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R. Bueno



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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.11 - Quantitative Clinical T Classification Criteria for Malignant Pleural Mesothelioma. (ID 2947)

      17:15 - 17:20  |  Author(s): R. Bueno

      • Abstract
      • Presentation
      • Slides

      Background
      Clinical T classification of Malignant Pleural Mesothelioma involves qualitative estimation of tumor involvement of the thorax and does not accurately predict prognosis (JTO 7(11):1631-9, 2012). We explored whether novel quantitative assessment of standard CT images might improve the prognostic accuracy of clinical T classification.

      Methods
      All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with available preoperative CT for retrospective review were included. Tumor volume was derived using Vitrea software (Vital) and binned into 3 categories (≤75cc, >75≤500cc, >500cc). Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival were computed for each combination of volume and septum thickness categories. Combinations with similar estimated survival functions were combined to create criteria for T classification levels. Cox regression was used to evaluate the relative hazard for death and disease recurrence associated with classification levels.

      Results
      406 patients met inclusion criteria (278 EPP, 128 PDC; 317 male; 297 epithelial histology on biopsy; median age 64). Alignment of survival functions yielded combinations of volume and septum thickness categories defining T1 through T4. These classifications were associated with progressively increasing hazard for death and recurrence (Table).

      Overall Survival Time to Recurrence
      T status N Median(mths) HR 95% C.I. Median(mths) HR 95% C.I.
      T1 85 37 1.0 - 16 1.0 --
      T2 118 21 1.5 1.0 - 2.1 11 1.6 1.1-2.1
      T3 105 14 2.5 1.7 - 3.5 8 2.3 1.7 -3.2
      T4 98 10 4.2 3.0 - 6.1 5 4.1 3.0 - 5.8

      Conclusion
      Tumor volume and septum thickness are readily measured on standard CT imaging and provide robust prognostic information not accounted for by current clinical T classification criteria. As quantitative measurements, they should be minimally affected by inter-observer variability. The feasibility and value of these simple and cost effective adaptations to clinical staging should be evaluated as the TNM staging system is revised.

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    MO14 - Mesothelioma II - Surgery and Multimodality (ID 121)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Mesothelioma
    • Presentations: 1
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      MO14.08 - Validation of a stage-independent pre-operative risk assessment algorithm for patients considering surgery for malignant pleural mesothelioma. (ID 2906)

      11:15 - 11:20  |  Author(s): R. Bueno

      • Abstract
      • Presentation
      • Slides

      Background
      We previously introduced a 3-level risk assessment algorithm based on tumor volume, gender and hemoglobin level (JTO 6:S486-7). Its applicability was limited to patients with epithelial disease undergoing surgery. We now report an expanded 4-level risk algorithm incorporating histologic subtype determined by pleural biopsy and interlobar septum thickness as additional predictors. We test its ability to stratify outcome among patients treated on a prospective phase I trial (protocol 07-091) of primary surgery and hyperthermic intraoperative intracavitary cisplatin plus dose-escalated gemcitabine.

      Methods
      All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with preoperative CT scan available for retrospective review were included. Patients enrolled on 07-091 were reserved for validation; the remaining patients were used to train the model. Maximal thickness among measurable interlobar septae was measured on CT and binned into 2 categories (≤5mm, >5mm). Kaplan-Meier estimates of overall survival functions were used to define risk strata. Cox regression was used to assess algorithm stratification of overall survival and time to recurrence.

      Results
      The model cohort comprised 308 patients (221 EPP, 87 PDC; 241 male; 244 epithelial histology on biopsy; median age 63). The validation cohort comprised 90 patients (53 EPP, 37 PDC; 70 male; 53 epithelial histology on biopsy; median age 66). Alignment of survival functions after stratification of 3-level risk by septum thickness and biopsy histology in the model cohort suggested 4 risk strata (A-D). The expanded algorithm stratified both model and validation cohorts into balanced groups with distinct overall survival and time to recurrence (Table).

      Overall Survival Time to recurrence
      N median HR 95% C.I. median HR 95% C.I.
      Model
      risk A 82 40 mo 1.0 23 mo 1.0
      risk B 90 19 mo 2.1 (1.5-3.1) 9 mo 2.3 (1.6-3.2)
      risk C 87 12 mo 3.5 (2.4-5.1) 7 mo 3.3 (2.4-4.7)
      risk D 49 6 mo 8.7 (5.7-13.3) 3 mo 9.3 (6.1-14.1)
      Validation
      risk A 21 NR 1.0 21 mo 1.0
      risk B 26 30 mo 2.3 (0.9-6.0) 13 mo 1.4 (0.7-2.9)
      risk C 29 15 mo 5.2 (2.1-12.8) 10 mo 4.0 (1.9-8.1)
      risk D 14 9 mo 19.6 (6.8-55.6) 4 mo 9.0 (3.9-20.8)

      Conclusion
      This expanded risk stratification algorithm is based on information available preoperatively for the majority of patients with pleural mesothelioma being considered for surgical resection. It provides important prognostic information that is not reflected in conventional clinical stage regarding the risks and potential benefits of aggressive management for individual patients.

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    MS04 - Mesothelioma Genetics and Novel Targets (ID 21)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Mesothelioma
    • Presentations: 1
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      MS04.2 - Sequencing the Mesothelioma Genome - Where Are We Now and Where Are We Going? (ID 472)

      14:25 - 14:45  |  Author(s): R. Bueno

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-026 - Validation of a Proliferation-based Expression Signature as Prognostic Marker in Early Stage Lung Adenocarcinoma (ID 1954)

      09:30 - 09:30  |  Author(s): R. Bueno

      • Abstract

      Background
      Use of adjuvant chemotherapy in non-small cell lung carcinoma (NSCLC) is based upon pathological stage and is not generally recommended for patients with Stage I disease despite a five-year overall mortality of 30% in Stage IA and 50% in Stage IB. Molecular biomarkers have the potential to guide treatment by identifying patients at highest risk for recurrent cancer. An evaluation of prognostic breast RNA profiles revealed a common component of cell cycle regulated mRNAs which contains the major prognostic power of each expression profile. The expression levels of cell cycle progression (CCP) genes measure tumor growth irrespective of the underlying genetic aberrations. CCP has been shown to be a highly significant predictor of cancer specific mortality at five years in three individual datasets. From these data a prognostic model was generated incorporating the CCP expression signature with pathological stage. The study herein will assess the validity of this combined clinical and gene expression score to predict five-year risk of lung cancer death in patients with early stage lung adenocarcinoma. A high combined prognostic score will identify patients with an increased risk for relapse whom may benefit significantly from adjuvant chemotherapy.

      Methods
      A cohort of patients with NSCLC adenocarcinoma was assembled with the following clinical covariates: age at diagnosis, gender, smoking status, tumor size and grade, pleural invasion, TNM Stage, adjuvant treatment status, and EGFR mutation status (if known). Outcome variables include cause of death and time to recurrence and death. An event is defined as death due to lung cancer within five years of surgery. If cause of death is unknown, death following recurrence will be used as a surrogate. A cohort with 150 events will have 99% statistical power at the 5% significance level to demonstrate an association between CCP and death from lung cancer outcome. A CCP score will be calculated from the mRNA expression levels of 31 proliferation genes in this cohort and combined with stage in a final prognostic score.

      Results
      To date, 631 Stage I and Stage II adenocarcinomas have been assembled. Two hundred and fifty-five deaths have occurred in the cohort with more than 100 deaths caused by lung cancer. Also, there have been over 150 instances of lung cancer recurrence documented. Two hundred and thirty-four samples have been processed with CCP scores ranging from -3.20 to 2.20. The distribution of CCP scores is consistent with those observed in previous cohorts of early stage lung adenocarcinoma. Complete analysis will be presented.

      Conclusion
      This validation cohort will provide adequate events to significantly demonstrate whether the prospectively defined prognostic score can define a high–risk group of early stage NSCLC patients with a high risk of death from lung cancer. This information may help guide adjuvant treatment decisions.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-009 - <b>Novel Clinical Assessment of Malignant Pleural Mesothelioma</b> (ID 2944)

      09:30 - 09:30  |  Author(s): R. Bueno

      • Abstract

      Background
      Clinical TNM staging of MPM is suboptimal for predicting prognosis of individual patients. Accurate clinical assessment of T classification is limited by poor contrast resolution of the tumor from adjacent structures. Involvement of interlobar septae (ILS) is a T2 classification criterion that is amenable to quantitative measurement owing to high contrast with surrounding lung parenchyma.

      Methods
      All patients who underwent primary extrapleural pneumonectomy (EPP) or pleurectomy (PDC) between 2001-2012 with preoperative CT scan available for retrospective review were included. ILS were measured at their maximum thickness evident on axial CT images. ILS thickness representing the optimal threshold for predicting pathologic involvement was determined by ROC analysis among patients who underwent EPP with complete pathologic analysis including microscopic examination of the ILS. Cox regression was used to determine the threshold associated with the maximal hazard ratio for death among all patients in the study cohort.

      Results
      406 patients met criteria for inclusion (278 EPP, 128 PDC; 319 male; 260 epithelial histology; median age 64). Maximal ILS thickness ranged 0 - 50mm, median 5.75mm. Among 269 EPP patients with ILS pathologically evaluated (229 positive), predictive accuracy was optimized at a threshold of >2mm on CT (83% sensitivity, 57% specificity, 79% accuracy). Among 406 patients, hazard ratios for death were optimized at threshold of >5mm on CT. The table lists the numbers of patients within the entire cohort and for the subsets undergoing EPP and PDC who scored positive for at the 5mm threshold, as well as the associated hazard ratios for death and disease recurrence.

      Overall Survival Time To Recurrence
      # Positive #Negative HR 95% C.I. HR 95% C.I.
      All 213 193 2.4 (1.9-3.0) 2.2 (1.7-2.7)
      EPP 167 111 1.9 (1.5-2.6) 2.0 (1.5-2.5)
      PDC 46 82 3.3 (2.1-5.2) 2.9 (1.9-4.4)

      Conclusion
      Pathologic ILS involvement is a T2 classification criterion characteristic of 85% of EPP cases. It is most accurately predicted by measured thickness >2mm on CT. However, ILS thickness of >5mm is a more discriminant and clinically useful indicator of poor outcome, particularly for patients undergoing PDC. As such, this measurement represents an available clinical prognostic marker not currently included among TNM staging criteria or standard radiology reports.