Keiko Nakao

Response Rate Is Associated with Prolonged Survival in Patients with Advanced Non-small Cell Lung Cancer Treated with Gefitinib or Erlotinib

Introduction: Gaining a higher response rate (RR) has usually been determined as a primary end point in phase II trials evaluating the efficacy of new molecular targeted drugs. However, a relationship between clinical response and survival benefit has not been well studied in the patients treated with molecular targeted agents. Methods: Prospective trials of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) monotherapy in non-small cell lung cancer were extracted from MEDLINE, EMBASE, and the annual meetings in 2007 of the American Society of Clinical Oncology, European Cancer Conference, and World Conference on Lung Cancer. Correlation between clinical response and survival was examined using linear regression analysis. We also tried to compare the significance of RR as surrogate markers for survival with that of disease control rate (DCR) by calculating the area under their receiver operating characteristic (ROC) curves. Results: We identified 24 phase II trials and 4 phase III trials with a total of 6171 patients and 30 treatment arms, including 22 arms for the gefitinib group and 8 arms for the erlotinib group. Both RR and DCR strongly correlated with median survival time (MST; p < 0.0001 and p = 0.003, respectively). In an ROC analysis, the area under the ROC curve predicting MST prolongation by RR was 0.918, which was higher than the area under the ROC curve by DCR. Conclusions: We found a significant relationship between RR and MST in clinical trials with EGFR-TKIs. RR could be an independent surrogate marker for MST in the current response criteria in the clinical trials of EGFR-TKIs.

Predictors of the clinical effects of pirfenidone on idiopathic pulmonary fibrosis

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with a poor prognosis. Recently, pirfenidone was reported to slow the rate of decline in vital capacity and improve progression-free survival in IPF. The purpose of this study was to clarify the factors that predicted a good response to pirfenidone, as well as its adverse effects. METHODS Forty-one IPF cases, treated with pirfenidone from January 2009 to January 2011, were enrolled in this investigation. Disease severity was classified into grades I-IV, as defined by the Japanese Respiratory Society (JRS). Short-term responsiveness to pirfenidone was evaluated by the modified criteria of the JRS. Predictors of nausea, anorexia, or both that represented important adverse effects were examined by multivariate Cox proportional hazard analyses. Predictors of short-time responsiveness were examined by multivariate logistic regression analyses. RESULTS Diagnosed by a surgical lung biopsy (SLB), the mild cases of grade I/II were predictors of good, short-term responsiveness. Patients taking acid-secretion inhibitors, including proton pump inhibitors and histamine H2-receptor antagonists, showed less anorexia, nausea, or both. Only 1 case was administered drugs to activate gastrointestinal motility. CONCLUSIONS We concluded that IPF patients with a mild disease, diagnosis by SLB, or both showed indications of a good response to pirfenidone. In addition, acid-secretion inhibitors may reduce the frequency of anorexia, nausea, or both from pirfenidone.

CYFRA 21-1 as a disease severity marker for autoimmune pulmonary alveolar proteinosis.

Serum markers, including Krebs von den Lungen (KL‐6), surfactant protein (SP)‐D, SP‐A and carcinoembryonic antigen (CEA), are reported to reflect autoimmune pulmonary alveolar proteinosis (APAP) disease severity. We evaluated serum CYFRA21‐1 levels as a marker of APAP.

Prospective phase II study of cisplatin plus pemetrexed with maintenance of pemetrexed for advanced non‐squamous cell non‐small cell lung cancer in Japan

A previous study showed a survival benefit with maintenance therapy with pemetrexed in patients with advanced non‐small cell lung cancer (NSCLC). However, it remains unclear whether continuation maintenance therapy with pemetrexed is beneficial in Japanese patients. Here, we present our phase II study that assessed the efficacy and safety of cisplatin plus pemetrexed as induction chemotherapy, followed by maintenance therapy with pemetrexed in advanced NSCLC patients in Japan.

Change in lung function in never-smokers with nontuberculous mycobacterial lung disease: A retrospective study

Purpose Never-smokers account for a large proportion of subjects in general population studies on nontuberculous mycobacteria lung disease (NTM-LD). However, the influence of NTM infection on the lung function of never-smokers has not yet been evaluated. The aim of this study was to determine how NTM-LD impairs the lung function in never-smokers, and whether there are an association between successful NTM-LD treatment in radiologic outcomes and improvement in lung function of never-smokers with NTM-LD or not. Methods We performed a retrospective study of patients (1) who have never smoked during their lifetime; (2) with at least two respiratory specimens from sputum, one bronchial washing sample, or one lung tissue that were culture positive for the same NTM species; and (3) who underwent at least two pulmonary function tests. We enrolled healthy never-smokers as the control group. Results In 22 never-smokers with NTM-LD, the median forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) at baseline was lower than those in 9 healthy never-smokers [1800 vs 2080 ml (p = 0.23) and 2230 vs 2620 ml (p = 0.06)], respectively. The median change in FEV1 in never-smokers with NTM-LD was lower than that in healthy never-smokers [−70 vs 20 ml per year (p = 0.07), respectively]. On univariate analysis, baseline %-predicted FEV1 in never-smokers with NTM-LD was associated with changes in FVC (p = 0.026) and FEV1 (p = 0.013). Anti-NTM treatment was administered for at least 1 year in 19 patients (86.4%). The relationship between worsening chest CT findings and rapid progressive decline in both FVC (p = 0.66) and FEV1 (p = 0.23) were not significant. Conclusion Never-smokers with NTM-LD showed lung function decline. There was no association between successful NTM-LD treatment in radiologic outcomes and improvement in lung function of never-smokers.

Combination of virtual bronchoscopic navigation, endobronchial ultrasound, and rapid on-site evaluation for diagnosing small peripheral pulmonary lesions: a prospective phase II study.

BACKGROUND The diagnostic yield of peripheral pulmonary lesions (PPLs) by flexible bronchoscopy (FB) is still insufficient. To improve the diagnostic yield of bronchoscopy, several techniques such as endobronchial ultrasound (EBUS), virtual bronchoscopic navigation (VBN), and rapid on-site evaluation (ROSE) have been examined. The primary purpose of the present study was to evaluate the usefulness of combining EBUS, VBN, and ROSE for diagnosing small PPLs. METHODS Patients with PPLs 30 mm or less on chest computed tomography (CT) were prospectively enrolled. We determined the responsible bronchus for the target lesions using VBN before bronchoscopy was performed. EBUS and ROSE were performed during the examination to determine whether the bronchus and specimen were adequate. On the basis of previous studies, we assumed that the diagnostic yield of 85% among eligible patients would indicate potential usefulness, whereas, the diagnostic yield of 75% would indicate the lower limit of interest. The required number of patients was estimated as 45 for a one-sided α value of 0.2 and a β value of 0.8. The primary study endpoint was the diagnostic yield. RESULTS Between June 2014 and July 2015, we enrolled 50 patients in the present study, and we excluded 5 patients. The total diagnostic yield of 45 PPLs was 77.7%. In cases of lung cancer, the diagnostic yield was 84.2%. The sensitivity, specificity, positive predictive value, and negative predictive value of ROSE were 90.6%, 92.3%, 96.7%, and 80.0%, respectively. The diagnostic yield of PPLs from 20 to 30 mm was 87.5%, and the diagnostic yield of PPLs less than 20 mm was 66.7%. PPLs for which the probe was located within the lesion had the highest diagnostic yield. CONCLUSIONS We could not demonstrate usefulness for diagnosing small PPLs by combining EBUS, VBN, and ROSE. However, combining these techniques may be useful for diagnosing lung cancer.

Serum biomarkers as prognostic factors of autoimmune pulmonary alveolar proteinosis after whole lung lavage

Background and aim: Whole lung lavage (WLL) is an effective therapy for autoimmune pulmonary alveolar proteinosis (APAP). The aim of this study is to clarify the prognostic factors after WLL in APAP, especially focusing on serum biomarkers. Subjects and Methods: 21 patients had been treated by WLL (total 26 laveges) in our institution from 2001 to 2015, as our prospective consecutive cohort of PAP. We measured serum biomarkers levels (KL-6, SP-D, SP-A, CEA, CYFRA, anti GM-CSF autoantibody) before (baseline levels) and one month after WLL. We analyzed the baseline biomarkers and the % decline of each biomarker (baseline and one month after WLL), changes of disease severity score (DSS) defined by AaDO 2 , efficacy of WLL defined by improvement of DSS, and recurrence-free survival (RFS) afterwards. Recurrence was defined by additional treatment or admission after WLL. Result: Baseline characteristics (M/F; 14/7, median age; 51.9 y.o., median DSS; 3, median % FVC: 77.0%, and median %DLco: 44.4%) had no significant relationship with efficacy or RFS time. Efficacy of WLL was predicted by baseline SP-A levels, delta SP-D, SP-A, CEA and CYFRA (Logistic analysis: p=0.0461, 0.0276, 0.0151, 0.0012, and 0.0040, respectively). RFS time was significantly longer in the patients with larger delta of CEA (cut-off level: 44.4%) and CYFRA (cut-off level: 56.6%) than the patients with smaller delta of the each biomarker (p=0.0212, p=0.0477, respectively). Serum levels of KL-6 and anti GM-CSF antibody had no significant relationship with efficacy of WLL and RFS time. Conclusion: Delta biomarkers levels, especially CEA and CYFRA, can predict efficacy of WLL and recurrence of APAP after WLL.