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Pier Luigi Filosso



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    MS 07 - Neuroendocrine Tumors other than SCLC: Pathology to Patient Management (ID 529)

    • Event: WCLC 2017
    • Type: Mini Symposium
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MS 07.05 - ESTS Registration for Neuroendocrine Tumors (ID 7673)

      15:45 - 17:30  |  Presenting Author(s): Pier Luigi Filosso

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Lung Neuroendocrine Tumors (NETs) are rare neoplasms derived from the neuroendocrine cells of the bronchopulmonary epithelium. They represent about 25% of all the neuroendocrine tumors, and no more than 2%-3% of all the primary tumors of the lung. Their incidence has recently increased by approximately 6% per year, probably due to the improved awareness as well as for the diffusion of lung cancer screening programs worldwide. NETs’ incidence now ranges from 0.2 to 2 per 100,000 individuals per year in the United States. Their rarity, along with the lack of randomized clinical trials, make lung NETs’ global management still questioned, especially in case of advanced diseases, and only few clinical recommendations currently exist. In 2012, during the Annual Meeting in Essen (Germany), the European Society for Thoracic Surgeons (ESTS) created a new Working Group (WG) specifically dedicated to the Lung NETs. The Steering Committees was composed by the following Thoracic Surgeons: Pier Luigi Filosso (Torino, Italy-Chair), Pascal Alexandre Thomas (Marseille, France), Mariano Garcia-Yuste (Valladolid, Spain), Eric Lim (London, UK), Federico Venuta (Rome, Italy), Alessandro Brunelli and Konstantinos Papagiannopoulos (Leeds, UK), Hisao Asamura (Tokyo, Japan). The aim of this WG was to create a group of physicians expert on Lung NETs in order to improve scientific knowledge on such rare neoplasms, and disseminate it among the scientific community. A specific database was rapidly designed, to retrospectively collect data of patients operated for lung NETs, and it was sent to all the ESTS Members who expressed their interest to this project. Moreover, a survey concerning lung NETs’clinical management was prepared and its results were recently published (Future Oncol. 2016;12:1985-1999). Up to now, 2040 operated NETs patients have been collected amongst 17 high-volume International Thoracic Surgery Institution worldwide. This retrospective database was used for several studies about lung NETs clinical behavior and outcome. In particular, the outcome and prognostic factors of two aggressive lung NETs: atypical carcinoids (ACs) and large-cell neuroendocrine carcinomas (LCNCs) were the object of the first publication (Eur.J.Cardiothorac Surg. 2015;48:55-64). For ACs, age (P<0.001), tumour size (P=.015) and sub-lobar resections (P=0.005) were independent negative prognostic factors; for LCNCs, only pTNM stage III tumors (P=0.016) negatively affected outcome in the multivariate analysis. Local recurrences and distant metastases were statistically more frequent in LCNCs (P=0.02), as expected. A prognostic model of survival for typical carcinoids (TCs) was the matter of the second publication (Eur.J.Cardiothorac Surg. 2015;48:441-447): an analysis of 1109 TC patients was performed. A prediction model for mortality, evaluating age, gender, previous malignancies, peripheral tumour location, TNM stage and ECOG PS was elaborated, and the final model showed a good discrimination ability with a C-statistic equal to 0.836 (bootstrap optimism-corrected 0.806). Moreover, this model has been recently validated by Cattoni and Coll. The treatment of biologically aggressive/advanced lung NETs was recently investigated in a paper published by the Journal of Thoracic Disease (J.Thorac. Dis. 2015;7:S163-S171). Surgery, whenever feasible, remains the mainstay of treatment, and chemo/radiotherapy should be reserved to progressive diseases. In case of resected N1-N2 carcinoids, a "watch and see" policy and a close clinical/radiological follow-up is also recommended. Surgery alone is not sufficient to treat high-grade NETs (e.g.: LCNC): adjuvant CT is suggested even in early stages. Platinum-Etoposide regimen demonstrated to be the most effective; Irinotecan and other biological drugs are also regarded to be very promising. The management of advanced lung NETs should be tailored by multidisciplinary teams including Medical and Radiation Oncologists, Surgeons, Pathologists, Pulmonologists, Endocrinologists, Interventional Radiologists; patients’ prognosis is mainly dependent on tumor grade and its anatomical extent. Large-cell neuroendocrine carcinoma (LCNC) is a rare tumor characterized by an aggressive biological behaviour and poor prognosis; its optimal treatment is still under debate. Some recent reports indicate that adjuvant chemotherapy (CT) may have a beneficial effect on survival. Data from 400 patients with resected LCNC were analyzed. The 3- and 5-year survival rates were 54.1% and 45%, respectively. With the multivariable model, increasing age, ECOG ≥2 and advanced TNM stage were indicators of poor prognosis. Weak evidence of a higher overall survival in patients receiving adjuvant CT (adjusted hazard ratio 0.73; 95% confidence interval: 0.56-0.96, P  = 0.022) was also observed (Eur.J.Cardio-Thorac.Surg. 2017;52:339-345). In Stage I TCs (SITCs) non-anatomical resections (wedge) are sometimes advocated because of their indolent behavior. An analysis on effect of surgical procedure on SITC patients’ survival was therefore done (Eur.J.Cardiothorac.Surg. 2017 submitted paper). Eight-hundred seventy-six SITC patients (569 females,65%) were included in this study; the 5-year OS rate was 94.3% (95%CI:92.2 –95.9). At univariable analysis, wedge resection resulted to be associated with a poor prognosis (5-year OS 82%,95%CI:0.71-0.89,P<.001) compared to other anatomical resections. At multivariable score-adjusted analysis, wedge resection confirmed to be an independent predictor of poor prognosis (HR2.17,95%CI: 1.19-3.96,P=.012). Since 2106, a lung NETs prospective database is active through the official ESTS European Database, and up to now, more than 150 new cases have been collected. Through this new platform, very easy to be used, we are confident to collect, in few years, more data especially on possible tumor recurrences and their treatment, as well as on the role of emerging biological drugs used in the adjuvant setting in advanced diseases. An active participation of Medical/Radiation Oncologists to this scientific project would be also desirable. The active role of the most important Scientific Societies could strongly support the success of this scientific project.

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    MTE 17 - Neuroendocrine Tumor (Sign Up Required) (ID 566)

    • Event: WCLC 2017
    • Type: Meet the Expert
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
    • Moderators:
    • Coordinates: 10/17/2017, 07:00 - 08:00, Room 418
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      MTE 17.02 - Surgical Strategy for the Treatment of Neuroendocrine Tumors (ID 7799)

      07:00 - 08:00  |  Author(s): Pier Luigi Filosso

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Neuroendocrine tumors (NETs) are a distinct subgroup of neoplasms arising from the neuroendocrine cells. Due to the peculiar morphological, immunohistochemical and molecular characteristics, NETs are usually classified as a separate group of tumors among solid malignancies. Thoracic NETs include the pulmonary and the thymic NET. Pulmonary NETs (PNETs) comprise well-differentiated neuroendocrine tumors (typical carcinoid), moderately-differentiated neuroendocrine tumors (atypical carcinoid), the latter two grouped as Bronchial Carcinoids (BCs); large cell neuroendocrine carcinoma (LCNEC) and small-cell lung carcinoma (SCLC). There are also two preneoplastic conditions, the Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) and the tumorlets whose role in the neuroendocrine carcinogenesis are yet to be fully clarified. PNETs represent about 25% of all lung cancers, most of them represented by SCLC. Thymic NETs (NeuroEndocrine Thymic Tumors, NETT) are considered as a subgroup of thymic carcinoma, although in most series they are classified separately, and are further classified as well-differentiated NETT (typical carcinoid), moderately-differentiated NETT (atypical carcinoid) and poorly-differentiated NETT (Large cell and small cell neuroendocrine carcinoma). NETTs are exceedingly rare and represent about 5% of all thymic tumors. The present lecture will focus on PNETs and NETTs, with a particular insight in the surgical management of these tumors. 1, Pulmonary NETs. The most recent TNM staging classifications of lung cancer (7[th] and 8[th] edition) suggest that PNETs should be staged similarly to Non-Small Cell Lung Cancer (NSCLC). Surgical indications largely depend on histology and stage. Bronchial carcinoids (BCs) represent about 10% of PNETs. The vast majority are typical carcinoids (TC, well-differentiated neuroendocrine tumors); they are usually located centrally in the lung parenchyma/airways (70%), and they are frequently confined to the lung without evidence of loco-regional or distant spread, which occur in about 5-10% of the cases. Atypical carcinoids (AT) share most of the characteristics of typical carcinoids, although they present a higher rate of mytoses and necrosis. They are more aggressive than TCs and they present with lymphnodal metastatic involvement in 30%-50% of the cases. LCNEC are usually diagnosed after resection, since a preoperative characterization on small biopsies is challenging. They are aggressive tumors, and more than 50% of the patients present with an advanced disease at diagnosis, for whom surgery is not indicated. As for SCLC, the vast majority of the patients present at an advanced stage, with hematogenous spread. The role of surgery in the treatment of PNETs is similar to what is currently employed for NSCLC. BCs are often amenable to surgery, due to the early stage at presentation. Anatomical resections (segmentectomy, lobectomy or more extended resections) offer the best outcome, while sublobar wedge resection should be avoided in fit patients, and should be reserved only for patients not amenable to anatomical resections. Parenchymal-sparing techniques (bronchial/vascular sleeve resection) should be employed whenever possible to avoid pneumonectomy in centrally-located tumors. Lymphadenectomy should be carried out according to the current guidelines (IASLC/ESTS), including a minimum of 6 nodes/stations of which 3 mediastinal including the subcarinal one. Endoscopic resection may have a role only in case of lobar/lung atelectasis to restore the bronchial patency before definite surgical resection Endobronchial resection is also employed with palliative intent in unresectable disease. Survival after resection of BCs is excellent, with more than 90% of the patients with typical carcinoids alive at 10 years, and 70% and 50% with atypical carcinoids alive at 5 and 10 years. The role of adjuvant therapy after complete resection of BCs is not fully determined and it is often discussed on an individual basis in a multidisciplinary tumour board setting. LCNEC are poor candidates for surgery, because of the loco-regional and distant spread at presentation. Anatomical resections, including extended resection to neighboring organs are needed in order to achieve a complete resection. Despite this, local recurrence and distant metastases are frequent after surgery. Adjuvant therapy (chemotherapy or chemoradiotherapy) is almost always needed after surgery for the disease control. SCLC has customarily been considered nonsurgical because of the high aggressiveness and the chemosensitivity of this neoplasm. However, in carefully selected patients with limited disease (T1-T2N0) surgery as part of a multidisciplinary protocol (chemoradiotherapy) may be proposed after a careful assessment of loco-regional (including mediastinal) and distant spread. 2, Thymic NETs. Thymic NETs (NETTs) are usually aggressive thymic tumors, very often presenting atypical features (atypical carcinoid). They express somatostatin receptors which may justify the use of Octreotide scintigraphy for the diagnosis and follow-up. About 30-40% have metastases at presentation and in some cases they are associated with endocrinopaties (Cushing syndrome, MEN-1 syndrome, etc). The staging system for NETTs has traditionally been the Masaoka system. The 7[th] edition of the TNM of thymic tumors included also the NETTs. As for other thymic malignancies, surgery is the treatment of choice for local and loco-regional disease (Stage I/II and selected Stage III). The resectability rate for NETTs is far lower than that of thymoma, ranging between 30% and 100% in most series. Complete (R0) resection is the most important prognostic factor. Median sternotomy and open surgical approaches are the optimal accesses for NETTs. The role of minimally-invasive techniques (MIT) in the treatment of NETT is extremely limited, due to the aggressive nature of the tumor. The role of induction and adjuvant treatments (radiotherapy or chemotherapy) has not been established yet, due to the rarity of the condition. 3, The collaborative effort. As for many rare diseases, also for NETs a collaborative, multi-Institutional, society-based effort is the single most important factor that can provide a real advancement in the research and management of this condition. The European Society of Thoracic Surgeons (ESTS) launched in 2012 a Neuroendocrine Tumors Working Group with the aim of collecting data from interested Institutions across the world. An amazing database collating more than 2100 patients has been designed which represents a tremendous opportunity for the study of these rare conditions. A number of studies have been published so far which constitute a solid backbone for the management of NETs.

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    OA 16 - Treatment Strategies and Follow Up (ID 686)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Early Stage NSCLC
    • Presentations: 1
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      OA 16.02 - Risk of Recurrence in Stage I Adenocarcinoma of the Lung: A Multi-Institutional Study on Interaction with Type of Surgery and Type of Nodal Staging (ID 9304)

      14:30 - 16:15  |  Author(s): Pier Luigi Filosso

      • Abstract
      • Presentation
      • Slides

      Background:
      In last years, an increasing interest emerges on the role of sub-lobar resection and lobe-specific lymphnode dissection in the treatment of early stage lung cancer. The aim of our study was to define impact on Cumulative incidence of recurrence (CIR) of type of surgical resection and type of nodal staging. Furthermore, we evaluated the effect of interactions between the different kinds of procedure.

      Method:
      An analysis of 969 consecutive stage I pulmonary adenocarcinoma patients, operated in six Thoracic Surgery Institutions between 2001 and 2013, was conducted. Type of surgical resection included lobectomy and sub-lobar resection; pneumonectomy and bilobectomy were excluded from the analysis. Nodal staging procedures were classified in nodal sampling (NS), lobe-specific lymph node dissection (LS-ND) and systematic lymph node dissection (SND). Multivariable-adjusted comparisons for CIR was performed using Fine and Grey model, taking into account death by any cause as competing event. Test of interaction between type of surgical resection and type of nodal staging was carried out and results presented in a stratified way. Missing data were multiple-imputed, combined estimates were obtained from 5 imputed datasets.

      Result:

      Multivariable-adjusted Fine and Grey model for Comulative Incidence of Recurrence (take into account age, gender, smoking habit, side of intervention, pTNM stage, vascular invasion, pTNM stage, predominant histologic pattern and histologic grade)(Results of test of interaction presented in a stratified way)
      Sub-lobar resection vs. Lobectomy HR (95%CI) P INTERACTION P-value
      Overall 1.52 (1.07 to 2.17) 0.02 0.268
      SND 1.98 (1.14 to 3.42)
      LS-ND 1.87 (0.94 to 3.74)
      NS 1.08 (0.61 to 1.93)
      LS-ND vs SND HR (95%CI) P INTERACTION P-value
      Overall 1.74 (1.16 to 2.6) 0.007 0.903
      Lobectomy 1.66 (1.03 to 2.69)
      Sub-lobar resection 1.58 (0.75 to 3.32)
      NS vs. SND HR (95%CI) P INTERACTION P-value
      Overall 1.49 (1.12 to 1.98) 0.007 0.131
      Lobectomy 1.61 (1.18 to 2.19)
      Sub-lobar resection 0.88 (0.43 to 1.82)
      Median follow-up was 63 months. Eight-hundred forty-six (87%) patients were submitted to lobectomy, while 123(13%) to sub-lobar resection. Four-hundred fifty-five (47%) patients received SND, 98(10%) LS-ND and 416(43%) NS. Two-hundred forty-seven (26%) patients developed a local/distant recurrence with a 5-year CIR of 24%. Multivariable-adjusted comparisons showed an independent negative effect of sub-lobar resection(HR 1.52;95%CI:1.07-2.17), LS-ND(HR 1.74;95%CI:1.16-2.6) and NS(HR 1.49;95%CI:1.12-1.98) on CIR(Table). Test of interaction showed an homogeneity of results among subgroups.

      Conclusion:
      In our series, lobectomy and systematic lymph node dissection confirmed to be the optimal strategy to achieve a favorable prognosis in stage I adenocarcinoma of the lung. The real value of sub-lobar resection and less aggressive nodal staging should be assessed by randomized clinical trial before being integrated in clinical practice.

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