Search

Purpose: Acute kidney injury (AKI) is a common and serious adverse effect of cisplatin-based chemotherapy. However, traditional markers of kidney function, such as serum creatinine, are suboptimal, because they are not sensitive measures of proximal tubular injury. We aimed to determine whether the new urinary biomarkers such as kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and neutrophil gelatinase-associated lipocalin (NGAL) could detect cisplatin-induced AKI in lung cancer patients in comparison with the conventional urinary proteins such as N-acetyl-β-D-glucosaminidase (NAG) and β2-microglobulin., Methods: We measured KIM-1, MCP-1, NGAL, NAG, and β2-microglobulin concentrations in urine samples from 11 lung cancer patients, which were collected the day before cisplatin administration and on days 3, 7, and 14. Subsequently, we evaluated these biomarkers by comparing their concentrations in 30 AKI positive (+) and 12 AKI negative (-) samples and performing receiver operating characteristic (ROC) curve analyses., Results: The urinary levels normalized with urine creatinine of KIM-1 and MCP-1, but not NGAL, NAG, and β2-microglobulin in AKI (+) samples were significantly higher than those in AKI (-) samples. In addition, ROC curve analyses revealed that KIM-1 and MCP-1, but not NGAL, could detect AKI with high accuracy (area under the curve [AUC] = 0.858, 0.850, and 0.608, respectively). The combination of KIM-1 and MCP-1 outperformed either biomarker alone (AUC = 0.871)., Conclusions: Urinary KIM-1 and MCP-1, either alone or in combination, may represent biomarkers of cisplatin-induced AKI in lung cancer patients.

Crizotinib is a potent and specific small-molecule inhibitor of both anaplastic lymphoma kinase (ALK) and c-MET tyrosine kinases, and patients with ALK rearrangement tumor benefit from crizotinib treatment; however, its penetration into calculated cerebrospinal fluid (CSF) is considered to be poor. Alectinib is a highly selective, next-generation ALK inhibitor, and both preclinical and clinical studies have indicated that alectinib is also effective in crizotinib-resistant tumors. A recent in vitro study demonstrated significant antitumor activity of alectinib for brain metastases using mouse models of ALK-positive non-small-cell lung cancer. In this paper, we report a first case alectinib was highly effective against brain metastases refractory to crizotinib. Further investigation of alectinib in this setting would be particularly valuable.

Introduction: To investigate the impact of pre-existing radiological interstitial lung disease (ILD) findings on the incidence of radiation pneumonitis (RP) and clinical outcomes after stereotactic body radiation therapy (SBRT) for stage I non-small-cell lung cancer., Methods: We included 157 consecutive patients who underwent SBRT alone for stage I non-small-cell lung cancer and whose pretreatment lung computed tomography images were available for retrospective review. The pretreatment computed tomography images were evaluated retrospectively for the presence of ILD. The incidence of RP, overall survival (OS) rate, and the incidence of disease progression and local progression were evaluated between patients with ILD (ILD[+]) and without ILD (ILD[-])., Results: Pre-existing ILD was identified in 20 patients. The median follow-up period was 39.5 months. The incidences of RP worse than grade 2 (≥ Gr2 RP) and worse than grade 3 (≥ Gr3 RP) were significantly higher in ILD(+) than ILD(-) (1 year ≥ Gr2 RP rate, 55.0% versus 13.3%; p < 0.001 and 1year ≥ Gr3 RP rate 10.0% versus 1.5%; p = 0.020). Multivariate analysis also indicated that ILD(+) was a risk factor for ≥ Gr2 and ≥ Gr3 RP, and the volume of the irradiated lung. The OS rate tended to be worse in ILD(+) than ILD(-) (3-year OS, 53.8% versus 70.8%; p = 0.28). No difference was observed in the disease progression or local progression rates., Conclusions: Pre-existing ILD was a significant risk factor for symptomatic and severe RP. Prescreening for ILD findings is important for determining the radiation pneumonitis risk when planning SBRT.

Background: Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420., Methods: A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C>T, 2677G>T/A, 3435C>T), ABCG2 (421C>A), and CYP3A5 (6986A>G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated., Results: The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p < 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p < 0.05). Furthermore, the incidence of grade ≥2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C0) levels on day 8 were an independent risk factor for the development of grade ≥2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C0 levels (≥1711 ng/mL) than that in patients having lower erlotinib C0 levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients (p = 0.62)., Conclusions: ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients.

Background: Single-agent chemotherapy with third-generation non-platinum agents, such as docetaxel, vinorelbine, is a standard therapeutic option for elderly patients with non-small-cell lung cancer (NSCLC). Subset analysis of a previous phase III study comparing pemetrexed with docetaxel in the second-line setting showed the superiority of pemetrexed in an elderly (≥70) population in both efficacy and toxicity., Patients and Methods: This was a single-arm phase II study of pemetrexed in elderly (≥75) Japanese patients with advanced non-squamous NSCLC. Patients received four cycles of pemetrexed (500 mg/m(2)) every 3 weeks. The primary endpoint was the response rate, and secondary endpoints were safety and survival., Results: Twenty-eight patients were enrolled between January 2010 and April 2012. The median age of the patients was 77 years (range 75-88). All but one patient had adenocarcinoma histology. The median number of chemotherapy cycles administered was 4 (range, 1-12). Seventeen (60 %) patients completed four cycles of chemotherapy. Partial response was achieved in 7 patients (response rate: 25 %) and stable disease in 11 patients (disease control rate: 64 %). Median progression-free survival and overall survival were 3.3 and 17.5 months, respectively. Grade 3/4 neutropenia and thrombocytopenia were observed in 8 patients (29 %) and 2 (7 %), respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths., Conclusions: Although this study did not meet our primary endpoint, pemetrexed showed favorable antitumor activity with mild toxicity in elderly patients with non-squamous NSCLC. Further investigations of pemetrexed in this population are warranted (UMIN-CTR number, 000002452).

Background: Preclinical data indicated that the combination of erlotinib and pemetrexed is synergistic when erlotinib is administered after pemetrexed., Patients and Methods: This was a phase II study of pemetrexed and erlotinib in patients with pretreated advanced non-squamous non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR). Chemotherapy consisted of pemetrexed (500 mg/m(2)) on day 1 and erlotinib (150 mg/body) on days 2-15 every 3 weeks. The protocol treatment was repeated until disease progression or intolerable toxicities occurred., Results: Seventeen patients were enrolled between January 2010 and January 2013, and 15 patients were evaluable for both safety and efficacy. The study was terminated due to slow patient accrual. There was 1 complete response. There was a partial response in 3 patients, stable disease in 4 and progressive disease in 7. The response rate was 27% and disease control rate was 53%. The median progression-free survival and overall survival were 2.5 months and 6.7 months, respectively., Conclusions: Statistical interpretation could not been made due to the early termination of the study. Further studies are needed to clarify the efficacy of this regimen in NSCLC patients without EGFR mutation (UMIN-CTR No. 0000024531)., (© 2014 S. Karger AG, Basel.)

Introduction: This study aimed to evaluate the association between BCL2 single-nucleotide polymorphisms and survival outcome in advanced non-small cell lung cancer (NSCLC)., Methods: One hundred and sixty-eight patients with advanced NSCLC who were treated with anti-cancer drugs and could be evaluated for therapeutic response between April 2005 and March 2010 at Kyoto University Hospital were enrolled. DNA was extracted from peripheral blood samples. The BCL2 polymorphisms -938 C→A (rs2279115) and +21 A→G (rs1801018) were genotyped using the 5'-nuclease assay. The univariate relationship between each independent clinicopathologic variable and BCL2 genotype was examined using Fisher's exact test. To evaluate risk factors associated with prognosis, a Cox proportional hazards regression model with a step-down procedure was used., Results: The median survival time of patients with the -938 AA and AC genotypes were significantly shorter than those with the -938 CC genotype (p = 0.027 by log-rank test). Based on multivariate analysis, poor performance status [hazard ratio (HR) 2.424, 95% confidence interval (CI) 1.727-3.262; p < 0.0001], non-adenocarcinoma histology (HR 1.512, 95% CI 1.167-1.938; p = 0.0048) and the BCL2 -938 AA + AC genotype (HR 1.219, 95% CI, 1.024-1.456; p = 0.0256) were significant independent prognostic factors for survival., Conclusions: Polymorphisms in BCL2 may be associated with survival in advanced-stage NSCLC patients who received chemotherapy., (Copyright © 2013 S. Karger AG, Basel.)

Purpose: Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them., Methods: We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry., Results: The concentration and penetration rate of gefitinib (mean ± standard deviation) in the CSF were 3.7 ± 1.9 ng/mL (8.2 ± 4.3 nM) and 1.13 ± 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 ± 16.8 ng/mL (66.9 ± 39.0 nM) and 2.77 ± 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P = 0.0008 and <0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib., Conclusions: This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.

A study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and serum hepatocyte growth factor (HGF) for their associations with response to gefitinib therapy and prognostic impact. An enzyme-linked immunosorbent assay was used to determine levels of HGF in serum from 96 Japanese patients with advanced non-squamous NSCLC. The peptic nucleic acid-locked nucleic acid clamp method was used to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and risk factors associated with prognosis. HGF-positive serum status (hazard ratio, 1.536; 95% confidence interval, 1.042-2.400; P = 0.0295) had a significant and independent negative effect on progression-free survival among patients with wild-type EGFR. We demonstrate that having HGF-positive serum is predictive of a negative response to gefitinib therapy in patients with advanced NSCLC who harbor wild-type EGFR.

Background: Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population., Patients and Methods: This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500 mg/m(2)) combined with carboplatin (area under the curve: AUC 6) every 3 weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival., Results: Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90 %) patients completed four cycles, and 33 (67 %) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51 %) and stable disease in 18 patients (37 %). Median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 24.3 months, respectively. The median PFS and OS were 7.9 months and 24.3 months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3 months and 21.0 months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p = 0.09) and OS (p = 0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33 %) and 9 (18 %) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths., Conclusions: The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).

Previous reports have shown that circulating endothelial progenitor cells (CEPs) are released in response to cytotoxic chemotherapy. We investigate the relationship between the kinetics of CEPs during one cycle of chemotherapy and the response to cytotoxic chemotherapy and prognostic impacts. Previously untreated patients (n = 38) receiving cytotoxic chemotherapy for non-small-cell lung cancer were included. Blood sampling was carried out on day 1, day 8, and just before the second cycle of chemotherapy. The mononuclear cell fraction was analyzed for CEPs by FACS analysis. We evaluated the relationship between the kinetics of CEPs, each independent clinicopathological variable, the response to chemotherapy, and the risk factors associated with prognosis. On the eighth day after chemotherapy, a significant decrease in CEPs was observed. In contrast, CEP counts before the second cycle of chemotherapy were significantly increased. The high percentage change in CEPs between day 1 and before the second cycle of chemotherapy is an independent predictive factor for response to chemotherapy. However, the change in CEP levels did not predict progression-free survival. These findings indicate that the late release of CEPs is a common phenomenon after chemotherapeutic treatment. The correlation with clinical response to chemotherapy provides further support for the biologic relevance of these cells in patients' prognosis and highlights the potential use of CEPs as therapeutic targets., (© 2012 Japanese Cancer Association.)

A standard, valid assay of comorbidities for elderly patients with advanced non-small-cell lung cancer (NSCLC) who have received antitumor therapy is needed to provide useful prognostic information. The aim of this study was to analyze prognostic factors and validate classic Charlson comorbidity index (CCI) and comorbidity scores in elderly patients with advanced NSCLC treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). A retrospective analysis was conducted on 162 patients with advanced NSCLC over 70 years old at diagnosis, who were treated with cytotoxic chemotherapy or with EGFR-TKIs between April 2003 and April 2009 at Kyoto University Hospital. Collected data included clinical assessments, treatments, toxicities, and outcomes. Survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated with log-rank and Cox regression tests. Based on multivariate analysis, unspecified NSCLC histology [Hazard ratio (HR), 1.631; 95% Confidence interval (CI), 1.184-2.263; P = 0.0016], more than 3 comorbidities (HR, 1.317; 95% CI, 1.020-2.675; P = 0.0350), and a CCI of more than 3 (HR, 1.321; 95% CI, 1.031-1.664; P = 0.0285) were significant independent negative prognostic factors for survival. Our results indicate that CCI and the number of comorbidities are independent predictors of survival in elderly patients undergoing systemic chemotherapy including EGFR-TKIs for advanced NSCLC. These factors should be taken into consideration in the pretreatment assessment as important factors predicting survival outcome.

Currently, platinum-based combination chemotherapy is the standard first-line chemotherapy for non-small-cell lung cancer (NSCLC). Historically, platinum-based chemotherapy has been recommended for up to six cycles even for responders, and second-line chemotherapy has been considered when disease progression is confirmed. In spite of extensive investigations into maintenance chemotherapy, no positive data have been obtained; however, the results of recent clinical trials suggest both the safety and efficacy of maintenance chemotherapy in patients with NSCLC, although it is still controversial. In this review, we summarize the major clinical trials of maintenance chemotherapy in patients with NSCLC, and discuss its clinical validity and present future perspectives., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: The maximum tolerated dose (MTD) of erlotinib (150 mg) is the approved daily dose. In contrast, the approved daily dose of gefitinib (250 mg) is only one-third of its MTD. Significantly different adverse events have been associated with gefitinib and erlotinib., Experimental Design: A retrospective investigation examining the adverse events and tolerances of 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer (NSCLC) was performed. Adverse events were assessed according to Common Terminology Criteria for Adverse Events version 3.0. To determine tolerance for each agent, failure was defined as dose reduction or discontinuation of the drug due to adverse events, and early failure as dose reduction or discontinuation due to adverse events before the first evaluation of response., Results: More adverse events including skin disorders, diarrhea, oral mucositis, asthenic conditions, anorexia, nausea, vomiting, and gastrointestinal bleeding were observed in the erlotinib group. Liver function test abnormalities and pneumonitis did not differ between the two groups. Based on multivariate analysis, failure, early failure, and discontinuation due to adverse events were independently associated with erlotinib use., Conclusion: Our data show that 150 mg daily erlotinib was associated with more toxicity and less tolerability than 250 mg daily gefitinib., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Purpose: Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor shown to provide a survival benefit for advanced non-small-cell lung cancer (NSCLC) patients. Adverse drug reactions of erlotinib in Japanese, which may be very different from those in Caucasians because of differences in genetic background, have not been fully reported. Therefore, we aimed to clarify the safety profile of erlotinib., Methods: Forty-eight patients with pretreated NSCLC were treated with erlotinib between March 2008 and January 2009 in this historical cohort study at Kyoto University Hospital Outpatients Oncology Unit. Erlotinib 150 mg/day was administered until progressive disease or discontinuation due to adverse events. The primary endpoint was frequency and degree of adverse events, and secondary endpoints were clinical efficacy including response rate, disease control rate, progression-free survival and overall survival., Results: Of 48 patients, 3 patients experienced erlotinib-induced interstitial pneumonitis, which appeared on day 15 and 70 in 2 patients who recovered and on day 8 in 1 patient who died. The incidences of pruritus, dry skin, diarrhea and stomatitis rapidly increased within 14 days after the start of medication with erlotinib. However, these adverse events were well controllable in outpatients treated with erlotinib. Overall response rate was 10% and disease control rate was 68%. The median progression-free survival was 58 days (95% confidence interval 30-118) and the median overall survival was 229 days (95% confidence interval 135-not available)., Conclusions: Outpatients with NSCLC can be treated with initial administration of erlotinib by careful management.

This study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and two serum markers, serum insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3), for their associations to response to gefitinib therapy and for their prognostic impact. An immunoradiometric assay determined levels of IGF1 and IGFBP3 in serum from 68 patients with advanced non-squamous NSCLC. The peptic nucleic acid locked nucleic acid clamp method determined their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis. Having IGF1-positive serum as determined by the 75th percentile and having wild-type EGFR were both independent negative predictive factors for geftinib treatment by multivariate logistic regression model analysis. Both having serum positive for IGF1 as determined by the 25th percentile and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. We demonstrated that having IGF1-positive serum predicts a negative response to gefitinib therapy independent of EGFR mutational status. We also demonstrated that both IGF1-positive serum and wild-type EGFR were independent poor prognostic factors in patients with non-squamous NSCLC who received gefitinib therapy.

Background: Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non-small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE)., Patients and Methods: We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration., Results: The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4., Conclusions: There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects., (Copyright © 2011. Published by Elsevier Inc.)

Internal jugular vein thrombosis is much less common than deep venous thrombosis of lower limbs and is generally caused by an indwelling venous catheter or otological infection. Several cases of internal jugular vein thrombosis associated with malignancy have been also reported. Bevacizumab, a monoclonal neutralizing antibody against vascular endothelial growth factor, has shown benefits in the treatment of many types of malignancy and its use is increasing. Serious adverse effects, however, are associated with the use of bevacizumab, including venous thromboembolism. In this article, we present a rare case of non-small cell lung cancer complicated by pulmonary embolism due to internal jugular vein thrombosis associated with bevacizumab.

The aims of this study are to: (a) confirm the prognostic significance of the procoagulant molecules D dimer, thrombin-antithrombin complex (TAT), and plasmin-α2-plasmin inhibitor complex (PIC); (b) to evaluate hemostatic activation in patients with advanced non-small cell lung cancer (NSCLC); and (c) to delineate the relationships between markers of hemostasis and other clinical characteristics. In this study, a low PIC/TAT ratio and poor PS were significant independent negative prognostic factors for survival in patients with advanced NSCLC. The PIC/TAT ratio may become a surrogate marker for treatment with anticoagulants in the future.

Transforming growth factor ß (TGF-ß) signaling can inhibit tumor growth in developing tumors. However, it promotes tumor invasiveness and metastasis in late-stage tumors. A number of TGF-ß gene polymorphisms have been identified that can affect the survival of patients with advanced non-small cell lung cancer (NSCLC). In this study, we investigated the association of the TGF-ß1 polymorphism, C-509T, with survival in patients with advanced NSCLC. Japanese patients who were treated for unresectable advanced NSCLC between April 2003 and March 2008 at Kyoto University Hospital, were enrolled in this study. Analyses of genotype associations with survival outcomes were performed using statistical tests. The median survival of patients with the TT genotype was shorter, although not significantly, than that of patients with either the CT or CC genotype. Based on both univariable and multivariable analyses, the TGF-ß1 polymorphism, C-509T, was not associated with prognosis. In patients with a smoking status of <40 pack-years, the median survival was significantly shorter with the TT genotype than with the CT or CC genotype. Based on univariable analysis, stage IV cancer and the TT genotype had a significant prognostic effect on survival. Based on multivariable analysis, the TT genotype was a significantly independent prognostic factor for survival. There was no association between the TGF-ß1 polymorphism, C-509T, and survival in patients with advanced NSCLC. In patients with a smoking status of <40 pack-years, however, the TGF-ß1 polymorphism, C-509T, was significantly associated with the prognosis of advanced NSCLC, and the TT genotype was an independent prognostic factor for poor survival.

Background: The aim of this study was to analyze the factors independent of epidermal growth factor (EGFR) gene mutations that affect the progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) after gefitinib therapy., Patients and Methods: Eighty patients with advanced NSCLC between January 2003 and April 2010 at Kyoto University Hospital were analyzed for EGFR somatic mutations and treated with gefitinib. We adopted the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method for determination of EGFR mutation status. To evaluate risk factors associated with PFS, Cox proportional hazards regression model with a step-down procedure was used. Proportional hazards assumptions were checked and satisfied; only those variables with statistically significant results in univariate analysis were included in a multivariate analysis., Results: The median PFS of patients with EGFR mutations were significantly longer than in patients with wild-type EGFR. The median PFS of patients after first-line gefitinib therapy was significantly longer than those who received treatment as a second-line therapy. The median PFS of patients over 75 years of age was significantly longer than in younger patients. Based on multivariate analysis, wild-type EGFR status and age < 75 years were significant and independent negative factors that affect PFS after gefitinib therapy., Conclusion: In this study, we showed the EGFR mutants and age > 75 years were good predictive factors for PFS after gefitinib therapy, suggesting that first-line gefitinib treatment for older patients is efficacious regardless of EGFR mutational status.

Background: Nitric oxide (NO) is a free radical that is involved in carcinogenesis. Endothelial NO, synthesized from L-arginine by endothelial NO synthase (eNOS), inhibits apoptosis and promotes angiogenesis, tumor cell proliferation and metastasis. The aim of this study was to evaluate the influence of polymorphisms in the eNOS gene on prognosis of patients with advanced stage non-small-cell lung cancer (NSCLC)., Methods: Unresectable, chemotherapy naïve stage III or IV NSCLC patients who were treated with standard platinum-containing doublet regimens were analyzed. All individuals were genotyped for the single-nucleotide polymorphism G894T in exon 7 of the eNOS gene and for a variable number of tandem repeats (VNTR) polymorphism in intron 4 that results in a rare smaller allele (a) and a common larger allele (b), to investigate the association between these polymorphisms and clinical outcomes. The primary endpoint was correlation with overall survival., Results: From October 2004 to December 2007, 108 patients (male/female, 66/42; Stage IIIA/IIIB/IV, 6/30/72) aged 29-77 years (median 63) with good performance status were consecutively enrolled in this study. Using Kaplan-Meier estimates, we showed that 5-year overall survival was significantly increased in patients carrying the VNTR a-allele compared with VNTR b/b patients (P = 0.015). In multivariate Cox proportional hazard analysis, the VNTR polymorphism was an independent prognostic factor for survival., Conclusions: The results support the role of the VNTR polymorphism in intron 4 as a marker for survival in patients with advanced stage NSCLC who are candidates for standard chemotherapy.

Background: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420., Method: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8., Results: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean +/- SD CSF concentrations of erlotinib and OSI-420 were 54 +/- 30 ng/ml and 10.8 +/- 8.2 ng/ml, respectively. The mean +/- SD CSF penetration rates of erlotinib and OSI-420 were 5.1% +/- 1.9% and 5.8% +/- 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC50) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene., Conclusion: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.

Introduction: Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC)., Method: We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8., Results: In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response., Conclusion: Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

Purpose: We examined patients with advanced nonsquamous, non-small cell lung cancer (NSCLC) to evaluate epidermal growth factor receptor (EGFR) mutation status and serum C-reactive protein (CRP) for their associations with response to gefitinib therapy and for prognostic impacts., Methods: Serum levels of CRP from 79 Japanese patients with advanced nonsquamous NSCLC were measured before the start of gefitinib. We used the peptic nucleic acid-locked nucleic acid clamp method to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis., Results: Having CRP-positive serum and having wild-type EGFR were both independent negative predictive factors for the response to gefitinib treatment by multivariate logistic regression model analysis. Having CRP-positive serum and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis., Conclusions: Having CRP-positive serum predicted a lack of response to gefitinib therapy independent of EGFR mutational status. Both CRP-positive serum and wild-type EGFR were independent poor prognostic factors in patients with nonsquamous NSCLC who received gefitinib therapy., (Copyright © 2011 S. Karger AG, Basel.)

Polymorphisms have been identified in the vascular endothelial growth factor (VEGF) gene that may affect VEGF production. We hypothesized that such polymorphisms may correlate with survival outcomes among advanced-stage non-small-cell lung cancer (NSCLC) patients. We evaluated the association between VEGF polymorphisms and overall survival among patients with advanced NSCLC who were treated with at least one cytotoxic regimen at Kyoto University Hospital between 2003 and 2008. We investigated the following VEGF polymorphisms: -460T > C (rs833061), +405G > C (rs2010963), +936C > T (rs3025039), -1154G > A (rs1570360), and -2578C > A (rs699947). Analyses of genotype associations with survival outcomes were performed using Cox proportional models, Kaplan-Meier methods, and the log-rank test. There were 126 patients and 80 deaths. On a Cox regression analysis of a current and former smoker (hazards ratio [HR], 1.422; 95% confidence interval [CI], 1.111-1.859; P = 0.0046), poor performance status (PS) (HR, 2.524; 95% CI, 1.483-3.827; P = 0.0019), the VEGF -460CC genotype (HR, 1.719; 95% CI, 1.166-2.390; P = 0.0084), VEGF -1154AA and AG genotypes (HR, 1.482; 95% CI, 1.144-1.897; P = 0.0034), and VEGF -2578AA genotype (HR, 1.797; 95% CI, 1.219-2.495; P = 0.0047) had a significant prognostic effect on survival based on univariate analysis. Based on multivariate analysis of a current and former smoker (HR, 1.407; 95% CI, 1.095-1.840; P = 0.0070), poor PS (HR, 2.249; 95% CI, 1.309-3.468; P = 0.0058), and the VEGF -1154AA and AG genotypes (HR, 1.419; 95% CI, 1.033-1.901; P = 0.0316) were significant independent prognostic factors for survival. In this study, polymorphisms in VEGF may affect survival in advanced NSCLC.

Background: ATP-binding cassette (ABC) transporter and DNA excision repair proteins play a pivotal role in the mechanisms of drug resistance. The aim of this study was to investigate the expression of ABC transporter and DNA excision repair proteins, and to elucidate the clinical significance of their expression in biopsy specimens from patients with small-cell lung cancer (SCLC)., Methods: We investigated expression of the ABC transporter proteins, P-glycoprotein (Pgp), multidrug resistance associated-protein 1 (MRP1), MRP2, MRP3, and breast cancer resistance protein (BCRP), and the DNA excision repair proteins, excision repair cross-complementation group 1 (ERCC1) protein and breast cancer susceptibility gene 1 (BRCA1) protein, in tumor biopsy specimens obtained before chemotherapy from 130 SCLC patients who later received platinum-based combination chemotherapy, and investigated the relationship between their expression and both response and survival., Results: No significant associations were found between expression of Pgp, MRP1, MRP2, MRP3, ERCC1, or BRCA1 and either response or survival. However, there was a significant association between BCRP expression and both response (p=0.026) and progression-free survival (PFS; p=0.0103)., Conclusions: BCRP expression was significantly predictive of both response and progression-free survival (PFS) in SCLC patients receiving chemotherapy. These findings suggest that BCRP may play a crucial role in drug resistance mechanisms, and that it may serve as an ideal molecular target for the treatment of SCLC.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), such as gefitinib or erlotinib, is mainly metabolized in liver. To date, the safety data on administrating EGFR-TKI to patients with liver dysfunction is quite limited. Here, we administered gefitinib to two adenocarcinoma patients with liver cirrhosis, and one patient with EGFR gene mutation in exon 21 achieved long stable disease (SD) without any toxicity. Pharmacokinetic data of alternate days administration in these patients were similar to those of daily administration in patients with normal liver function. Although further studies are needed, a reduced dose of gefitinib might be feasible for patients with liver dysfunction.

Circulating amphiregulin and transforming growth factor-alpha (TGF-alpha) have been found to be correlated with an unfavorable response to gefitinib based on the identification of patients with a higher probability of resistance to the drug. However, the association between an epidermal growth factor receptor (EGFR) somatic mutation and the overexpression of its ligands has not been determined. To verify the clinical significance of the two serum markers and EGFR mutation status, we determined serum amphiregulin and TGF-alpha levels by enzyme-linked immunosorbent assay in 93 patients with advanced non-squamous, non-small cell lung cancer and EGFR somatic mutation status using the peptic nucleic acid-locked nucleic acid clamp method in 46 cases. The relationship between each independent clinicopathological variable and the response to gefitinib therapy was examined. We also evaluated the risk factors associated with prognosis. Fourteen (41.0%) of 34 progressive disease cases were positive for amphiregulin (P = 0.007). Eleven (32.4%) of 34 progressive disease cases were positive for TGF-alpha (P = 0.005). The median survival time of patients with the EGFR somatic mutation was significantly longer (P = 0.01). The same was true of amphiregulin- (P = 0.046) and TGF-alpha-negative patients (P < 0.01). In multivariate analysis, serum TGF-alpha positivity (hazard ratio, 2.558; P = 0.005) and the wild type EGFR gene (hazard ratio, 1.894; P = 0.003) were significant independent prognostic factors. Our study demonstrates that the status of the serum EGFR ligand, in addition to EGFR activating mutation, is a predictive factor for response to gefitinib therapy.

Background: The importance of an epidermal growth factor receptor (EGFR) gene mutation has been recognized in patients with non-small cell lung cancer (NSCLC), and many reports have indicated that the presence of somatic mutations in the EGFR gene is a strong predictor of both clinical and in vitro sensitivity to EGFR tyrosine kinase inhibitors; thus necessitating the standardization of a mutation screening system based on the sources of tissue samples., Methods: In this study, we compared the results of EGFR mutation analyses in 19 small biopsy specimens with results obtained in surgical materials from the same patients with NSCLC. We used a laser microdissection method and a direct sequencing method, and we confirmed the accuracy of EGFR mutation analysis with small biopsy specimens., Results: The results obtained from the biopsy specimens were identical to those obtained from the surgical materials in 18 of the 19 patients analyzed. For the 1 patient in whom the results obtained from the two sets of materials were not identical, the number of cancer cells in one bronchoscopic specimen was insufficient to perform analyses of all three exons of interest (i.e., exons 18, 19, and 21), and so only exon 19 was sequenced, and no mutation was demonstrated., Conclusion: We conclude that satisfactory accuracy can be achieved by the genomic analysis of a small biopsy specimen from a patient with NSCLC and we note that it is possible to conduct prospective clinical trials that include patient assignment for treatment based on the results obtained.

Objective: This study evaluates the risks of postoperative complications in 124 patients with non-small-cell lung cancer who received pre-operative induction chemoradiotherapy and surgery., Methods: All patients with non-small-cell lung cancer who underwent surgery after induction therapy between January 1990 and December 2003 were reviewed. We adopted univariate and multiple logistic regression models to identify predictors that increased the incidence of postoperative complications., Results: Of 124 patients, 59 received carboplatin and docetaxel, 53 received cisplatin and etoposide, and 12 received other platinum-based combinations. Pre-operative thoracic radiotherapy was performed concurrently with chemotherapy. The median dose to the primary tumor was 40 Gy, and 29 patients (23.4%) received radiotherapy of more than 45 Gy before surgery. There were 25 pneumonectomies (20.2%). The overall postoperative mortality was 9 of 124 patients (7.3%), and complications developed in 54 patients (43.5%). Multivariate analysis demonstrated that only thoracic radiotherapy of more than 45 Gy predicted postoperative complications (P = 0.021; odds ratio, 3.620; 95% confidence interval, 1.214-10.797)., Conclusions: Thoracic radiotherapy of more than 45 Gy, in combination with chemotherapy, was a significant risk factor for postoperative complications.