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F. Oshita



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.10 - Phase II study of bevacizumab, cisplatin and docetaxel plus maintenance bevacizumab as first line treatment for patients with advanced non-small cell lung cancer (n-Sq NSCLC) combined with exploratory analysis of circulating cells (CEC): Thoracic Oncology Research Group (TORG)1016 (ID 1211)

      16:15 - 17:45  |  Author(s): F. Oshita

      • Abstract
      • Presentation
      • Slides

      Background
      Bevacizumab has been shown to amplify efficacy against n-Sq NSCLC in combination with platinum doublet, especially taxane including regimens. Docetaxel is one of best taxane composition combined with cisplatin for first line treatment for NSCLC, and known to have anti-angiogenic effect and may act synergistically with VEGF inhibiting agent. The object of this study was to assess the efficacy and safety of bevacizumab, cisplatin and docetaxel combination treatment in patients with chemonaive n-Sq NSCLC patients. (Trial Registry: UMIN 000004368)

      Methods
      Eligible patients had advanced or recurrent n-Sq NSCLC with no prior chemotherapy. Patients having brain metastasis or history of hemoptysis were ineligible. Patients received 4 cycles of docetaxel (60mg/m[2]), cisplatin (80mg/m[2]) and bevacizumab (15mg/kg) on day1 every 3 weeks followed by Bev alone as maintenance every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was response rate (RR) and planned sample size of this phase II study was 47 patients (Simon's two-stage minimax design). We measured circulating endothelial cells (CEC) count day1 and 8 of first cycle for exploratory analysis of efficacy and safety prediction.

      Results
      From Oct 2010 to Apr 2012, 47 patients (28 males/ 19 females, median age, 61 years, 39-73) were enrolled. Stage IIIB/IV/recurrent: 5/39/3, ECOG PS 0/1: 31/16. All patients were adenocarcinoma, EGFR status: mutated/wild/unknown: 13/31/3. Bevacizumab maintenance were administered in 87% (41/47) of the patients and 9 was median number of delivered course, 4 course of induction and 5 course of maintenance. Dose reduction was required in 28% (13/47) of the patients. Thirty-five partial responses and 11 stable diseases were observed among 47 patients, yielding a RR of 74.5% (95% confidence interval: 59.7-86.1%) and disease control rate of 97.9% (88.7-99.9%), respectively. The median progression free survival duration in the patients was 9.0 (7.0-11.3) months. Grade 3/4 leukopenia, neutropenia, hypertension, nausea and febrile neutropenia were observed in 60, 96, 47, 13 and 9% of the patients, respectively. Alveolar hemorrhage (Grade 5) after 4 cycle occurred in one patient.

      Conclusion
      Bevacizumab, cisplatin and docetaxel combination followed by bevacizumab maintenance treatment was highly effective in patients with n-Sq NSCLC, with acceptable toxicity. Exploratory analysis of CEC is ongoing and will be presented.

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    MO13 - SCLC I (ID 118)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO13.08 - A pilot study of adjuvant chemotherapy with irinotecan and cisplatin for completely resected high grade pulmonary neuroendocrine carcinona (Large cell neuroendocrine carcinoma and small cell lung cancer) (ID 1562)

      10:30 - 12:00  |  Author(s): F. Oshita

      • Abstract
      • Presentation
      • Slides

      Background
      Large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are recognized as high grade neuroendocrine carcinoma (HGNEC) of the lung. In patients with completely resected HGNEC, platinum-based adjuvant chemotherapy may be considered. However, the optimum chemotherapy regimen has not been determined. We conducted a multicenter single-arm phase II trial to evaluate irinotecan and cisplatin in postoperative adjuvant chemotherapy for HGNEC patients.

      Methods
      Patients with completely resected stage I- IIIA HGNEC received 4 cycles of irinotecan (60 mg/m[2], day 1, 8, 15) plus cisplatin (60 mg/m[2], day 1). This regimen was repeated every 4 weeks. Other eligibility criteria included ECOG PS 0–1, age 20, and <75 years old, adequate organ function, and no prior chemotherapy or radiotherapy. Patients with UGT1A1 polymorphisms (homozygous for *6 or *28, or simultaneously heterozygous *6 and *28), associated with irinotecan-related severe toxicity, were excluded. The primary endpoint was the rate of completion of chemotherapy (defined as underwent 3 or 4 cycles), and secondary endpoints were 3-year relapse free survival (RFS), rate of 3-year survival and toxicities.

      Results
      Forty patients were enrolled between September 2007 and April 2010. Patients’ characteristics were as follows: median age (range) 65 (45-73) years; male 85%; ECOG-PS 1 60%; LCNEC 57% and SCLC 43%; stage IA/IB/IIB/IIIA 32/35/8/5%; 95% received lobectomy. The rate of completion of chemotherapy was 83% (90% C.I.; 71-90%). The rate of overall survival at 3 years was estimated at 81%, and of RFS at 3 years was 74%. The rates of overall survival and RFS at 3 years were 86% and 74% among 23 LCNEC patients, and 74%, 76% among 17 SCLC patients, respectively. Nineteen patients (48%) experienced grade 3 or 4 neutrophils, but only five patients (13%) developed febrile neutropenia. Two patients (5%) developed grade 3 diarrhea, and 4 patients (10%) had grade 3 nausea. No treatment related deaths were observed in this study. All 40 specimens were also diagnosed as HGNEC at pathological central review among 7 pathologists. There were two specimens that showed the difference in between institutional diagnosis and central pathological diagnosis.

      Conclusion
      The combination of irinotecan and cisplatin as postoperative adjuvant chemotherapy was feasible and possibly efficacious for resected HGNEC.In Japan, a randomized phase III trial is ongoing to evaluate adjuvant chemotherapy of irinotecan and cisplatin, compared with etoposide and cisplatin, for completely resected HGNEC.

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 2
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      P2.18-019 - Clinicopathological features in non-small cell lung cancer patients with EGFR and KRAS mutations. (ID 2985)

      09:30 - 16:30  |  Author(s): F. Oshita

      • Abstract

      Background
      Some of molecular pathways have been shown to have prognostic impact in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations predict the effect of EGFR tyrosine kinase inhibitors. KRAS is also critical oncogene, and it has been reported that KRAS pathway might interact with EGFR. But, the role of KRAS in NSCLC is unclear. We investigated the relationship between EGFR and KRAS mutation status and clinicopathological features in NSCLC.

      Methods
      A total of 383 consecutive patients with NSCLC underwent complete resection from 2006 to 2008 were examined retrospectively. The expression of EGFR and KRAS were evaluated by tissue microarray.

      Results
      The mutations of EGFR and KRAS were detected in 181/383 (47.3%) and 32/383 (8.4%) patients, respectively. On analysis of EGFR mutations, female were 107/181 (59.1%) and 51/202 (25.2%), adenocarcinoma were 177/181 (97.8%) and 123/202 (60.9%), no vascular invasion were 147/181 (81.2%) and 110/202 (54.5%), and non-smoker were 99/181 (54.7%) and 41/202 (20.3%) patients in EGFR mutation and wild type patients, respectively. As a result, EGFR mutation was found more frequently in female, adenocarcinoma, no vascular invasion, and non-smoker. The number of patients with pathological T1a were 49/181 (27.0%) and 42/202 (20.8%), T1b were 63/181 (34.8%) and 41/202 (20.3%) in EGFR mutation and wild type patients, respectively. Moreover, average tumor diameter was smaller in patients with EGFR mutation (2.68 cm±0.92) than wild type (3.34cm±1.70) (P<0.001). There were no differences in clinicopathological characteristics between exon19 and 21 EGFR mutations. In contrast, there were no significant differences between KRAS mutation and gender, histopathological type, vascular invasion and.smoking. Although KRAS status was not correlated with pathological T factors, average tumor diameter was larger in patients with KRAS mutation (3.49 cm±2.00) than wild type (2.98 cm±1.35) (P<0.001).

      Conclusion
      Our results suggest that EGFR mutation may suppress vascular invasion, and tumor growth, on the other hand, KRAS mutation may correlate with activation of tumor growth.

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      P2.18-020 - Appropriateness Evaluation of Handling Method for the Small Lung Adenocarcinoma in the Frozen Section Diagnosis by Radiological-Pathological Correlation (ID 3007)

      09:30 - 16:30  |  Author(s): F. Oshita

      • Abstract

      Background
      The frozen section diagnosis is often performed in the sublobar resection of lung tumor. As no standard of preparation method for the frozen section is proposed, its methodology differs depending on institutions. In this study, we examine appropriateness of our preparation method for a resected specimen with a small adenocarcinoma by comparing between radiological and pathological tumor size.

      Methods
      We retrospectively reviewed the records of 59 resected lung specimens for the frozen section diagnoses (54 wedges and 5 segmentectomies) of lung adenocarcninomas from January to December 2008. After the specimen was well inflated with saline using injector, the pathologist cut it into segments with a width of 3-5mm and immersed them in saline. Taking the segment with maximum diameter of tumor as a sample, the pathological tumor sizes were measured (I) macroscopically by using metal straight ruler, (II) microscopically on the frozen section, and (III) microscopically on the permanent paraffin section. For obtaining the stereoscopic tumor size (Ⅱ and Ⅲ), we used a stereoscopic image analysis software, Leica Application Suite (Leica Microsystems; Tokyo, Japan). CT tumor size was measured by using 1-2mm thin-section CT (X-Vigor/Real or Aquillion, Toshiba Medical Systems, Tokyo, Japan). We obtained the tumor shadow disappearance rate (TDR) by comparing tumor size on the lung and mediastinal window image, to classify 59 cases into two groups according to TDR; TDR≧50% defined as the air-containing type (Group A, n=44) and TDR＜50% as the solid-containing type (Group S, n=15). We also calculated the diremption rate (DR%) between the pathological and the CT tumor size (DR% = |CT tumor size － each pathological tumor size|/CT tumor size×100(%)) and compared Group A and Group S.

      Results
      Mean CT tumor size and its standard deviation(SD) were 18.36±5.23mm, and mean pathological tumor sizes and SD of Ⅰ, Ⅱ, and Ⅲ were 17.17±6.12, 14.29±3.66, and 14.23±4.38mm, respectively. Mean CT tumor size was statistically larger than that of Ⅱ and Ⅲ (p<0.001 using Paired t-test). All the three pathological tumor sizes were correlated to the CT tumor size by Pearson’s correlation analysis (correlation coefficient were 0.766, 0.700, and 0.682, respectively). DR% of Ⅱ and Ⅲ were significantly higher in Group A than Group S by Mann-Whitney U-test (Mean DR% of group A / S (p-values) of Ⅰ, Ⅱ, and Ⅲ were 17.0/13.8% (p=0.196), 25.8/19.3% (p=0.093), and 27.3/15.5% (p=0.032) , respectively).

      Conclusion
      There was a strong correlation between CT tumor size and each pathological tumor size, which shows that our preparation method of the specimen for the frozen section is appropriate to obtain sufficient information about the lung tumor. Furthermore, we found that the pathological tumor size is considerably underestimated by measuring tumor size on the frozen or permanent paraffin section, especially the tumor classified as “air-containing type” including adenocarcinoma with good prognosis. It is therefore important to inflate the lung specimen sufficiently and to transfer it to microscopical examination without tissue shrinking.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-007 - Preliminary safety results of MONET-A: A Prospective, Asian Phase 3, Randomized, Placebo-controlled, Double-blind Trial of the Investigational agent Motesanib in Combination with Paclitaxel and Carboplatin for Asian patients of Advanced Non-squamous Non-small Cell Lung Cancer (ID 889)

      09:30 - 16:30  |  Author(s): F. Oshita

      • Abstract

      Background
      Inhibition of the vascular endothelial growth factor receptor (VEGFR) pathway appears to be an effective treatment strategy for frontline non-small cell lung cancer (NSCLC), but small molecule VEGFR kinase inhibitors have failed to show survival benefit. Motesanib is an orally administrated small molecule antagonist of VEGFR 1, 2, and 3, platelet-derived growth factor receptor (PDGFR), and stem cell factor receptor (c-kit). In a subgroup analysis of Asian patients (n = 227) from the global phase 3 study (MONET-1), treatment of motesanib in combination with paclitaxel and carboplatin demonstrated significant improvements in overall survival (HR, 0.65; 95% CI, 0.46-0.91), progression free survival (HR, 0.59; 95% CI, 0.44-0.79), and overall response rate compared to placebo. To prospectively evaluate efficacy and safety of motesanib in Asian patients with NSCLC, this phase 3 study has initiated.

      Methods
      Stage IV/recurrent non-squamous NSCLC patients without prior chemotherapy receive oral motesanib (125 mg) or placebo once daily in combination with paclitaxel (200 mg/m[2]) and carboplatin (AUC = 6) every 3 weeks up to 6 cycles and continue motesanib or placebo until disease progression, consent withdrawal, or unmanageable adverse event. ECOG performance status 0 or 1 are eligible for this study regardless of epidermal growth factor receptor (EGFR) mutation status. Patients with untreated or symptomatic central nervous system metastases are excluded. Approximately 400 patients will be randomized in a double-blind 1:1 ratio to motesanib or placebo. Stratification factors include EGFR mutation status, weight loss of ≥ 5% in the previous 6 months, and region. This MONET-A trial will be assessed twice by the Independent Data Monitoring Committee (IDMC), at the time 50 and 150 patients complete their first cycle for unblinded safety data.

      Results
      This study initiated in July 2012 and is being conducted in Japan, Korea, Taiwan, and Hong Kong. The enrollment is ongoing. First evaluation by IDMC was performed using the data as of 26 December 2012. A total of 64 patients were enrolled and 63 patients (63 Japanese; median age, 64.5 years) received study treatment. All the blinded patients who received study treatment experienced adverse events (AEs); Grade 3 to 5 AEs were reported in 38 patients (60.3%). Common AEs included alopecia (63.5%), peripheral sensory neuropathy (57.1%), and decreased appetite (50.8%). 7 patients had 8 serious AEs (SAEs). SAEs considered to be related to blinded study drug were cholecystitis in 2 patients, gastric ulcer haemorrhage, nausea, and upper gastrointestinal haemorrhage in 1 patient. A treatment-related fatal AE (interstitial lung disease) was reported in one patient (blinded). AEs leading to permanent discontinuation of unblindedunblinded study drug (motesanib or placeco) were cholecystitis (Grade 2), liver injury (Grade 3), purpura (Grade 2), rash (Grade 3), eye haemorrhage (Grade 2), upper gastrointestinal haemorrhage (Grade 3), and gamma-glutamyltransferase increased (Grade 4).

      Conclusion
      The first IDMC recommended continuation of the study after the review of unblinded data of 63 patients. Updated safety data will be presented after the second IDMC (JapicCTI-121887).

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    P3.19 - Poster Session 3 - Imaging (ID 181)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 2
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      P3.19-003 - The correlation between computed tomography findings and the clinicopathological factors in small-sized adenocarcinomas of the lung (10 mm or less in diameter) (ID 1220)

      09:30 - 16:30  |  Author(s): F. Oshita

      • Abstract

      Background
      We previously reported the correlation among the thin-section computed tomography (TS-CT) findings, the pathological factors (Noguchi’s classification) and the prognosis of the patients. The purpose of this study was to examine the tumor shadow disappearance rate (TDR) on TS-CT findings, clinical course and pathological factors of small-sized adenocarcinomas of the lung according to the 2011 IASLC/ERS Classification.

      Methods
      We retrospectively analyzed 111 peripheral non-mucinous adenocarcinomas of the lung ≤ 10 mm in diameter that were surgically resected at our institute between January 1997 and February 2013. CT scans were obtained by commercially available scanners (X-Vigor/Real or Aquilion M/16 CT scanner; Toshiba Medical Systems; Tokyo, Japan). TS images were obtained with a 1 mm section thickness, pitch of 1, section spacing of 1 mm, 512 × 512 pixel resolution and 1 second scanning time. TDR was defined as the ratio of the maximum diameter of the tumor opacity of the mediastinal window to that of the lung window on TS-CT. We also examined the relationship among the TDR, the patient backgrounds, pathological findings (i.e., lymph node metastasis, pleural invasion, vascular invasion and lymphatic invasion) and clinical course. The histologic subtypes were analyzed according to the 2011 IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma.

      Results
      The median age of the patients was 64 (range, 23-83) years, and 66 patients (59.5%) were female. Sixty-four patients (57.7%) were never-smokers. The average tumor size was 8.7 mm (range, 5-10 mm). Regarding the histological subtypes, 70 cases were adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA), 19 were acinar predominant (AP), 13 were papillary predominant (PP) and seven were solid predominant (SP). Two cases could not be determined. Seventy cases diagnosed AIS or MIA were all stage IA, and none of these patients relapsed. Six cases relapsed after surgery; three cases of AP, two of PP and one of a SP tumor. In a comparison of the clinical course, the pathological differentiation and the TS-CT findings, all six cases relapsed after surgery showed ≤ 40% in TDR. Four cases diagnosed with lymph node metastasis (i.e., cases diagnosed in stage IIA or higher) showed ≤ 22% in TDR. Twelve cases with pleural invasion or vascular invasion or lymphatic invasion in the pathological factors of the resected lesions showed ≤ 28% in TDR. The TDR of AIS and MIA cases were all ≥ 50%.

      Conclusion
      There are sometimes pathologically invasive lesions even in small-sized adenocarcinomas of the lung. We found that the TDR is related to the clinical course and pathological factors in small-sized adenocarcinomas of the lung (10 mm or less in diameter). The lesions with a TDR ≤ 40% in the TS-CT images may be a group of highly malignant with an increased risk of relapse. The TDR may contribute to the determination of the optimal therapeutic strategy. We need a more robust prospective study to validate the efficacy of TDR.

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      P3.19-010 - The Status of EGFR Mutations in Mixed Ground-Glass Opacity (part-solid GGO) on Thin-section CT (ID 1826)

      09:30 - 16:30  |  Author(s): F. Oshita

      • Abstract

      Background
      Thin-section CT (TS-CT) provides us with a more precise image of small pulmonary carcinomas. Thin-slice sections with thicknesses of 0.5 mm-1mm reflect, with some accuracy, the histopathological findings; mixed ground-glass opacity (part-solid GGO) is one characteristic finding of pulmonary adenocarciomas. These findings are vary in appearance, for example; some contain mainly GGO components, and some contain mainly solid portions. CT findings of mixed GGO, pathological findings and prognoses have been reported. Presently, we do not fully understand the correlation between TS-CT findings of mixed GGO and the status of EGFR mutation.

      Methods
      We retrospectively reviewed the records and TS-CT scans of 115 patients with mixed GGO tumors. All patients had undergone surgical resection between 2002 and 2008. Tumor diameters measured 20mm or less in size. All TS-CT images were acquired by Aquillion CT scanner (Toshiba Medical System). TS-CT images of tumors were obtained at 135kVp at 250mAs with 0.5-1mm section thickness. All images were photographed using mediastinal (level, 40HU; width, 400HU) and lung (level, -600HU); width, 1600HU) window settings. All TS-CT images on lung window setting were classified as: (1) Predominant GGO type (pGGO; solid portion areas less than 50% of tumor), (2) Heterogeneous type (heterogenous increased density), (3) Predominat solid type (pSolid; Solid portion areas took up more than 50% of tumor). We analyzed EGFR and Kras mutations, and then studied the correlations between these TS-CT findings and the status of EGFR mutations.

      Results
      The tumors in all 115 cases were well-differentiated adenocarcinomas. GwS type; 24 cases, Heteogenous type; 30 cases, and SwG type 61 cases. The EGFR mutation ratio was 66.6% in pGGO type, 90% in Heterogenous type and 52.7% in pSolid type. The ratio of EGFR mutation was greater in Heterogenous types compared to pGGO and pSolid types. (pGGO/Hetero p=0.045, pSolid/Hetero p=0.00038).

      Conclusion
      There is a correlation between the thin-section findings of mixed GGO and the status of EGFR mutations.