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M.A. Paul



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    E13 - High Risk Patients and Low Risk Surgeons (ID 13)

    • Event: WCLC 2013
    • Type: Educational Session
    • Track: Surgery
    • Presentations: 1
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      E13.1 - Salvage Surgery After Radiation: Residual Tumour and Complications (ID 432)

      14:05 - 14:25  |  Author(s): M.A. Paul

      • Abstract
      • Presentation
      • Slides

      Abstract
      Salvage surgery after Radiation: Residual Tumor and Complications Definitive chemoradiotherapy is increasingly used in the treatment of patients with stage III non-small-cell lung cancer. Historically, local control and overall survival rates have been poor. To improve local control higher doses of radiotherapy are being investigated, with or without new chemotherapeutic agents. Dose-escalation appears to provide a modest benefit in terms of preventing local failure and improving overall survival, but the benefit comes at a price: The risk of both early and late toxicity appears to increase as well. Despite improved treatment remnants of vital tumor often persist. In many patients this has no clinical significance because prognosis is determined by the occurrence of distant metastases. However, some tumors do not metastasize and local recurrence becomes a problem. These patients are then referred for possible surgical resection. Because of this possibility of isolated local recurrence, doctors Increasingly perform early re-staging procedures after definitive chemoradiotherapy. In case of persistent tumor patients are referred for resection as “late-induction cases”. Another category consists of patients presenting with complications caused by high-dose irradiation. These late sequalae of radiotherapy are: bronchial stenosis, fatal haemoptysis, esophageal stenosis, fistula’s, cardiac complications and the occurrence of 2nd primary tumors. They may occur as early as 3 months, but an interval of one or more years is not uncommon (1) Some of these complications, such as fistula’s or bronchial stenosis , require urgent surgical correction, due to their severe symptoms. Late surgical resection in irradiated patients has been described with good success (2). However, the impaired wound healing capacity of irradiated tissue makes surgery hazardous and the liberal use of non-irradiated tissue flaps is recommended. We describe our experience of surgical correction of late complications after concurrent chemoradiotherapy: Fistulae: A tracheo-esophageal fistula or broncho-esophageal fistula is best treated by esophageal resection and tube-stomach replacement, because the esophagus is often stenotic and mere interposition of a muscle flap between airway and esophagus will not suffice. Stenosis: Bronchial stenosis requires resection, but re-anastomosis carries a high risk of dehiscence. We have seen two cases of dehiscence after 6 and 8 weeks, after the sutures had been absorbed, in spite of wrapping the suture line with an intercostal muscle flap. Tracheomalacia requiring temporary stenting has also occurred following partial tracheal resection. Hemoptysis: Necrosis and cavitation of an irradiated area may be complicated by a fungal infection (aspergillus), causing haemoptysis. These patients, who are often weak and malnourished, are treated by a staged procedure: First thoracic wall fenestration for adequate drainage of the infectied area together with insertion of a gastrostomy or jejunostomy catheter for nutritional support. We try to avoid nasogastric tubes in these patients, to avoid aspiration. At a second stage the cavity is filled with a pedicled muscle flap. Depending on the size and location of the cavity, a partial thoracoplasty is also performed. The interval between the two operations should be limited if the cavity extends towards the hilum, because erosion of a vessel wall may cause fatal hemorrhage. New treatments for lung cancer create new situations for the thoracic surgeon. Good skill, knowledge of old techniques such as thoracoplasty and the use of muscle flaps, and emphasis on nutritional support are mandatory to solve these problems.

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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)

      14:45 - 15:05  |  Author(s): M.A. Paul

      • Abstract
      • Presentation
      • Slides

      Abstract
      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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    P1.17 - Poster Session 1 - Bronchoscopy, Endoscopy (ID 182)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      P1.17-007 - A proposal for a new clinical strategy and follow-up in patients with bronchial carcinoids initially treated bronchoscopically. (ID 2468)

      09:30 - 09:30  |  Author(s): M.A. Paul

      • Abstract

      Background
      Bronchial carcinoids (BC) belong to the wide spectrum of neuroendocrine tumors; ranging from tumorlets, typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), to highly malignant large cell neuroendocrine and small cell carcinoma. The Travis classification (Am J SurgPathol 1998; 22:934) seems essential for choosing the best treatment strategy based on retrospective analyses of surgically resected specimens. We implemented an initial bronchoscopic treatment (IBT) strategy and its long term outcome have been reported with update of the final analysis (J Thorac Cardiovasc Surg. 2007 Apr;133(4):973; Abstract IASLC Sydney submitted). The long-term outcome seems to justify IBT and the histological differentiation between typical versus atypical seems to matter much less, while conservation of normal lung parenchyma is optimal. We question how optimal the close surveillance strategy of IBT protocol should be, i.e. in performing regular high resolution CT (HRCT) and/or bronchoscopy after the initial success of bronchoscopic treatment.

      Methods
      In the IBT protocol, HRCT and bronchoscopy were performed 6-monthly in the first two years and annually until the fifth year. Thereafter a yearly check-up was advised to the referring pulmonologists. We analyzed retrospectively the value of HRCT and/or bronchoscopy in this IBT cohort for early detection of local recurrences, that require surgical salvage.

      Results
      So far, IBT was successful in 57 of the 133 patients (43%). Sixty-seven patients (50%) could be immediately identified to be surgical candidates without further delay due to obvious extraluminal tumor growth. Four patients (3%) developed extraluminal tumor recurrence and surgical salvage was performed at 47, 104, 115, 192 months. In all four cases follow-up HRCT suggested local extraluminal tumor growth, which were confirmed by bronchoscopy. The surgical outcome was radical and did not lead to more extensive resections than initially anticipated. Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

      BT Completion Surgery Remark
      Number of patients 62 71
      Histology TC AC 56 (90%) 6 (10%) 43 (61%) 28 (39%)
      Follow up (median) in months 87.5 (2-223) 87 (12-264)
      Completely resected 57 (92%) 64 (90%)
      Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery 3 4 0 0 Interval in months: 10,13,63 47,104,115,192
      Alive with disease 5 0 2 unfit for surgery 3 refused surgery
      Alive with metastatic disease 0 1 40 months
      Carcinoid related mortalities 0 2 Pulmonary metastases
      Treatment related mortalities 0 1
      Non-carcinoid related mortalities 8 3

      Conclusion
      Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable. Local regrowth after successful bronchoscopic removal was infrequent (3%) and was timely detected by HRCT. HRCT can be performed much less frequent and regular bronchoscopy was redundant if IBT attempt was successful. The significance of an iceberg phenomenon is questionable.

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    P2.17 - Poster Session 2 - Bronchoscopy, Endoscopy (ID 183)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      P2.17-006 - Long term outcome of initial bronchoscopic treatment strategy in patients with bronchial carcinoids (ID 2447)

      09:30 - 09:30  |  Author(s): M.A. Paul

      • Abstract

      Background
      Bronchial carcinoids are considered low-grade malignancies and, traditionally, are treated surgically. Tumor biology and advances in diagnostic and therapeutic techniques, however, enable a less invasive approach such as surgical bronchoplasty can preserve normal lung parenchyma. We previously reported favourable outcome for initial bronchoscopic treatment (BT) strategy in patients with intraluminally located bronchial carcinoids. We now present our long term results.

      Methods
      In patients presenting with a bronchial carcinoid, an initial diagnostic therapeutic bronchoscopy is attempted for complete tumor eradication for sampling sufficient tissue for the proper differentiation between typical (TC) and atypical (AC) histologic type apart from to optimally improve pre-surgical condition. A high resolution computed tomography is performed six weeks later, to determine intra- versus extraluminal tumor growth. In case of intraluminal growth of TC bronchoscopic removal attempt can be repeated. We perform surgical resection in case of extraluminal disease, or failure to bronchoscopic radical resection (i.e. recurrence or persistent residual tumor). Complete bronchoscopic resection of AC histological type is currently not followed by surgical resection.

      Results
      So far, 133 patients have been treated; 76 females, 67 males, median age 46 (range 16 – 85 years). Median follow up was 87 (range 2 – 264) months. Ninety-nine patients (84%) had TC, and 34 (26%) had AC. Bronchoscopic eradication was successful in 57 (43%) patients (51 TC, 6 AC). Detailed treatment results are shown in table 1. Table 1. Initial bronchoscopic treatment strategy in patients with bronchial carcinoids

      BT Completion Surgery Remark
      Number of patients 62 71
      Histology TC AC 56 (90%) 6 (10%) 43 (61%) 28 (39%)
      Follow up (median) in months 87.5 (2-223) 87 (12-264)
      Completely resected 57 (92%) 64 (90%)
      Residual after CT/recurrences Additional treatment bronchoscopy Additional treatment surgery 3 4 0 0 Interval in months: 10,13,63 47,104,115,192
      Alive with disease 5 0 2 unfit for surgery 3 refused surgery
      Alive with metastatic disease 0 1 40 months
      Carcinoid related mortalities 0 2 Pulmonary metastases
      Treatment related mortalities 0 1
      Non-carcinoid related mortalities 8 3

      Conclusion
      Initial bronchoscopic treatment strategy in patients with bronchial carcinoids is justifiable with excellent long term outcome. It should be implemented in the standard algorithm for patients with bronchial carcinoids.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-024 - Retrospective analysis of rebiopsies in a cohort of EGFR-mutated NSCLC-patients with TKI-resistance; incidence of the T790M mutation. (ID 2162)

      09:30 - 09:30  |  Author(s): M.A. Paul

      • Abstract

      Background
      Epidermal Growth Factor Receptor mutated (EGFR+) NSCLC patients have a median progression free survival (PFS) of approximately 12 months when treated with EGFR-tyrosine kinase inhibitors (TKI). One of the resistance mechanisms described is the T790M mutation. This mutation is reported in 49-65% of patients who are rebiopsied at disease progression. Here, we report on the incidence of T790M mutation in a cohort of patients who were sequentially rebiopsied.

      Methods
      EGFR+ patients or with TKI-response>24weeks and progressive disease on TKI’s were retrospectively analysed. Patients should have had at least 2 separate biopsies. All biopsies and treatments were collected from the medical record and pathological reports. Survival was calculated according to Kaplan-Meier. Overall survival (OS) was calculated from date of 1[st] diagnosis until death or June 2013, which ever was first

      Results
      68 patients with 2 biopsies or more were available for analysis. In the first biopsy at TKI-resistance; T790M mutation was detected in 34 patients (50,0%). 26/68 patients had later biopsies available; showing gain and loss of T790M in later biopsies (figure 1). Overall development of T790M was 57.4% (39/68). 7 patients had >3 biopsies available (figure 2). Patients developing T790M had numerically longer median OS of 3.8 years (range 2.8 – 4.9) as compared to median OS in T790M-patients (2.5 years, range 1.0 – 3.9) (P = 0.204).Figure 1Figure 2

      Conclusion
      57.4% of patients developed T790M. OS in patients developing T790M was longer than in patients not developing T790M, however the difference was not significant. Sequential data show that some patients ‘loose’ the T790M later on in the course of the disease. Data from this cohort suggests that T790M development is a dynamic process.