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T. Kawaguchi



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    O18 - Cancer Control and Epidemiology II (ID 133)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O18.02 - Impacts of environmental tobacco smoke on EGFR mutations and ALK rearrangements in never smokers with non-small cell lung cancer: Analyses on a prospective multinational ETS registry (ID 1255)

      10:40 - 10:50  |  Author(s): T. Kawaguchi

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR and ALK are important driver mutations in never smokers. While we reported the significant association of increased environmental tobacco smoke (ETS) with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), it has not been fully understood in other ethnicities and also the correlation of ETS with ALK has not been reported yet. In this study, we evaluated the association of ETS with the prevalence of EGFR mutations and ALK translocations in various ethnicities including East-Asia (Japan, Korea, China, and Singapore) and the USA.

      Methods
      ETS exposure on never smokers with non-small cell lung cancer (NSCLC) was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood/ adulthood and at home/ workplace, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3).

      Results
      From March 2008 to December 2012, 498 never smokers with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/ female, 114/ 384; age <65/ >=65, 286/ 212; histology of adenocarcinoma/ BAC/ squamous cell carcinoma/ adenosquamous cell carcinoma/ other NSCLC, 459/ 12/ 13/ 5/ 9; frequency (%) of CETS < median CETS (40 years) in Japanese/ Korean/ Chinese/ Caucasian, 32.8/ 44.1/ 71.7/ 83.3. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (+), ALK (+) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n=384) were 1.084 (95% CI, 1.003-1.171; p=0.0422) for each increment of 10 years in CETS while OR in male (n=114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p=0.2627). OR for ALK rearrangements in female (n=238) and those in male gender (n=74) were 0.930 (0.791-1.094; p=0.3814) and 0.854 (0.620-1.178; p=0.3319).

      Conclusion
      Increased ETS exposure was closely associated with EGFR mutations in never smokers with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in never smokers with NSCLC was not significant.

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    P2.12 - Poster Session 2 - NSCLC Early Stage (ID 205)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.12-010 - Does presence of chronic obstructive pulmonary disease (COPD) influence clinical behavior in patients with early stage non-small cell lung cancer (ES-NSCLC)? (ID 1369)

      09:30 - 09:30  |  Author(s): T. Kawaguchi

      • Abstract

      Background
      CDPD and lung cancer sometimes occurs simultaneously. COPD has been recognized as an inflammatory disease mainly by smoking effects and may potentially affect biology of the accompanying tumor. It is not fully understood whether presence of CDPD influences clinical characteristics, pathological findings and/or clinical outcomes in patients with operable ES-NSCLC.

      Methods
      Retrospective and consecutive data were collected from the medical records of patients who underwent surgical resections of lung cancer at Kinki-chuo Chest Medical Center, Japan, between January 2009 and December 2010. CDPD status was classified as absence of COPD, stage I and II COPD based on the criteria of Global Initiative for Chronic Obstructive Lung Disease (GOLD2009). Histology, vascular / lymphatic invasion and the status of epidermal growth factor receptor (EGFR) were determined using the surgical materials.

      Results
      A total of 319 surgical cases was included in this study with median age of 67 (range, 36 - 89). There were 81 cases of relapse and 40 cases of death during the median follow up of 28 months (11 days to 49 months). According to the subgroups of no COPD, stage I and II COPD, the median age, the number of case in gender (male/female), performance status (PS, 0/1), histology (squamous cell carcinoma [SQ] /non SQ), smoking status (never/ever), and EGFR status (wild type/mutant) were as follows respectively; 67, 72, 72 (p<0.001) and 105/110, 48/12, 38/6 (p<0.001) and 170/40, 53/7, 27/14 (p=0.029) and 31/184, 12/48, 14/28 (p<0.001) and 89/122, 7/53, 2/39 (p=0.002) and 47/37, 21/3, 9/3 (p=0.013), respectively. No significant difference was observed in disease-free survival (DFS, log-rank p=0.411) and overall survival (OS, log-rank p=0.127) between the patients with and without COPD. In multivariate analysis adjusted for age, gender, PS, histology, smoking status, pathological stage, vascular / lymphatic invasion and EGFR status, presence of COPD did not affect DFS (HR=1.457, p = 0.279) nor OS (HR=0.993, p = 0.990).

      Conclusion
      Although COPD was significantly associated with the elderly, male gender, presence of symptoms, SQ histology, ever smoking, and wild type EGFR, it did not add values of prognostic factors in patients with operable ES-NSCLC.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.10-009 - Phase II study of bevacizumab in combination with carboplatin plus paclitaxel as first-line chemotherapy for non-squamous non-small cell lung cancer with malignant pleural effusion (ID 902)

      09:30 - 09:30  |  Author(s): T. Kawaguchi

      • Abstract

      Background
      Vascular endothelial growth factor (VEGF) plays an important role in non small cell lung cancer (NSCLC) with malignant pleural effusion (MPE), but there are little evidence regarding the efficacy of bevacizumab (Bev) with carboplatin-paclitaxel (CP) for treatment of NSCLC with MPE. Therefore, we prospectively evaluated the efficacy and safety of Bev and CP in non-squamous (SQ) NSCLC patients with MPE.Vascular endothelial growth factor (VEGF) plays an important role in non small cell lung cancer (NSCLC) with malignant pleural effusion (MPE), but there are little evidence regarding the efficacy of bevacizumab (Bev) with carboplatin-paclitaxel (CP) for treatment of NSCLC with MPE. Therefore, we prospectively evaluated the efficacy and safety of Bev and CP in non-squamous (SQ) NSCLC patients with MPE.

      Methods
      Chemotherapy-naive non-SQ NSCLC patients with MPE were eligible to participate. Pleurodesis before chemotherapy was not allowed. In the first cycle, the treated patients received only CP to prevent Bev-induced wound healing delayed after chest drainage. Subsequently, they received 2–6 cycles of CP with Bev. Patients who completed more than 4 cycles of CP and Bev without disease progression or severe toxicities continued to receive Bev alone as a maintenance therapy. The primary endpoint was overall response, although an increase in MPE was allowed in the first cycle. The VEGF levels in plasma and MPE were measured at baseline and the VEGF levels in plasma were measured after 3 cycles of chemotherapy.

      Results
      Between September 2010 and June 2012, 23 patients were enrolled. The overall response rate was 60.8%, the disease control rate was 87.0%, and one patient was not evaluated response because of sudden death after 1 cycle treatment. Sixteen patients received maintenance therapy, following a median of 3 cycles. The median progression-free survival and the median overall survival were 7.1 months (95% CI, 5.6 - 9.4 months) and 11.7 months (95% CI, 7.4 – 16.6 months). Almost all patients experienced severe hematological toxicities, including ≥ grade 3 neutropenia. And there was no patient who experienced severe bleeding events. The median baseline VEGF levels in MPE was 1798.6 (range; 223.4 - 35,633.4) pg/mL. The VEGF levels in plasma showed a significant decrease after 3 chemotherapy cycles (baseline; 513.6 ± 326.4 pg/mL, post chemotherapy; 25.1 ± 14.1 pg/mL, p < 0.01), regardless of efficacy of CP with Bev.

      Conclusion
      The combination of CP with Bev was confirmed to be effective and tolerable in chemotherapy-naïve non-SQ NSCLC patients with MPE.

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      P3.10-015 - Final analysis of dose escalation study of carboplatin plus pemetrexed followed by maintenance pemetrexed for elderly patients (≥75 years old) with advanced non-squamous non-small cell lung cancer (ID 1349)

      09:30 - 09:30  |  Author(s): T. Kawaguchi

      • Abstract

      Background
      This study was designed to determine the recommended dose of carboplatin plus pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced non-squamous non-small cell lung cancer (NSCLC).Patients and methods: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for 4 cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed.

      Methods
      Patients received escalated doses of carboplatin area under the concentration–time curve (AUC) of 4 (cohort 0) or 5 (cohort 1) or 6 (cohort 2) and pemetrexed 500mg/m2 every 3 weeks for 4 cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed.

      Results
      In cohort 0, a dose-limiting toxicity (DLT) was not observed in three patients, and no DLTs were seen in the first three patients of cohort 1. In cohort 2, DLTs were observed in three of the seven patients: two of grade 4 thrombocytopenia and one of grade 3 febrile neutropenia. And in additional cohort 1, no DLTs were seen in the next four patients. Therefore, the combination of carboplatin at an area under the concentration–time curve (AUC) of 5, plus 500 mg/m[2 ]pemetrexed, was determined to be the recommended dose for elderly patients (≥75 years old) with advanced non-squamous NSCLC. Of a total of 17 patients, 10 received a median of 5 cycles of pemetrexed maintenance therapy without unexpected or cumulative toxicities. No complete responses and 8 partial responses were observed, and the study had an overall response rate of 47.1%. The median progression-free survival time was 5.5 monthes (95% confidence interval [CI], 2.4–8.9 monthes) and the median overall survival time was 12.6 monthes (95% CI, 7.4–17.9 monthes) in he final analysis of this study.

      Conclusion
      Figure 1 This combination was a tolerable and effective regimen, and recommended dose was carboplatin (AUC of 5) / pemetrexed (500 mg/m2) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced non-squamous NSCLC.