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7518 Background: We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that the disease-free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome. Methods: cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated withCDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Expression of each gene was dichotomized according to its median value of expression. Results: The only gene with interaction P

8098 Background: EGFR-TKIs, gefitinib and erlotinib can demonstrate dramatic and durable response in patients with EGFR-mutant non-small cell lung cancer. Approximately one-third of patients develop central nervous system (CNS) metastases, including leptomeningeal metastases (LM) after initial response to EGFR-TKIs. Pharmacokinetic failure due to insufficient penetration of EGFR-TKIs is suggested as a cause of CNS failure. Therefore, high-dose EGFR-TKIs are considered reasonable therapeutic options for refractory CNS metastases after failure of standard dose EGFR-TKIs, but there is little present evidence of high-dose EGFR-TKI’s efficacy and tolerability. Methods: Between 2007 and 2012, we screened 279 patients harboring EGFR sensitive mutations, and identified 31 patients with LM. Ten of 31 patients received high-dose erlotinib, and the other 21 underwent only standard dose EGFR-TKIs (gefitinib and/or erlotinib). In these 10 patients, erlotinib was administered at 200 mg on alternating days (n=2), 300 mg on alternating days (n=6), 300 mg every 3 days (n=1), or 600 mg every 4 days (n=1). We retrospectively investigated the efficacy and tolerability of high-dose erlotinib. Additionally, survivals from the diagnosis of LM to death were compared in patients with or without high-dose erlotinib. Results: Regarding high-dose erlotinib, five of 10 patients were radiologically evaluable, and partial response was observed in 60% (3/5), stable disease in 20% (1/5), and progressive diasease 20% (1/5). Median time to CNS progression was 3.4 months (range, 0.3-6.6 months). Improvement of neurological symptoms was observed in 9 (90%) of 10 patients. No severe adverse events (≥ grade 3) associated with high-dose erlotinib were confirmed. Median survival from the diagnosis of LM in patients with high-dose erlotinib was 6.5 months (95% CI: 2.5-12.3 months), and that in those without was 5.8 months (95% CI: 1.1-7.8 months) (p =0.51). Conclusions: The efficacy and tolerability of high-dose erlotinib were suggested for refractory LM. It can be a therapeutic option in patients after failure of standard dose erlotinib. Optimal dose and schedule are unclear, and further investigations are warranted.

Although the influence of high dose inhaled steroids on hypothalamo-pituitary-adrenal (HPA) function in patients with asthma has been extensively studied worldwide, there has been limited information on Japanese asthmatics, especially in terms of a prospective analysis of HPA function in the course of time. We analyzed the changes in HPA function using 2 serial short tetracosactrin tests (STT) separated by an interval of one year in 11 Japanese asthmatics who were treated with high dose inhaled steroids alone [beclomethasone dipropionate (BDP); mean dose 982 micrograms/day] during the period between 2 STTs. Mean values of plasma cortisol before administration of ACTH, maximum cortisol and the rise in cortisol in response to ACTH in the 2 STTs were 7.8, 20.5 and 12.7 micrograms/dl for the 1st test, and 8.9, 23.6 and 14.7 micrograms/dl for the 2nd test, respectively. Overall, there was no significant change in the course of time in each of these 3 values. Although the results of the 1st STT proved to be abnormal in 3 patients who had been receiving systemic steroids before their 1st STT, they improved uniformly in their 2nd STT. In the remaining 8 patients, who had never received systemic steroids, 4 patients showed improvements while the other 4 showed deterioration in HPA function in their serial STTs over the course of time. The dose of BDP was 800 micrograms/day in the former 4 patients, while it was 1,200 micrograms/day in the latter 4. Furthermore, only one patient, in whom BDP had been increased from 800 micrograms/day to 1,200 micrograms/day between the 2 tests, developed an abnormal response in the 2nd STT. On the other hand, one patient whose BDP dose was increased from 800 micrograms/day to 1,600 micrograms/day showed an improvement in HPA function in the 2nd test. These results indicate that the threshold dose of BDP which may cause HPA suppression in Japanese asthmatics lies between 800-1,200 micrograms/day, although there is a large inter-individual variation in terms of such doses.

BACKGROUND We performed a Phase I-II trial to determine the maximum tolerated dose of carboplatin (CBDCA) with a fixed dose of VP-16 and granulocyte-colony stimulating factor (G-CSF) in small cell lung cancer (SCLC) patients. METHODS Treatment consisted of a starting dose of CBDCA, 400 mg/m2 (i.v., Day 1); VP-16, 100 mg/m2 (i.v., Days 1-3), and G-CSF, 2 μg/kg (s.c., Days 4-17) every 4 weeks for four cycles. The dose of CBDCA was escalated in increments of 50 mg/m2 until Grade IV toxicity on the World Health Organization scale developed in two-thirds or more of the patients. RESULTS Seventy-five previously untreated patients with pathology confirmed SCLC were entered into the trial. Seventy-one patients were eligible and 70 patients were evaluated for response. Forty-five patients had limited disease (LD) and 26 had extensive disease (ED). The response rate of the 70 patients who could be evaluated was 81%, with 23% attaining a complete response (CR) and 58% attaining a partial response (PR). The response rate was 80% in LD patients (CR, 23%; PR, 57%) and 85% in ED patients (CR, 23%; PR, 62%). The major dose-limiting toxicity was thrombocytopenia. Nephrotoxicity, neurotoxicity, and ototoxicity were uncommon. The doses of CBDCA that resulted in unacceptable thrombocytopenia were 700 mg/m2 in patients younger than 70 years and 500 mg/m2 in patients older than 70 years. Overall median survival time (MST) was 9 months. MST of LD patients and ED patients were 11 months and 7 months, respectively. The dose-limiting toxicity of CBDCA with a fixed dose of VP-16 and using G-CSF as bone marrow rescue was age-related thrombocytopenia. The maximum tolerated dose of CBDCA was 650 mg/m2 if patients were younger than 70 years and 450 mg/m2 if they were 70 years or older. CONCLUSIONS When we retrospectively compared our results with those using standard chemotherapy regimens, we saw no therapeutic benefit from increasing planned doses of CBDCA up to 700 mg/m2 in combination with G-CSF in patients with SCLC. Cancer 1996;77:63-70.

We retrospectively studied the use of inhaled corticosteroids in patients who experienced near fatal episodes (NFE) to determine whether such therapy reduces the risk of death. Forty-eight patients who had near fatal episodes of asthma between January 1981 and December 1989 were divided into two groups. Group A comprised 19 patients who received beclomethasone dipropionate (BDP) daily (mean dose of BDP: 687 μg/day: 200-2, 000) following NFE, and Group B, 28 patients who did not take BDP or who took less than 6 mg BDP/month. During the follow-up period (Group A: 82.9 months, Group B: 66.2 months), no patients in Group A died, but eight deaths occurred in Group B (mean period between near fatal episode and death was 31.5 months: 12-66). These results suggest that the regular use of inhaled corticosteroids, even at low doses, may reduce the risk of death in patients who experience NFE.(Internal Medicine 34: 77-80, 1995)

CCRT to SCN+ patients did not increase the toxicities. The grade 3 or more pneumonitis occurred in 5 patients (5.1%) of SCN+ patients and in 3 patients (3.6%) in SCNpatients. Grade 3 or more esophagitis was occurred in 17 patients (17.1%) of SCN+ patients and 11 patients (13.3%) of SCNpatients. Conclusions: SCN+ patients have similar overall survival compared to SCN-patients in N3 stage NSCLC when treated with CCRT, although time to distant metastasis is shorter in SCN+ patients. CCRT should be the first choice for SCN+ NSCLC patients with good performance and non-large cell histology. Author Disclosure: D. Oh: None. H. Pyo: None. Y. Ahn: None. H. Park: None. D. Lim: None.

Background The secondary EGFR mutation (MT) T790M accounts for approximately half of acquired resistances to EGFR-TKI. A recent report has demonstrated that the presence of T790M predicts a favorable prognosis and indolent progression, compared with the absence of T790M after TKI failure. However, rebiopsy to confirm the T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known about the differences among patients with or without T790M. Methods We investigated 73 patients harboring EGFR MTs who had undergone rebiopsy to confirm the emergence of T790M after TKI failure. The PNA-LNA PCR clamp method was used in EGFR MT analyses. Pt characteristics (age, gender, smoking history, performance status, EGFR MT site, initial TKI, response to initial TKI, line of initial TKI, PFS with initial TKI and biopsy site) and postprogression survivals (PPS) after initial TKI failure were retrospectively compared in patients with and without T790M. Results We identified T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions (25 lung tissue, 24 pleural effusion and 3 lymph node) (P = 0.0225). Other characteristics had no statistical association with the detection of T790M. Median PPS in patients with T790M was 34.0 months, and in those without T790M, 14.5 months (P = 0.0038). Although none of our patients received TKIs continuously after initial failure, 56 (77%) patients were re-administered TKIs. Regardless of T790M status, PPS in patients with TKI re-administration (23.4 months) was significantly longer than without re-administration (10.4 months) (P = 0.0085). Conclusions The emergence of T790M in CNS is rare compared with other lesions. Patients with T790M after TKI failure have significantly better prognosis than those without T790M. The effectiveness of TKI re-administration or continuous administration beyond progression is suggested after initial TKI failure.

Background Platinum-based chemotherapy has been a standard of care in patients with advanced non-small-cell lung cancer (NSCLC). S-1 plus cisplatin (SP) was shown good activity and tolerability in previous phase II trials. Docetaxel plus cisplatin (DP) is the only third-generation regimen that demonstrated statistically significant improvement of overall survival (OS) and quality of life (QOL), compared with a second-generation regimen, vindesine plus cisplatin, in patients with advanced NSCLC. Method This randomized phase III study compared the OS between SP and DP in patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions. Patients received oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks in SP arm, or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks in DP arm, both up to six cycles. The non-inferiority study design was employed as upper confidence interval (CI) limit for HR Results From April 2007 to December 2008, 608 patients from 66 sites in Japan were randomized to SP (n = 303) or DP (n = 305). Patient demographics were well balanced between the two arms. Two interim analyses were preplanned. At the final analysis, a total of 480 death events were observed. OS for SP was non-inferior to DP (median survival, 16.1 versus 17.1 months, respectively; HR = 1.013; 96.4% CI, 0.837–1.227). PFS was 4.9 months in the SP arm and 5.2 months in the DP arm. Statistically significantly lower rate of febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), grade 1/2 alopecia (59.3% versus 12.3%) were observed in the SP arm than in the DP arm. QOL data investigated by EORTC QLQ-C30 and LC-13 favored for the SP arm. Conclusion S-1 plus cisplatin is a standard first-line chemotherapy regimen for advanced NSCLC.

Background Cancer cachexia, mainly characterized by muscle atrophy and subsequent cancer induced weight loss (CIWL), is attributed to about a third of cancer deaths. Despite worsening prognoses with the symptoms, clinical factors involved and the effect of CIWL to the overall status remain unexplained. We planned a prospective cohort study, Japan Nutrition and QOL survey in patients with advanced NSCLC study to investigate changes in CIWL in relation to grip, QOL, and clinical parameters to understand their effects on prognosis. Method Untreated stage IV NSCLC patients with ECOG PS of 0-2 were registered. Their body weight (BW), grip, QOL, Karnofsky Performance Scale, biochemical assay, and survival were recorded every four weeks for one year from the start of cancer treatments. Patients were classified by BW loss ≥ 5% and cachexia diagnosis by BW loss, fatigue, anorexia, and abnormal assay results. Estimated survival curves were drawn by Kaplan-Meier method, and Log-rank test was applied. To evaluate the effect of cancer cachexia attribution to QOL, we performed principal component analysis, factor analysis, and analysis on time course data using generalized estimating equation (GEE). Results Out of 466 patients registered, 406 were evaluable and analyzed. Patient characteristics were: median age: 67 (33-87) years, male/female ratio: 280/126, median BW: 56.5kg, PS 0: 39.2%, and PS 1: 51.5%. The patients with BW loss of ≥ 5% (n = 219) reported more early deaths than those without (n = 166, p Conclusion Cancer cachexia decreased QOL and possibly affected prognoses. Cachexia preventions and treatments based on the further elucidation of its pathology are needed. Disclosure All authors have declared no conflicts of interest.

Background EGFR mutation is considered to be a strong predictive marker for EGFR tyrosine kinase inhibitor (TKI). Several phase III trials have shown that EGFR-TKI is superior to chemotherapy for NSCLC patients with EGFR mutation. On the other hand, there is no prospective trial which compares EGFR-TKI to chemotherapy for NSCLC patients without EGFR mutation. It remains unclear whether there is a difference between EGFR-TKI and chemotherapy for these types of patients. Methods We retrospectively investigated efficacy and safety of E, P and D in non-squamous NSCLC patients without EGFR mutation who had a history of one or two prior chemotherapy treatments, by using individual patient data. To examine the comparability in patient's clinical backgrounds between treatment groups, propensity score analysis was conducted. EGFR mutation analysis was performed with highly sensitive PCR methods. Results Between December 2007 and September 2011, data of 370 patients who were treated either with E, P or D was collected in five institutions. There were distinct differences between the clinical characteristics of patients who received E and those of patients who received P or D.Propensity score analysis showed that clinical characteristics in a subgroup of patients with PS 0-1 and 2nd line chemotherapy were almost the same in each group.We analyzed this subgroup of patients (167pts, E 19 pts, P 53 pts, D 38 pts).The PFS was 2.80 months, 2.53 months, 1.90 months, respectively (p = 0.7745). The OS was 16.13 months, 7.40 months, 9.97 months, respectively (p = 0.4258). Grade 3 or worse hematologic toxicities were reported more frequently in P and D group. In all patients, three treatment-related deaths occurred in the E group (two deaths as a result of interstitial lung disease, one as a result of diarrhea). Conclusions This is the first report of retrospective analysis which compared E, P and D in pre-treated NSCLC without EGFR mutation. There was no efficacy difference between E, P and D in patients with PS 0-1 and 2nd line chemotherapy.Future prospective randomized trials need to be conducted in pre-treated NSCLC patients without EGFR mutation. Disclosure N. Katakami: I receive honoraria from chuugai Pharma Japan, Lilly Japan, and sanofi-aventis Japan. I receive research funding from chuugai Pharma Japan, Lilly Japan, and sanofi-aventis Japan. H. Yoshioka: I receive honoraria from Chuugai Japan, Lilly japan,and Sanofi-aventis Japan. All other authors have declared no conflicts of interest.

7515 Background: Although molecularly targeted therapy improves outcome of selected patients with advanced non-small-cell lung cancer (NSCLC), most of the patients ultimately become candidates of cytotoxic chemotherapy, which is the cornerstone of patient management. S-1 plus cisplatin (SP) has shown activity and good tolerability in phase II settings. Docetaxel plus cisplatin (DP) is the only third-generation regimen that demonstrated statistically significant improvement of overall survival and quality of life by head to head comparison with a second-generation regimen, vindesine plus cisplatin, in patients with advanced NSCLC. Methods: Patients with previously untreated stage IIIB or IV NSCLC, an ECOG PS of 0-1 and adequate organ functions were randomized to receive either oral S-1 80 mg/m2/day (40 mg/m2 b.i.d.) on days 1 to 21 plus cisplatin 60 mg/m2 on day 8 every 5 weeks or docetaxel 60mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3 weeks, both up to 6 cycles. The primary endpoint is overall survival (OS). Non-inferiority study design was employed as upper confidence interval (CI) limit for HR

7528 Background: The secondary epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitors (TKI). A recent report has demonstrated the presence of T790M predicts a favorable prognosis and indolent progression, compared to the absence of T790M after TKI failure. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M. Methods: We investigated 73 patients harboring EGFR sensitive mutations who had undergone rebiopsy to confirm the emergence of T790M after TKI failure. The peptide nucleic acid-locked nucleic acid PCR clamp method was used in EGFR mutational analyses. Patient characteristics (age, gender, smoking history, performance status, EGFR mutation site, initial TKI, response to initial TKI, line of initial TKI, progression-free survival with initial TKI, and biopsy site) and postprogression survivals (PPS) after initial TKI failure, were retrospectively compared in patients with and without T790M. Results: We identified T790M in 2 (10%) of 21 central nervous system (CNS) (19 cerebrospinal fluid and 2 brain tissue) specimens, and in 20 (38%) of 52 other lesions (25 lung tissue, 24 pleural effusion, and 3 lymph node) (p = 0.0225). Other characteristics had no statistical association with the detection of T790M. Median PPS in patients with T790M was 34.0 months, and in those without T790M, 14.5 months (p = 0.0038). Although none of our patients received TKIs continuously after initial failure, 56 (77%) patients were re-administered TKIs. Regardless of T790M status, PPS in patients with TKI re-administration (23.4 months) was significantly longer than without re-administration (10.4 months) (p = 0.0085). Conclusions: The emergence of T790M in CNS is rare compared with other lesions. Patients with T790M after TKI failure have significantly better prognosis than those without T790M. The effectiveness of TKI re-administration or continuous administration beyond progression is suggested after initial TKI failure.

10610 Background: EGFR mutation is independently associated with a favorable response in NSCLC patients receiving EGFR-TKIs, regardless of gender or smoking history. However, recent reports have indicated that squamous cell carcinoma patients harboring EGFR mutations show a worse response to EGFR-TKIs than adenocarcinoma patients. We hypothesized that serum CYFRA21-1 is a predictive marker in EGFR mutated patients treated with EGFR-TKIs. Methods: We retrospectively screened 160 NSCLC patients harboring EGFR mutations (exon 19 deletions, L858R in exon 21, or other minor mutations) who received either gefitinib or erlotinib between 1992 and 2011. Patients were screened for histology, sex, age, smoking status, efficacy of EGFR-TKI and tumor markers (CEA/CYFRA21-1) at initial diagnosis. Results: Out of 160 eligible patients treated with EGFR-TKIs, 77 patients with high CYFRA21-1 level (>2 ng/ml) showed statistically shorter progression-free survival (PFS) than 83 patients with normal CYFRA21-1 level (median PFS 7.5 vs 14.0 months, p=0.006). No significant difference in PFS was observed between high CEA group (>5 ng/ml) and normal CEA group (median PFS 8.6 vs 11.2 months, p=0.2423). Multivariate analysis revealed that high CYFRA21-1 level is independently associated with PFS (HR 1.35; p=0.002) as well as squamous cell carcinoma (HR 1.40; p=0.020) and performance status 2-4 (HR 2.63; p=0.003). No statistically significant difference in overall survival (OS) was observed between high CYFRA21-1 group and normal group (median OS 24.8 vs 39.1 months, p=0.104). Conclusions: High CYFRA level patients have significantly shorter PFS, which may indicate that this subgroup has a larger squamous component and thus less response to EGFR-TKIs. Serum CYFRA21-1 level is a predictive marker of EGFR-TKIs efficacy and EGFR mutated patients can be divided into two subgroups according to CYFRA21-1 level at initial diagnosis.

7521 Background: WJTOG3405 met its primary endpoint of progression free survival (PFS) (9.2 months (mo.) for G vs. 6.3 mo. for CD, hazard ratio (HR) 0.489, 95% confidence interval (CI): 0.336-0.710). (Mitsudomi et al., Lancet Oncol., 2010). However, the impact on overall survival (OS) was not clear then because of relatively short follow-up period. Methods: Overall survival (OS) was re-evaluated using updated data (data cutoff, 31 July, 2011, median follow-up, 34 months) for 172 patients. Results: Eighty-two events had occurred (48%). Median survival time (MST) for G arm was 36 mo. (95% CI: 26.3 -) which was not significantly different from 39 mo. (95% CI: 31.2 -) for CD arm (HR 1.185, 95% CI 0.767-1.829). Multivariate analysis using Cox proportional hazards model revealed that none of covariates (treatment arm, smoking status, sex, age, postoperative recurrence or IIIB/IV, and mutation type) significantly affected OS. In the G arm, MST of patients with exon 19 deletion (36 mo.) was comparable to that of patients with L858R (35 mo.). In the CD arm, 78 patients (91%) received EGFR-TKI as the 2nd or later line treatment, whereas in the G arm, 52 patients (61%) received platinum doublet. Accordingly, 130 patients received both platinum doublet and EGFR-tyrosine kinase inhibitor (TKI) and 34 patients received EGFR-TKI without platinum doublet in their whole courses of therapy. MST for the former and the latter group were 36 months (95% CI: 31.2-45.7) and 45 months (95% CI: 25.6-), without significant difference. Conclusions: This update OS analysis revealed that G for advanced NSCLC with EGFR mutation offers distinct survival benefit of 3 years. There was no difference in OS whether the first-line treatment was G or CD, in accordance with the precedent studies. The reason why PFS difference was not translated into OS difference is probably due to high cross over rate to EGFR-TKI. However, it was noteworthy that 40% of patients in the G arm could be managed without platinum doublet and yet had similar outcome.

7524 Background: An unmet medical need exists in NSCLC pts after failure of E or G [reversible EGFR tyrosine kinase inhibitors (TKIs)], particularly in pts with T790M EGFR mutations, the most common mechanism of acquired resistance. Afatinib (A), an irreversible erbB family blocker, has preclinical activity against T790M. A was tested in this phase II study in pts enriched for acquired resistance to E or G. Methods: Pts in Japan with Stage IIIB/IV NSCLC (ECOG PS 0–1) who had progressed according to RECIST after 1–2 lines of chemotherapy and ≥12 wks of E or G received 50 mg A orally qd. The primary endpoint was objective tumor response. Results: Of 62 pts (F:48; M:14), 11.3%, 79% and 9.7% had received prior erlotinib, gefitinib or both, respectively. 65% of pts had achieved a prior response with E/G. Median duration between end of prior treatment with E/G and the start of A was 3 wks. 73% of pts were EGFR mutation-positive in their primary tumors. 82% of pts met the definition of acquired resistance to E/G...

7609 Background: The efficacy of epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs; gefitinib and erlotinib) has been demonstrated in patients with non-small cell lung canc...

®Background: Bone metastasis (BM) is a frequent complication in patients with advanced lung cancer and it causes skeletal-related events (SREs). Our study aim is to prospectively investigate the incidence of BM, incidence and types of SRE, and predictive factors of BM and SREs. Methods: Newly diagnosed, advanced non–small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC) patients were enrolled into the study. Patients were followed up every 4 weeks to monitor the development of SREs. Treatment for lung cancer was performed at the discretion of the investigator. Results: Two hundred seventy-four patients were enrolled in this study between April 2007 and December 2009 from 12 institutions. Patients included 77 cases of SCLC and 197 of NSCLC (stage IIIB/ IV = 73/124). Median follow-up time was 13.8 months. The incidence of BM at initial diagnosis was 48% in stage IV NSCLC and 40% in extensive stage (ED)-SCLC. Forty-five percent of patients who developed BM had SREs consisting of pathologic fracture (4.7%), radiation to bone (15.3%), spinal cord compression (1.1%), and hypercalcemia (2.2%). Multivariate analysis revealed that factors predicting BM are stage IV, performance status 1 or greater and higher bone alkaline phosphatase in NSCLC patients, higher lactate dehydrogenase, and lower parathyroid hormone–related peptide in SCLC patients. Factors predicting SREs were stage IV, age 64 or younger, and lower albumin in NSCLC patients. Multivariate analysis of SRE was not performed for SCLC because of the small number of events. Conclusion: Predictive factors should be taken into consideration in future randomized studies evaluating BM and SREs.

7025 Background: We previously reported (J Clin Oncol 2008) the safety and efficacy of preoperative chemoradiotherapy followed by surgical resection in superior sulcus tumor (SST). Seven-year follo...

7559 Background: Elderly patients are more vulnerable to toxicity from chemotherapy, possibly from progressive organ failure and comorbidities. Activating epidermal growth factor receptor (EGFR) mu...

7556 Background: Standard treatment of resectable N2 disease is not yet established. To gain insights on significance of preoperative chemoradiotherapy, we tried to evaluate feasibility and efficacy of induction chemotherapy with or without radiotherapy followed by surgery in patients with stage IIIA NSCLC with mediastinal lymph node metastases. Methods: Patients with histologically proven N2 disease were randomized either to receive induction chemotherapy (taxotere 60 mg/m2 and carboplatin AUC 5x2 cycles) with concurrent radiation therapy of 40Gy/20fr (CRS group) or without it (CS group). Patients subsequently underwent pulmonary resection if the tumor was judged resectable. Original sample size was 180 to detect a 20% of survival difference (2 sided P=0.05) with a power of 0.8. The primary endpoint was overall survival. Results: Between Jan. 2001 and Dec 2005, 60 patients were randomized Because of poor accrual of the patients, the study was prematurely terminated. Two patients assigned to CRS group were ineligible due to staging misconducts. Median age was 57 years (range 34–70 years), and 66% were male. Two groups were well balanced with regard to age, gender, histology, and operative procedures. Induction therapy was well tolerated, and there was no treatment related death. Grade 3 and 4 neutropenia occurred in 74 and 89%, respectively. Objective response rate was 25% for the both groups. Surgical resection was performed in 86% and 89%of the patients in CS and CRS groups, respectively. There have been 37 deaths to date. Event free survival at 3 year was 18% and 32% for patients in CS and CRS group, respectively (HR=0.64; 95% CI: 0.36–1.17, P=0.15). Overall survival at 3 year was 44.4 %. and 52.7% (HR=0.84; 95% CI: 0.44–1.62, P=0.62), respectively. Conclusions: Because of small sample size, there was no statistically significant difference. However, our study suggested that addition of radiotherapy to induction chemotherapy could potentially prolong survival of NSCLC patients with N2 disease. [Table: see text]

e19008 Background: Both gefitinib (G) and erlotinib (E) belong to the family of epidermal growth factor receptor-tyrosine kinase inhibitors that has shown positive results in the treatment of advanced/recurrent non-small-cell lung cancer (NSCLC). Recent studies suggested a distinction in efficacy between G and E. In fact, there is a subgroup of patients who had clinically meaningful benefit with E therapy after G failure, but little is known about the factors that predict disease control or the risk factors that develop toxicity in these patients. Our aim is to evaluate the efficacy and toxicity of E after G failure in the largest scale study to date. Methods: We retrospectively evaluated the efficacy and toxicity of E therapy and analyzed factors that contributed to disease control in patients had experienced G failure. EGFR mutational analysis was performed in evaluable cases. Results: From January 2008 to December 2008, seventy-seven patients were treated with E after G failure in our institutions. Of these 77 patients, 11 had a partial response (PR) and 21 had a stable disease (SD), resulting in a best response rate of 14% and a disease control rate (DCR) of 42%. Thirty of 56 (54%) patients who had benefited from prior G therapy achieved disease control, while only 2 of 20 (10%) patients who had experienced initial progressive disease to G therapy obtained SD (P No significant financial relationships to disclose.

LBA8012 Background: Gefitinib is a small molecule inhibitor of the EGFR tyrosine kinase. When combined with chemotherapy, no survival gain was observed compared to chemotherapy alone (INTACT I and ...

14553 Background: In lung adenocarcinomas, especially Bronchiolo Alveolar Carcinomas (BACs), it has been reported that Epidermal Growth Factor Receptor- Tyrosine Kinase Inhibitors (EGFR-TKIs) have ...

8103 Background: TS-1, a novel oral fluorouracil derivative, has been shown to have anti-tumor activity with relatively mild adverse effects, and it is used in the treatment of NSCLC in Japan. The ...

8084 Background: S-1 is an oral anticancer drug combining tegafur, oxonic acid, and CDHP. We have conducted a phase II trial to evaluate the efficacy and toxicity of irinotecan in combination with ...

18209 Background: Amrubicin, a totally synthetic 9-amino-anthracycline, has been demonstrated to have excellent antitumor activity against previously untreated SCLC. However, severe hematological toxicities were observed in previously treated SCLC when given at doses of 40 to 45 mg/m2, days 1–3. We sought to determine the maximum tolerable dose (MTD) and toxicity of amrubicin for pts with previously treated SCLC. Methods: Pts with confirmed SCLC, ECOG PS 0–1, and 20 to 74 years of age, with a history of receiving one or two regimens were eligible for the study. Pts were divided into two groups. Group R (-) consisted of pts without history of radiotherapy except prophylactic cranial irradiation. Group R (+) consisted of pts with history of irradiation up to two fields including thoracic radiotherapy. AMR was initially given at 35 mg/m2, iv, days 1–3, every 3 weeks in both groups. The dose was then increased to 40 and 45 mg/m2. Three pts were treated at each dose level in the absence of a dose limiting toxicity (DLT). All pts received prophylactic hG- CSF between days 8–13. DLT was defined as neutrophil nadir 2. A response rate of 62% was observed. Median survival time was 12 months. No treatment-related death was observed. Conclusions: The MTD in group R (-) was not determined. The MTD in group R (+) was determined as 40 mg/m2. Further data will be presented. No significant financial relationships to disclose.

18060 Background: Although doublet chemotherapy is a standard treatment regimen for PS 0–1 patients with advanced non- small cell lung cancer (NSCLC), the optimal chemotherapy for PS 2 patients with advanced NSCLC still remains to be established. We conducted a randomized phase II study to compare the efficacy and safety of a platinum-doublet regimen (CP) versus a non-platinum doublet regimen (GV) in PS 2 patients with advanced NSCLC. Methods: Chemotherapy-naive patients with stage IIIB (malignant effusion) and IV NSCLC were eligible for this study. The patients were randomly assigned to carboplatin area under the curve of 6 plus paclitaxel 200 mg/m2 on day 1 every 3 weeks (the CP arm) or gemcitabine 1000 mg/m2 plus vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks (the GV arm). The primary endpoint was the 1-year survival rate while the secondary endpoints were the response rate, the time to progression and the quality-of-life (QOL). The sample size was 41 assessable patients in each arm. Results: Of the 89 patients enrolled, 84 were assessable for efficacy and toxicity: 41 patients (median age 65 years, male/female 30/11, stage IIIB/IV 7/34) in the CP arm and 43 patients (median age 67 years, male/female 31/12, stage IIIB/IV 7/36) in the GV arm. The overall response and 1-year survival rates were 29.3% (95% CI, 16.1 to 45.5%) and 22% (95% CI, 9.3 to 34.6%) for the CP and 20.9% (95% CI, 10 to 36%) and 27.9% (95% CI, 14.5 to 41.3%) for the GV arm, respectively. The median survival time and time to progression were 5.9 and 2.9 months, respectively, for the CP arms and 6 and 2.6 months for the GV arm. The selected Grade 3/4 toxicity in the CP and GV arms included neutropenia (67.5% vs 65.1%, respectively), anemia (12.5% vs 30.2%), thrombocytopenia (7.5% vs 11.6%), febrile neutropenia (17.1% vs 11.6%), infection (29.3% vs 23.3%), pneumonitis (4.9% vs 11.6%), liver dysfunction (2.5% vs 9.3%), and neuropathy (5.1% vs 0%). The QOL improved after each treatment and it was similar between the two arms. Conclusions: Both CP and GV appear to be active in PS 2 patients with advanced NSCLC . The toxicity profiles were different between the two arms. [Table: see text]

7115 Background: Efficacy and safety in fit, elderly NSCLC pts receiving platinum-based treatment have been reported to be similar to those in younger pts. However, there is controversy about which platinum-based regimens are suitable for the elderly. To compare efficacy and safety of platinum-based chemotherapy regimens in the elderly, we conducted an age specific subgroup analysis on FACS, a phase III randomized trial comparing four platinum-based regimens for advanced NSCLC. Methods: FACS was designed to compare three platinum-based combination regimens to cisplatin (80 mg/m2, day 1) plus irinotecan (60 mg/m2, days 1, 8, 15) (IP) as the reference arm. The experimental regimens were: carboplatin (AUC 6, day 1) plus paclitaxel (200 mg/m2, day 1) (TC); cisplatin (80 mg/m2, day 1) plus gemcitabine (1000 mg/m2, days 1, 8) (GP); cisplatin (80 mg/m2, day 1) plus vinorelbine (25 mg/m2, days 1,8) (NP). Results: Of the 105 pts ≥ 70 years (17% of 602 enrolled pts), 27 were on the IP arm, 27 on TC, 28 on GP, and 22 on NP. Patient characteristics were similar in each arm. Response rates were 26% in IP, 20% in TC, 32% in GP, 50% in NP. Frequency of grade 3 or greater leukocytopenia (IP/TC/GP/NP: 52%/33%/36%/86%) was higher in NP, and thrombocytopenia (IP/TC/GP/NP: 11%/19%/43%/0%) was higher in GP, however anemia (IP/TC/GP/NP: 56%/19%/29%/55%) was lower in TC and GP. Frequency of grade 2 or greater vomiting (IP/TC/GP/NP: 52%/22%/39%/41%) was lower in TC, and diarrhea (IP/TC/GP/NP: 48%/7%/4%/14%) was lower in TC, GP and NP, however, grade 2 or greater sensory neuropathy (IP/TC/GP/NP: 0%/22%/0%/0%) was higher in TC. One year survival rates were 48% for the IP arm, 48% for TC, 61% for GP, and 46% for NP. There were no significant survival differences between IP and each experimental regimen. In addition, no significant differences between ≥ 70 and < 70 years were observed in each treatment regimen regarding hematological and non-hematological toxicities, response rates, and survival, except that grade 3 or greater anemia was significantly higher in ≥ 70 years pts in IP and NP arms. Conclusions: These platinum-based four regimens were similarly active and tolerable for fit, elderly NSCLC pts, and their efficacy and toxicity in the elderly were similar to those in younger pts. No significant financial relationships to disclose.

7090 Background: Efficacy of high dose chemotherapy with autologous PBSCT has been demonstrated in the treatment of lymphoma. The purpose of this trial is to determine progression-free survival and long-term survival for LD-SCLC patients (pts) who responded to first-line concurrent chemo-radiotherapy followed by HD-ICE with PBSCT. Methods: Patients (pts) with pathologically proven SCLC without malignant pleural and pericardial effusion, stage II-IIIB, ECOG-PS 0–1 were eligible. All pts were treated with cisplatin (P) 60 mg/m2 day1 and etoposide (E) 100 mg/m2, days 1–3, with concurrent hyperfractionted radiotherapy initially (1.5Gy X 2/day X 15 days, total 45Gy) and then two or three cycles of chemotherapy consisted of P 60 mg/m2, day 1, and E 120 mg/m2, days 1–3, or APE (adriamycin 30 mg/m2, day 1, P 60 mg/m2, day1 and E 100 mg/m2, days 1–3) were repeated. Pts with tumor shrinkage more than 90% after initial therapy received HD-ICE (ifosfamide 3 g/m2, days 1–3, carboplatin 400 mg/m2, days 1–3, etoposide 400 mg/m2, days 1–3) followed by PBSCT. All pts received prophylactic cranial irradiation (1.5 Gy × 2/day × 9 days, total 27 Gy). Results: Between 1996 and 2001, 15 pts were eligible and all 15 pts received HD-ICE with PBSCT. Patient characteristics included M/F:14/1, median age: 55 (47–62), PS 0/1: 7/8 stage IIIA/IIIB: 7/8. Grade IV neutropenia and thorombocytopenia were observed in all pts and 93% of pts experienced neutropenic fever after HD-ICE. There was no toxic death. Median follow up time was 83.2 months. Median progression free survival time was 10. 7 months and overall median survival time (MST) was 30.9 months. Two, 3 and 5-year survival rates after initial chemoradiotherapy were 67%, 33%, 25%, respectively. Conclusion: HD-ICE with PBSCT for LD-SCLC revealed promising MST and a 5-year survival rate with manageable treatment-related toxicity. A randomized phase III study comparing chemo-radiotherapy followed by HD-ICE with PBSCT to standard chemo-radiotherapy for LD-SCLC is ongoing. No significant financial relationships to disclose.

7151 Background: A platinum-based chemotherapy is a standard treatment in PS 0–1 patients with advanced NSCLC and a non-platinum doublet is an alternative option. However, the role of combination chemotherapy remains to be defined in PS 2 patients with advanced NSCLC. We have conducted a randomized phase II study to compare the efficacy and safety of CP versus GV in PS 2 patients with NSCLC. Methods: Chemotherapy-naive ECOG PS 2 patients with stage IIIB (malignant effusion) or IV NSCLC were enrolled in this study. Patients were randomized to carboplatin AUC 6 and paclitaxel 200 mg/m2 day 1 every 3 weeks or gemcitabine 1,000 mg/ m2 and vinorelbine 25mg/m2 day 1, 8 every 3 weeks. The primary endpoint was 1-year survival rate and secondary endpoint were response rate, toxicity, time to progression and quality of life. Results: A total of 89 patients were enrolled and 86 were eligible: 42 patients (median age 64 years, male/female 31/11, stage IIIB/IV 7/35) in CP and 44 patients (median age 67 years, male/female 33/11, stage IIIB/IV 7/37) in GV. Of 84 patients evaluable for response, one complete response and 11 partial responses were obtained in CP (29.3%) and 9 partial responses in GV (20.9%). As of 12/05, toxicity data were available in 80 patients. Grade 3/4 toxicity in CP and GV included neutropenia 65.8% vs 63.4%, anemia 13.2% vs 31.7%, thrombocytopenia 7.9% vs 12.2%, liver dysfunction 2.6% vs 9.8%, febrile neutropenia 15.4% vs 12.2%, infection 30.8% vs 22%, nausea/vomiting 15.4% vs 2.4%, constipation 23.1% vs 7.3% pulmonary infiltrates 5.1% vs 12.2% and neuropathy 5.1% vs 0%. Conclusions: CP and GV were feasible and effective in PS 2 patients with advanced NSCLC. GV caused more anemia, thrombocytopenia, liver dysfunction and pulmonary infiltrates, while CP produced more nausea/vomiting, constipation and neuropathy. Response and toxicity data in all pts in each arm will be presented at the meeting. No significant financial relationships to disclose.

7237 Background: Despite surgical resection, patients with clinical T2N0, T1–2N1 and T3N0 NSCLC have poor 5-year survivals (30% to 50%). Since a significant proportion of patients with early-stage ...

7009 Background: Monotherapy of V is currently the standard treatment for elderly pts with advanced NSCLC based on improved survival and quality of life (QOL). D has also shown promising results ag...