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S. Atagi



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    MO25 - NSCLC - Combined Modality Therapy II (ID 112)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO25.02 - Thoracic Radiotherapy With or Without Concurrent Daily Low-Dose Carboplatin in Elderly Patients With Locally Advanced Non-small Cell Lung Cancer: Updated Results of the JCOG0301 and Pooled Analysis With the JCOG9812 Trial. (ID 734)

      10:30 - 12:00  |  Author(s): S. Atagi

      • Abstract
      • Presentation
      • Slides

      Background
      The Japan Clinical Oncology Group (JCOG) undertook 2 randomized phase III trials (JCOG9812 and JCOG0301) to assess whether daily low-dose carboplatin plus radiotherapy could improve survival in elderly patients with stage III non-small cell lung cancer (NSCLC) when compared to radiotherapy alone. Although JCOG9812 was prematurely terminated because of a high incidence of treatment-related deaths (TRDs) and instances of protocol violation, especially with regard to radiotherapy planning, the trial regimen was assumed promising. Therefore, JCOG0301 was conducted for the same subjects using the same protocol regimen with modified inclusion criteria regarding pulmonary function and radiotherapy quality control (RTQC) measures. We then carried out a preplanned pooled analysis of these 2 studies.

      Methods
      The eligibility criteria for both trials were age of ≥71 years and unresectable stage III NSCLC. Patients were randomized to receive radiotherapy alone (60 Gy, RT arm) or chemoradiotherapy (radiotherapy, 60 Gy plus concurrent carboplatin, 30 mg/m[2] per fraction up to the first 20 fractions, CRT arm). The primary endpoint for both studies was overall survival (OS). The pooled analysis included OS, progression-free survival (PFS), response rate, and toxicities.

      Results
      In JCOG9812, 46 patients (RT arm, n=23; CRT arm, n=23) were enrolled from November 1999 to August 2001. In JCOG0301, 200 patients (RT arm, n=100; CRT arm, n=100) were enrolled from September 2003 to May 2010, and in total, 246 patients were included in the pooled analysis. Patient characteristics for the RT (n=123) and CRT (n=123) arms were as follows: median age, 77 years (range, 71–93) and 77 years (range, 71–89); stage IIIA/IIIB, 65/58 patients and 63/60 patients; performance status (PS) 0/1/2, 44/74/5 patients and 50/69/4 patients; men/women, 103/20 patients and 96/27 patients, respectively. The median OS for the RT (n=121) and CRT (n=122) arms were 16.3 months (95% CI, 13.4–18.6) and 20.7 months (95% CI, 16.3–26.9), respectively (HR, 0.672; 95%CI, 0.502–0.898, stratified log-rank test one-sided p=0.0034). The pooled HR for PFS was 0.671 (95%CI, 0.514–0.875, stratified log-rank test one-sided p=0.0015). Response rates for the RT and CRT arms were 46.3% and 53.3%, respectively. The number of patients with grade 3/4 hematological toxicities was higher in the CRT arm than in the RT arm: leucopenia (62.2% vs 1.7%), neutropenia (54.6% vs none), and thrombocytopenia (30.3% vs 3.3%). The incidence of grade 3/4 pneumonitis decreased from 4.4% (JCOG9812; RT, 4.5% and CRT, 4.3%) to 2.1% (JCOG0301; RT, 3.1% and CRT, 1.0%), and that of late lung toxicity, from 14.0% (JCOG9812; RT, 10.0% and CRT, 17.4%) to 5.9% (JCOG0301; RT, 5.3% and CRT, 6.5%). The incidence of TRD also decreased from 8.9% (JCOG9812; RT, 1 patient and CRT, 3 patients) to 3.6% (JCOG0301; RT, 4 patients and CRT, 3 patients). As per subgroup analyses, ≤75 years, stage IIIA, male, PS 0, and smoking history were associated with statistically significant improvement in OS in the CRT arm.

      Conclusion
      This combination chemoradiotherapy for elderly patients with locally advanced NSCLC provides clinically significant benefits and RTQC measures are imperative to improve treatment outcome.

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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 - 16:30  |  Author(s): S. Atagi

      • 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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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-007 - Update data of biomarker analysis of WJOG4107 (A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC)) (ID 1504)

      09:30 - 16:30  |  Author(s): S. Atagi

      • Abstract

      Background
      We conducted a randomized phase II trial for patients with resected stage II-IIIA NSCLC comparing postoperative oral S-1 (80 mg/m2/day for consecutive 2 weeks q3w for 1 year) (S) (N=100) or cisplatin (CDDP) (60 mg/m2 day1) plus oral S-1, (80 mg/m2/day for 2 weeks) q3w for 4 cycles (PS)(N=100). We reported that disease free survival rate at 2 years (DFS@2) (95% confidence interval: CI), a primary endpoint, was 66 (55-74) % for S and 58 (48-67)% for PS. Here, we report the preliminary results of preplanned biomarker analysis, a co-primary endpoint, to identify molecules whose expression is significantly associated with patient outcome.

      Methods
      　cDNA extracted from macro-dissected formalin-fixed paraffin-embedded specimens were available for 197/200 patients. Thirty-one genes including those whose expressions have been potentially associated with　CDDP (e.g. ERCC1, XRCC1, BRCA1, GSTpi, HMG1, TBP) or fluorouracil (FU) sensitivity (TS, DHFR, DPD, UMPS, UPP1) were measured by QGE analysis (MassArray, Sequenom, CA). Additional analysis are being performed to assess ERCC1 isoform expression with an isoform-specific TaqMan probe (Applied Biosystems, CA). The expression of each gene was dichotomized according to its median value.

      Results
      Molecules such as ERCC1 and GSTpi whose expression have been previously associated with CDDP sensitivity did not emerge as predictive markers (P=0.7908, 0.6406, respectively). We quantitated ERCC1 by isotype (202 and 204 cannot be distinguished). There was a trend in patients with high 201 or 202/204, CDDP/S-1 was worse than S-1.

      Conclusion
      Quantitation of ERCC1 by isotype may define a patient subset that would benefit from postoperative platinum therapy.

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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 - 16:30  |  Author(s): S. Atagi

      • 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 - 16:30  |  Author(s): S. Atagi

      • 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.