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Introduction: In Japan, adjuvant tegafur-uracil (UFT) chemotherapy is recommended for patients with completely resected, stage I NSCLC. This treatment requires real-world re-evaluation because of recent advances in target-based and immuno-oncological treatments and refinement of lung cancer staging., Methods: The Japan Clinical Oncology Group (JCOG) 0707, a phase 3 trial comparing the benefits of UFT and S-1 (tegafur-gimeracil-oteracil) in patients with completely resected stage I NSCLC (T1 >2 cm and T2 in the TNM sixth edition), was conducted in Japan. A multicenter observational cohort study (Comprehensive Support Project for Oncology Research [CSPOR]-LC03) was also conducted for those patients excluded from JCOG 0707 during the study enrollment period. Physicians from institutions that participated in JCOG 0707 retrospectively assessed the medical records of each patient. The efficacy of UFT was evaluated in the CSPOR-LC03 cohort., Results: In the entire study population (n = 5005), patients treated with UFT (n = 1549) had significantly longer overall survival (OS) than those without any adjuvant chemotherapy (n = 3338). There was no significant difference in OS between the patients treated with UFT (n = 1061) and those without adjuvant chemotherapy (n = 1484) in the JCOG 0707-eligible population (logrank p = 0.755). For tumors without ground-glass attenuation and size greater than 3 cm, patients treated with UFT had significantly longer survival than those without adjuvant chemotherapy, on univariate but not on multivariate analysis., Conclusions: There was no significant difference in OS between the patients treated with UFT and those without adjuvant chemotherapy in the clinical trial-eligible population. Adjuvant UFT for patients with completely resected NSCLC may be recommended only in patients with a tumor without ground-glass attenuation and size greater than 3 cm. In patients with node-negative early NSCLC, further study is needed to select patients who will benefit from adjuvant chemotherapy., (© 2022 The Authors.)

Introduction: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used as the first-line treatment for EGFR mutation-positive non-small cell lung cancer (NSCLC). Nevertheless, most cases ultimately acquire resistance to osimertinib, and no effective treatment has been currently established for cases having progressive disease (PD) with osimertinib. In clinical practice, EGFR-TKI therapy could be continued beyond response evaluation criteria in solid tumours (RECIST)-defined PD cases when they are clinically stable. Currently, the progression pattern of osimertinib and criteria for identifying patients who might benefit from osimertinib beyond PD are unknown. In addition, the efficacy and safety of osimertinib as the first-line treatment in real-world clinical practice remain unclear in Japan. This multicentre study was designed to evaluate the real-world data on first-line osimertinib and its post-treatment., Methods and Analysis: The study enrols patients with EGFR mutation-positive, advanced or recurrent NSCLC who received EGFR-TKI as the first-line therapy after 1 September 2018, from October 2019 to August 2020, and those started on osimertinib will be followed up until August 2022. We will evaluate the efficacy and safety of the first-line osimertinib treatment, adherence to it, progression patterns on RECIST PD and subsequent treatment., Ethics and Dissemination: All participating patients will provide written informed consent before entering the study. The protocol, amendments and patients' informed consent forms will be approved before study commencement by the institutional review board or independent ethics committee at each participation site (Lead Ethics Committee; Japan Red Cross Medical Center (26 April 2019, order number 976)). Patients will be anonymised before registration into the study and their anonymised data will be collected from the case report form. The results of this study will be presented at the national and international conferences and submitted for publication., Trial Registration Number: UMIN000038683., Competing Interests: Competing interests: KW, KY, YH, KaU, GN, KK and HK have received personal fees from AstraZeneca. KY and GN have received research grants from AstraZeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Japan's healthcare expenditures, especially on oncology, are rapidly growing; however, there are scant data on actual costs and cost-effectiveness in the real world. The aim was to assess the medical costs and outcomes of patients with advanced lung cancer., Methods: We retrospectively investigated all patients who were diagnosed with advanced lung cancer at the Japanese Red Cross Medical Center between 1 January 2008 and 31 December 2018. Patients were classified into three cohorts according to the year of diagnosis-Cohort 1: 2008-2010, Cohort 2: 2011-2014 and Cohort 3: 2015-2018-and assessed for medical costs and outcome. Medical costs were divided into outpatient and inpatient costs and were calculated on a monthly basis., Results: Ninety-five patients with small cell lung cancer (SCLC) and 330 with nonsmall cell lung cancer (NSCLC) were included. There was a trend toward increased costs during the first two years after diagnosis in NSCLC patients, without changes in monthly costs, reflecting improved survival. Compared to Cohort 1, Cohort 3 patients with NSCLC had longer survival (median: 24 versus 12 months, P < 0.001), with a median incremental cost of Japanese Yen 6 million during the initial two years. The proportion of outpatient costs increased over time, especially for NSCLC patients (P < 0.001). No changes in costs or survival were observed in SCLC patients., Conclusions: In NSCLC patients, medical costs increased with prolonged survival during the last decade. The costs on a monthly basis did not change. The proportion of outpatient costs increased., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Objective: The medical costs associated with cancer treatment have increased rapidly in Japan; however, little data exist on actual costs, especially for end-of-life care. Therefore, this study aimed to examine the medical costs of lung cancer patients during the last 3 months before death and to compare the costs with those of initial anticancer treatment., Methods: We retrospectively evaluated all patients who died from lung cancer at the Japanese Red Cross Medical Center between 1 January 2008 and 31 August 2019. Patients were classified into three cohorts (2008-2011, 2012-2015 and 2016-2019) according to the year of death; the medical costs were evaluated for each cohort. Costs were then divided into outpatient and inpatient costs and calculated per month., Results: Seventy-nine small cell lung cancer and 213 non-small cell lung cancer patients were included. For small cell lung cancer and non-small cell lung cancer patients, most end-of-life medical costs were inpatient costs across all cohorts. The median monthly medical costs for the last 3 months among both small cell lung cancer and non-small cell lung cancer patients did not differ significantly among the cohorts, but the mean monthly costs for non-small cell lung cancer tended to increase. The monthly medical costs for the last 3 months were significantly higher than those for the first year in SCLC (P = 0.013) and non-small cell lung cancer (P < 0.001) patients and those for the first 3 months in non-small cell lung cancer patients (P = 0.005)., Conclusions: The medical costs during the end-of-life period for lung cancer were high and surpassed those for initial treatment., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: The Cancer-VTE Registry evaluates the occurrence and management of venous thromboembolism in Japanese participants with major solid tumors. Using Registry data, we evaluated the frequency of concurrent venous thromboembolism in cancer patients prior to treatment initiation by cancer type., Methods: The Cancer-VTE Registry is an ongoing (March 2017-September 2020) prospective cohort study using a nationwide, multicentre clinical registry. Participants aged ≥20 years with colorectal, lung, stomach, pancreatic, breast or gynecologic cancer, confirmed staging, ≥6 months life expectancy post-registration and who had undergone venous thromboembolism screening were managed with routine clinical care. Venous thromboembolism frequency at registration was evaluated., Results: Of 9735 participants, 571 (5.9%) had venous thromboembolism at baseline, including asymptomatic [5.5% (n = 540)] and symptomatic venous thromboembolism [0.3% (n = 31)]. Most participants with venous thromboembolism (n = 506, 5.2%) had deep vein thrombosis only; 65 (0.7%) had pulmonary embolism with/without deep vein thrombosis. The prevalence of distal and proximal deep vein thrombosis was 4.8% (n = 466) and 0.9% (n = 83), respectively. The highest prevalence of venous thromboembolism was for pancreatic cancer (8.5%) and the lowest for breast cancer (2.0%). Venous thromboembolism prevalence increased as cancer stage advanced., Conclusions: Although there was a marked difference in venous thromboembolism by cancer type, the data suggest that cancer stage is an important risk factor for venous thromboembolism. Thus, metastasis seems a critical risk factor for venous thromboembolism. This is the first demonstration of venous thromboembolism prevalence and risk factors in Japanese cancer patients prior to treatment., Trial Registration: UMIN000024942., (© The Author(s) 2020. Published by Oxford University Press.)

Objective: To evaluate efficacy of S-1 (tegafur/gimeracil/oteracil), an active novel fluoropyrimidine, as compared to UFT (tegafur/uracil) as a postoperative adjuvant therapy in patients with node-negative non-small cell lung cancer (NSCLC)., Methods: Eligible patients had undergone complete resection of p-stage I (T1 with tumor diameter >2 cm or T2-N0M0 by 5th edition Union for International Cancer Control TNM) NSCLC, and were randomized to receive oral UFT 250 mg/m 2 /day for 2 years (Arm A) or oral S-1 80 mg/m 2 /day for 2 weeks with a 1-week rest period, for 1 year (Arm B). The primary end point was relapse-free survival (RFS), with 80% power and a one-sided type I error of 0.05., Results: From November 2008 to December 2013, 963 patients were enrolled (Arm A: 482, Arm B: 481). Toxicities (hematologic/nonhematologic) of grade 3 or more were observed in 15.9 (1.5/14.7)% in Arm A, and in 14.9 (3.6/12.1)% in Arm B, respectively. At data cut-off in December 2018, the hazard ratio for RFS was 1.06 (95% confidence interval, 0.82-1.36), showing no superiority of S-1 over UFT. The hazard ratio of overall survival (OS) was 1.10 (95% confidence interval, 0.81-1.50). The 5-year RFS/OS were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. The original NSCLC accounted for 58%/53%, respectively, of the Arm A/Arm B OS events. Secondary malignancies were observed in 85 (17.8%) and 84 (17.8%) individuals in Arm A and Arm B, respectively., Conclusions: S-1 was not superior to UFT as postoperative adjuvant therapy in node-negative NSCLC. Future investigation should incorporate identification of high-risk populations for recurrence., (© 2020 The Authors.)

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients., Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer., Design, Setting, and Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study., Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks., Main Outcomes and Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms., Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome., Conclusions and Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option., Trial Registration: UMIN-CTR Identifier: UMIN000015949.

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women., (Copyright © 2019. Published by Elsevier Inc.)

Objective: Adjuvant chemotherapy is standard of care for patients with completely resected stage IB, II and IIIA NSCLC. However, optimum chemotherapy regimen has not been determined. TORG0503 was undertaken to select a preferred platinum-based 3 rd generation regimen in this clinical setting., Materials and Methods: Patients with completely resected stage IB, IIA, IIB or stage IIIA NSCLC were stratified by stage (IB/IIA vs. IIB/IIIA) and institutions, and randomized to receive 3 cycles of docetaxel (60 mg/m 2 ) plus cisplatin (80 mg/m 2 ) (arm A) or paclitaxel (200 mg/m 2 ) plus carboplatin (AUC 6) (arm B) on day 1, every 3 weeks. The primary endpoint of the study was 2-year relapse free survival, and the key secondary endpoints included overall survival, feasibility and toxicity., Results: 111 patients were randomized, 58 patients to arm A and 53 to arm B. Patient demographics were balanced between the two arms. 93 % (54/58) of patients on the arm A and 92 % (49/53) patients on the arm B completed the planned 3 cycles of chemotherapy. There was no treatment-related death in both arms. The 2 and 5 year relapse free survival was 74.5 % (95 %CI: 68.6-80.4) and 61.6 % in the arm A, and 72.0 % (95 %CI: 65.7-78.3) and 46.0 % in the arm B. The overall 2, 5-year survival was 89.7 %, 73.9 % in the arm A and 86.9 %, 67.5 % in the arm B., Conclusion: Both docetaxel plus cisplatin and paclitaxel plus carboplatin are safe and feasible regimens as adjuvant chemotherapy. We choose docetaxel plus cisplatin as the control regimen for the next clinical trial., Competing Interests: Declaration of Competing Interest All remaining authors have declared no conflicts of interest, (Copyright © 2019. Published by Elsevier B.V.)

Objective: Solitary pulmonary nodules after liver transplantation are challenging clinical problems. Herein, we report the causes and clinical courses of resected solitary pulmonary nodules in patients who underwent liver transplantation., Methods: We retrospectively obtained medical records of 68 patients who underwent liver transplantation between March 2009 and June 2016. This study mainly focused on patients with solitary pulmonary nodules observed on computed tomography scans during follow-ups that were conducted until their deaths or February 2019., Results: Computed tomography scans revealed solitary pulmonary nodules in 7 of the 68 patients. Definitive diagnoses were obtained using video-assisted lung resection in all seven patients. None experienced major postoperative complications. The final pathologic diagnoses were primary lung cancer in three patients, pulmonary metastases from hepatocellular carcinoma in one patient, invasive pulmonary aspergillosis in one patient, post-transplant lymphoproliferative disorder in one patient, and hemorrhagic infarction in one patient. The three patients with lung cancer were subsequently treated with standard curative resection., Conclusions: Solitary pulmonary nodules present in several serious but potentially curable diseases, such as early-stage lung cancer. Patients who present with solitary pulmonary nodules after liver transplantation should be evaluated by standard diagnostic procedures, including surgical biopsy if necessary., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non-small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP., Methods: In this retrospective cohort study, CIP severity, CIP-related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients' medical charts., Results: All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≥2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011)., Conclusion: CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre-existing ILD, should be carefully assessed., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Medical tourism has grown globally, especially in oncology field, but it may cause serious problems. We aimed to elucidate concerns generated by medical tourism at a Japanese hospital and recommend solutions., Methods: We evaluated 72 consecutive patients with cancer who had traveled from abroad to receive second opinions, clinical examinations or treatments at our hospital between January 2015 and December 2016. Data were retrospectively collected to include the purpose of patients' visits, presence and content of referral documents, details of treatments provided at our hospital, concordance between treatments received and patients' expectations, troublesome hospital incidents, risks of travel and problems with payment., Results: The purpose of the visit was actual cancer treatment in the majority of the cases. Thirteen patients could speak neither Japanese nor English. Inadequate content in patient referral documents and discordance between information from the referring physician and findings at first examination were the main issues observed in the pre-treatment phase; 33 patients decided to receive treatment at our hospital. Language differences caused problems in patients' understanding of instructions and explanations during treatment. Additional problems included inaccurate self-evaluation of disease status, differences in cultural habits and requests for inappropriate and/or unavailable therapies. No major issues that could lead to injury in patients or medical staff were observed. Risks involved with returning home and transfer of treatment to local physicians were the main post-treatment issues., Conclusion: Medical tourism raises various issues. Institutional and medical staff should be adequately prepared by developing working systems., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Osimertinib, a third generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is active against EGFR-mutant non-small cell lung cancer (NSCLC) resistant to first-/second-generation EGFR-TKIs with the T790M mutation. T790M monitoring in plasma circulating tumor DNA (ctDNA) in patients receiving EGFR-TKIs is less invasive than re-biopsy and could provide valuable clinical information., Methods: Patients with advanced or postoperative recurrent NSCLC with sensitizing EGFR mutations who were planned to receive or were receiving first-/second-generation EGFR-TKI treatment without disease progression were eligible for enrollment. Plasma samples at baseline and every 1-2 months thereafter were analyzed for EGFR mutation status using the cobas®EGFR Mutation Test v2., Results: Between September 2016 and March 2017, 122 patients at 15 Japanese institutions were enrolled. In August 2018, 1291 plasma samples from 121 patients were analyzed for EGFR mutation status. At baseline, a sensitizing EGFR mutation was detected in 29 (23.9%) of 121 patients and T790M mutation was detected in three (2.5%). At follow-up, 66 (54.5%) patients experienced disease progression and 64 (52.9%) discontinued first-line EGFR-TKI treatment. Twenty-two (18.2%) patients showed T790M in plasma ctDNA, of which 15(68.2%) received osimertinib. Although 31 patients received re-biopsy to examine EGFR status at disease progression, T790M was detected in only nine (22.0%) patients, of which 7 (77.8%) received osimertinib., Conclusions: ctDNA monitoring during EGFR-TKI treatment is useful for detecting T790M mutation. The efficacy of osimertinib treatment based on T790M status in plasma ctDNA remains to be established, warranting further research., (© The Author(s) 2019. Published by Oxford University Press.)

Aim: To assess the relationship of treatment effects between immune checkpoint inhibitor (ICI) and salvage chemotherapy, with the safety profile of salvage chemotherapy., Patients & Methods: 18 patients with advanced NSCLC treated using salvage chemotherapy following ICI treatment were retrospectively included. We assessed the overall response rate to and adverse events of salvage chemotherapy., Results: The overall response rate to salvage chemotherapy was 33.3% and that of ICI responders was significantly higher than that of ICI nonresponders (66.7 vs 16.7%, respectively, p = 0.03). The incidence rate of adverse events to salvage chemotherapy was 55.6%., Conclusion: The efficacy of salvage chemotherapy was similar to that preceding ICI. Moreover, the safety of salvage chemotherapy was good., Competing Interests: Financial & competing interests disclosure The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2019 Takehiro Izumo.)

Background: Radiation therapy might modify the cancer immune environment to enhance the antitumor effect of immune checkpoint inhibitors. We performed a feasibility study of nivolumab following stereotactic radiation therapy for chemotherapy pretreated advanced non-small-cell lung cancer., Patients and Methods: Pretreated advanced/recurrent non-small-cell lung cancer patients received stereotactic radiation therapy to one of the disease sites. Nivolumab at a dose of 3 mg/kg was given within 2 weeks after the completion of stereotactic radiation therapy and continued every 2 weeks thereafter until disease progression or unacceptable toxicities. The primary endpoint was the occurrence rate of Grade 3 pneumonitis (within 12 weeks) or other non-hematological toxicity (within 8 weeks)., Results: From September 2016 to September 2017, six patients were enrolled. Five received stereotactic radiation therapy to their primary lesions. All patients received nivolumab on the following day after stereotactic radiation therapy completion. Grade 3 pneumonitis occurred in one patient, but no other serious adverse events were reported for the other patients. One complete response and two partial responses were achieved. Four patients had measurable lesions outside the irradiated area, of whom three patients responded to the treatment. The initial progression sites were mainly outside the irradiated field, including one brain metastasis., Conclusions: Nivolumab therapy immediately following stereotactic radiation therapy was well tolerated. This sequential combination warrants further study.

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.

Objectives: The TORG0809 study was a multicenter feasibility study of long-term single-agent therapy with S-1 after docetaxel plus cisplatin therapy in patients with completely resected stage II or stage IIIA non-small cell lung cancer. We report the results of the final overall survival (OS) analysis., Patients and Methods: A total of 129 eligible patients received 3 cycles of docetaxel (60 mg/m, day 1) plus cisplatin (80 mg/m, day 1), followed by S-1 at 40 mg/m twice daily for 14 consecutive days, for >6 months (maximum, 1 y)., Results: At the cutoff date of April 13, 2016, the median follow-up time was 6.0 years. Of the 129 patients, 43 had died, and 74 patients developed disease recurrence or died. The median OS had not been reached. The 5-year OS rate was 71% [95% confidence interval (CI), 62-78]. The 5-year OS rates in the patients with stage II and stage IIIA were 76% and 68%, respectively. The median recurrence-free survival (RFS) duration was 3.4 years (95% CI, 2.3-5.7). The 5-year RFS rate was 44% (95% CI, 36-53). The 5-year RFS rates in patients with stage II and stage IIIA disease were 57% and 38%, respectively. Disease recurrence occurred in 68 patients, and 62 of these patients received second-line chemotherapy. The most common sites of recurrence were the brain (n=22) and mediastinal lymph nodes (n=22)., Conclusion: The survival data obtained from this study are promising and comparable to those reported from a previous study conducted in Japan.

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.

Introduction: Patients with cancer are at higher risk of venous thromboembolism (VTE) than the general population as the malignancy itself and treatment modalities, including medication and surgery, contribute to the risk of developing VTE. Furthermore, patients with cancer developing VTE have a worse prognosis than those without cancer. There are no multicentre prospective data on the occurrence and treatment of VTE in patients with cancer in Japan, and data on the outcomes, complications and incidence of VTE in these patients have not been reported. In addition, Japanese patients with cancer are traditionally treated with unfractionated heparin or warfarin; however, the use of direct oral anticoagulants, which became available in 2014, has not been sufficiently examined in this patient group. Therefore, this multicentre, prospective registry has been designed to capture VTE data from Japanese patients presenting with six cancer types., Methods and Analysis: This registry will enrol 10 000 patients with colorectal, lung, stomach, breast, gynaecological (including endometrial, cervical, ovarian, fallopian tube and peritoneal) or pancreatic cancer between March 2017 and March 2019 and follow them for 1 year. We plan to collect data on the incidences of symptomatic VTE, bleeding events, stroke, systemic embolic events, incidental VTE requiring treatment in patients, overall survival and symptomatic VTE event-free survival., Ethics and Dissemination: All patients will provide written informed consent. Data will remain anonymous and will be collected using an online electronic data capture system. Study protocol, amendments and informed consent forms will be approved by the institutional review board/independent ethics committee at each site prior to study commencement. Results will be disseminated at national meetings and published in peer-reviewed journals., Trial Registration Number: UMIN000024942., Competing Interests: Competing interests: All authors have received personal fees from Daiichi Sankyo during the conduct of study. KF has received research grants from Daiichi Sankyo. TK and KI are employees of Daiichi Sankyo., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The Guideline Committee of the Japan Lung Cancer Society (JLCS) for Thymic Tumors published the Medical Practice Guideline for Thymic Tumors in Japanese as Chapter 3 of the Medical Practice Guidelines for Lung Cancers according to evidence-based medicine in December 2016. This medical practice guideline is the first for thymic epithelial tumors in Japan, and comprises a set of recommendations covering clinical diagnosis, treatment and pathological diagnosis. Thymic epithelial tumors include thymoma, thymic carcinoma and thymic neuroendocrine tumor. The recommendations for clinical diagnosis concern detection of the symptoms, blood and serum tests according to clinical presentation, essential imaging for differential diagnosis and staging, and the necessity and methods of definitive diagnosis. The recommendations for treatment are dependent on tumor stage and recurrence status, and the treatment modalities included surgery, radiation therapy, chemotherapy and multimodality therapy. Those for pathological diagnosis deal with the handing methods of resected specimen and essential reporting contents for pathological diagnosis. Since data from large-scale analyses or clinical studies of thymic epithelial tumor are limited due to its low prevalence, the relevant recommendations and grading were based on available reported evidence and expert opinions as well as diagnostic methods and treatments commonly used in Japan. This report summarizes the recommendations concerning each topic addressed by this JLCS guideline for thymic tumors., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

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.)

The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group was organized in 1986. Initially, 26 collaborative institutions participated. In the early period, the Lung Cancer Surgical Study Group focused on combined modality therapies and conducted nine trials, including JCOG9101: adjuvant chemotherapy for resected small-cell lung cancer, and JCOG9806: induction chemoradiotherapy followed by surgery for superior sulcus tumor, which greatly impacted the treatment strategies for some special kinds of lung cancer. Since the 2000s, the Lung Cancer Surgical Study Group has defined radiologically noninvasive adenocarcinoma: JCOG0201 and investigated adequate modes of surgical resection for small-sized non-small cell lung cancer: JCOG0802, JCOG0804 and JCOG1211. The accrual of these trials is now complete and we are waiting for the maturation of follow-up data. In addition, two adjuvant trials have been conducted: JCOG0707; a Phase III study of adjuvant chemotherapy for resected pathological stage I (T1 > 2 cm) non-small cell lung cancer, and JCOG1205; a Phase III study of adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine tumor. The accrual of JCOG0707 is complete and we are waiting for the maturation of follow-up data. At present, 44 institutions are active members of the Lung Cancer Surgical Study Group. In addition to thoracic surgeons, medical oncologists, pathologists and radiotherapists are participating in the Lung Cancer Surgical Study Group. The Lung Cancer Surgical Study Group continues to conduct various clinical trials in an effort to improve survival in patients with lung cancer. In this review, we provide an overview of the past 30 years, as well as the present status and future direction of the Lung Cancer Surgical Study Group., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications., (Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.)

Lung adenocarcinoma driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). Here we investigate genetic factors underlying the risk of this disease by conducting a genome-wide association study, followed by two validation studies, in 3,173 Japanese patients with EGFR mutation-positive lung adenocarcinoma and 15,158 controls. Four loci, 5p15.33 (TERT), 6p21.3 (BTNL2), 3q28 (TP63) and 17q24.2 (BPTF), previously shown to be strongly associated with overall lung adenocarcinoma risk in East Asians, were re-discovered as loci associated with a higher susceptibility to EGFR mutation-positive lung adenocarcinoma. In addition, two additional loci, HLA class II at 6p21.32 (rs2179920; P =5.1 × 10(-17), per-allele OR=1.36) and 6p21.1 (FOXP4) (rs2495239; P=3.9 × 10(-9), per-allele OR=1.19) were newly identified as loci associated with EGFR mutation-positive lung adenocarcinoma. This study indicates that multiple genetic factors underlie the risk of lung adenocarcinomas with EGFR mutations.

Lung adenocarcinoma (LADC), the most frequent histological type of lung cancer, is often triggered by an aberration in a driver oncogene in tumor cells. Examples of such aberrations are EGFR mutation and ALK fusion. Lung adenocarcinoma harboring such mutations can be treated with anticancer drugs that target the aberrant gene products. Additional oncogene aberrations, including RET, ROS1, and NRG1 fusions, skipping of exon 14 of MET, and mutations in BRAF, HER2, NF1, and MEK1, were recently added to the list of such "druggable" driver oncogene aberrations, and their responses to targeted therapies are currently being evaluated in clinical trials. However, approximately 30% and 50% of LADCs in patients in Japan and Europe/USA, respectively, lack the driver oncogene aberrations listed above. Therefore, novel therapeutic strategies, such as those that exploit the vulnerabilities of cancer cells with non-oncogene aberrations, are urgently required. This review summarizes the current status of research on precision medicine against LADC and enumerates the research priorities for the near future., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings., (Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Background: Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients., Methods: Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy., Results: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts., Conclusions: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted., Trial Registration: UMIN Clinical Trial Registry; UMIN000004240 .

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites., Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers., Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures., Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation., (Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: Most of the previous studies of amrubicin in patients with previously treated small-cell lung cancer were conducted at a dose of 40 mg/m(2). The aim of this study was to assess the efficacy and safety of amrubicin at a dose of 45 mg/m(2) in patients with relapsed or refractory small-cell lung cancer., Methods: Previously treated small-cell lung cancer patients were eligible. Amrubicin at a dose of 45 mg/m(2) was administered on Days 1-3 every 3 weeks. The primary endpoint was the response rate., Results: From June 2003 to January 2005, 35 patients were enrolled, of whom 34 received this study treatment. Four cycles or more could be administered in 21 patients (62%). Dose reduction was required in 15 (52%) of the 29 patients who had received two cycles or more. Three complete responses and 15 partial responses were observed among the 34 treated patients, yielding a response rate of 53% (95% confidence interval, 35-71%). Median progression-free survival of the patients was 4.4 months (95% confidence interval, 2.4-5.1 months). Median survival time was 8.2 months (95% confidence interval, 6.6-10.0 months) and 1-year survival rate was 24% (95% confidence interval, 9-39%). Grade 3/4 leukopenia, neutropenia and thrombocytopenia were observed in 76, 97 and 38% of the patients, respectively. Febrile neutropenia occurred in 12 patients (35%), and one patient died from pneumonia., Conclusions: While amrubicin at a dose of 45 mg/m(2) showed high response rate for both sensitive and refractory relapse, the incidence of febrile neutropenia was also high. The utility of amrubicin at 45 mg/m(2) might accordingly be limited., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Low-dose erlotinib may be as effective as gefitinib or erlotinib at full dose in non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR) gene., Methods: Patients with chemotherapy pretreated NSCLC harbouring EGFR mutations received erlotinib at 50 mg/d until disease progression or unacceptable toxicities. The dose was escalated to 150 mg/d in patients showing no response (i.e. without major tumour shrinkage according to Response Evaluation Criteria in Solid Tumours (RECIST)) to the initial dose during the first 4 weeks. The primary end-point was the objective response rate at the dose of 50 mg/d., Results: Thirty-four patients from seven institutes were enrolled. The study was closed early when no response was confirmed in 15 patients, excluding the possibility that the primary end-point would be met. The objective response and disease control rates at the dose of 50 mg/d as determined by an independent review committee were 54.5% and 84.8%, respectively. Four additional patients achieved partial response with increased 150 mg/d dose. Progression-free survival and median survival times during the entire period of the study were 9.5 and 28.5 months, respectively. Treatment-related toxicities were generally mild, the most common being skin disorders and diarrhoea. Only one case experienced grade 3 toxicity, which was transient increase of hepatic enzymes., Conclusion: The primary end-point was not met; low-dose erlotinib is not recommended for fit patients with NSCLC harbouring EGFR mutations. However, it may merit further evaluation for elderly or frail patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: In the first-line treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has been shown to yield a longer progression-free survival (PFS) rate than platinum-doublet chemotherapy; however, after the initial response, most patients develop resistance to the EGFR-TKIs. We hypothesized that the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKIs might prevent the emergence of acquired resistance to EGFR-TKIs and prolong survival., Methods: We carried out a phase II study of the following first-line treatment for patients with advanced NSCLC harboring EGFR mutations. Gefitinib (250 mg) was administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Thereafter, gefitinib was re-started on day 134 and continued until disease progression. The primary endpoint was the two-year PFS rate., Results: A total of 34 patients were enrolled. Of the 33 eligible patients and 12 achieved a two-year PFS. Thus, this therapeutic strategy met the criterion for usefulness. The 1-, 2-, 3-, and 5-year PFS rates were 67.0%, 40.2%, 36.9%, and 22.0%, respectively, and the median PFS was 19.5 months. The 1-, 2-, 3- and 5-year survival rates were 90.6%, 71.9%, 64.8%, and 36.5% respectively, and the median survival time was 48.0 months., Conclusion: These results indicate that the insertion of platinum-doublet chemotherapy might prevent the development of acquired resistance to EGFR-TKIs in patients with advanced NSCLC harboring EGFR mutations., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk., (Published 2014. This article is a US Government work and, as such, is in the public domain of the United States of America.)

Background: Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL)., Patients and Methods: Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles., Results: A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin., Conclusion: Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC., Clinical Trial Number: UMIN000000608., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Post-operative adjuvant chemotherapy has been considered an effective strategy to reduce cancer recurrence and improve survival for resected non-small-cell lung cancer. The Japan Clinical Oncology Group has completed patient accrual for a randomized Phase III study (JCOG0707), which compares the survival benefit of UFT and S-1 for completely resected pathological Stage I (T1 >2 cm and T2 in TNM classification version 6) non-small-cell lung cancer. However, there is a growing concern that those who participated in clinical trials are highly selected patients and do not represent the 'real-world' population. This multicenter observational cohort study aims to analyze the backgrounds, pattern of care and outcomes of the patients who were excluded from the JCOG0707 study during the accrual period. The results of this cohort study will be useful for external validity of the results of clinical trial such as JCOG0707., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci., (Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Purpose: To examine the clinical utility of intratumor microRNAs (miRNA) as a biomarker for predicting responses to platinum-based doublet chemotherapy in patients with recurring lung adenocarcinoma (LADC)., Experimental Design: The expression of miRNAs was examined in LADC tissues surgically resected from patients treated with platinum-based doublet chemotherapy at the time of LADC recurrence. Microarray-based screening of 904 miRNAs followed by quantitative reverse transcription-PCR-based verification in 40 test cohort samples, including 16 (40.0%) responders, was performed to identify miRNAs that are differentially expressed in chemotherapy responders and nonresponders. Differential expression was confirmed in a validation cohort (n = 63 samples), including 18 (28.6%) responders. An miRNA signature that predicted responses to platinum-based doublet chemotherapy was identified and its accuracy was examined by principal component and support vector machine analyses. Genotype data for the TP53-Arg72Pro polymorphism, which is associated with responses to platinum-based doublet chemotherapy, were subsequently incorporated into the prediction analysis., Results: A signature comprising three miRNAs (miR1290, miR196b, and miR135a*) enabled the prediction of a chemotherapeutic response (rather than progression-free and overall survival) with high accuracy in both the test and validation cohorts (82.5% and 77.8%). Examination of the latter was performed using miRNAs extracted from archived formalin-fixed paraffin-embedded tissues. Combining this miRNA signature with the TP53-Arg72Pro polymorphism genotype marginally improved the predictive power., Conclusion: The three-miRNA signature in surgically resected primary LADC tissues may by clinically useful for predicting responsiveness to platinum-based doublet chemotherapy in patients with LADC recurrence., (©2014 American Association for Cancer Research.)

Background: We conducted a multicentre feasibility study for single agent long-term S-1 chemotherapy following docetaxel plus cisplatin in patients with curatively resected stage II-IIIA non-small cell lung cancer., Methods: Patients received three cycles of docetaxel (60 mg m(-2)) plus cisplatin (80 mg m(-2)) and then received S-1 (40 mg m(-2) twice daily) for 14 consecutive days with a 1-week rest for >6 months (maximum, 1 year). The primary end point was feasibility, which was defined as the proportion of patients who completed eight or more cycles of S-1 chemotherapy. If the lower 95% confidence interval (CI) of this proportion was 50% or more, then the treatment was considered as feasible. The sample size was set at 125 patients., Results: One hundred and thirty-one patients were enrolled, of whom 129 patients were eligible and assessable. In all, 109 patients (84.5%) completed 3 cycles of docetaxel plus cisplatin and 66 patients (51.2%, 95% CI: 42.5-59.8) completed 8 or more cycles of S-1 treatment. Grade 3/4 toxicities during the S-1 chemotherapy included anaemia (7.3%), neutropaenia (3.7%), and anorexia (3.7%)., Conclusion: The toxicity level was acceptable, although the results did not meet our criterion for feasibility. Modification of the treatment schedule for S-1 chemotherapy might improve the treatment compliance.

Transcription factor Nrf2 (NF-E2-related factor 2) is essential for oxidative and electrophilic stress responses. While it has been well characterized that Nrf2 activity is tightly regulated at the protein level through proteasomal degradation via Keap1 (Kelch-like ECH-associated protein 1)-mediated ubiquitination, not much attention has been paid to the supply side of Nrf2, especially regulation of Nrf2 gene transcription. Here we report that manipulation of Nrf2 transcription is effective in changing the final Nrf2 protein level and activity of cellular defense against oxidative stress even in the presence of Keap1 and under efficient Nrf2 degradation, determined using genetically engineered mouse models. In excellent agreement with this finding, we found that minor A/A homozygotes of a single nucleotide polymorphism (SNP) in the human NRF2 upstream promoter region (rs6721961) exhibited significantly diminished NRF2 gene expression and, consequently, an increased risk of lung cancer, especially those who had ever smoked. Our results support the notion that in addition to control over proteasomal degradation and derepression from degradation/repression, the transcriptional level of the Nrf2 gene acts as another important regulatory point to define cellular Nrf2 levels. These results thus verify the critical importance of human SNPs that influence the levels of transcription of the NRF2 gene for future personalized medicine.

To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.