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C. Dooms



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    MO23 - Radiotherapy II: Lung Toxicity, Target Definition and Quality Assurance (ID 107)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO23.10 - Addition of EBUS-mapping of the mediastinum to PET/CT based selective nodal irradiation in NSCLC decreases geographical miss and nodal GTV volume (ID 2841)

      11:25 - 11:30  |  Author(s): C. Dooms

      • Abstract
      • Presentation
      • Slides

      Background
      FDG-PET/CT based selective lymph node (LN) irradiation is the standard when using 3D-conformal techniques (3D-CRT) for locally advanced NSCLC. With 3D-CRT, adjacent LN not included in the target volume still receive a substantial radiation dose. With current new techniques (IMRT/VMAT), the radiation dose to non-involved LN decreases, which raises the question whether selective nodal irradiation based on PET/CT is still safe. We therefore evaluated the impact of adding EBUS-TBNA (endobronchial ultrasound guided transbronchial needle aspiration)-mapping of the mediastinal LN to PET/CT in avoiding geographical miss, and on the size of nodal GTV (gross tumor volume).

      Methods
      Consecutive NSCLC-patients referred for radiotherapy (RT) in 2012 who underwent EBUS-TBNA were included. False negative (FN) LN for different constellations of PET, CT and EBUS-TBNA based on literature data were calculated, to evaluate the safety of excluding LNs based on CT, PET and EBUS findings. A practical algorithm when to include LN in the GTV was made, and tested on our patients. Results are expressed as mean +/- SD and range.

      Results
      Twenty-five consecutive patients with a full EBUS-TBNA mapping before RT were included: 11 women, 14 men; 17 adenocarcinoma, 8 squamous cell carcinoma; 14 right-sided and 11 left-sided tumors. Mean age: 62.5 +/- 9.7 years. All patients had stage III-disease based on PET-CT. LN stations 1,2R,2L,3,4R,4L,5,6,7,8,9,10-11L,10-11R were analyzed on CT- and PET-scan (=325 LN). Sixty-seven were enlarged (≥10mm), of which 63 were PET-positive. Twelve normal-sized LNs were PET-positive. Fifty LNs were investigated with EBUS-TBNA (mean: 2/patient +/-0.96;1-5): 28 were malignant, 22 normal. EBUS-TBNA detected 1 cancer-containing normal-sized LN without FDG-uptake, thus 1/25 geographical miss (4%). The cancer prevalence, taking into account the FN rate of EBUS of 20%, was calculated (Fig.1). With addition of EBUS, in PET-negative patients FN decreases with 10% for enlarged LN, and with 5% for normal-sized LN. An algorithm when to include a LN in the GTV is proposed (Fig.1). According to this algorithm, in our population 3/79 (4%) enlarged or PET-positive LN would be excluded from the GTV. At patient level, this was a GTV decrease in 3 (12%) patients.

      Conclusion
      When incidental nodal irradiation is low such as in IMRT or VMAT, EBUS-TBNA should be added to FDG-PET/CT for mediastinal staging. This avoids geographical miss in 4% of patients, and decreases the radiation volume in 12% of patients. A practical algorithm is proposed.

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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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      P1.17-003 - Endobronchial valve treatment for pulmonary air leak after anatomical resection for cancer. (ID 1125)

      09:30 - 09:30  |  Author(s): C. Dooms

      • Abstract

      Background
      Around 50,000 patients undergo each year a surgical resection for early stage lung cancer in the United States. Their median hospital stay after a lobectomy is 4-7 days. The European Society of Thoracic Surgery database shows that the percentage of pulmonary air leak present on day 5 is 6.8% for segmentectomy and 8.3% for lobectomy. This postoperative pulmonary expiratory air leak is usually managed conservatively. However, this is independently associated with prolonged hospital length of stay, decreased patient satisfaction, increased morbidity or postoperative complications. The use of endobronchial valves is a minimal invasive method that may be effective for the treatment of such a persistent postoperative pulmonary air leak.

      Methods
      In a prospective study, the efficacy of endobronchial valve treatment in 10 patients with a prolonged persistent pulmonary air leak after anatomic surgical resection for cancer was investigated. The primary study endpoint is the clinical efficacy on air leak cessation assessed using a digital thoracic drainage system and allowing chest tube removal. Other evaluations included avoidance of Heimlich valve, avoidance of additional surgical intervention, safety issues including complications related to endobronchial valve treatment, evaluation of consequences of airway closure on pulmonary function, and timing of endobronchial valve removal.

      Results
      Of all included patients, 90% was scheduled for valve treatment. We demonstrated air leak cessation at a median of 2 days after endobronchial valve placement, which resulted in chest tube removal at a median of 4 days after valve placement. Three patients were discharged with a Heimlich valve despite a significant reduction of their air leak after valve implantation. No single patient required additional surgical intervention. No deaths or implant-related events (such as infection distal to the endobronchial valve, hemoptysis, persistent cough, pneumothorax or expectoration of a valve) did occur. A significant decrease in FEV1 was found at airway closure by valve implantation, as compared to the functional status after valve removal (mean FEV1 53% versus 61% of predicted; p=0.0002). A 5-10% decrease in FEV1 was observed in patients when a right upper lobe was treated with endobronchial valves, while a 10-15% decrease in FEV1 was observed when a lower lobe was treated with endobronchial valves. Elective removal of the endobronchial valves was safely performed at a median of 23 days (range 14-28) after valve implantation.

      Conclusion
      Endobronchial valve treatment is an effective therapy for patients with a prolonged pulmonary air leak after anatomic resection for cancer. The aid of a digital thoracic drainage system is required as it guides endobronchial valve placement and allows a safe fast-tracking chest tube removal.

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    P2.04 - Poster Session 2 - Tumor Immunology (ID 154)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.04-002 - Differential expression of PD-L1, PD1 and CTLA4 receptor according to histology and tumour vs. surrounding non-malignant lung tissue in non-small cell lung cancer: RNA sequencing data (ID 2427)

      10:30 - 11:30  |  Author(s): C. Dooms

      • Abstract

      Background
      Immune modulatory strategies directed against CTLA4 (Cytotoxic T-Lymphocyte Antigen 4), PD1(Programmed cell Death 1) and PD-L1 (Programmed cell Death 1 Ligand 1) either in monotherapy or in combination with chemotherapy and radiotherapy offer great promise as novel treatments against lung cancer. Its outcome and therapeutic ratio may depend on the expression of the target molecules in tumours and the surrounding non-malignant lung tissue. We here report the expression of CTLA4, PD1 and PD-L1 in primary resected NSCLC and in the surrounding non-malignant lung.

      Methods
      RNA sequencing was performed on tumor tissue and normal lung tissue from resection specimens of NSCLC patients. The association between CTLA4, PD1 and PD-L1 expression levels and histology, gender, age, smoking status (current smoker vs. smoking cessation of at least one year), COPD and CRP blood levels was calculated both in the primary tumour and the normal lung. Results are expressed as mean +/- SD and range. Means were compared using Wilcoxon’s signed rank test for the distributions were non-parametrical. P-values <0.05 were considered significant.

      Results
      Fourteen patients were studied, 11 males and 3 females, with a mean age of 64.6 +/- 10.0 years (41-79). All patients had a smoking history: 6 were current smokers, 8 former smokers. COPD status: 8 no COPD, 1 GOLD class I, 3 GOLD class II, 2 GOLD class III. Pre-operative CRP (mg/dL): 15.0 +/- 2.9 (0.20-54.7). Seven patients had squamous cell cancer, 7 adenocarcinoma. PD-L1 expression in the lung was 3833 +/- 787 (372-5072), PD-L1 in the tumour 2595 +/- 1657 (788-6689), with a tumour/lung ratio of 0.67 +/- 0.37 (0.21-1.32). PD-L1 squamous vs. adenocarcinoma was 1840 +/- 1012 vs. 3350 +/- 1896, p<0.001. PD-L1 in the lung of ex-smokers vs. current smokers: 4136 +/- 811 vs. 3430 ± 591, p<0.001. These associations were not found for CTLA4 and PD1 receptor: CTLA4 tumour squamous vs. adenocarcinoma: 100.9 +/- 46.3 vs. 95.3 +/- 73.6, p=0.86; CTLA4 lung smokers vs. ex-smokers: 78.4 +/- 41.3 vs. 107.0 +/- 75.1, p=0.75. PD1 receptor tumour squamous vs. adenocarcinoma: 591 +/- 244 vs. 689 +/- 263, p=0.31 PD1 receptor in the lung of smokers vs. ex-smokers: 599 +/- 278 vs. 695 +/-216, p=0.46. No associations between CTLA4, PD1 and PD-L1 in the tumour or the lung and gender, age, COPD and CRP blood levels were found.

      Conclusion
      RNA sequencing is a useful method to dissect relevant molecules in the tumour and the lungs. Our results show more PD-L1 expression in adenocarcinoma than in squamous cell cancer, more PD-L1 expression in the non-malignant lung of ex-smokers than in current smokers and reduced PD-L1 in tumours compared to adjacent lung tissue.

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    P2.08 - Poster Session 2 - Radiotherapy (ID 198)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P2.08-002 - Modern post-operative radiotherapy for stage III non-small cell lung cancer may improve local control and survival: A publication-based meta-analysis (ID 89)

      09:30 - 09:30  |  Author(s): C. Dooms

      • Abstract

      Background
      We hypothesized that modern postoperative radiotherapy (PORT) could decrease local recurrence (LR) and improve overall survival (OS) in patients with stage IIIA-N2 non-small-cell lung cancer (NSCLC).

      Methods
      To investigate the effect of modern PORT on LR and OS, we identified published phase III trials for PORT and stratified them according to use or non-use of linear accelerators. We modelled the potential benefit of modern PORT in stage IIIA-N2 NSCLC treated with induction chemotherapy and resection.

      Results
      Of the PORT phase III studies, eleven trials (2387 patients) were included for OS analysis and eight (1677 patients) for LR. PORT decreased LR, whether given with cobalt, cobalt and linear accelerators, or with linear accelerators only. An increase in OS was only seen when PORT was given with linear accelerators, along with the most significant effect on LR (relative risk for LR and OS 0.31 (p=0.01) and 0.76 (p=0.02) for PORT vs. controls, respectively). Four trials (357 patients) were suitable to assess LR rates after surgery and/or induction chemotherapy in stage III NSCLC. LR as first relapse was 30 % (105/357) after 5 years. In the modelling part, PORT with linear accelerators was estimated to reduce LR rates to 10 % as first relapse and to increase the absolute 5-year OS by 13 %.

      Conclusion
      This modelling study generates the hypothesis that modern PORT may increase both LR and OS in stage IIIA-N2 NSCLC even in patients being treated with induction chemotherapy and surgery.

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    P2.19 - Poster Session 2 - Imaging (ID 180)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.19-004 - Characterization of solitary pulmonary lesions combining visual perfusion and quantitative diffusion MR imaging (ID 1000)

      09:30 - 09:30  |  Author(s): C. Dooms

      • Abstract

      Background
      To evaluate the diagnostic accuracy of dynamic contrast enhanced (DCE)magnetic resonance (MR) and diffusion weighted imaging (DWI) sequences for defining benign or malignant character of solitary pulmonary lesion (SPL) in a preoperative setting.

      Methods
      This study was approved by the local ethics committee; all patients provided written informed consent. First, 54 consecutive patients with SPL, clinically staged (CT and PET or integrated PET-CT) as N0M0, were included in this prospective study. An additional MR examination including DCE and DWI was performed one day before the surgical procedure. Histopathology of the surgical specimen served as standard of reference. Subsequently, this functional method for SPL characterization was validated with a second cohort of 54 patients.

      Results
      In the feasibility group, 11 benign and 43 malignant SPL were included with a maximal diameter that varied from 3 to 71 mm (mean 23.2 mm). Using the conventional MR sequences with visual interpretation of DCE-MR curves sensitivity, specificity, accuracy were respectively 100%, 55% and 91%. By additional interpretation of quantitative apparent diffusion coefficient (ADC) values (with a cutoff value of 1.52x10-3 mm2/sec for ADC calculated from high b-values (ADChigh) these results improved to 98%, 82% and 94% respectively. In the validation group, with 14 benign and 40 malignant SPL (diameter ranged between 7 mm and 10 cm - mean 26.5 mm), these results were confirmed with a sensitivity, specificity and accuracy of 95%, 79%, and 91%, respectively.

      Conclusion
      Visual DCE-MR-based curve interpretation can be used for initial differentiation of benign from malignant SPL, while additional quantitative DWI-based interpretation can further improve the specificity.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-004 - Oligometastatic non-small cell lung cancer: a simulation expert multidisciplinary tumor board. (ID 1122)

      09:30 - 09:30  |  Author(s): C. Dooms

      • Abstract

      Background
      Series on aggressive local treatment in selected patients with oligometastatic non-small cell lung cancer (NSCLC) are mostly retrospective, and prospective data are scarce (De Ruysscher et al, JTO 7:1547-1555, 2012). Although a precise definition is lacking, ‘oligometastatic NSCLC’ is considered an intermediate biologic state of restricted metastatic capacity with a limited number of metastases. The turning point between oligometastatic and polymetastatic is merely based on personal opinion and situated somewhere between 1 and 5 distant metastases. In the absence of clear definitions or clinical practice recommendations, a treatment decision is mainly driven by the opinion of each local multidisciplinary tumor board (MDTB).

      Methods
      As the consideration of and the treatment modality for oligometastatic NSCLC is a controversial area in respiratory oncology, in preparation of a recent dedicated workshop, we simulated a MDTB with international experts in the field. Multiple disciplines from 7 different centers participated in the MDTB, including pathology (1), nuclear medicine physician (1), thoracic surgery (3), radiation oncology (3), and respiratory oncology (3). Participants were asked to assess an electronic file describing 10 clinical ‘oligometastatic NSCLC’ cases, with 2 simple questions per case: 1. Do you consider this case ‘oligometastatic’ (Yes/No) and 2. What is your preferred treatment proposal.

      Results
      A full response was returned by all 11 specialists taking part in the simulated MDTB. Only 1 case was considered ‘oligometastatic NSCLC’ by all MDTB members. The presented cases were considered by a median of 78% (range 36-100%) of responders as true oligometastatic disease. Despite the fact that each responder gave only one treatment proposal, a median of 4 different treatment proposals (range 2-6) was made per case. Except for brain metastases, most team members would treat the locoregional thoracic disease before the distant metastases. No preference towards neo-adjuvant or adjuvant chemotherapy could be found. The option for surgery or radiation therapy as part of a combined modality treatment was mainly driven by the physicians’ preference.

      Conclusion
      Our simulated MDTB shows that oligometastatic NSCLC is an entity with many unanswered questions, and thus a major challenge for clinicians. Patients with oligometastatic NSCLC are in the need of 1. discussion at an experienced multidisciplinary tumor board to select patients for a radical combined modality approach; 2. multidisciplinary prospective research protocols to set better definitions of oligometastic NSCLC, evaluate the validity of a radical approach, and to optimize therapeutic modalities.