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F. Rea

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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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      MS05.3 - Mediastinal Neuroendocrine Tumours (ID 478)

      14:00 - 15:30  |  Author(s): F. Rea

      • Abstract
      • Presentation
      • Slides

      INTRODUCTION Mediastinal Neuroendocrine Tumors occur most frequently in the thymus. Primary Thymic Neuroendocrine Tumors (NETs) are rare and highly aggressive neoplasms; a little more than 350 cases have been described in the literature, many of which are single case reports. We collected one of the largest series ever reported through a multicenter International study, with the aim to evaluate factors influencing survival and recurrence development in patients with Thymic NETs. MATERIAL AND METHODS A multicenter retrospective study of patients operated for NETs between 1989 and 2012 in 9 high-volume International Thoracic Surgery Institutions, was conducted. According to the International Thymic Malignancy Interest Group (ITMIG) outcome measures, primary and secondary outcome were Cause Specific Survival (CSS) and Disease Free Survival (DFS). Competing-risks regression models (Fine and Gray method), taking into account death by any causes as competing event, were used to identify the association between individual factors and tumor related death. Cox proportional hazards regression models were used to define association between individual factors and DFS, considering R0 cases only. Univariate and multivariate analyses were also performed. RESULTS There were 52 patients (41 males –79%-, median age 49 years). The tumor was asymptomatic in 22 cases (42%). Endocrine paraneoplastic syndromes were observed in 23 cases (44%): 13 Cushing’s syndrome and 10 MEN-1 syndrome. Well differentiated neuroendocrine carcinoma (Typical and Atypical Carcinoid) was the commonest histological subtype (30 cases –58%-). Eight patients (15%) received induction therapy (3 chemotherapy, 2 chemo+radiotherapy, 2 biological therapy and 1 chemo+radio+biological therapy), because of their radiological invasiveness. Median sternotomy was the commonest surgical approach (29 cases). The median tumor size was 8 cm (range 1 – 31 cm); a complete resection (R0) was achieved in 48 cases (92%). Advanced Masaoka-Koga stage (III-IV) was observed in 35 patients (67%). Postoperative treatment was offered to 26 (50%): radiotherapy in 17, chemotherapy in 1, chemo+radiotherapy in 5 and chemo+radio+biological therapy in 3 patient, respectively. Three, 5 and 10-year survival rates were 89%, 76% and 51% (Figure 1). Recurrences were observed in 32 cases (62%): 11 local, 10 intrathoracic and 11 distant. Cumulative incidence of recurrence was 41% at 2 years and 70% at 3 years (Figure 2). Variables influencing survival were: tumor size (p< 0.00) and recurrences (p=0.01). Independents DFS predictors were: age > 50 (p= 0.02), paraneoplastic syndromes (p=0.02), symptoms at presentation (p= 0.01) and poor differentiated histology (p= 0.04). CONCLUSIONS We have confirmed that Thymic NETs are rare mediastinal tumors presenting with an aggressive biological behavior; surgery remains the mainstay of treatment and it should be proposed whenever possible, even in case of advanced diseases. Recurrences are frequent, especially in the first years after operation. Survival is statistically related to the tumor size and to the presence of recurrences, whereas, surprisingly, it is not influenced by induction/adjuvant treatment. A global International effort is needed to collect larger series and to confirm these conclusions. Figure 1: Thymic NETs overall survival curveFigure 1Figure 2: Thymic NETs: cumulative incidence of tumor recurrencesFigure 2

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-001 - Recombinant human Apo2L/TRAIL (Dulanermin) in combination with carboplatin/pemetrexed in Malignant Pleural Mesothelioma (MPM): anticancer effects in vitro and in vivo. (ID 136)

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

      • Abstract

      Malignant pleural mesothelioma (MPM) is an aggressive tumour linked to chronic inhalation of asbestos fibers, with poor prognosis and increasing incidence in industrialized countries. Currently available chemotherapeutic regimens achieve a median progression free and overall survival of 6 and 12 months respectively. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family, which induces cancer cell death through extrinsic apoptotic pathway, while sparing normal cells. The aim of this study was to investigate the antitumor activity of recombinant human Apo2L/TRAIL (Dulanermin, Amgen;Genentech) in combination with antifolate-based chemotherapy in MPM cell lines and in vivo preclinical mouse model.

      In vitro apoptosis assay was performed using Annexin-V-Fluos staining kit (Roche) according to the manufacturer’s instructions. Epithelioid (ZL55) and sarcomatoid (ZL34) cell lines were treated with carboplatin plus pemetrexed (CP), dulanermin (D) or CPD and then Annexin V positive cells were detected by flow cytometry using a FACSCalibur apparatus and CellQuest software (BD Biosciences). p53 protein expression level was detected by western blot analysis using a specific antibody. TRAIL death receptors (DR4 and DR5) and decoy receptors (DcR1 and DcR2) expression levels were assessed by flow cytometric analysis. In vivo experiments were performed in 30 SCID male mice, implanted subcutaneously in the right flank with 2x10[6 ]ZL55 cells suspended in 0.1 ml volume of RPMI, aged 6 weeks. When tumor volume reached 50-150 mm[3], the mice were randomized in 4 treatment groups: 1) not treated (NT); 2) C (75 mg/Kg day 1) plus P(100 mg/Kg day 1); 3) D (60 mg/Kg days 1 to 3); 4) CPD. Tumor volumes were recorded every second day, and mice suppressed at the 21[th] day or when tumor volume reached 500 mm[3].

      We observed a significant increase of specific cell death in epithelioid and sarcomatoid cell lines treated with CPD compared to those receiving CP or D as single agent (p<0.001). We then observed p53 activation in both cell lines after chemotherapy, and a subsequent significant increase of DR4/5 expression levels (p<0.005) without upregulation of decoy receptors. We finally assessed antitumor activity of CP and/or D in a ZL55 mouse model. We observed a statistically significant reduction of tumor volume at every time point in the three treatment groups compared to not treated; moreover, tumor volume was significantly reduced in mice treated with CPD (mean volume 58 mm[3]) compared to CP (mean volume 175 mm[3]) or D (mean volume 109 mm[3]) as single agent at the 21th day (p= 0.005). Finally, no difference in tumor growth was observed between mice treated with D compared to CP.

      CP sensitizes MPM cell lines to TRAIL-dependent apoptosis in vitro, probably through p53 activation and subsequent upregulation of death receptors. CPD significantly reduces tumor volume in epithelioid mesothelioma mouse model compared to chemotherapy alone or dulanermin as a single agent; furthermore antitumor activity of dulanermin was comparable to that reported with chemotherapy. In vivo experiments in a sarcomatoid mouse model are currently ongoing.