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R. Kratzke



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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.01 - Prognostic and predictive value of a new IASLC/ATS/ERS lung adenocarcinoma classification in a pooled analysis of four adjuvant chemotherapy trials: a LACE-Bio study (ID 3255)

      10:30 - 10:40  |  Author(s): R. Kratzke

      • Abstract
      • Presentation
      • Slides

      Background
      A new IASLC/ATS/ERS classification for lung adenocarcinoma has been proposed to classify invasive lung adenocarcinoma patients according to the predominant growth pattern present in the tumor: lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MPP) and solid (SOL). Several studies have reported consistently that early stage resectable lung adenocarcinoma patients with LEP predominant pattern have a better prognosis, while MPP and SOL predominant patterns have a significantly poorer prognosis. However, the prognostic significance of these histological patterns has not been tested in clinical trials. Furthermore, the clinical utility of this new classification for predicting benefit from adjuvant chemotherapy is unknown.

      Methods
      The representative single H&E slide of 1766 non-small cell lung cancer patients from IALT, JBR.10, CALGB 9633 and ANITA adjuvant chemotherapy trials who participated in the LACE-Bio study were reviewed to confirm the histological diagnosis. These cases were independently assessed by two pathologists involved in the development of this new IASLC/ATS/ERS classification for subtyping. Discordant cases were resolved by consensus. Clinical outcomes were overall survival (OS, main outcome), disease-free survival (DFS) and specific disease-free survival (SDFS) (DFS with censoring deaths not related to cancer). Multivariable Cox models stratified by trial were used for prognostic analyses and the interaction between treatment (chemotherapy / control) and histology subtypes added for predictive analyses. The five histology subtypes were first analysed separately and 3 groups (LEP, PAP+ACN and MPP+SOL) were considered.

      Results
      573 patients were classified as 23 (4%) as LEP, 148 (26%) as ACN, 99 (17%) as PAP, 39 (7%) as MPP and 264 (46%) as SOL. The distribution of histology subtypes was different across trials (p=0.02) but not related with standard prognostic variables. The number of deaths, events and cancer-related events were 269, 320 and 292 respectively. No significant difference was observed between the survival curves of 5 subtypes whatever the endpoint. No prognostic value of 3 histological subtypes was observed for OS (p=0.21 in the control arm) contrary to DFS (p=0.04) and SDFS (p=0.03). These last 2 results were explained by the difference between PAP+ACN and MPP+SOL with hazard ratio (HR)~ACN+PAP vs. MPP+SOL~=0.66 95% confidence interval (CI)=[0.47-0.91] and HR~ACN+PAP vs. MPP+SOL~=0.67 [0.44-0.89] for DFS and SDFS, respectively. Due to the small number of patients with LEP predominant pattern, the predictive value was assessed after excluding this subtype. MPP+SOL patients reported significant DFS benefit from adjuvant chemotherapy (HR=0.58 [0.43-0.80], p<0.001) compared to ACN+PAP patients (HR=1.12 [0.79-1.59], p=0.53; p interaction < 0.01). A similar result was observed for SDFS with HR=0.58 [0.42-0.80], p<0.005 in MPP+SOL compared to HR=1.13 [0.78-1.63], p=0.52 in ACN+PAP (p interaction <0.01) while no predictive effect for OS.

      Conclusion
      Resectable lung adenocarcinoma patients with micropapillary and solid predominant patterns showed a trend for poorer DFS and SDFS compared to patients with the other subtypes, and they show a significantly higher benefit from adjuvant chemotherapy on these outcomes. Histological subtypes according to the IASLC/ATS/ERS classification may be proposed as a stratification factor in design of future adjuvant chemotherapy trials.

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    P1.14 - Poster Session 1 - Mesothelioma (ID 194)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P1.14-005 - Preliminary Results - "A Phase I Trial of Oncolytic Measles Virotherapy in Mesothelioma" Investigating the Intrapleural Administration of the Modified Vaccine Strain Measles Virus (MV-NIS) to Patients with Malignant Pleural Mesothelioma (ID 1922)

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

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) remains an almost universally fatal disease. Preclinical models indicate that the oncolytic modified vaccine strain measles virus (MV) carrying the gene for the human sodium-iodine symporter (NIS) - MV-NIS preferentially targets MPM tumors cell. In patients with refractory ovarian cancer the intraperitonial administration of MV-NIS was recently found to be safe and induced an anti-tumor immune response.

      Methods
      Phase I dose escalation study (3+3 design). MV-NIS is administered intrapleurally. Starting dose level was 10[8] TICID 50 (Level 1) and the current dose level is 3 x 10[8] TICID 50 (Level 2). In the absence of dose limiting toxicity and disease progression patients continue MV-NIS therapy for up to six 28-day cycles. MV-NIS infection and replication is monitored by Iodine[123] SPECT/CT and RT-PCR and anti-tumor and anti-viral immunity are monitored in correlative studies. Patients are followed clinically using modified RECIST criteria.

      Results
      Up to now 4 patients have received MV-NIS therapy. Three patients were treated at Level 1 and the fourth patient at Level 2. No dose limiting adverse events occurred. The best therapeutic response was stable disease, observed in patient #1 for 6 months and patient #2 for 2 months. The remaining two patients progressed radiologically after one treatment cycle. I[123] SPECT-CT imaging did not demonstrate changes in iodine uptake compared to baseline in any of these patients. However, we detected MV RNA by QRT-PCR within the pleural cells 24-48 hours after the intrapleural administration of MV-NIS in 3/4 patients. In patient #4, treated with 3x10[8] TCID 50, MV replication was detectable within the pleural space by plaque assay 24 hours after MV-NIS administration. Following MV-NIS therapy a profound influx of neutrophils into the pleural space occurred in 3/4 patients and pleural fluid cytokine concentrations changed significantly. In addition, a humoral anti-tumor immune response emerged in patients #2.

      Patient # Age Disease Stage Histology Line therapy
      1 75 II (T2N0M0) Epitheloid First
      2 53 IV (T4N0M0) Epitheloid Second
      3 84 IV (T4N0M0) Epitheloid First
      4 73 IV (T2N3M0) Mixed First

      Conclusion
      Thus far the intrapleural administration of MV-NIS appears to be safe and well tolerated in MPM. Our study will continue to enroll patients.

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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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      P2.14-002 - Validation of the CALGB and EORTC Prognostic Models for Mesothelioma Based on Multiple CALGB Trials (Alliance) (ID 922)

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

      • Abstract

      Background
      Prognostic models play an important role in the design and analysis of mesothelioma treatment trials. The European Organisation for Research and Treatment of Cancer (EORTC) and the Cancer and Leukemia Group B (CALGB) prognostic models are two well-known tools to predict survival in patients with malignant mesothelioma. In this retrospective validation study, we aim to assess the performance of these two mesothelioma prognostic models for overall survival (OS) with multiple clinical trials data from CALGB.

      Methods
      Using 204 patients with malignant pleural mesothelioma, the EORTC model (Curran et al 1998) was developed using a Cox regression with white blood cell (WBC) count, ECOG performance status (PS), diagnosis, histological type, and gender as prognostic variables. Using 337 patients with malignant mesothelioma, the CALGB model (Herndon et al 1998) was developed using a cross-validated exponential regression tree with PS, age, haemoglobin (Hgb) level, WBC count, chest pain indicator, and weight loss indicator as prognostic variables. In this validation study, 602 mesothelioma patients from fifteen completed CALGB treatment trials accrued between June 1984 and August 2009 were included. As the CALGB model was developed using the seven earlier studies, 266 patients from eight recent studies were included in the validation. For the EORTC model, we analysed all studies as well as just those eight recent studies. The concordance of predicted survival times and risk scores was estimated by c-index (Harrell et al 1996). Secondary endpoint of interest includes progression-free survival (PFS). Sensitivity analysis and multiple imputations were used to handle missing data. We also compared our results with PS alone.

      Results
      (1) For OS, the EORTC model produced c-indices equal to 0.592 and 0.610 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.618 and 0.593 without and with imputation respectively. PS alone produced c-indices equal to 0.591 and 0.564 for the fifteen and eight studies respectively. (2) For PFS, the EORTC model produced c-indices equal to 0.569 and 0.598 for the fifteen and eight studies respectively. For the eight recent studies, the CALGB model produced c-indices equal to 0.585 and 0.560 without and with imputation respectively. PS alone produced c-indices equal to 0.568 and 0.553 for the fifteen and eight studies respectively. See Table 1. Figure 1

      Conclusion
      The EORTC and CALGB models perform similarly, with little improvement in prognostic ability from either compared to using PS alone. Further improvement on these existing prognostic models is warranted.