancer drug approval, the important of economic analysis during the approval of new anticancer drug. The other information related to man power including specialist in all related subspecialties and the availability and accessibilty to diagnostic and treatment will be captured by questionnaires. Pattern of Health Insurance and other cost was also the information gathered at the same time.

Abstract
The chronic disease burden of developed countries is increasing as the postwar “baby boomers” enter their senior years. The cost of managing these chronic diseases is compounded by the increasing availability and use of expensive technologies. Cancer drug costs are a key driver of health care costs and the expenditure on cancer drugs is rising faster than spending in most other areas of healthcare. Because of this and the fiscal constraint most developed countries have put in place a rigorous drug review process. The United Kingdom’s National Institute for Health and Care Excellence (NICE), amongst others has led the way in establishing drug review processes. These reviews are generally viewed by the pharmaceutical industry, healthcare providers and the public itself as a barrier to access. The pan-Canadian Oncology Drug Review (pCODR) evaluates the clinical benefits and safety of new cancer drugs, as well as their cost-effectiveness and alignment with patient values using a standardized clinical and economic review process, an expert panel, a deliberative framework and broad public engagement (1). Commonly, recommendations are conditional on the drug price being lowered because the drug is not felt to be cost-effective. The determination of incremental cost-effectiveness or cost-utility is critical to drug funding approval in most jurisdictions except the United States. This is determined by assessing the incremental cost of the new drug or regimen over the standard treatment and dividing by the incremental benefit usually measured as years of life gained. In Canada, $50,000 per life year gained or less was generally accepted as cost-effective. As drug costs have increased, this "threshold" has crept higher and $100,000 per LYG is increasingly accepted as “reasonable”. To take account of morbidity from the disease and its treatment, the quantity of life gained is weighted by the quality of that life into a single multidimensional measure (i.e. the quantity adjusted life year or QALY). The availability of other resources, not related to the cost of drugs, can be a barrier to access. In 2008, Cancer Care Ontario began to measure concordance with guidelines developed through its Program in Evidence-based Care and to report this information through a Cancer System Quality Index (CSQI) (3). In 2010- 2011, it was noted that only 41% of resected stage II/IIIA patients received guideline recommended adjuvant chemotherapy (AC) at Ontario’s regional cancer centres. There was also substantial variation in guideline adherence between centers ranging from 42.9% to 72.1%. Men were significantly less likely to be treated with AC (38.2% compared to 52.7% for women) (p=0001), as were patients over age 65 (65% < 65 yrs. vs. 34% > 65 yrs.)(p=.0001). Patients from regions with the highest tercile of immigrants were significantly less likely to be treated: 14.3% for the highest, 46% for the middle and 51% for the lowest tercile. Similar variations were seen for the uptake of the guideline recommendation for the use of combined modality therapy in the treatment of stage III NSCLC. To better understand the reasons for these variances, a survey and key informant interviews were undertaken with clinicians and administrators. The perception of respondents was that the most common barriers to implementing practice guidelines were the slow referral process of patients to the treatment centers, lack of support from the organization’s leadership to implement the recommended regimens and the difficulties that patients had in getting to the treatment centers. These results suggested that greater efforts are required to communicate best practices to providers, (including primary care physicians), to improve the efficiency of clinic processes and to arrange patient transportation. For aboriginal and immigrant populations, culture and language are known barriers. Resources to lower language barriers, to assist patients in health system navigation and to educate health providers in the provision of culturally sensitive care may be necessary to ensure equitable access to appropriate care. Some developed countries have experienced resource constraints that have delayed access to cancer surgery and to radiation treatment. Excessive wait times result from inadequate capacity and/or inefficiencies in the health system. To resolve these issues first requires recognition of the problem, the development of a plan of action, appropriate funding to address capacity issues, process improvements to increase efficiency and incentives to providers to prioritize cancer treatments. In a recent review of access to cancer care services in Canada, Maddison et al. noted that inequity of access occurs across the continuum of care for different disease sites (4). The review suggested that access to cancer services is most inequitable at the beginning (i.e. screening) and at the end (i.e. end-of-life care). Income level appeared to have the most influence on screening while age and geography were most influential on access to end-of-life services. As the results of the NLST are implemented as population-based screening programs, low dose CT will compete for diagnostic service resources and other services. Smokers at risk from lower socioeconomic levels, in particular, may encounter barriers to access. At the other end of the cancer spectrum, access to palliative care resources varies widely in developed countries. Conclusions: Access to optimal lung cancer care across the continuum from screening and early detection through treatment and end-of-life care can encounter numerous resource barriers, which are not all monetary in nature. Although the cost of new drugs is the most significant potential resource barrier, numerous other barriers can exist in developed countries related to the resources available for screening or diagnosis, radiation and surgery, access to knowledge specialists, supportive care services and accessible end-of-life care in the home or community. References: 1. Pan-Canadian Oncology Drug Review (pCODR) (website). Toronto, Ontario. (Accessed August 1, 2013) Available at http://www.pCODR.org 2. Cancer System Quality Index (CSQI) (website). Toronto, Ontario: Cancer Quality Council of Ontario (accessed August 6, 2013). Available from: http://www.csqi.on.ca 3. Maddison AR, Asada Y, Urquhart R. Inequity in access to cancer care: a review of the Canadian literature. Cancer Causes Control 2011; 22:359-366

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

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

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

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

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

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

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

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

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

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

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

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

Abstract not provided

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

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

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

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

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

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

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

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

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

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

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

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

Abstract not provided

Background
The purpose of this study is to examine the patterns of recurrence for stage I lung adenocarcinoma and to identify clinicopathologic factors associated with post-recurrence survival (PRS).

Methods
We performed a retrospective review of 1027 patients with stage I lung adenocarcinoma who underwent a surgical resection between 1999 and 2009 (median follow-up 35 months). The manner of recurrence detection, either by scheduled CT scan, presentation with new symptoms, or by other means, was noted. Tumors were classified using the new IASLC/ATS/ERS nomenclature and grading as low (adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic-predominant), intermediate (papillary-predominant or acinar-predominant), and high (micropapillary-predominant, solid-predominant, colloid-predominant, or invasive mucinous) grade. The Kaplan-Meier method was used to analyze recurrence-free survival (RFS). Log-rank tests and Cox proportional hazard models were used to analyze the association between predictive factors and PRS.

Results
Of the 1027 patients with follow-up data available, 151(15%) had recurrent disease (table), five-year RFS was 80%. Of the 151 patients with recurrence, 80 (52%) were detected by a scheduled CT scan (51 locoregional and 29 distant). Symptomatic recurrences were seen in 70 (46%) patients (9 locoregional and 61 distant). Overall, 5-year PRS was 27.8%. On multivariate analysis, recurrences identified by new symptoms (HR, 2.15; 95% CI, 1.36- 3.40; p=0.001), a recurrence free interval ≤ 24 months (HR, 2.52; 95% CI, 1.31- 4.84; p=0.006), and tumors with high architectural grade (HR, 1.69; 95% CI, 1.07- 2.67; p=0.024) and vascular invasion (HR, 1.79; 95% CI, 1.14- 2.81; p=0.012) were significantly associated with a worse PRS (Figure).Figure 1Figure 2

Conclusion
Our study demonstrates the recurrence patterns in patients who underwent surgical resection for stage I lung adenocarcinoma. We identify a symptomatic recurrence, a recurrence-free interval ≤ 24 months, high architectural grade, and vascular invasion, as independent factors associated with worse post recurrence survival.

Background
Since the incidence of lung cancer death increases from 50 years-old, the surgical results of young lung cancer patients remains unclear.

Methods
Seven hundred and four patients with lung cancer, aged up to 50 years, were enrolled from among the 11,663 patients registered in the Japanese Lung Cancer Registry Study 2004, and their clinical data were compared with those of 10959 patients older than 50 years.

Results
In the young/old groups, pneumonectomy was performed in 5.7%/3.2%; adjuvant therapies were given preoperatively in 10.4%/4.7% (p<0.001) and postoperatively in 31.4%/24.5% (p<0.001). The proportions of patients with p-stage IIIA and adenocarcinoma histology were higher in the young group. The 5-year overall survival rate (5Y-OS) was 94.8%/86.2% for p-stage IA (p<0.001), 87.0%/73.2% for p-stage IB (p=0.001), 61.0%/61.6% for p-stage IIA (p=0.595), 71.0%/48.4% for p-stage IIB (p=0.003), 49.6%/39.4% for p-stage IIIA (p=0.020), and 80.0%/24.8% for p-stage IIIB (p=0.012); it was 83.5%/80.7% for females (p=0.106) and 75.1%/62.3% for males (p<0.001) in the young/old groups. The postoperative survival was significantly better with all operative procedures in the young group. The 5Y-OS after recurrence was better in the young group (17.9%, p=0.016). In the young group, the 5Y-OS was better in females (83.5%) than in males (75.1%, p=0.002), and for patients with adenocarcinoma (80.3%) than for those with squamous cell carcinoma (68.5%, p=0.013). Age up to 50 years was identified as an independent prognostic factor on multivariate analysis. Figure 1

Conclusion
The postoperative survival in lung cancer patients aged up to 50 years was better than that in patients older than 50 years.

Background
Outcome after surgery is the result of many components of the care pathway.. The Thoracic Surgery Community of Practice of Cancer Care Ontario developed quality indicators which reflected processes of care as well as outcomes.

Methods
A systematic review of the literature identified potential indicators in the care of lung cancer patients which were relevant to thoracic surgery. These were then evaluated using a modified Delphi process. Seventeen indicators were chosen from seven domains: pre-operative assessment, staging, surgery, pathology, adjuvant therapy, surgical outcomes and miscellaneous based on actionability, validity, usefulness, discriminability, and feasibility. Data obtained from administrative databases is reported for 4 process indicators and 3 outcome indicators.

Results
Of the 3242 patients diagnosed with Stage I and Stage II non-small cell lung cancer in 2009 and 2010, 2172 (67%) received a surgical consultation and 1524 (47%) underwent resection within 3 months of diagnosis. For the 1075 Stage I and Stage II patients over age 75 only 634 (59%) received a surgical consultation and 322 ( 32%) underwent resection. Of the 2302 patients resected in total (all stages), only 736 (32%) had invasive mediastinal staging(IMS) prior to resection:15% for sublobar resections; 30% for stage I; and 42% for stage II. Surprisingly only 42% of patients with stage III disease had IMS. IMS was also performed in an additional 23% of patients for whom stage data was unavailable. In a similar cohort of patients resected in 2011-2012, only 28% had ≥10 lymph nodes removed at the time of resection but this did not include nodes assessed by IMS. However, for 20% of patients lymph node resection data was not available or could not be determined. Positive resection margins were reported in 7% of patients, however in a further 7% of patients margins could not be assessed. 30 day mortality for lobectomy was 1.9%, reoperation rate was 2.8% (2.0% for same day as resection).

Conclusion
Initial results of 7 quality indicators in thoracic surgery identified some quality gaps in processes of care as well as limitations in databases. Evaluation of process indicators allowed feedback to thoracic surgeons and pathologists who identified quality improvement opportunities. Rate of surgical consultation and resection for stage I and II disease was lower than expected as were rates of invasive mediastinal staging especially for patients with stage III disease for whom cytologic or histologic confirmation is recommended. To address variable intraoperative lymph node assessment, systematic lymph node sampling or complete mediastinal lymphadenectomy was recommended to standardize intraoperative lymph node assessment. Quality improvement opportunities for pathologists also included dissection of intralobar lymph nodes, standardization of pathological processing and margin assessment. Feedback of quality indicator data was important in stimulating quality improvement initiatives by thoracic surgeons and pathologists.

Abstract not provided

Background
Limited resection of primary lung cancer or sublobar resection of pulmonary metastatic tumor can result in cut-end recurrence. It is important to confirm the absence of tumor cells at the cut-end. Since 2004, all autostapling cartridges used for wedge or segmental resection of pulmonary malignancies are washed with 50 ml saline. Washing saline is centrifuged and the sediment is stained using Papanicolaou’s method and examined for cancer cells during surgery to confirm negative margin. The aim of this study is to evaluate the efficacy of the intraoperative autostapling cartridge lavage cytology in preventing surgical cut-end recurrence.

Methods
The intraoperative cytology analysis was performed in 271 patients undergoing wedge or segmental resection for 319 lesions including primary lung cancers and pulmonary metastatic tumors between April 2004 and April 2010. We retrospectively reviewed the clinicopathologic features of patients with positive cytology results and those who developed recurrence at the surgical margins.

Results
The median age of the 271 patients at surgery was 67 years (range: 31−92 years). The median size of the 319 lesions was 1.4 cm (range: 0.4−3.5 cm), and there were 149 primary lung cancers and 170 pulmonary metastatic tumors (primary site: 116 colorectal and 54 others). Twenty-two lesions (7%) showed positive cytology results (11 primary and 11 metastatic). In primary lung cancers, tumor size (≧ 21 mm, p = 0.02), moderate to poor differentiation (p ＜ 0.01), vascular invasion or lymphatic permeation (p ＜ 0.01), and visceral pleural invasion (p ＜ 0.01) were significant predictors of a positive result. In contrast, there were no significant predictors in pulmonary metastatic tumors. The cut-ends of the 19 lesions among the 22 positive cytology margin lesions were additionally resected, but those of the remaining 3 lesions were not because of impaired respiratory function. With the median follow-up period of 42 months, surgical cut-end recurrence occurred in 2 of the 19 lesions for which additional resection had been performed (11%, 1 primary and 1 metastatic). Of the 3 lesions for which additional resection was impossible, cut-end recurrence developed in 2 (67%, 1 primary and 1 metastatic). Among the 297 lesions showing negative cytology result, cut-end recurrence occurred in 5 (2%, 4 primary and 1 metastatic).

Conclusion
Intraoperative autostapling cartridge lavage cytology in sublobar resection for primary or metastatic lung tumor may be useful in preventing surgical cut-end recurrence.

Background
There is little information about prognosis after pulmonary resections for non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD). In this study, we examined the long-term outcome and the factors that affect long-term survival after resection for NSCLC in patients with ILD.

Methods
Between September 1996 and May 2011, 71 NSCLC patients were diagnosed as having ILD based on the CT and pathological findings. The extent of ILD on CT was scored visually at the level of 3 cm above the diaphragm as follows: minimal, <2 cm from the subpleura at the base of the lungs; moderate, >2 cm from the subpleura, but less than one-third of the lung area at the base of the lungs; severe, more than one-third of the lung area at the base of the lungs. Various clinical values such as gender, age, preoperative chemotherapy, severity of ILD on CT, preoperative pulmonary function test results, arterial blood gas studies, operative procedure, pathologic stage, cell type, and adjuvant treatment were evaluated using univariate and multivariate analysis.

Results
The mean age was 65.9 years, and the majority of patients were male(65:91.5%). In-hospital mortality was 9.9% (7/71). The causes of early mortality included pneumonia (n=4), acute respiratory distress syndrome (n=2), and acute exacerbation of ILD (n=1). The 5-year overall survival rate was 43.1% (stage I: 59.4%, stage II: 41.3%, stage III: 35.0%, respectively). In univariate analysis, the risk factors for long-term mortality were lower preoperative FEV~1~, FVC, severe ILD on CT, presence of pathologic pulmonary fibrosis, and non-squamous cell type. In multivariate analysis, severity of ILD on CT and non-squamous cell type remained as poor prognostic factors.Figure 1

Conclusion
Although patients with ILD undergoing pulmonary resection for NSCLC has resulted in a high in-hospital mortality, long-term survival can be expected in highly selected patients. NSCLC patients with severe ILD on CT findings and those with non-squamous cell type should be carefully selected for major pulmonary resection.

Background
Posterolateral thoracotomy has been extensively used for non-cardiac thoracic surgery. Although this procedure provides excellent access for cancer surgery, it is responsible for considerable postoperative pain and contributes to postoperative pulmonary insufficiency. Post-thoracotomy pain has been reported to occur in 10 to 70% of patients. Intercostal nerve injury has been implicated as a major factor in the etiology of post-thoracotomy pain. We performed a study to compare post-thoracotomy pain in patients undergoing posterolateral thoracotomy with and without the preservation of the intercostal neurovascular bundle.

Methods
This randomized double-blind phase II trial was carried out in a tertiary-referral cancer centre. We included adult patients undergoing posterolateral thoracotomy for pulmonary resection. Patients were randomized into two groups – standard posterolateral thoracotomy (PoT) where no attempt was made to preserve the intercostals neurovascular bundle or modified nerve-sparing thoracotomy (NeST) which involved preservation of the intercostal neurovascular bundle while opening the intercostal space and closure by drilling holes in the lower rib, thereby avoiding pericostal sutures. All surgeries were performed under general anaesthesia with fentanyl, morphine, diclofenac and paracetamol for intra-operative analgesia. Post-operatively, all patients received round-the-clock paracetamol and diclofenac with an intravenous morphine patient-controlled analgesia pump for additional analgesia. Worst and average pain scores (on a Numerical Rating Scale) and morphine requirements on the first three post-operative days were assessed. Patients and assessors were blinded to study group. Chronic pain was assessed 6 months after surgery using a standard questionnaire. The primary outcome was the mean worst pain score over the first three post-operative days. Secondary outcomes were mean average pain score over the first three post-operative days, morphine consumption and incidence of post-thoracotomy pain at 6 months.

Results
We recruited 90 patients between May 2010 and July 2012. Groups were comparable in terms of age, gender, weight and type of surgery. There was no significant difference between the PoT and the NeST group in mean worst pain scores over the first three post-operative days (3.83 versus 3.71, difference 0.12, 99% CI -0.7 to 0.9). Mean average pain scores were also similar between the groups (1.85versus 1.77, difference 0.08, 99% CI -0.4 to 0.6) as was the mean morphine consumption in milligram per kilogram body weight (1.40 versus 1.45, difference of -0.05, 99% CI -0.4 to 0.3). Chronic pain was present in 18 of 39 assessable patients (46.1%) in the PoT group and 17 of 41 assessable patients (41.2%) in the NeST group (difference 4.7%, 99% CI -22.8% to 30.7%).

Conclusion
Preservation of the neurovascular bundle during thoracotomy using a modified nerve-sparing approach has no impact on acute or chronic post-thoracotomy pain or analgesic requirements as compared to a standard posterolateral approach.

Abstract not provided

Background

Methods
Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice but recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity.

Results
Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed >4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Unblinded results showing the effect of pravastatin on OS, PFS, local PFS and toxicity will be presented.

Conclusion
This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients.

Background
IP showed superior survival outcomes compared with EP in Japanese patients. However, IP failed to show the superiority in subsequent studies in Western population. We conducted a multi-center randomized controlled trial to determine whether IP regimen is superior to EP regimen in Korean patients (ClinicalTrials.gov Identifier: NCT00349492)

Methods
Patients were randomly assigned (simple randomization, stratified by ECOG performance status and center) to IP (irinotecan 65 mg/m2 IV on D1&8 plus cisplatin 70 mg/m2 IV on D1, every 3 weeks) or EP (etoposide 100 mg/m2 IV on D1-3 plus cisplatin 70 mg/m2 IV on D1, every 3 weeks) for maximum 6 cycles, until disease progression, or until unacceptable toxicity occurred. The primary objective was to compare overall survival (OS).

Results
A total of 362 patients were randomized to IP (N=173) and EP (N=189) arms. Median OS was 10.9 and 10.3 months (m) for IP and EP, respectively (hazard ratio for death in the IP group, 0.879; 95% one-sided confidence interval, 0 to 1.054; P=0.1207). Objective response rate was higher with IP than with EP (62.4%, 48.2%, P=0.0064), however, there was no significant difference in median progression free survival between IP and EP (6.5 and 5.8 m, P=0.1158). In the pre-planned subgroup analyses, IP was associated with longer OS than with EP in male (11.3 vs 10.1 m, P=0.0361), <65 years old (12.7 vs 11.3 m, P=0.0240), ECOG performance status 0/1 (12.4 vs 10.9 m, P=0.0407) patients group. Grade 3/4 anemia, nausea and diarrhea were more frequent in patients treated with IP. There was no difference in the frequency of grade 3/4 neutropenia, thrombocytopenia, neutropenic fever, infection between both arms.

Conclusion
IP failed to show superiority in overall survival compared to EP in Korean patients with ED SCLC. However, prolongation of OS was observed with IP in pre-defined subgroup of patients with male gender, young age, or good performance status.

Background
Background: NTX-010 is a naturally occurring replication-competent picornavirus with potent and selective tropism for SCLC tumor cells expressing neuroendocrine markers. A phase I study of NTX-010 showed evidence of antitumor activity in patients with SCLC.

Methods
Methods: ES-SCLC patients (pts) with SD, PR or CR after at least 4 cycles of platinum-based chemotherapy were pre-registered to confirm diagnosis of SCLC with > 1 neuroendocrine marker by a central pathology review. Eligible pts were.randomized 1:1 to placebo (B) or NTX-010 (A). NTX-010 or placebo was administered intravenously as a 1-hour infusion in 100 mL normal saline as a single dose of 1 x10[11]vp/kg. Viral studies to determine distribution, clearance of the virus and the presence of neutralizing antibodies were done. The primary goal of this trial was to compare the progression-free survival (PFS) of arm A to B based on a sample size of 45 patients per arm to detect an improvement in median PFS from 3 to 5 months (m). A pre-planned interim futility analysis was done after 40 PFS events, and reported here.

Results
Results: The trial is permanently closed to accrual. One-hundred and twenty pts were pre-registered, of whom 58 were randomized. Baseline age, gender, ECOG performance status, and histology were balanced between arms. Median age was 63 (range: 44 - 82). 31% of pts had a PS of 0 and 69% of 1. Grade 4 adverse events were seen in 3 (12.5%) patients in arm A and none in arm B. Based on the interim futility analysis, PFS was 1.7 m (95% CI: 1.3-3.1) for arm A and 1.7 m (95% CI: 1.4-4.3) for arm B. Pts with viral RNA at 7 (7 pts) and 14 (6 pts) days had worse PFS compared to those with no detectable levels within arm A (1.0 vs 1.6 m, p=0.02; 0.9 vs. 1.2 m, p=0.06). Median follow-up in pts is 6.1 m. The 3-month OS estimates are 83% (95% CI: 69%-100%) and 85% (70%-100%) for arms A and B respectively.

Conclusion
Conclusion: This phase II study showed no benefit in PFS for ES-SCLC patients receiving NTX-010. Pts with detectable virus at 7 and 14 days had worse PFS

Abstract not provided

Background
The type 1 insulin-like growth factor receptor (IGF1R) and MET, the receptor for hepatocyte growth factor (HGF)/scatter factor, appear to play key roles in SCLC. Ganitumab and rilotumumab are investigational, fully human monoclonal antibodies targeting IGF1R and HGF, respectively. A phase 1b/2 study evaluated ganitumab or rilotumumab combined with etoposide plus carboplatin (CE) or cisplatin (PE) in extensive-stage SCLC. The phase 1b results were previously reported (Lorigan et al. Ann Oncol 2010;21[supplement 8]: abstract 444P). Here, the phase 2 results are reported.

Methods
Key eligibility criteria: ≥18 years, confirmed SCLC, ECOG performance status ≤1, no prior chemotherapy. Patients were randomized 1:1:1 to receive blinded investigational product (IP) either ganitumab (18 mg/kg IV, day 1) or rilotumumab (15 mg/kg IV, day 1) or placebo, with etoposide (100 mg/m[2] IV, days 1-3) plus, at investigator’s discretion, either carboplatin (AUC=5 mg/mL*minute IV, day 1) or cisplatin (75 mg/m[2] IV, day 1) every three weeks for 4-6 cycles followed by IP monotherapy. Patients were stratified by gender and chemotherapy (CE; PE). Primary endpoint: overall survival (OS). Key secondary endpoints included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), pharmacokinetics.

Results
185 patients (ganitumab/rilotumumab/placebo: 62/62/61) were enrolled between 2 February 2010 and 12 January 2011. Male: 77%/76%/77%. Median age: 60/61/61 years. More patients received carboplatin (41/40/40) than cisplatin (21/22/21). Most common reason for discontinuation of IP was disease progression (69%/61%/74%). Among 179 patients (59/61/59) who received IP, the most frequent any grade AEs (occurring in ≥30% of patients in any arm) were neutropenia (69%/59%/71%), anemia (39%/34%/36%), nausea (41%/30%/22%), alopecia (41%/23%/27%), thrombocytopenia (22%/30%/12%), and vomiting (19%/10%/31%). Grade ≥3 AEs and serious AEs were reported in 69%/72%/80% and 39%/38%/36% of patients, respectively. There were three IP-related grade 5 AEs: cardiac arrest (rilotumumab, n=1), febrile neutropenia (rilotumumab, n=1), gastric ulcer hemorrhage (placebo, n=1). No neutralizing antibodies were observed for either ganitumab or rilotumumab. Efficacy is shown in the table. Ganitumab and rilotumumab combined with chemotherapy showed comparable exposures as those under monotherapy and did not affect the pharmacokinetics of chemotherapy.

Conclusion
In this study of chemonaïve patients with extensive-stage SCLC, the combination of ganitumab or rilotumumab with CE or PE was tolerable; no unexpected toxicities were observed. There were no meaningful improvements in OS, PFS, or ORR with either combination. Survival analyses in biomarker and pharmacokinetic subgroups are ongoing.

Background
AAK, a key mitotic regulator, plays an important role in carcinogenesis. AAK is frequently overexpressed/amplified in a variety of human cancers. Inhibition of AAK has been associated with tumor inhibition in SCLC patients; thus, AAK is an attractive target in SCLC treatment. The investigational, oral, selective AAK inhibitor MLN8237 is under evaluation in patients with advanced hematologic and non-hematologic malignancies. A phase 1/2 study (NCT01045421) evaluated MLN8237 in patients with solid tumors; phase 2 data for the SCLC cohort are presented.

Methods
Patients aged ≥18 years with relapsed/refractory SCLC, ECOG PS 0–1, and ≤2 prior cytotoxic chemotherapy regimens were eligible (symptomatic and untreated brain metastases were excluded); sensitive and resistant/refractory was defined as recurrence > or ≤90 days of frontline therapy respectively. MLN8237 50 mg was administered twice-daily for 7 days (21-day cycles). Using a Simon’s optimal 2-stage design, ≥2 objective responses were required in the first 20 response-evaluable patients to proceed to the expansion stage. Primary objective: overall response rate (ORR) by RECIST v1.1. Secondary objectives: safety, duration of response (DOR), and progression-free survival (PFS). Exploratory studies included whole-exome sequencing in banked tumor specimens to identify genetic markers/mutated pathways associated with differential response.

Results
As of April 2013, 60 patients were enrolled; median age, 62 years (range 43–76); median number of cycles 2 (range 1–15). 48 patients (80%) were response-evaluable (chemo-sensitive, n=36; chemo-refractory, n=12). Prior lines of therapy and efficacy data are shown in the table. ORR was 21%, median PFS 2.11 months. Most common grade ≥3 drug-related AE included neutropenia (53%) and febrile neutropenia (8%); all AEs were reversible.14 patients discontinued due to AEs (treatment-related in 3 patients: hyponatremia, thrombocytopenia, acute generalised exanthematous pustulosis; each, n=1). 13 on-study deaths were reported; none were considered drug-related (most frequent cause was disease progression [n=6]). Whole-exome sequencing of selected tumor samples was completed. Preliminary results will be presented.

Conclusion
MLN8237 has a generally manageable toxicity profile; data from this study suggests it has single agent antitumor activity in SCLC patients with sensitive or resistant-refractory relapse, supporting further evaluation of MLN8237 in different combination strategies in this tumor type.

Background
ES-SCLC patients (pts) with progressive disease (PD) following plat-based chemo have traditionally been categorized as plat-sensitive (PD >/= 90 days from last plat dose) or refractory (PD < 90 days). Plat-sensitivity status has previously been strongly associated with response and survival in the 2[nd]/3[rd] line treatment setting. However, in a recent pooled analysis of SWOG trials in 2[nd]/3[rd] line SCLC pts, plat-sensitivity status was found to no longer be a significant independent variable for survival (Lara, ASCO 2013). We subsequently developed a new SCLC prognostic model for overall survival (OS) for potential clinical trial and bedside application.

Methods
Updated data from recent SWOG trials in 2nd and/or 3rd line ES-SCLC (S0802: topotecan + aflibercept: S0435: sorafenib; and S0327: PS-341) were pooled. Accrual goals were specified for sensitive and refractory in each trial. Hazard ratios (HRs) for OS were calculated using Cox Proportional Hazard (PH) models [unadjusted and adjusted]. To investigate a predictive model for OS, recursive partitioning was performed using the likelihood tree model of LeBlanc and Crowley. The minimum node size was set at 20.

Results
Of 329 pts, 151 were classified as sensitive, 178 refractory; median age = 63 years; males = 52%; Performance Status (PS) 1 = 67%; weight loss >5% = 28%; > 2 prior chemo = 16%; and elevated LDH = 43%. HRs from unadjusted Cox models for OS for refractory vs. sensitive were 1.0 (95% CI 0.81-1.25, p=0.98) and 1.24 (95% CI 0.99, 1.57; p=0.06). Cox PH models adjusted for baseline prognostic factors showed that plat-sensitivity status was not significantly associated with OS. Elevated LDH was significantly associated with PFS while LDH, PS, weight loss, and male sex were independently associated with OS. Clinically relevant prognostic risk groups (High, Intermediate, and Low) were identified by recursive partitioning analysis, as shown below (MST= median survival time). High Risk (MST = 2 months: Elevated LDH And > 5% Weight Loss Or PS >0) Intermediate Risk (MST = 5 months: Elevated LDH but not High Risk Or Male) Low Risk (MST=8 months: Normal LDH And Female)

Conclusion
In this large database analysis, clinically relevant prognostic risk groups were identified, categorized as low, intermediate, and high risk, with differential survival outcomes observed for each group. Validation of these risk groups in an independent SCLC dataset is warranted. If validated, these risk groups will have important implications for individualized patient counseling in clinic and stratification of patients in prospective trials in the second and third line setting.

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Abstract
Adaptive clinical trials designs are sometimes claimed to have many benefits over conventional group sequential designs. Such claims are generally unfounded, though adaptive designs may be quite useful in specific situations. Adaptive designs can be quite useful in early phase dose finding trials, where the purpose is to minimize the number of patients exposed to inefficacious or overly toxic doses. Adaptive designs can also be useful in later phase trials when a biomarker (or baseline patient characteristic) is suspected to be strongly predictive of the effect of the treatment under investigation; in this case, an adaptive enrichment of the trial can greatly improve its power. Adaptive designs can also prove useful when the assumptions underlying a trial design are subsequently found to be grossly inadequate, but this is an undesirable as well as uncommon situation. Adaptive randomization, which consists of allocating more patients to the treatment that appears to have more efficacy ("play-the-winner"), is justified neither statistically nor ethically. This strategy may produce slight reductions in the number of patients exposed to the inferior treatment, but it may increase the total sample size of the trial as compared to using a fixed allocation ratio (e.g. 1:1). More importantly, this adaptive strategy conveys the misealding impression that one treatment is known to be better than the other, a situation in which equipoise is not maintained and randomization no longer ethical.