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Background: Adjuvant tegafur/uracil (UFT) chemotherapy is recommended for patients with completely resected Stage I non-small cell lung cancer (NSCLC) in Japan. A Phase III trial, the Japan Clinical Oncology Group (JCOG) 0707, comparing the survival benefit of UFT and S-1 (tegafur/gimeracil/oteracil) for this population is being conducted. However, the selection of patients in the randomized clinical trial (RCT) may not represent the real-world population. The present study aimed to investigate the pattern of care for patients receiving adjuvant chemotherapy for completely resected NSCLC., Methods: Patients with completely resected pathological Stage I (T1 > 2 cm and T2 in 6th TNM edition) NSCLC eligible for the JCOG0707 trial but excluded from it during the enrollment period (2008-13) were eligible for this study. Physicians from institutions that participated in the JCOG0707 retrospectively assessed the medical records of each patient., Results: This study enrolled 5006 patients, 85% of those initially considered for participation in the JCOG0707 trial (5006 of 5923 patients). Among them, 2389 were ineligible for the trial and 2617 had not been enrolled despite being eligible. The most frequent reason for non-enrollment despite eligibility was the decline in patients' participation, and the major reasons for trial ineligibility were concomitant malignancy and comorbidities. Of all the patients enrolled in our study, 1659 received adjuvant chemotherapy, mainly UFT., Conclusions: Our study indicates that only 15% of the real-world patients with completely resected NSCLC were enrolled into the adjuvant chemotherapy RCT, and among those not participating in the trial, one-third received adjuvant chemotherapy.

Background: Epidermal growth factor receptor (EGFR) is one of the most common oncogenes in non-small cell lung cancer (NSCLC). EGFR-tyrosine kinase inhibitor (TKI) and platinum-doublet chemotherapy (PT) are effective regimens in patients with NSCLC harbouring EGFR mutations. Among these patients, progression-free survival (PFS) has been used as a surrogate endpoint; however, it may not correlate with overall survival (OS) due to crossover. Time to failure of strategy (TFS) has been proposed as an alternative endpoint in advanced colorectal cancer clinical trials where multiple effective therapies are provided either in combination or sequentially. Nevertheless, it remains unclear whether TFS is useful in lung cancer trials., Patients and Methods: We retrospectively reviewed patients with NSCLC harbouring EGFR mutations who chose a treatment strategy consisting of EGFR-TKI and PT as the initial two regimens at the National Cancer Center Hospital. We evaluated the relationship between PFS and OS and between TFS and OS., Results: Between May 2005 and April 2015, a total of 374 patients were diagnosed with NSCLC harbouring EGFR mutations. Among them, 158 patients were eligible for analysis. The median PFS, TFS and OS of the patients were 11.2 months (95% CI 9.9 to 12.6), 21.3 months (95%  CI 18.6 to 26.2) and 36.6 months (95%  CI 32.0 to 41.8), respectively. OS and TFS, but not PFS, were better in patients who received PT then EGFR-TKI compared with those who received the opposite schedule. The non-parametric Spearman's rank correlation coefficients (r) between PFS and OS and between TFS and OS were 0.54 and 0.85, respectively., Conclusions: This is the first report describing TFS data among patients with NSCLC with EGFR mutations who received EGFR-TKI and PT as the initial two regimens. TFS was acceptable as a surrogate endpoint for OS. Further validation in clinical trials is needed., Competing Interests: Competing interests: YG has had consulting/advisory roles for Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer and Novartis; served on speakers’ bureaus for AstraZeneca, Eli Lilly, Chugai, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, Pfizer, MSD, Shionogi Pharma and Novartis; and received research funding from AbbVie, Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb and Ono Pharmaceutical. YM has served on speakers’ bureau for Cook Medical, Olympus and AstraZeneca; and received research funding from Hitachi, Hitachi High-Technologies and Boston Scientific. SK has received research funding from AstraZeneca, Ono Pharmaceutical and AbbVie; and received honoraria from AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb and Chugai. HH has received research funding from MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Merck Serono, Novartis, Astellas, Chugai, Taiho Pharmaceutical and Genomic Health; and received honoraria from Eli Lilly. YF has received research funding from AbbVie, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Incyte, Merck Serono, MSD, Novartis and Bristol-Myers Squibb; and served on speakers’ bureaus from AstraZeneca, MSD, Taiho Pharmaceutical, Bristol-Myers Squibb and Ono Pharmaceutical. NY has had consulting/advisory roles for Eisai, Takeda, Otsuka and Boehringer Ingelheim; and received research funding from Eli Lilly, Quintiles, Astellas, Chugai, Eisai, Taiho Pharmaceutical, Bristol-Myers Squibb, Pfizer, Novartis, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kyowa Hakko Kirin, Takeda and Ono Pharmaceutical; and served on speakers’ bureaus from Bristol-Myers Squibb, Pfizer, AstraZeneca, Eli Lilly, Ono Pharmaceutical and Chugai. YO has received research funding from AstraZeneca, Chugai, Eli Lilly, Taiho Pharmaceutical, Pfizer, MSD, Novartis, Kyorin, Dainippon-Sumitomo and Ignyta; and received honoraria from AstraZeneca, Chugai, Eli Lilly, Taiho Pharmaceutical, Pfizer, MSD, Novartis, Daiichi Sankyo, Boehringer Ingelheim and Bayer. All remaining authors have declared no conflicts of interest.

Objectives: Nivolumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has been shown to yield a durable response and significant prolongation of the survival in some patients with non-small-cell lung cancer (NSCLC). However, identification of patients who are likely to respond to nivolumab remains difficult at present., Materials and Methods: We conducted a retrospective analysis of the clinical data of 87 consecutive patients with advanced NSCLC seen in clinical practice who received nivolumab monotherapy at the National Cancer Center Hospital in Japan between January 2016 and July 2016 (discovery cohort). In addition, we also collected the clinical data of 75 patients who were administered nivolumab monotherapy between August 2016 and March 2017 (validation cohort). For this study, we focused on the changes in the lymphocyte-to-monocyte ratio (LMR) observed after nivolumab monotherapy., Results: In the discovery cohort, increase (≥10%) of the LMR at 4 weeks after the start of nivolumab monotherapy relative to the pretreatment LMR was positively correlated with an objective response (objective response rate (ORR); 39.4% vs 11.8%, p = 0.0065). When this cutoff value of ≥10% was used, increase of the LMR was significantly associated with a prolonged progression-free survival (PFS) (median PFS [mPFS]; 7.3 months vs 2.5 months, p = 0.0049) and overall survival (OS) (median survival time; 15.6 months vs 8.9 months, p = 0.014). In the validation cohort also, increase of the LMR was significantly associated with higher ORR (50.0% vs 20.0%, p = 0.015) and prolonged PFS (mPFS; not reached vs 3.1 months, p = 0.0092). On the other hand, no such correlation was observed among patients treated with docetaxel., Conclusion: A rapid increase of the LMR was significantly associated with the effects of nivolumab monotherapy in our study cohort. Therefore, early change of the LMR may be used as a novel effective surrogate marker to decide on continuation of anti-PD-1 therapy., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to analyze the characteristics and outcomes of patients suffering from non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor mutations (EGFRm+) receiving gefitinib who remained clinically stable following confirmation of progressive disease (PD) using Response Evaluation Criteria in Solid Tumors (RECIST) (R-PD) and identify those who benefited from tyrosine kinase inhibitor therapy beyond PD., Research Design and Methods: The clinical courses of patients with EGFRm+ advanced NSCLC who received first-line gefitinib were investigated. Clinical PD (C-PD) was defined as one or more of the following: (1) symptomatic PD, (2) worsening performance status resulting from PD, (3) threat to a major organ(s), or (4) unequivocal multiorgan PD., Results: Of 529 patients, 258 experienced R-PD without C-PD. Among 258 patients, 91 received gefitinib beyond R-PD. Females were more likely to receive gefitinib beyond R-PD and exhibit a longer time from R-PD to C-PD than males (median days, 175 vs. 79.5). Survival beyond R-PD tended to be longer for elderly patients who received gefitinib beyond PD than for those who did not (median days, 458 vs. 336), but this was not the case for non-elderly patients (median days, 481 vs. 487)., Conclusions: Some patients may benefit from continuation of gefitinib beyond PD.

Background: Conventional hydration (CH) in chemotherapy containing cisplatin (CDDP) has been recommended to prevent renal toxicity. Although an increasing number of studies have demonstrated the feasibility of short hydration (SH), few large studies have reported the superiority of SH, compared with CH, in terms of nephrotoxicities., Methods: We conducted a consecutive retrospective analysis of 467 patients who had been treated with chemotherapy including CDDP. Statistical analyses were performed to evaluate the risk factors for nephrotoxicities. The following factors were included in the analyses: age, sex, performance status (PS), concomitant thoracic radiotherapy, CDDP dose, magnesium supplementation, baseline creatinine values and method of hydration., Results: The patients' characteristics were as follows: male/female, 323/144 patients; median age (range), 62 (27-69) years; PS 0/1/2/3, 238/217/10/2 patients and SH/CH, 111/356 patients. The proportion of patients requiring a CDDP dose reduction in the SH group was 6.3%, while that in the CH group was 12.9%. Patients who discontinued CDDP because of nephrotoxicities accounted for 0.9% of the patients in the SH group and 2.2% of the patients in the CH group. After CDDP-based chemotherapy, a creatinine increase of more than grade 1 was observed in 14.4% and 33.1% of the patients in the SH and CH groups, respectively. A logistic regression analysis revealed a significantly lower incidence of grade 1 or higher creatinine toxicity after the first cycle of chemotherapy in the SH group (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006)., Conclusions: SH resulted in a significantly lower incidence of nephrotoxicity., Competing Interests: Competing interests: None declared.

Background: Among patients with metastatic non-small-cell lung cancer (NSCLC), patients with TNM stage N0 to N1 and brain oligometastases (BOM) (less than 5 metastases) as the sole distant lesion (N0-1 BOM) who receive surgical treatments for the primary and metastatic sites reportedly have a better prognosis. Little data is available regarding the outcomes of patients treated with only systemic chemotherapy for the primary site and definitive treatment for synchronous BOM, compared with the outcomes of patients receiving surgical treatment for the primary site., Methods: Stage IV NSCLC patients with or without N0-1 BOM, who underwent chemotherapy for the primary site between January 2000 and December 2010 were identified from the records of our institution., Results: Among 936 advanced NSCLC patients treated with systemic chemotherapy, 19 patients had N0-1 BOM at presentation. The median overall survival (OS) period of the N0-1 BOM patients was 16.0 months (95% CI, 11.8-20.2 months), while that of the N2-3 BOM + non-BOM patients was 14.5 months (95% CI, 13.2-15.8 months), compared with 7-9 months in previous reports. The median 3- and 5-year survival rates of the N0-1 BOM patients were 28% and 19%., Conclusions: The treatment outcomes of the N0-1 BOM patients who did not receive surgery for the primary site were better than those of the N2-3 BOM + non-BOM patients. A randomized trial evaluating the efficacy of surgery for the primary site in N0-1 BOM patients is warranted., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Competing Interests: Competing interests: None declared.

Background: The standard treatment for limited-disease small-cell lung cancer (LD-SCLC) is a combination of chemotherapy and concurrent thoracic radiotherapy. In selected cases, sequential radiotherapy is preferred because of the need for a large irradiation field, patient age, comorbidities or performance status. Nevertheless, the efficacy of sequential chemoradiotherapy in patients in whom concurrent chemoradiotherapy is contraindicated is not well known., Methods: We retrospectively analyzed 286 patients with LD-SCLC at two institutions in Japan between 2000 and 2014. We compared the clinical characteristics and treatment outcomes of patients undergoing sequential radiotherapy with those undergoing concurrent radiotherapy., Results: One hundred and seventy-five patients received concurrent chemoradiotherapy, 33 received sequential chemoradiotherapy and 46 received chemotherapy only. The median patient age was 64 years (range, 18-82 years) for the concurrent group and 71 years (49-82 years) for the sequential group. Conventional radiotherapy was selected more frequently than accelerated hyperfractionated radiotherapy (27 patients [82%] with conventional radiotherapy, and six patients [18%] with hyperfractionated radiotherapy). The major reasons for the selection of sequential radiotherapy were advanced age (12 patients) and a large irradiation field (11 patients). The median overall survival time was 41.1 months for the sequential group and 38.1 months for the concurrent group. The 5-year survival rates were 36.0% for the sequential group and 41.6% for the concurrent group., Conclusions: In clinical situation, since the treatment outcomes for patients with sequential radiotherapy were comparable to those receiving concurrent radiotherapy, sequential chemoradiotherapy can be a choice for the treatment of patients who are not candidates for concurrent chemoradiotherapy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The optimal treatment strategy for locoregional recurrences developing after surgical resection in patients with non-small-cell lung cancer (NSCLC) is yet to be clearly established., Patients and Methods: To investigate the efficacy and safety of radiotherapy (RT) and chemoradiotherapy (CRT), we reviewed the consecutive data of patients with NSCLC with postoperative locoregional recurrences treated at the National Cancer Center Hospital between January 2000 and April 2010., Results: We reviewed the data of 74 patients (including 56 who received RT alone and 18 who received CRT) according to our study criteria. The median age was lower and the N factor at the recurrence site was higher in the CRT group compared with the RT group. Most patients received 60 Gy/30 Fr RT in both groups. The 2-year progression-free survival (PFS) rate, median PFS, and overall survival (OS) were 44.4%, 19.0 months (95% confidence interval [CI], 0-41.9 months), and 79.6 months (95% CI, 8.2-151.0 months), respectively, in the CRT group, although those were 25.0%, 10.6 months (95% CI, 8.7-12.9 months), and 33.1 months (95% CI, 17.9-48.3 months), respectively, in the RT group. The adverse event profile was acceptable, with no treatment-related death in either group. Multivariate analysis identified CRT as being significantly associated with a longer PFS and OS., Conclusion: CRT tended to yield better results than RT in terms of the survival outcomes, with acceptable safety profiles of both. We consider that a randomized study comparing RT and CRT is warranted to identify the optimal treatment strategy for patients with NSCLC with postoperative locoregional recurrences., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Lung cancer with a few to several metastases is so-called oligometastatic disease. Patient with recurrence only to limited site is also known as oligo-recurrence, and may be included as oligometastatic disease. From biological aspect, any existence of metastases is a sign of systemic disease. Due to the reports of long survival with only local treatment and without systemic disease in oligometastatic lung cancer, word of oligometastasis is used with fascinating expectation of cure to advanced lung cancer. Most of the previous reports are retrospective and no comprehensive data exists for selecting patient for local treatment to oligometastasis. Recent positive result of randomize phase II study is followed up with phase III study. Progress in treatment of advanced non-small cell lung cancer with targeted therapy to oncogenic-driver(EGFR, ALK, ROS1 and others) and immune-checkpoint inhibitor(PD-1 pathway inhibitors)makes it difficult to define the appropriate indication of local treatment to oligometastatic lung cancer.

Background: Some patients with advanced or recurrent, epidermal growth factor receptor (EGFR) mutation-positive (EGFR M+) non-small-cell lung cancer (NSCLC) continue to receive EGFR tyrosine kinase inhibitors (TKIs) beyond radiological progression., Methods: We analysed a cohort of 577 patients with EGFR M+ NSCLC, who had received a first-line EGFR-TKI. We classified patients according to clinical course and treatment patterns at Response Evaluation Criteria in Solid Tumors (RECIST) progressive disease (PD). We evaluated the period from RECIST PD to TKI discontinuation or clinical PD and also evaluated survival after RECIST PD and compared it between groups., Results: RECIST PD was documented in 451 cases, of which 283 (62.7%) were clinically stable. 186 (65.7%) discontinued and 97 (34.3%) continued the EGFR-TKI. In those who continued EGFR-TKI, median time between RECIST PD and clinical PD or TKI discontinuation was 5.1 months. Median survival after RECIST PD in patients who discontinued and continued EGFR-TKI after clinically stable RECIST PD was 14.6 and 15.3 months (p=0.5489), respectively. In multivariate analysis, continuing EGFR-TKI therapy, female gender, better performance status and exon 19 deletion subtype were likely positive predictive factors for survival after clinically stable RECIST PD., Conclusion: Our study suggests that some patients could benefit from receiving an EGFR-TKI beyond radiological progression., Competing Interests: Competing interests: YG has received personal fees as honoraria from Pfizer Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, AstraZeneca, Boehringer Ingelheim Japan, Ono Pharmaceutical, Novartis Pharma, GlaxoSmithKline and Bristol-Myers Squibb. His institution has received research funding from Merck Serono, Pfizer Japan, Taiho Pharmaceutical, Eisai, Chugai Pharmaceutical, Eli Lilly Japan, AstraZeneca, Boehringer Ingelheim Japan, Ono Pharmaceutical, Novartis Pharma, Daiichi Sankyo, GlaxoSmithKline, Yakult Honsha, Quintiles, Astellas Pharma and Bristol-Myers Squibb. KY has received personal fees as honoraria from Chugai Pharmaceutical, Eli Lilly Japan, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Ono Pharmaceutical and Pfizer Japan. YH has received personal fees as honoraria from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb and Boehringer Ingelheim Japan. TK has received personal fees as honoraria from Chugai Pharmaceutical, Roche, Boehringer Ingelheim Japan, Ono Pharmaceutical, Eli Lilly Japan, AstraZeneca, Taiho Pharmaceutical, Pfizer Japan and Kyowa Hakko Kirin. His institution has received research funding from Chugai Pharmaceutical, MSD, Takeda Pharmaceutical, Kyowa Hakko Kirin, Daiichi Sankyo, Yakult Honsha, Boehringer Ingelheim Japan, Pfizer Japan, Taiho Pharmaceutical, Shionogi, AstraZeneca, Eli Lilly Japan and Bristol-Myers Squibb. MN has received personal fees as honoraria from Pfizer Japan, Chugai Pharmaceutical, Eli Lilly Japan, Taiho Pharmaceutical, Nichirei Biosciences, Elekta, AstraZeneca, Sanofi, Bristol-Myers Squibb and Ono Pharmaceutical and consulting fees from Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Taiho Pharmaceutical, Daiichi Sankyo and Pfizer Japan. His institution has received research funding from Novartis, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Takeda Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Eli Lilly Japan and Pfizer Japan. YHK has received personal fee as Speakers’ Bureau from Chugai Pharmaceutical, AstraZeneca and Boehringer Ingelheim Japan. AI has received personal fee as honoraria from AstraZeneca. YH has received personal fees as honoraria from AstraZeneca, Chugai Pharmaceutical and Boehringer Ingelheim Japan. His institution has received research funding from AstraZeneca, Chugai Pharmaceutical and Boehringer Ingelheim Japan. HI institution has received research funding from Ono Pharmaceutical, Takeda Pharmaceutical and MSD. KM institution has received research funding from Ono Pharmaceutical and Chugai Pharmaceutical. KY has received personal fees as honoraria from Pfizer Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, AstraZeneca, Ono Pharmaceutical and Bristol-Myers Squibb. YO has stock in Statcom and received personal fees as executive salaries from Statcom; honoraria from Sanofi and Eisai; consulting fees from Chugai Pharmaceutical, Taiho Pharmaceutical, Shionogi, Kowa and Eisai; and travel expenses from Yakult Honsha and Takeda Pharmaceutical. His institution has received research funding from Eisai. HK has received personal fees as honoraria from AstraZeneca, Taiho Pharmaceutical, Sanofi, Johnson & Johnson, Eli Lilly Japan, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer Japan, Boehringer Ingelheim Japan, MSD, Dainippon Sumitomo, Daiichi Sankyo, Bristol-Myers Squibb, Novo Nordisk Pharma, Nippon Chemiphar, Nihon Medi-Physics, Kyorin Pharmaceutical, Nippon Kayaku and Kyowa Hakko Kirin and travel expense from Taiho Pharmaceutical. No other disclosures are reported.

Introduction: Alectinib has shown marked efficacy and safety in patients with anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement-positive NSCLC and a good performance status (PS). It has remained unclear whether alectinib might also be beneficial for such patients with a poor PS., Methods: Eligible patients with advanced ALK rearrangement-positive NSCLC and a PS of 2 to 4 received alectinib orally at 300 mg twice daily. The primary end point of the study was objective response rate (ORR), and the most informative secondary end point was rate of PS improvement., Results: Between September 2014 and December 2015, 18 patients were enrolled in this phase II study. Of those patients, 12, five, and one had a PS of 2, 3, or 4, respectively, whereas four patients had received prior crizotinib treatment. The ORR was 72.2% (90% confidence interval: 52.9-85.8%). The ORR did not differ significantly between patients with a PS of 2 and those with a PS of 3 or higher (58.3% and 100%, respectively [p = 0.114]). The PS improvement rate was 83.3% (90% confidence interval: 64.8-93.1%, p < 0.0001), with the frequency of improvement to a PS of 0 or 1 being 72.2%. The median progression-free survival was 10.1 months. Toxicity was mild, with the frequency of adverse events of grade 3 or higher being low. Neither dose reduction nor withdrawal of alectinib because of toxicity was necessary., Conclusions: Alectinib is a treatment option for patients with ALK rearrangement-positive NSCLC and a poor PS., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Second-generation anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib and ceritinib, have recently been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). An optimal strategy for using 2 or more ALK inhibitors has not been established. We sought to investigate the clinical impact of sequential use of ALK inhibitors on these tumors in clinical practice., Patients and Methods: Patients with ALK-rearranged NSCLC treated from May 2010 to January 2016 at the National Cancer Center Hospital were identified, and their outcomes were evaluated retrospectively., Results: Fifty-nine patients with ALK-rearranged NSCLC had been treated and 37 cases were assessable. Twenty-six received crizotinib, 21 received alectinib, and 13 (35.1%) received crizotinib followed by alectinib. Response rates and median progression-free survival (PFS) on crizotinib and alectinib (after crizotinib failure) were 53.8% (95% confidence interval [CI], 26.7%-80.9%) and 38.4% (95% CI, 12.0%-64.9%), and 10.7 (95% CI, 5.3-14.7) months and 16.6 (95% CI, 2.9-not calculable), respectively. The median PFS of patients on sequential therapy was 35.2 months (95% CI, 12.7 months-not calculable). The 5-year survival rate of ALK-rearranged patients who received 2 sequential ALK inhibitors from diagnosis was 77.8% (95% CI, 36.5%-94.0%)., Conclusion: The combined PFS and 5-year survival rates in patients who received sequential ALK inhibitors were encouraging. Making full use of multiple ALK inhibitors might be important to prolonging survival in patients with ALK-rearranged NSCLC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the T790M mutation of EGFR. In 2016, AstraZeneca conducted a compassionate use program for osimertinib in Japan., Methods: Eighteen consecutive patients with histologically proven non-small-cell lung cancer (NSCLC) and harboring the T790M EGFR mutation participated in the compassionate use program between 1 April and 25 May 2016, at the National Cancer Center Hospital. We examined the efficacy and safety of osimertinib in a compassionate use program., Results: All patients had been previously treated with both cytotoxic chemotherapy and EGFR TKIs. Overall response rate was 62.5% (95% confidence interval (CI): 35.9-89.1%). Among the six patients pretreated with a third-generation EGFR TKI, two (33%) responded to osimertinib. On administration with osimertinib, median progression-free and overall survival rates at six months were 66.7% (95% CI: 44.9-88.5) and 88.9% (95% CI: 74.4-100), respectively. Although the toxicity of osimertinib was mild in most patients, three patients had severe adverse events: two developed interstitial lung disease (ILD) and one developed Grade 3 hepatotoxicity. Among these, two (33%) of the six patients who received osimertinib following nivolumab treatment developed severe adverse events, with one each developing Grade 3 hepatotoxicity and Grade 3 ILD. Only one patient visited our hospital seeking to participate in the compassionate program from another hospital., Conclusion: Osimertinib demonstrated efficacy even in patients with heavily pretreated NSCLC harboring the T790M mutation. Some patients pretreated with another third-generation EGFR TKI also responded to osimertinib., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Introduction: Programmed death ligand 1 (PD-L1) expression determined by immunohistochemistry (IHC) may serve as a predictive biomarker for anti-PD-1/PD-L1 therapies; however, little is known about intertumoral heterogeneity of PD-L1 expression determined by IHC in lung adenocarcinomas (ADCs), and there have been conflicting results on the prognostic role of PD-L1 expression in ADCs., Methods: PD-L1 expression was evaluated in resected stage II and III ADCs by using various cutoffs and correlated with clinicopathologic parameters and survival. PD-L1 expression was also compared between the primary tumor and lymph node metastases., Results: There were 109 study cases. PD-L1 expression was seen in 56 (51%), 43 (39%), and 19 (17%) when cutoffs of at least 1%, at least 5%, and at least 50%, respectively, were used. Abundant intratumoral CD8-positive T cells were a significant predictor of the expression in the primary tumor, with cutoffs of 1% and 5% (p < 0.001 for both) by multivariate analysis, whereas they were a nonsignificant predictor of the expression with a 50% cutoff (p = 0.076). PD-L1 expression was concordant between the primary tumor and nodal metastasis in most of the cases, but it was discrepant in up to 38%. The discrepancy was attributed in part to different predominant histologic patterns between the primary and metastatic tumors. In the entire cohort, PD-L1 expression with all cutoffs had no bearing on 5-year recurrence-free survival., Conclusions: PD-L1 expression is associated with abundant intratumoral CD8-positive T cells in resected ADCs, suggesting a predictive role of PD-L1 expression in anti-PD-1/PD-L1 therapies; however, the possible intertumoral heterogeneity of PD-L1 expression raises a concern about selecting the most appropriate sample for PD-L1 IHC., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to explore the role of maintenance therapy for patients with advanced non-small cell lung cancer (NSCLC) in a real-world setting., Patients and Methods: This was a prospective observational cohort multicenter study. Eligible patients were observed from initiation of first-line platinum-based chemotherapy until final follow-up., Results: Between 2010 and 2011, a total of 864 patients were enrolled in this study. The primary study population was 396 patients who had progressive disease during observation after first-line chemotherapy without maintenance. Of these, 113 patients (29%) did not receive second-line therapy. In contrast, only 18% of patients who had progressive disease during maintenance therapy missed second-line therapy. Overall survival of patients without maintenance who received second-line therapy was similar to that of those who received maintenance, but no second-line therapy., Conclusion: Maintenance therapy for patients with advanced NSCLC might be an appropriate strategy to maximize the chance of receiving more active therapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Although several agents have been introduced for the treatment of relapsed small-cell lung cancer (SCLC), there is still only limited evidence regarding second- and later-line chemotherapies for these patients., Patients and Methods: Consecutive patients with relapsed SCLC treated at the National Cancer Center Hospital between 2000 and 2014 were analyzed. Patients' characteristics and treatments to explore factors associated with the survival outcomes were reviewed., Results: A total of 580 patients diagnosed as having SCLC received first-line chemotherapy/chemoradiotherapy, of which 343 (59%) received second-line chemotherapy. Among the 343 patients, 193, 148, and 2 patients were diagnosed sensitive relapse, refractory relapse, and relapse of unknown sensitivity status, respectively. Second-line chemotherapy regimens used were as follows: amrubicin (AMR) in 188 (55%) patients; weekly cisplatin/etoposide/irinotecan (PEI) in 56 (16%) patients; topotecan in 18 (5.2%) patients; others in 81 (24%) patients. In the analysis including all patients, the following outcomes were obtained for the patients treated with AMR and PEI, respectively: objective response rate: 51% and 73%; median progression-free survival: 4.5 and 4.2 months; median overall survival: 10.0 and 10.8 months. Multivariate analysis identified sensitive relapse to first-line treatment (vs. refractory relapse) (P = .007) and AMR as second-line treatment (vs. PEI) (P = .005) as independent favorable prognostic factors for survival., Conclusion: AMR showed a favorable trend compared with PEI in terms of the progression-free survival and feasibility in SCLC patients with relapsed disease. Based on our findings, we suggest that a randomized trial comparing AMR and PEI is warranted., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The US National Cancer Institute (NCI) has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to capture patients' self-reported symptomatic adverse events in cancer clinical trials. The aim of this study was to develop and linguistically validate a Japanese translation of PRO-CTCAE. Forward- and back-translations were produced, and an independent review was performed by the Japan Clinical Oncology Group (JCOG) Executive Committee and the US NCI. We then conducted cognitive interviews with 21 patients undergoing cancer treatment. Participants were asked to complete the PRO-CTCAE and were interviewed using semi-structured scripts and predetermined probes to investigate whether any items were difficult to understand or answer. The interviews were recorded and transcribed, and a thematic analysis was performed. The data were split into two categories: 1) remarks on the items and 2) remarks on the questionnaire in general., Results: Twenty-one cancer patients undergoing chemotherapy or hormone therapy were interviewed at the University of Tokyo Hospital and the Kansai Medical University Hirakata Hospital during 2011 and 2012. Thirty-three PRO-CTCAE items were evaluated as "difficult to understand," and 65 items were evaluated as "difficult to answer" by at least one respondent. However, on further investigation, only 24 remarks were categorized as "comprehension difficulties" or "clarity" issues. Most of these remarks concerned patients' difficulties with rating their experience of individual symptomatic events., Conclusions: The study provides preliminary evidence supporting the linguistic validity of the Japanese version of PRO-CTCAE. Further cognitive interviewing is warranted for PRO-CTCAE items relating to sexuality and anxiety and for response options on severity attribute items., Competing Interests: The study was performed in accordance with the Helsinki Declaration and Japanese ethical guidelines for epidemiology research. The study protocol was approved by the institutional review boards of the Kansai Medical University Hirakata Hospital and the University of Tokyo Hospital. All patients gave written informed consent before participating. In order to safeguard the participants’ privacy, the interviews were performed one-on-one in private rooms.This research was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (24590595). The authors declare that they have no competing interests. Informed consent was obtained from all individuals involved in the study.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib was initially approved in Japan in 2002 for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC); however, the optimal order of conventional cytotoxic chemotherapy (carboplatin and paclitaxel) and gefitinib administration has not been determined. We conducted a randomized phase II study of carboplatin and paclitaxel followed by gefitinib vs. gefitinib followed by carboplatin and paclitaxel to select a candidate for further development in a phase III study of chemotherapy-naïve patients with advanced or metastatic NSCLC, regardless of their EGFR mutation status. A total of 97 patients meeting this description were randomly assigned to arm A (carboplatin and paclitaxel followed by gefitinib; n=49) or B (gefitinib followed by carboplatin and paclitaxel; n=48) from June, 2003 to October, 2005. Carboplatin and paclitaxel were administered in 4 cycles every 3 weeks; gefitinib was continued until disease progression or development of unacceptable toxicity. The primary endpoint was overall survival; the secondary endpoints were response rate and adverse event prevalence. The median overall follow-up was 65.1 months (range, 28.7-75.1 months). The major toxicities were hematological (carboplatin and paclitaxel) or skin rash, diarrhea and hepatic dysfunction (gefitinib). Interstitial lung disease was observed in 1 patient from each arm. In arms A and B, the carboplatin and paclitaxel response rate, gefitinib response rate, and median survival durations were 34.8 and 26.5%, 33.3 and 35.7%, and 18.8 and 17.2 months, respectively. Arm A was selected for a subsequent phase III study.

YAP1, the main Hippo pathway effector, is a potent oncogene and is overexpressed in non-small-cell lung cancer (NSCLC); however, the YAP1 expression pattern in small-cell lung cancer (SCLC) has not yet been elucidated in detail. We report that the loss of YAP1 is a special feature of high-grade neuroendocrine lung tumors. A hierarchical cluster analysis of 15 high-grade neuroendocrine tumor cell lines containing 14 SCLC cell lines that depended on the genes of Hippo pathway molecules and neuroendocrine markers clearly classified these lines into two groups: the YAP1-negative and neuroendocrine marker-positive group (n = 11), and the YAP1-positive and neuroendocrine marker-negative group (n = 4). Among the 41 NSCLC cell lines examined, the loss of YAP1 was only observed in one cell line showing the strong expression of neuroendocrine markers. Immunostaining for YAP1, using the sections of 189 NSCLC, 41 SCLC, and 30 large cell neuroendocrine carcinoma (LCNEC) cases, revealed that the loss of YAP1 was common in SCLC (40/41, 98%) and LCNEC (18/30, 60%), but was rare in NSCLC (6/189, 3%). Among the SCLC and LCNEC cases tested, the loss of YAP1 correlated with the expression of neuroendocrine markers, and a survival analysis revealed that YAP1-negative cases were more chemosensitive than YAP1-positive cases. Chemosensitivity test for cisplatin using YAP1-positive/YAP1-negative SCLC cell lines also showed compatible results. YAP1-sh-mediated knockdown induced the neuroendocrine marker RAB3a, which suggested the possible involvement of YAP1 in the regulation of neuroendocrine differentiation. Thus, we showed that the loss of YAP1 has potential as a clinical marker for predicting neuroendocrine features and chemosensitivity., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: The objective of this study was to evaluate the utility of analyzing cell-free plasma DNA (cfDNA) by picoliter-droplet digital polymerase chain reaction (ddPCR) to detect EGFR mutations that confer resistance to tyrosine-kinase inhibitors (TKIs) used for treatment of lung adenocarcinoma (LADC)., Experimental Design: Thirty-five LADC patients who received epidermal growth factor receptor (EGFR)-TKI therapy, including ten who received tumor rebiopsy after development of resistance, were subjected to picoliter-ddPCR-cfDNA analysis to determine the fraction of cfDNA with TKI-sensitive (L858R and inflame exon 19 deletions) and -resistant (i.e., T790M) mutations, as well as their concordance with mutation status in rebiopsied tumor tissues., Results: cfDNA samples from 15 (94%) of 16 patients who acquired resistance were positive for TKI-sensitive mutations. Also, 7 (44%) were positive for the T790M mutation, with fractions of T790M (+) cfDNA ranging from 7.4% to 97%. T790M positivity in cfDNA was consistent in eight of ten patients for whom rebiopsied tumor tissues were analyzed, whereas the remaining cases were negative in cfDNA and positive in rebiopsied tumors. Prior to EGFR-TKI therapy, cfDNAs from 9 (38%) and 0 of 24 patients were positive for TKI-sensitive and T790M mutations, respectively. Next-generation sequencing of cfDNA from one patient who exhibited innate resistance to TKI despite a high fraction of TKI-sensitive mutations and the absence of the T790M mutation in his cfDNA revealed the presence of the L747P mutation, a known driver of TKI resistance., Conclusion: Picoliter-ddPCR examination of cfDNA, supported by next-generation sequencing analysis, enables noninvasive assessment of EGFR mutations that confer resistance to TKIs., Implications for Practice: Noninvasive monitoring of the predominance of tumors harboring the secondary T790M mutation in the activating mutation in EGFR gene is necessary for precise and effective treatment of lung adenocarcinoma. Because cells harboring the T790M mutation are resistant to epidermal growth factor receptor-tyrosine-kinase inhibitors (TKIs), the predominance of tumor cells harboring the T790M mutations influences the choice of whether to use conventional or next-generation TKIs. Digital polymerase chain reaction-based examination of cfDNA is a promising method; however, its feasibility, including its consistency with examination of rebiopsied tumor tissue, has not been fully proven. Here, picoliter-droplet digital polymerase chain reaction technology is presented as a candidate method for testing cfDNA and assessing the predominance of T790M-mutant tumors., (©AlphaMed Press.)

Background: Infections are an important cause of morbidity and mortality in patients with rheumatoid arthritis. Patients receiving immunosuppressive or anti-tumor necrosis factor (TNF) agents are vulnerable to fungal infections, including those derived from Aspergillus species. Detection of the Aspergillus galactomannan antigen in serum is useful for the early diagnosis of invasive aspergillosis in patients with hematological malignancies. However, its usefulness for detecting early invasive aspergillosis in rheumatoid arthritis patients remains unestablished., Methods: Galactomannan antigen levels were measured in 340 patients (311 female patients). For patients who exhibited galactomannan antigen levels ≥0.5 during the initial examination, a second examination was performed 3-6 months later. Conventional blood tests and chest radiography were also performed., Results: Elevated galactomannan antigen levels (≥0.5) were observed in 62 (18.2%) of 340 patients during the initial examination. A second examination was performed in 56 of 62 patients, 50 of whom exhibited elevated antigen levels. Elevated antigen levels were not associated with the use of any drug including anti-TNF agents. Serum galactomannan antigen levels were correlated with the albumin/globulin ratio (r=-0.19, p<0.001), γ-globulin (%; r=0.17, p=0.001), and hemoglobin concentration (r=-0.15, p=0.005). No patient was clinically diagnosed with invasive aspergillosis during the study period., Conclusions: Serum galactomannan antigen levels are frequently elevated in a nonspecific manner in patients with rheumatoid arthritis., (Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to refine the heterogeneous clinical stage IIIA non-small cell lung cancer (NSCLC) with N2 nodes status (cIIIA-N2) by clinicopathological characteristics before treatment., Methods and Materials: We analyzed data of consecutive patients with cIIIA-N2 NSCLC diagnosed between 1997 and 2010 and treated by chemoradiation therapy (CRT). The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete or infiltrative according to the criteria proposed by the American College of Chest Physicians. In addition, the extent of MLN involvement (MLNI) was classified as limited (close to the primary tumor) or extensive (including upper MLNI in the case of tumors in the lower lobes and vice versa)., Results: A total of 148 patients with cIIIA-N2 NSCLC was treated by CRT. The patient characteristics were as follows: males: 118; females: 30; median age: 62 years; appearance of the involved MLNs: 85 discrete, 63 infiltrative; extent of MLNI: 82 limited, 66 extensive; histology: 36 squamous, 112 nonsquamous. The median progression-free survival (PFS) and median overall survival (OS) in the entire subject population were 9.9 and 34.7 months, respectively. A discrete appearance of the involved MLNs and a limited extent of MLNI contributed significantly to a better PFS and OS. The percentages of cases with relapses within the irradiated field classified according to the characteristics of the MLNs were as follows; appearance of the MLNs (24.6% discrete, 18.9% infiltrative); extent of MLNI (25.9 limited, 17.9% extensive)., Conclusions: Those with a discrete appearance of the involved MLNs and a limited extent of MLNI at diagnosis could show relatively more favorable outcomes and could be candidates for multimodality therapy., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

We herein describe a patient with Behçet's disease in whom we followed the development and resolution of pulmonary artery aneurysms. He presented with intermittent hemoptysis, pulmonary thromboembolism was initially diagnosed, and anticoagulant therapy was started. Over the next several months, the expansion of pulmonary arteries was noted. Five months after his initial admission, he was readmitted for massive hemoptysis, and further examinations revealed that he had Behçet's disease. Corticosteroids and intravenous cyclophosphamide were started. Over the next five months, the pulmonary artery aneurysms and thrombosis resolved. The development of pulmonary artery aneurysms led to the diagnosis of Behçet's disease, and they resolved after immunosuppressive therapy.

Lung metastasis showing radiographic findings of air-space consolidation is considered to be rare. This report describes the case of a man with progressive left lower lobe air-space consolidation with a history of hepatocellular carcinoma. The pulmonary lesion was initially suspected to be infection and later clinically diagnosed as primary adenocarcinoma of the lung. Although the patient was treated with systemic chemotherapy, the disease progressed very rapidly. A postmortem examination revealed that the alveolar spaces were filled with neoplastic cells subsequently proven to be metastases of combined hepatocellular and cholangiocarcinoma.

Objectives: The insulin-like growth factor (IGF) signaling pathway has been implicated in the pathogenesis of numerous tumor types, including non-small cell lung cancer (NSCLC). Figitumumab is a fully human IgG2 monoclonal antibody against IGF-1 receptor (IGF-1R)., Methods: This phase I, open-label, dose-escalation study (ClinicalTrials.gov: NCT00603538) assessed the safety and tolerability of figitumumab (6, 10 and 20 mg/kg) in combination with carboplatin (area under the curve: 6 mg·min/mL) and paclitaxel (200 mg/m(2)) in Japanese patients (N = 19) with chemotherapy-naïve, advanced NSCLC. Treatments were administered intravenously on day 1 of a 21-day cycle for four to six cycles. Pharmacokinetics, biomarkers, and antitumor activity were also evaluated., Results: Figitumumab in combination with carboplatin and paclitaxel was well tolerated at doses up to 20 mg/kg; no dose-limiting toxicities were observed at this dose level. When given in combination, figitumumab plasma exposure increased in an approximately dose-proportional manner. The approximate 2-fold accumulation following repeated administration supported the 21-day regimen as appropriate for figitumumab administration. Serum total IGF-1 and IGF binding protein-3 concentrations increased following figitumumab dosing, but a clear dose-dependent relationship was not demonstrated. Seven of 18 evaluable patients experienced a partial response., Conclusions: Figitumumab 20 mg/kg in combination with carboplatin and paclitaxel was well tolerated in chemotherapy-naïve Japanese patients with NSCLC. Further analysis of biomarker data is necessary for the development of figitumumab therapy.

Owing to new developments in Internet technologies, the amount of available oncology information is growing. Both patients and caregivers are increasingly using the Internet to obtain medical information. However, while it is easy to provide information, ensuring its quality is always a concern. Thus, many instruments for evaluating the quality of health information have been created, each with its own advantages and disadvantages. The increasing importance of online search engines such as Google warrants the examination of the correlation between their rankings and medical quality. The Internet also mediates the exchange of information from one individual to another. Mailing lists of advocate groups and social networking sites help spread information to patients and caregivers. While text messages are still the main medium of communication, audio and video messages are also increasing rapidly, accelerating the communication on the Internet. Future health information developments on the Internet include merging patients' personal information on the Internet with their traditional health records and facilitating the interaction among patients, caregivers and health-care providers. Through these developments, the Internet is expected to strengthen the mutually beneficial relationships among all stakeholders in the field of medicine.

Olaparib (AZD2281) is an orally active Poly(ADP-ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose-finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single-dose on day 1, followed by twice-daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400-mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose-limiting toxicities were not observed up to and including the 400-mg b.i.d. dose level. Following twice-daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single-dose pharmacokinetics. PARP-1 inhibition was observed from the 100-mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post-dose on day 1 during the multiple-dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400-mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400-mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed., (© 2011 Japanese Cancer Association.)

A 77-year-old woman was diagnosed as having advanced non-small cell lung cancer, and was started on treatment with gefitinib. Fifty days after the start of treatment, the patient was admitted to the hospital with complaints of dry cough, fever, and shortness of breath. A diagnosis of gefitinib-induced interstitial lung disease was made, and administration of high-dose prednisolone (1 g/day of intravenous methylprednisolone for three consecutive days, followed by oral prednisolone at 50 mg/day) was started. Although progression to respiratory failure could be stopped by the corticosteroid treatment, there was still no improvement in either the lung opacities seen on radiologic imaging, or in the symptoms; moreover, the patient developed corticosteroid-induced myopathy. Therefore, in order to allow reduction of the daily steroid dose, the patient was started on intravenous cyclophosphamide (500 mg/day). This additional treatment allowed the daily dose of oral prednisolone to be reduced to 15 mg/day. Thus, it is considered that intravenous cyclophosphamide may be a valid treatment option for gefitinib-induced lung injury.

Introduction: Quality of information available over the Internet has been a cause for concern. Our goal was to evaluate the quality of information available on lung cancer in the United States and Japan and assess the differences between the two., Methods: We conducted a prospective, observational Web review by searching the word "lung cancer" in Japanese and English, using Google Japan (Google-J), Google United States (Google-U), and Yahoo Japan (Yahoo-J). The first 50 Web sites displayed were evaluated from the ethical perspective and for the validity of the information. The administrator of each Web site was also investigated., Results: Ethical policies were generally well described in the Web sites displayed by Google-U but less well so in the sites displayed by Google-J and Yahoo-J. The differences in the validity of the information available was more striking, in that 80% of the Web sites generated by Google-U described the most appropriate treatment methods, whereas less than 50% of the Web sites displayed by Google-J and Yahoo-J recommended the standard therapy, and more than 10% advertised alternative therapy. Nonprofit organizations and public institutions were the primary Web site administrators in the United States, whereas commercial or personal Web sites were more frequent in Japan., Conclusion: Differences in the quality of information on lung cancer available over the Internet were apparent between Japan and the United States. The reasons for such differences might be tracked to the administrators of the Web sites. Nonprofit organizations and public institutions are the up-and-coming Web site administrators for relaying reliable medical information.

A 60-year-old woman with a history of ovarian carcinoma and complaining of gait instability, dizziness, nausea, and a right temporal headache visited a neurologist. A diagnosis of leptomeningeal metastasis was made, based on the results of a cerebrospinal fluid examination. After the administration of intrathecal methotrexate, her neurological complaints disappeared. An Ommaya intraventricular reservoir was inserted, and methotrexate administration was continued for 11 months, until another recurrence was found in her pelvis. Although uncommon, the possibility of leptomeningeal metastasis from ovarian carcinoma should be considered; in such cases, treatment with intraventricular methotrexate may be effective and feasible and should be considered as a treatment strategy.

We report a patient with therapy-related acute promyelocytic leukemia (APL) that may have been caused by regional radiation or hormonal therapy after surgery. A 36-year-old Japanese woman developed right breast cancer and underwent breast-conserving surgery and regional radiation to the right breast without adjuvant systemic therapy because she wished to preserve her fertility. Two years later, she developed multiple bone metastases of breast cancer and received hormonal therapy. During the second line hormonal therapy, she developed APL and received induction and consolidation chemotherapy with all-trans retinoic acid (ATRA) and a combination of anthracycline and cytarabine. After she achieved a complete remission (CR) of the APL, her bone metastases of breast cancer progressed. She received weekly paclitaxel treatments and her bone marrow function recovered. However, 9 months later, her APL relapsed; she achieved a second CR after undergoing ATRA therapy again. This patient is thought to be a rare case of secondary leukemia, since the leukemia might have been caused by hormonal therapy and regional radiation without chemotherapy.

Purpose: To identify factors, particularly the previous use of paclitaxel, that might influence the efficacy of subsequent docetaxel therapy., Patients and Methods: The patient characteristics, responses, and survivals were compared between the two groups that had received a combination of carboplatin and paclitaxel (group P), and a combination of a platinum and an agent other than paclitaxel (group NP)., Results: A total of 227 patients (127 in group P, and 100 in group NP) were recruited from a hospital-based registry. Two hundred twenty patients were evaluated for the survival, and 210 patients were evaluated for the response of docetaxel therapy. The response rate to docetaxel therapy (14.2% versus 16.0%, p = 0.702) or the median survival time (10.9 months versus 11.1 month, p = 0.567) did not differ between groups P and NP. The results of multivariate analysis, adjusted for sex, age, and performance status at the start of docetaxel therapy, showed that not the regimen per se, but the response to previous chemotherapy significantly influenced the response rate of docetaxel therapy (odds ratio [OR]: 1.38, 95% confidential interval [CI]: 0.63-3.01; and OR: 2.93, 95% CI: 1.28-6.72, respectively). As for the overall survival, neither the response to nor the previous chemotherapy regimen had any impact (hazard ration [HR]: 0.90, 95% CI 0.66-1.22; HR 0.88, 95% CI 0.65-1.20, respectively)., Conclusion: The previous use of paclitaxel had no impact on the response or survival to subsequent docetaxel therapy. In contrast, the response to previous chemotherapy had a predictive value in relation to responses to subsequent docetaxel therapy in patients with advanced non-small cell lung cancer.