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Simple Summary Advanced thymic carcinoma (ATC) is rare. Owing to its rarity, there is limited information on the prognostic factors, and the optimal serum tumor markers are also unknown. We conducted a multi-institutional retrospective study of patients with ATC. In this study, we collected data on patient characteristics, progression-free survival (PFS), overall survival (OS), and tumor marker values, and investigated the relationship between tumor marker values and PFS/OS. We found that the neuron-specific enolase (NSE) level may be a useful prognostic tumor marker for ATC, regardless of histology. The findings of the analysis limited to squamous cell carcinoma suggested that the NSE and squamous cell carcinoma antigen levels may be useful prognostic factors. Abstract The optimal tumor marker for predicting the prognosis of advanced thymic carcinoma (ATC) remains unclear. We conducted a multi-institutional retrospective study of patients with ATC. A total of 286 patients were treated with chemotherapy. Clinicopathological information, including serum tumor markers, was evaluated to determine the overall survival (OS) and progression-free survival (PFS). The carcinoembryonic antigen, cytokeratin-19 fragment, squamous cell carcinoma (SCC) antigen, progastrin-releasing peptide, neuron-specific enolase (NSE), and alpha-fetoprotein levels were evaluated. In the Kaplan–Meier analysis, the OS was significantly shorter in the patients with elevated NSE levels than in those with normal NSE levels (median, 20.3 vs. 36.8 months; log-rank test p = 0.029; hazard ratio (HR), 1.55; 95% confidence interval (CI), 1.05–2.31 (Cox proportional hazard model)); a similar tendency regarding the PFS was observed (median, 6.4 vs. 11.0 months; log-rank test p = 0.001; HR, 2.04; 95% CI, 1.31–3.18). No significant differences in the OS and PFS were observed among the other tumor markers. In both univariate and multivariate analyses of the patients with SCC only, the NSE level was associated with the OS and PFS. Thus, the NSE level may be a prognostic tumor marker for thymic carcinoma, regardless of histology.

Purpose This phase II study was designed to evaluate the efficacy and safety of S-1 combined with weekly irinotecan as second- or third-line treatment for patients with advanced or recurrent squamous cell lung cancer. Methods Patients received oral S-1 on days 1–14 at 80 mg/day for patients with a body surface area of 2, 100 mg/day for patients with a body surface area of 1.25–1.5 m2, and 120 mg/day for patients with a body surface area of > 1.5 m2 and irinotecan (70 mg/m2) on days 1 and 8 every 3 weeks. The primary endpoint was overall response rate, and the secondary endpoints were progression-free survival, overall survival, and the frequency and the degree of adverse effects. The trial was registered in the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000006065. Results Between September 2011 and December 2014, 30 patients were enrolled in this study. The overall response rate was 6.7% (95% CI 0.8–22.1) and the disease control rate was 73.3%. The median progression-free survival was 3.0 months (95% CI 2.5–3.4) and median overall survival was 10.5 months (95% CI 5.6–13.7). Grade 3 or 4 treatment-related toxicities were reported in ≥ 10% of patients including leukopenia (21%), neutropenia (21%), anemia (17%), anorexia (10%), and hypokalemia (10%). Conclusion Adding weekly irinotecan to S-1 did not show the expected effect though toxicities were manageable.

Background/aim Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. Patients and methods We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. Results Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. Conclusion This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

Summary Background Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer. Methods We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants. Findings Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5–13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2–16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96–1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six [6%] of 106 in the prophylactic cranial irradiation group vs two [2%] of 111 in the observation group), malaise (three [3%] vs one [ vs six [5%]). No treatment-related deaths occurred in either group. Interpretation In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up. Funding The Ministry of Health, Labour and Welfare of Japan.

Purpose Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation. Patients and Methods Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m2 on days 1 through 3) or topotecan (1.0 mg/m2 on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile. Results From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival. Conclusion Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (> or = 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70 mg/m2 on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted.

Summary Fibrosing mediastinitis is an extremely rare disease in which fibrous tissue is formed progressively within the mediastinum due to various causes. Here, we report two cases of the idiopathic form of fibrosing mediastinitis. We investigated the pathogenesis of fibrosing mediastinitis by immunohistochemical methods, and demonstrated the expression of transforming growth factor β in this disease. These results suggest that transforming growth factor β plays an important role in the pathogenesis of fibrosing mediastinitis.

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.

Background We conducted a phase I dose escalation study to evaluate the feasibility, maximum tolerated dose (MTD), and recommended dose (RD) of weekly irinotecan combined with fixed-dose carboplatin for patients with untreated small-cell lung cancer (SCLC). Methods Fifteen patients with chemotherapy-naive SCLC less than 75 years old were enrolled from 3 institutions. Patients received irinotecan (50–80mg/m 2 on days 1 and 8) and carboplatin (area under the curve, 5.0 on day 1) every 3 weeks, with 3–6 patients treated at each irinotecan dosage level (levels I–IV). The MTD was defined as the dose at which 33% of patients experienced dose-limiting toxicity. Results Eleven patients had a performance status of 1, and 7 patients were more than 70 years old. All but 1 patient were diagnosed with extensive disease. In total, 2 of 3 patients enrolled at level IV (80mg/m 2 ) experienced grade 3 diarrhea. Therefore, the MTD was defined as the level IV dose, and the RD was defined as the level III dose (70mg/m 2 ). Grade 3 or 4 neutropenia was observed in 60% of patients, and febrile neutropenia was observed in 13% of patients. Four patients experienced grade 3 or 4 anemia, and 6 patients experienced grade 3 or 4 thrombocytopenia. The most common non-hematological adverse events were nausea/vomiting, diarrhea, hypokalemia, and hyponatremia. Conclusions The MTD of weekly irinotecan was 80mg/m 2 , resulting in an RD of 70mg/m 2 for phase II trials.

Author Summary Background. Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. Methods. Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m2) (CP regimen) or to single-agent docetaxel (60 mg/m2). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile. Results. Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%–69%) and 24% (95% confidence interval: 11%–37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm. Conclusion. The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC.

A newly identified gene, p51, is a functional and structural homologue of the p53 gene and thus a candidate tumor suppressor gene. To elucidate the role of the p51 gene in lung carcinogenesis, we determined the sequences of exon-intron boundaries and the 5′- and 3′-flanking regions of all the 15 coding exons and performed a mutation analysis, as well as detailed analysis for gene expression. A frameshift mutation was detected in 1 of 44 lung cancer cell lines, whereas no mutation was detected in 45 primary lung cancers. Thus, p51 mutation occurs only in a small subset of lung cancer. Expression of the p51 gene was detected in 23 of 43 cell lines by Northern blot analysis and 34 of 44 by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Thus, p51 expression is low or absent in a subset of lung cancer. The ΔN isotype of p51 transcripts was dominantly expressed in several cell lines, particularly in cell lines with high levels of p51 expression. Because the ΔN isotype encodes a protein that transdominantly suppresses the transactivation function of the TA type of p51, it is possible that p51 protein is not functionally active, even in lung cancer cells with p51 mRNA expression, due to expression of dominant-negative p51 protein. These results suggested that the p51 gene is inactive in a considerable proportion of lung cancers. RT-PCR analysis also revealed the presence of a novel type of mRNA transcript, p51δ, which lacks exons 12 and 13 by alternative splicing. The δ isotype was expressed in 18 of 44 lung cancer cell lines and in diverse normal tissues. Further analysis on p51 expression in cancerous as well as noncancerous cells will provide us with valuable information for the understanding of multiple functions of the p53 family proteins in human carcinogenesis.

Background Amrubicin (AMR), a new anthracycline agent, has shown promising results for advanced small-cell lung cancer (SCLC), although the efficacy of AMR alone against refractory relapsed SCLC is insufficient. This study was conducted to evaluate the safety and efficacy of the combination of AMR and carboplatin (CBDCA) in patients with refractory relapsed SCLC. Methods Patients with advanced SCLC who relapsed within 90 days after the completion of first-line chemotherapy received AMR (30mg/m 2 , days 1–3) and CBDCA (area under the curve 4.0mgmL −1 min −1 , day 1) every 3 weeks. The primary endpoint of this study was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival, and the toxicity profile. Assuming that an ORR of 45% in eligible patients would indicate potential usefulness and an ORR of 20% would be the lower limit of interest, with α =0.10 and β =0.10, at least 24 patients were required. Results Among 29 eligible patients, the ORR was 34% (90% confidence interval, 20–48). The median PFS was 3.5 months, whereas the median survival time was 7.3 months. The most common grade 3–4 toxicity was neutropenia (79%), although only one patient (3%) suffered from febrile neutropenia. Non-hematological toxicities were of moderate severity and no treatment-related death was observed. Conclusions This is the first prospective study of AMR combined with CBDCA for refractory relapsed SCLC, which was effective and well tolerated. However, further investigation of this regimen is warranted.

8567Background: Prognostic factors and efficacy of chemotherapy remain unclear in patients with advanced thymic carcinoma. Methods: We performed a multi-institutional, retrospective study named NEJ...

Background We aimed to evaluate the efficacy and safety of irinotecan monotherapy as a third- or fourth-line treatment for advanced non-small cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC refractory to 2 or more previous regimens were treated with 80mg/m 2 irinotecan on days 1, 8, and 15, every 4 weeks. The primary endpoint was the overall response rate (ORR), whereas secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity profiles. Results From December 2007 to April 2009, 32 patients (median age, 60 years) were enrolled. Most of the patients (75.0%) were male, and 18.8% had a performance status of 2. Six partial responses to irinotecan monotherapy were observed (ORR, 18.8%: 95% confidence interval, 5.3%–32.3%). The disease control rate (DCR) was 78.1%, median PFS was 4.0 months, and median survival time (MST) was 10.4 months. Grade 3–4 neutropenia was observed in 22% of patients, but other toxic effects were moderate. No cases of grade 3–4 diarrhea or treatment-related death were noted. Of the 15 patients for whom progressive disease represented the best response to previous treatment regimens, 2 exhibited a partial response and 9 showed stable disease after irinotecan monotherapy, with a DCR of 73.3%, median PFS of 4.4 months, and MST of 8.2 months. Conclusions Irinotecan monotherapy is effective for advanced NSCLC patients who have previously failed 2 or more treatment regimens.

Objectives: We conducted a phase II study to evaluate the combination of bi-weekly docetaxel and S-1, a novel oral fluorouracil derivative, for patients with previously treated non-small cell lung cancer. Methods: Patients received S-1 on days 1-14 and docetaxel on days 1 and 15 of each 28-day cycle. The primary endpoint was overall response rate (ORR). Results: We enrolled 35 pts from 7 institutions (Feb. 2007-Sep. 2008). Patient characteristics: male/female, 23/12; median age, 64 years; and PS, 0/1 (17/18). The ORR was 26% (95% confidence interval, 11-40). The median progression-free survival was 4.1 months and the median overall survival was 16.3 months. Hematologic grade 3/4 toxicity included neutropenia (31%) and anemia (11%). Major non-hematologic grade 3 toxicity included diarrhea (17%). Conclusions: The combination of S-1 and bi-weekly docetaxel is an active regimen with a tolerable toxicity for previously treated NSCLC. Further evaluation of this regimen is warranted.

Background Amrubicin, a new anthracycline agent, has shown high activity for small-cell lung cancer (SCLC) in previous studies. However, a combination regimen with amrubicin and platinum has been investigated little. On the basis of previous phase I study, we conducted this study to evaluate the efficacy and the safety of amrubicin and carboplatin for elderly patients with SCLC. Methods Chemotherapy-naive elderly patients with SCLC received amrubicin (35 mg/m2, days 1–3) and carboplatin [area under the curve (AUC) 4.0, day1] every 3 weeks. The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival and toxicity profile. Results From January 2005 to November 2007, 36 patients were enrolled [median age 76 (range 70–83); ECOG performance status of zero and one in 17 and 19 patients, respectively]. One complete response and 31 partial responses were observed (ORR 89%). Median PFS was 5.8 months and median survival time was 18.6 months. Grade 3–4 neutropenia was observed in 97% of the patients and six patients (17%) suffered from grade 3–4 febrile neutropenia. Other toxic effects were moderate and treatment-related death was not observed. Conclusions Amrubicin combined with carboplatin is quite effective for SCLC with acceptable toxic effects even for the elderly population. Further evaluation of this regimen is warranted.

Sensitivity to an inhibitor of epidermal growth factor receptor (EGFR) kinase strongly correlates with EGFR somatic mutations in non-small cell lung cancer. These mutations are frequently found in patients with adenocarcinoma, never- or light-smokers, women, and East Asians. In this study, we show an aggregation of three non-small cell lung cancer cases with EGFR gene mutations in one family. The subjects were all female, never- or light-smokers with adenocarcinoma. Two of the patients responded to treatment with gefitinib. A genetic study of these cases would be useful in elucidating genetic susceptibility to lung cancer in persons with EGFR mutations.

S-1 is a novel oral fluorouracil prodrug active against non-small cell lung cancer (NSCLC). To determine the feasibility of S-1 combined with weekly irinotecan for patients with advanced NSCLC, we performed a phase I study to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan.Patients with advanced NSCLC received S-1 (80 mg/m(2)) on days 1-14 and irinotecan (50-80 mg/m(2)) on days 1, 8, and 15 of each 28-day cycle. Three to six patients were treated with each dose of irinotecan, with the MTD defined as the dose at which dose-limiting toxicity (DLT) appeared in 33% of patients.At doses of 50-70 mg/m(2), no patients experienced any DLT, whereas, at a dose of 80 mg/m(2), two of four patients experienced DLTs. Two patients experienced grade 3 toxicities - neutropenia and diarrhea.The MTD of weekly irinotecan was 80 mg/m(2), making its RD for phase II trials 70 mg/m(2).

The anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GM-CSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages.

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated good response in NSCLC harboring EGFR gene mutation. However, survival benefit from erlotinib was observed also in NSCLC patients with wild-type (wt) EGFR gene in subsets of several phase III trials. Additionally, smoking status could be a predictive factor of erlotinib efficacy. This study aimed to evaluate the efficacy of erlotinib in Japanese NSCLC patients with wt-EGFR and find a biomarker that predicts the efficacy of erlotinib other than EGFR gene mutation. Methods The primary end point was an objective response rate. Secondary end points included disease control rate, overall survival, safety and a biomarker finding. Advanced NSCLC patients without EGFR gene mutation who had received one to three prior chemotherapy regimens and who had never smoked or light smoked (smoking index: Results Forty-seven patients were enrolled between March 2010 and November 2011. One patient was excluded for evaluation because having mutation of EGFR. Efficacy and safety were evaluated among 46 patients. Best responses were: PR 7 (15.2%), SD 12 (26.1%), PD 26 (46.4%), NE 1 (2.2%). Response rate and disease control rate were 15.2% (95% CI: 4.9–25.5%) and 41.3 % (95% CI 27.1–55.5%), respectively. Grade 3 or 4 adverse events were anorexia (4), skin rash (2), neutropenia (1), leukopenia (1), anemia (2), elevation of AST/ALT (1), rectal ulcer (1) and cerebral infarction (1).Two patients suffered grade 3 interstitial lung disease. Conclusion This is the first report to evaluate Erlotinib efficacy in selected NSCLC who do not possess EGFR gene mutation. Erlotinib showed significant anti-tumor activity in pretreated never or light smoked Japanese NSCLC patients without EGFR gene mutation.

p73, a recently identified gene highly homologous to p53, can transactivate p53 target genes and induce apoptosis. Here we report the identification of an NH(2)-terminal truncated isoform of human p73, DeltaNp73, which is capable of suppressing p53- and p73-dependent transactivation. We speculate that this suppression is achieved by competing for the DNA binding site in the case of p53 and by direct association in the case of TAp73. Expression of DeltaNp73 in cancer cell lines also inhibited suppressive activity of p53 and TAp73 in colony formation, implying possible involvement of DeltaNp73 in oncogenesis by inhibiting the tumor-suppressive function of p53 and TAp73. Also reported is the identification of TAp73eta, a new member of the COOH-terminal truncated isoform of p73 and tissue-specific expression of these isoforms, along with other previously identified p73 isoforms.

e19116 Background: Personalized peptide vaccination (PPV) could offer a novel approach to cancer vaccines that boost anticancer immunity. We conducted non-randomized controlled study to investigate...

7503 Background: A previous study has shown that PCI reduced the risk of brain metastases (BM) and prolonged the OS of patients with ED-SCLC (Slotman B et al, NEJM 2007). There were, however, sever...

Backgroud: Basic experiments showed high sensitivity offluoropyrimidine agent to EGFR-TKI resistant cell-line and the synergistic effect of S-1 (a novel oral fluorouracil derivative) and irinotecan combination. We therefore conducted a phase II trial to evaluate the efficacy and safety of S-1 and irinotecan combination for EGFR-mutated NSCLC resistant to both platinum-based chemotherapy and EGFR-TKI. Methods: Eligible patients (pts) had NSCLC with EGFR mutation, ECOG performance status (PS) 0 to 1, failure of EGFR-TKI following one or two

Background Standard first-line chemotherapy for elderly NSCLC patients has been considered as a monotherapy with vinorelbine or gemcitabine globally. However, we have demonstrated the high efficacy of CwP for elderly patients in our previous trial (Ann Oncol 2010). Meanwhile, D has been considered as an alternative option for this population in Japan according to the result of WJTOG9904 (JCO 2006). Thus we compared the two regimens to select the proper candidate for future phase III trial. Methods Eligible patients were aged 70 years or older with newly diagnosed stage IIIB/IV NSCLC; ECOG performance status 0-1; adequate organ function; written informed consent. Patients were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel (70 mg/m2 on day 1, 8, and 15) every 4 weeks or D (60 mg/m2 on day 1) every 3 weeks. The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that the ORR of 40% would be potential usefulness while the ORR of 20% would be the lower limit of interest, 40 patients in each arm were required if we expect 10% loss to follow-up. Results Between July 2006 and September 2010, 84 patients were enrolled and 41 patients in CwP arm and 42 patients in D arm were eligible (median age, 76 years; 75% male; 72% stage IV). Median treatment cycle was four in each arm (CP, range 1–6; D, range 1–8). ORRs were 51% (95% CI: 36–66%) and 26% (95% CI: 12–39%) in the CP and D arm, respectively. With a median follow-up of 18.4 months, median PFS were 6.5 and 3.9 months in the CP and D arm, respectively. Grade 3 or severer toxic effects were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and D, 25%). One treatment-related death occurred in D arm (neutropenia, pneumonia, and lethal arrhythmia in the same patient) and none in CP arm. Conclusions The platinum doublet CwP achieved higher activity with an acceptable toxicity profile for elderly patients with advanced NSCLC compared with monotherapy with D, which is consistent with the result of recent IFCT-0501 trial (Lancet 2011).

7561 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated good response in NSCLC harboring EGFR gene mutation. However, survival benefit from erlotinib was observed also in NSCLC patients with wild type (wt) EGFR gene in subsets of several phase III trials. Additionally, smoking status could be a predictive factor of erlotinib efficacy, This study aimed to evaluate the efficacy of erlotinib in Japanese NSCLC patients with wt-EGFR and find a biomarker that predicts the efficacy of erlotinib other than EGFR gene mutation. Methods: The primary endpoint was an objective response rate. Secondary endpoints included disease control rate, overall survival, and safety. Advanced NSCLC patients without EGFR gene mutation who had received one to three prior chemotherapy regimens and who had never smoked or light smoked (Brinkman Index: less than200) were eligible in this study. EGFR gene status was evaluated by the PNA-LNA PCR clamp method. Erlotinib was administered daily (150mg/day) until disease progression or unacceptable toxicities. Results: Forty seven patients were enrolled between March 2010 and November 2011. One patient was excluded for evaluation because having mutation of EGFR. Efficacy and safety were evaluated among 46 patients. Best responses were PR 7 (15.2%), SD 12 (26.1%), PD 26 (46.4%), NE 1 (2.2%). Response rate and disease control rate were 15.2% (95%CI: 4.9-25.5%) and 41.3 % (95%CI 27.1-55.5%) respectively. Grade 3 or 4 adverse events were anorexia (4), skin rash (2), neutropenia (1), leukopenia (1), anemia (2), elevation of AST/ALT (1), rectal ulcer (1), and cerebral infarction (1).Two patients suffered grade 3 interstitial lung disease. Conclusions: This is the first report to evaluate Erlotinib efficacy in selected NSCLC who do not possess EGFR gene mutation. Erlotinib showed significant anti-tumor activity in pretreated never or light smoked Japanese NSCLC patients without EGFR gene mutation. The results of biomakr analysis will be presented at the meeting.

e19521 Background: Diarrhea after antibiotic treatment is primarily ascribed to the development of mucosal lesion for which Clostridium difficile infection (CDI) is held responsible. Evidence on CDI in patients on chemotherapy without antibiotic treatment prior to chemotherapy is on the rise. However there have been few reports describing diarrhea in relation to regimens of chemotherapy. The aim of our study was to find out whether the incidence of CDI in patients on cancer chemotherapy increases even in the absence of prior antibiotic treatment. Methods: From March 2010 through September 2011, we investigated the presence of Clostridium difficile (C.difficile) and its toxin in any patients undergoing diarrhea while receiving cytotoxic anticancer agents or epidermal growth factor receptor tyrosine kinase inhibitors. Whenever Grade2 or worse diarrhea defined by the Common Terminology Criteria for Adverse Events version4 occurred, we examined their stool samples for anaerobic culture and simultaneously tested for toxins A and B. A case of CDI is defined by the presence of symptoms (usually diarrhea) and either a stool test positive for C.difficile toxins or toxigenic C.difficile according to criteria of the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Results: A total of 345 consecutive patients (492 in terms of chemotherapy -regimens) were enrolled in this study. 36 of 492 regimens (7.3%) showed Grade2 or worse diarrhea. CDIs without prior antibiotic exposure were confirmed in as many as 8 out of these 36 regimens (22.2%). CDI was more frequently observed in patients of the regimens including S-1 or irinotecan than other anticancer drugs. Conclusions: CDI may remain undetected among patients who had diarrhea defined as above unless due attention is paid to this possibility. It is highly recommended to perform tests for the detection of C.difficile toxins so that necessary measures can be instituted without delay in the treatment of diarrhea of patients on chemotherapy. Further analysis for drugs specificity and prevention against CDI is necessary.

7086 Background: AMR, a new anthracycline agent, has achieved some promising results for advanced SCLC both in the first-line and the second-line setting. However the efficacy of AMR alone against refractory relapsed SCLC was relatively low in previous studies. This study was conducted to evaluate the safety and efficacy of the combination of AMR plus CBDCA in patients with refractory relapsed SCLC. Methods: Patients with advanced SCLC who relapsed within 90 days after the completion of first-line chemotherapy received AMR (30 mg/m2, day1-3) and CBDCA (AUC 4.0, day 1) every 3 weeks. The primary endpoint of this study was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 45% in eligible patients would indicate potential usefulness while ORR of 20% would be the lower limit of interest, with alpha = 0.10 and beta = 0.10, at least 24 patients were required. Results: From September 2008 to May 2011, 30 patients were enrolled from 10 institutions. One patient was excluded because of ineligible histology. Patient characteristics were: Male/Female 26/3; median age 67 (range 50-81); Performance status 0/1/2 9/16/4. The median number of treatment cycles were 4 (range 1-7). The objective responses evaluated by RECIST were: CR 0, PR 10, SD 14, PD 5. The ORR was 34% and the disease control rate was 83%. Median PFS was 3.5 months and median survival time was 7.3 months. Grade 3-4 neutropenia was observed in 23 patients (79%) and grade 3-4 thrombocytopenia was observed in 7 patients (24%). One patient (3%) suffered from grade 3-4 febrile neutropenia. Other grade 3 non-hematological toxicities such as infection, interstitial lung disease, hyponatremia, hypoglycemia, were observed in 7 patients (24%). No treatment related death was observed. Conclusions: This is the first prospective study of AMR combined with CBDCA for refractory relapsed SCLC, which was effective and well tolerated. Further investigation of this treatment is warranted.

7565 Background: Standard first-line chemotherapy for elderly NSCLC pts has been considered as a monotherapy with vinorelbine or gemcitabine globally. However, we have demonstrated the high efficacy of CP for elderly pts in our previous trial (Ann Oncol 2010). Meanwhile, D has been considered as an alternative option for this population in Japan according to the result of WJTOG9904 (JCO 2006). Thus we compared the two regimens to select the proper candidate for future phase III trial. Methods: Eligible pts were aged 70 years or older with newly diagnosed stage IIIB/IV NSCLC; ECOG performance status 0-1; adequate organ function; written informed consent. Pts were randomized to receive carboplatin (AUC 6) on day 1 and paclitaxel (70mg/m2 on day 1, 8, and 15) every 4 weeks or D (60mg/m2 on day 1) every 3 weeks. The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival, and toxicity profile. Assuming that ORR of 40% would be potential usefulness while ORR of 20% would be the lower limit of interest, 40 pts in each arm were required if expect 10% loss to follow up. Results: Between July 2006 and September 2010, 84 pts were enrolled and 41 pts in CP arm and 42 pts in D arm were eligible (median age, 76 years; 75% male; 72% stage IV). Median treatment cycle was 4 in each arm (CP, range 1-6; D, range 1-8). ORRs were 51% (95%CI: 36-66%) and 26% (95%CI: 12-39%) in the CP and D arm, respectively. With a median follow-up of 18.4 months, median PFS were 6.5 and 3.9 months in the CP and D arm, respectively (Logrank, P=0.0027). Grade 3 or severer toxicities were as follows: neutropenia (CP, 56% and D, 79%), anemia (CP, 15% and D, 7%), thrombocytopenia (CP, 10% and D, 0%), infection (CP, 20% and D, 25%). One treatment-related death due to neutropenia, pneumonia, and lethal arrhythmia occurred in D arm but none in CP arm. Conclusions: The platinum doublet CP achieved higher activity with an acceptable toxicity profile for elderly pts with advanced NSCLC compared to monotherapy with D. The superiority of CP to the monotherapy in this trial is consistent with results of recent IFCT-0501 trial (Lancet 2011).

7604 Background: S-1, a novel oral fluorouracil derivative, is active against non-small cell lung cancer (NSCLC). A preclinical study showed the synergistic effect of docetaxel and S-1 in vivo. On ...

8054 Background: AMR, a new anthracycline agent, is active for SCLC. We had previously reported a phase I study of AMR combined with CBDCA for elderly patients with SCLC (J Thorac Oncol 1:551, 2006). The objective of this study is to evaluate the efficacy and the safety of this combination for elderly patients with SCLC. Methods: Chemotherapy naïve elderly patients (70 years or older) with SCLC received AMR (35 mg/m2, day1–3) and CBDCA (AUC 4.0, day1) every 3 weeks. The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival and toxicity profile. Assuming that ORR of 60% in eligible pts would indicate potential usefulness while ORR of 40% would be the lower limit of interest, with alpha = 0.10 and beta = 0.20, the estimated accrual was 30 patients. Results: From January 2005 to November 2007, 36 pts were enrolled from 11 institutions. Patient characteristics were: Male/Female 27/9; median age 76 (range 70–83); Performance status 0/1 17/19. The median numbers of treatment cycles were 4 (range 2–7). The objective responses were CR 1, PR 31, SD 2, PD 2, and the ORR was 89%. Median PFS was 5.8 months and median survival time was 18.6 months. Grade 3–4 neutropenia was observed in all the patients and 5 patients (14%) suffered from grade 3–4 febrile neutropenia. Other toxicities were moderate and no treatment related death was observed. Conclusions: AMR combined with CBDCA is quite effective for SCLC with acceptable toxicities even for the elderly population. Further evaluation of this regimen is warranted. No significant financial relationships to disclose.

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 ...

Clarke's normal cone has been frequently used to formulate the marginal cost pricing rule for nonconvex firms. The author provides examples where a firm with convex iso-output sets is not minimizing its cost at a price vector in the normal cone. For a firm to be cost minimizing under any price in the normal cone, lower hemicontinuity of the iso-output correspondence is sufficient. The author also provides an extension of the second welfare theorem with a price vector in the normal cone of each firm and cost minimization of firms. Copyright 1994 by Economics Department of the University of Pennsylvania and the Osaka University Institute of Social and Economic Research Association.

Background The combination of carboplatin and docetaxel has been considered one of the standard treatments for advanced non-small cell lung cancer (NSCLC). To investigate a safer and more convenient schedule for outpatient, we conducted a phase II study to evaluate the efficacy and the safety of carboplatin plus biweekly docetaxel for advanced NSCLC. Patients and Methods Patients with stage IIIB, IV, or postoperative recurrent NSCLC with good performance status were administered docetaxel at a dose of 35 mg/m 2 on days 1 and 15 and carboplatin at an area under the curve (AUC) of 6 on day 1 every 4 weeks for at least three cycles. Results Fifty patients were treated with median of three cycles (range 1–6). Grade 3/4 toxicities included neutropenia in 18 patients (36%), thrombocytopenia in 4 patients (8%), and anemia in 10 patients (20%). No patient experienced febrile neutropenia. Nonhematological toxicities were also mild to moderate, and there were no treatment-related deaths. The overall response rate was 30%, and the disease control rate was 70%. Among the elderly population, 54% of patients achieved partial response. Median progression-free survival was 4.8 months, and median overall survival was 11.8 months. Conclusions Biweekly docetaxel plus carboplatin has a similar efficacy and lower toxicity compared with a standard triweekly regimen of docetaxel plus carboplatin, which is a suitable regimen for outpatients, including elderly patients.