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K. Shibuya



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    MS05 - Modern Management of Neuroendocrine Tumours (ID 22)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Surgery
    • Presentations: 1
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      MS05.1 - Bronchopulmonary Carcinoids (ID 476)

      14:05 - 14:25  |  Author(s): K. Shibuya

      • Abstract
      • Presentation
      • Slides

      Abstract
      In the 1970s, pulmonary neuroendocrine tumors were classified into three histologically defined categories: typical carcinoid (TC), atypical carcinoid (AC) and small cell lung carcinoma (SCLC) [1)] . Later, a fourth high-grade neuroendocrine tumor of the lung, large cell neuroendocrine carcinoma (LCNEC) was recognized [2)] , and in 1999, the World Health Organization (WHO) classified LCNEC as a variant of large cell carcinoma [3)] . To date, in neuroendocrine tumors of the lung, the major categories of morphologically identifiable neuroendocrine tumors are TC, AC, LCNEC, and SCLC. Lung tumors with neuroendocrine morphology by light microscopy encompass a three-grade spectrum of low grade TC, intermediate-grade AC, and high-grade LCNEC and SCLC. WHO criteria show that the mitotic range for TC was less than two mitoses per 2 mm[2] (10 high-power field [10 HPF]), and that for AC was between two and ten mitoses per 10 HPF. A mitotic count of eleven or more mitoses per 10 HPF is the main criterion for distinguishing LCNEC and SCLC from AC. A criterion for distinguishing AC from TC is necrosis. Therefore, we classify TC as a tumor with carcinoid morphology, lacking necrosis with less than two mitoses per 2 mm[2]. Tumors with carcinoid morphology, areas of necrosis and/or 2-10 mitoses per 2 mm[2 ]are classified as AC [4)] . Immunohistochemically, neuroendocrine markers such as chromogranin, synaptophysin, and N-CAM are typically positive in TC [4)] . Analyses of molecular markers revealed that low-grade TC and intermediate-grade AC exhibit a low proliferative rate compared with high-grade LCNEC and SCLC [5)] , and TC and AC have different genetic alterations from high-grade LCNEC and SCLC [6)] . Analyses of their genetic alterations show that neuroendocrine lung tumors may represent a spectrum ranging from low-grade TC and intermediate-grade AC to highly malignant LCNEC and SCLC tumors [6)] . Carcinoid tumors can be diagnosed by cytology of bronchoscopic fine needle aspiration or bronchoscopic biopsy specimens. Distinguishing TC from AC requires examination of a surgical specimen, unless mitoses between two and ten per 10 HPF and/or necrosis are seen on a bronchoscopic biopsy [4)] . Preoperative FDG-PET imaging is frequently positive in carcinoid tumors [7)] . TC and AC occur equally in males and females, and patients with TC and AC are younger than those with LCNEC and SCLC. TC is classified as a malignant epithelial tumor of the lung [3,4)] . However, the overall survival rate is better for TC than for AC [4,8)] , and the frequency of lymph node metastases in TC is lower than in high-grade LCNEC and SCLC [8)] . Therefore, some investigators have advocated limited resection in patients with carcinoid [9, 10)] . Some reports revealed that sublobar resection was noninferior to lobectomy for survival in patients with carcinoid tumor [10)] . However, other reports advised that radical oncologic surgery with radical node dissection was needed, and segmental and other limited procedures had to be avoided because of the high frequency of lymph node involvement and multicentric forms[11,12)] . A randomized controlled trial is the best method to compare surgical efficacies. However, it may be impractical due to the rarity of carcinoid tumors. Moreover, AC has a poorer prognosis and a higher frequency of lymph node metastases than TC, and preoperative diagnoses and/or diagnoses of intraoperative frozen sections are often difficult for differentiating AC from TC because small amounts of necrosis or few mitoses are sometimes unclear in those specimens. Therefore, sublobar resection for TC might be the optimal surgical method because of lung preservation and lower mortality than lobectomy; however, limited resection for TC remains an area of controversy. References 1) Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg 1972;64:413-21 2) Travis WD, Linnoila RI, Tsokos MG, et al. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. Am J Surg Pathol 1991;15:529-53 3) Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, editors. Histological Typing of Lung and Pleural Tumours. World Health Organization International Histological Classification of Tumors, XIII, 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999 4) Travis W.D, Brambilla E, Müller-Hermelink H.K, Harris C.C (Eds.): World Health Organization Classification of Tumours. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. IARC Press:Lyon 2004 5) Rusch VW, Klimstra DS, Venkatraman ES. Molecular markers help characterize neuroendocrine lung tumors. Ann Thorac Surg 1996;62:798-810 6) Onuki N, Wistuba II, Travis WD, et al. Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer 1999;85:600-7 7) Moore W, Freiberg E, Bishawi M, Halbreiner MS, Matthews R, Baram D, Bilfinger TV. FDG-PET Imaging in Patients With Pulmonary Carcinoid Tumor. Clin Nucl Med. 2013;38:501-5 8) Iyoda A, Hiroshima K, Baba M, Saitoh Y, Ohwada H, Fujisawa T. Pulmonary large cell carcinomas with neuroendocrine features are high-grade neuroendocrine tumors. Ann Thorac Surg. 2002 ;73:1049-54 9) Afoke J, Tan C, Hunt I, Zakkar M. Is sublobar resection equivalent to lobectomy for surgical management of peripheral carcinoid? Interact Cardiovasc Thorac Surg. 2013;16:858-63 10) Fox M, Van Berkel V, Bousamra M II, Sloan S, Martin RC II. Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. Am J Surg. 2013;205:200-8 11) Daddi N, Ferolla P, Urbani M, Semeraro A, Avenia N, Ribacchi R, Puma F, Daddi G. Surgical treatment of neuroendocrine tumors of the lung. Eur J Cardiothorac Surg. 2004;26:813-7 12) Chen F, Sato T, Fujinaga T, Sakai H, Miyahara R, Bando T, Date H. Surgical management of bronchopulmonary typical carcinoid tumors: an institutional experience. Interact Cardiovasc Thorac Surg. 2010;11:737-9

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-052 - A Feasibility Study of Vinorelbine and Bevacizumab in Patients with Previously Treated Advanced Non-Squamous Non-Small Cell Lung Cancer (ID 2152)

      09:30 - 09:30  |  Author(s): K. Shibuya

      • Abstract

      Background
      In recent clinical trials for non-squamous non-small cell lung cancer (NonSq-NSCLC), platinum regimens with bevacizumab (BEV) resulted in better prognosis and acceptable toxicity profile. However, there have been few studies on their feasibility or efficacy of BEV in NonSq-NSCLC patients who were previously treated with a platinum regimen. Therefore, we conducted a prospective study of combination therapy with vinorelbine (VNR) and BEV in NonSq-NSCLC patients who were previously treated with a platinum regimen.

      Methods
      Eligible patients had recurrent NonSq-NSCLC, PS 0-1, and adequate organ functions. The primary endpoint was feasibility. Secondary endpoints were response rate and safety. Patients received combination therapy with VNR (25mg/kg on day 1, 8) and BEV (15mg/kg, day 1). The treatment cycles were repeated every 3 weeks until progressive disease (PD)

      Results
      From June 2011 to January 2013, 15 NSCLC patients were eligible for this study. The patients consisted of 7 men and 8 women, and their median age was 68 (range 57-82) years. The patients received the treatment with a median of 4 (range 1-12) cycles. The histological classification was adenocarcinoma in all. The PS (ECOG) was 0 in 2, 1 in 11, and 2 in 2, respectively. The incidence of grade 3-4 neutropenia, anemia, thrombocytopenia and febrile neutropenia was 26.7%, 6.7%, 6.7%, and 13.3%, respectively. Response rate and disease control rate in the overall study population (n=15) were 26.7% and 73.3%, respectively. Median PFS was 2.8 months. Grade 3-4 phlebitis occurred in 3 patients; phlebitis improved by central venous catheter in 1, and by administration with corticosteroid in other two patients.

      Conclusion
      Combination therapy with VNR and BEV was safe and effective in NonSq-NSCLC patients who were previously treated with a platinum regimen. However, a few patients had a risk of developing phlebitis.