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Background/aim: The aim of this retrospective study was to detect the frequency, reasons, and significant factors for not receiving immunotherapy after chemoradiotherapy in non-small cell lung cancer (NSCLC) patients., Patients and Methods: Thirty-four patients with NSCLC received definitive chemoradiotherapy. The endpoint of this study was receiving durvalumab within 45 days after chemoradiotherapy for NSCLC., Results: Twenty-five of 34 (73%) patients received immunotherapy within 45 days after chemoradiotherapy. The reasons for not receiving immunotherapy were radiation pneumonitis (50%), radiation esophagitis (10%), and four other reasons (40%). Univariate analysis showed that significant factors for not receiving immunotherapy were elective nodal irradiation (ENI)+ and chronic obstructive pulmonary disease (COPD)+. The rate of immunotherapy was 100% (17/17 cases) in the COPD- and ENI- group, and 16% (1/6 cases) in the COPD+ and ENI+ group., Conclusion: ENI for NSCLC complicated with COPD decreased the rate of immunotherapy after definitive chemoradiotherapy., (Copyright © 2020 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Although nivolumab improves progression-free (PFS) and overall (OS) survival of patients previously treated for metastatic non-small-cell lung cancer (NSCLC), approximately 50% of treated patients experience disease progression within 3 months. As predictive biomarkers of response are not yet established, development of biomarkers to predict longer PFS and OS of patients treated with nivolumab is crucial. Therefore, we analyzed the impact of predictive markers of response to nivolumab and quantified the impact of each factor using nomograms., Patients and Methods: Clinical data at nivolumab commencement were retrospectively collected from 201 patients treated with nivolumab between December 2015 and July 2016. Immunohistochemistry for programmed cell death ligand 1 (PD-L1) was performed using two assay systems (22C3 and 28-8). OS was calculated from nivolumab treatment initiation. Multivariate Cox regression analysis was conducted to identify independent predictors of OS. A nomogram was constructed to estimate OS., Results: The median patient age was 68 years (135 males). Thirty-nine patients had driver mutations (epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement). In 22C3 and 28-8 immunostaining assays, 36.3% and 36.8% patients had PD-L1-negative cells, 17.4% and 14.4% had 1-49% PD-L1-positive cells, 11.9% and 14.9% had ≥50% PD-L1-positive cells, and 34.3% and 33.8% had unknown PD-L1 status, respectively. Kendall's rank correlation coefficient between the staining assays was 0.8414. The median OS of the whole patient cohort was 12.27 months [95% confidence interval (CI)=10.87-15.6]. Performance status ≥2 [hazard ratio (HR)=2.15, 95% CI=1.35-3.42, p=0.001) and high baseline lactate dehydrogenase (HR=1.15, 95% CI=1.05-1.26, p=0.004] were independent predictors of shorter OS. There was no significant correlation between PD-L1 status and OS. We constructed a nomogram to estimate the OS of patients previously treated with nivolumab., Conclusion: The multivariate analysis-based nomogram might be useful to estimate the OS of patients previously treated with nivolumab for advanced NSCLC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Treatment with EGFR-tyrosine kinase inhibitor (TKI) shows a durable response against NSCLC harboring EGFR mutation; however, treatment resistance occurs within 1-1.5 years following first-line EGFR-TKIs [first- and second-generation (G) TKIs]. When resistant NSCLC exhibits T790M mutations, osimertinib is the standard therapy. However, intratumoral heterogeneity and clonal evolution may occur in NSCLC. Afatinib may overcome tumor heterogeneity, leading to T790M colonal purity. We aimed to determine whether NSCLC treatment with afatinib followed by osimertinib (afatinib group) provides higher therapeutic efficacy than other 1st-G EFGR-TKIs followed by osimertinib (1st-G group)., Materials and Methods: This multicenter retrospective study evaluated outcomes between afatinib group and 1st-G group. We analyzed clinical data from NSCLC patients receiving osimertinib after progression following 1st- or 2nd-G EGFR-TKIs between March 28, 2016 and March 31, 2018. Patients with performance status (PS) 0-2 were enrolled to reduce bias of patients' conditions., Results: We enrolled 111 patients treated with osimertinib. The median age was 69 (range: 39-88) years. Out of 111 patients, 33 (29.7%) were men, 100 (90%) had PS 0-1, and 35 (31.5%) were in the afatinib group. The objective RR and DCR were significantly higher in the afatinib group than in the 1st-G group [82.9% vs. 53.9% (p=0.0065); 91.4% vs. 71.1% (p=0.032)]. The median PFS tended higher in the afatinib group than in the 1st-G group (15.6 vs. 8.9 months, p=0.195)., Conclusion: Afatinib followed by osimertinib may provide better outcomes for T790M-positive NSCLC than 1st-G EGFR-TKIs. Afatinib followed by osimertinib may be a therapeutic option for NSCLC harboring EGFR mutation., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: To identify the clinical and dosimetric predictors of severe acute radiation esophagitis (RE) in patients with non-small cell lung cancer (NSCLC) treated with accelerated hyperfractionated concurrent chemoradiotherapy (AH-CCRT) with concomitant boost technique., Patients and Methods: A total of 159 patients who underwent AH-CCRT (64 Gy in 40 fractions twice daily) were retrospectively identified. Severe RE was designated as grade 3 or higher according to the Common Terminology Criteria for Adverse Events, version 4.0., Results: The incidence rate of grade 3 RE was 15.1% (24/159). The multivariate analysis that incorporated the Eastern Cooperative Oncology Group performance status (ECOG PS, ≥1 vs. 0) and the relative esophagus volume irradiated with at least 60 Gy (V 60 ) was optimal. Patients with a V 60 of ≥15% had a 37.8% risk of grade 3 RE compared to a 6.1% risk among those with a V 60 of <15%., Conclusion: ECOG PS (≥1 vs. 0) and the V 60 were found to be significant risk factors for severe RE in NSCLC patients who underwent AH-CCRT., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: To identify clinical benefits of dose escalation in accelerated hyperfractionated radiotherapy (AH-RT) for stage III non-small-cell lung cancer (NSCLC) using propensity score-matched (PSM) analysis., Materials and Methods: Our study retrospectively examined 294 patients undergoing definitive radiotherapy [131 patients, conventional once-daily radiotherapy (OD-RT); and 163, AH-RT] who were followed-up for a median of 40.4 months. The impact of overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) was investigated., Results: Pre-PSM, the median OS, PFS, and LRC durations were 23.1 vs. 39.9 (p=0.03), 8.9 vs. 13.5 (p<0.01), and 12.9 vs. 50.3 (p<0.01) months in the OD-RT and AH-RT groups, respectively. After-PSM (two matched groups of 144 patients), AH-RT was associated with better LRC [adjusted hazard ratio (aHR)=0.59, 95% confidence interval (CI)=0.33-0.99, p=0.04] and marginally better PFS (aHR=0.65, 95% CI=0.41-1.03; p=0.06), but not OS (aHR=0.75, 95% CI=0.46-1.24; p=0.26)., Conclusion: After PSM analysis, dose escalation using AH-RT improved LRC and PFS in patients with locally advanced NSCLC. AH-RT can be a promising option for patients with advanced NSCLC., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Recent studies have revealed that liver metastasis is associated with poor outcomes after treatment using immune checkpoint inhibitors, although the cause remains unclear., Patients and Methods: We retrospectively identified 201 patients at three Japanese Centers who received nivolumab for advanced non-small cell lung cancer between December 2015 and July 2016. The patients' baseline clinical characteristics and subsequent outcomes were compared according to liver metastasis status., Results: Liver metastasis was associated with inferior progression-free survival (PFS) and a lower response rate. Additionally, liver metastasis was significantly associated with younger age, poorer Eastern Cooperative Oncology Group performance status (ECOG PS), and more metastatic sites. Multivariate analyses revealed that poor PFS was independently associated with poor baseline ECOG PS (p=0.039) and high number of metastatic sites (p=0.007), although liver metastasis (p=0.2) was not., Conclusion: Baseline clinical characteristics were a strong predictor of outcome in nivolumab-treated patients with liver metastasis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We investigated whether the efficacy and type of pre-nivolumab chemotherapy influence outcomes in non-small cell lung cancer patients following nivolumab treatment., Patients and Methods: In this multicenter study, 199 patients treated with nivolumab were retrospectively reviewed. We analyzed the relationships between the clinical response to nivolumab and to chemotherapy administered immediately beforehand., Results: Patients who achieved objective responses to pretreatments showed higher disease control rates with nivolumab than patients who did not (64% vs. 47%, p=0.03), as did those who achieved disease control with pretreatments (62% vs. 35%, p<0.001). Bevacizumab-pretreated patients tended to show better objective response rates with nivolumab (27% vs. 13%, p=0.06); the objective response rate to nivolumab was significantly higher in bevacizumab-pretreated patients who showed clinical responses (42% vs. 9.1%, p=0.02)., Conclusion: Achievement of a clinical response to chemotherapy immediately before nivolumab, particularly when combined with bevacizumab, increases the likelihood of disease control post-nivolumab., Competing Interests: Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. S. Isa, Dr. K. Nakahama, Dr. T. Shiroyama, Dr. H. Suzuki, Dr. T. Inoue, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report grants from Ono Pharmaceutical and Bristol-Myers Squibb. Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. T. Shiroyama, Dr. H. Suzuki, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report personal fees from Ono Pharmaceutical. Dr. Y. Taniguchi, Dr. A. Tamiya, Dr. M. Tamiya, Dr. T. Hirashima, Dr. F. Imamura, and Dr. S. Atagi report personal fees from Bristol-Myers Squibb during the conduct of the study. Dr. Y. Taniguchi reports personal fees from Chugai Pharmaceutical outside the submitted work. Dr. A. Tamiya reports personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, and Boehringer Ingelheim outside the submitted work. Dr. K. Okishio reports personal fees from Ono Pharmaceutical outside the submitted work. Dr. T. Shiroyama reports personal fees from Taiho Pharmaceutical, Boehringer Ingelheim, and AstraZeneca outside the submitted work. Dr. H. Suzuki reports personal fees from Taiho Pharmaceutical, Boehringer Ingelheim, Pfizer, and Eli-Lilly outside the submitted work. Dr. M. Tamiya reports personal fees from Chugai Pharmaceutical, Pfizer, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Asahi Kasei Pharmaceutical, Daichi Sankyo CO. LTD. Alere Medical and Boehringer Ingelheim outside the submitted work. Dr. K. Nishino reports personal fees from Chyugai, Boehringer Ingelheim, Eli Lilly, and AstraZeneca outside the submitted work. Dr. T. Kumagai reports personal fees from Ono Pharmaceutical, Astra Zeneca, and Boehringer Ingelheim outside the submitted work. Dr. T. Hirashima reports grants and personal fees from MSD Oncology, Lilly Japan, AstraZeneca, Chugai Pharma, and Boehringer Ingelheim, grants from Eisai, Daiichi Sankyo, Merck Serono, Taiho Pharmaceutical, Kyowa Hakko Kirin, and Takeda, and personal fees from Bayer outside the submitted work. Dr. F. Imamura reports personal fees from Pfizer Inc., AstraZeneca K.K., Novartis Pharma K.K., Kyowa Hakko Kirin Co. Ltd., Boehringer Ingelheim GmbH, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Chugai Pharmaceutical Co. Ltd. outside the submitted work. Dr. S. Atagi reports grants from Pfizer, Chugai Pharmaceutical, AstraZeneca, MSD, Taiho Pharmaceutical, Yakult Pharmaceutical Industry, Eli Lilly, and Boehringer Ingelheim, and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, and Boehringer Ingelheim outside the submitted work., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Nivolumab has shown promising effects in patients with non-small-cell lung cancer (NSCLC) as a second- or later-line treatment. This study aimed to identify patients who would not experience any benefit from nivolumab treatment., Materials and Methods: In this study, data for 201 patients treated with nivolumab during 17 December 2015 to 31 July 2016 at three respiratory medical centers in Japan were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment commencement. We investigated the relationship between progression-free survival (PFS) and patient characteristics., Results: In both univariate and multivariate analysis, performance status (PS) score ≥2, steroid use at baseline and lactate dehydrogenase (LDH) level >240 IU/l were significantly associated with poor PFS (all p<0.05)., Conclusion: PS score ≥2, steroid use at baseline and a high LDH level were predictive of poor PFS in patients with NSCLC treated with nivolumab. Careful monitoring is recommended for treating such patients with nivolumab (UMIN-ID: UMIN000025908)., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Nivolumab has a promising efficacy for patients with non-small-cell lung cancer (NSCLC) as second-line or later treatment, and after radiotherapy as abscopal effect. However, the effects of radiation pneumonitis history before nivolumab have not been clarified. Therefore, we retrospectively analyzed the correlation of a history of radiation pneumonitis before nivolumab with onset of interstitial lung disease (ILD) and progression-free survival (PFS) after nivolumab treatment in patients with previously treated NSCLC., Patients and Methods: A total of 201 patients treated with nivolumab were retrospectively reviewed. We collected clinical data of patients at the time of starting nivolumab and we evaluated ILD incidence and PFS in relation to patient characteristics, including radiation pneumonitis history., Results: The median age was 68 years; 135 patients were men, 157 had a smoking history, and 153 had performance status of 0 or 1. Thirty-four patients experienced radiation pneumonitis before nivolumab, and 50 patients received radiotherapy to the chest (31 patients received curative radiotherapy). The overall median PFS was 2.8 months and the overall ILD rate was 12.4%. Higher ILD incidence was observed in the group with a history of radiation pneumonitis (26.5%) compared to the group without radiation pneumonitis (9.6%). The median PFS was 3.6 and 2.3 months, respectively. On multivariate analysis, a history of radiation pneumonitis was also significantly correlated with good PFS (p=0.023)., Conclusion: Although increasing the risk of ILD, a history of radiation pneumonitis before nivolumab also contributes to the prolongation of PFS after nivolumab., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: Non-small cell lung cancer (NSCLC) with minor mutations in the epidermal growth factor receptor (EGFR) gene, except for the common 15 base-pair deletions in exon 19 and the L858R mutation in exon 21, is rare, and only few data exist on this patient population. The aim of the present study was to describe the clinical characteristics and to clarify the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in patients with NSCLC harboring minor mutations of the EGFR gene., Patients and Methods: This was a multicenter, retrospective study that analyzed specimens from patients with NSCLC who had minor EGFR gene mutations and were treated with EGFR-TKIs between June 2002 and March 2012., Results: Out of 56 patients with minor mutations of the EGFR gene, 44 were treated with either gefitinib or erlotinib. Mutation sites were G719X in exon 18 (n=35), L861Q in exon 21 (n=11), and G874S in exon 21 (n=1). Three patients had both the G719S and the L861Q mutation. The response rate to TKI treatment was 29.5%, and the disease control rate was 63.6%. The median progression-free survival (PFS) was 6.7 months [95% confidence interval (CI)=2.06-8.66 months]. The median PFS was 7.2 months (95% CI=4.23-12.3 months) in 32 patients who received first- or second-line treatment with EGFR-TKIs, whereas the median PFS was 1.57 months (95% CI=0.73-3.8 months) in 12 patients treated with EGFR-TKIs as a third-line or later treatment. In multivariate Cox analysis, erlotinib therapy was associated with a longer PFS than gefitinib (p=0.025)., Conclusion: Patients with NSCLC harboring minor mutations of the EGFR gene exhibited a modest response to EGFR-TKI treatment. Treatment with first-generation EGFR-TKIs, in particular erlotinib, may be considered a first- or second-line option for patients with NSCLC with minor EGFR mutations., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: We conducted a phase II study to evaluate the efficacy and safety of pemetrexed continuation-maintenance after carboplatin-based induction for advanced non-squamous non-small cell lung cancer (NSCLC)., Patients and Methods: Thirty-four patients with advanced or recurrent non-squamous NSCLC received carboplatin (area under the concentration-time curve 6 mg/ml×min) plus pemetrexed (500 mg/m(2)) on day 1 tri-weekly. After four cycles of induction, patients without disease progression received pemetrexed maintenance until disease progression or unacceptable toxicity., Results: Twenty-five patients completed induction and 22 received maintenance. The 1-year survival, objective response and disease control rates were 70.3%, 32.4% and 88.2%, respectively. The median progression-free survival and overall survival of all patients were 5.2 and 23.3 months. The incidental rates of grade 3 or more severe adverse events were low., Conclusion: This regimen appears to be an appropriate option for chemonaïve patients with advanced non-squamous NSCLC.

Background: Co-stimulation with lysophosphatidic acid (LPA) and fibronectin (FN) is essential for migration of rat ascites hepatoma MMI cells. We examined the roles of LPA and FN in Rho-FAK pathway to migration., Materials and Methods: We evaluated the morphology, phagokinetic motility and the status of Rho activation and tyrosine-phosphorylation of FAK after stimulation of MMI or HT-1080 cells with LPA + FN or each alone., Results: On FN-coated dishes without LPA, MM1 cells could not migrate and harbored undetectable levels of activated RhoA. Stimulation with LPA + FN enabled the MM1 cells to migrate and bear active RhoA and sustained tyrosine-phosphorylation of FAK. To the contrary, HT-1080 cells could migrate and harbored a significant amount of active RhoA accompanied by sustained tyrosine-phosphorylation of FAK even without LPA., Conclusion: Rho-dependent adhesion to FN leading to sustained tyrosine-phosphorylation of FAK is essential for cancer cell migration.