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A.K. Nowak

Moderator of

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    MS04 - Mesothelioma Genetics and Novel Targets (ID 21)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Mesothelioma
    • Presentations: 4
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      MS04.1 - BAP1 Gene Mutation and Mesothelioma Pathogenesis (ID 471)

      14:05 - 14:25  |  Author(s): A. Napolitano, M. Carbone

      • Abstract
      • Presentation
      • Slides

      Abstract
      Malignant mesothelioma (MM) is a lethal cancer whose pathogenesis results from complex interactions between host genetics and environmental carcinogens, such as asbestos and erionite fibers. Recently, BAP1 (BRCA associated protein 1) has been identified as a novel MM tumor suppressor gene. BAP1 is located at the 3p21, a region frequently deleted in MM, and encodes for a deubiquitinase enzyme known to target histones and other proteins. Originally discovered as a BRCA1 interacting protein, BAP1 appears to exert its anti-tumor activities mainly in a BRCA-independent manner, through its association in multi-protein complexes with diverse functions. For example, when associated to the Polycomb protein ASXL1, BAP1 is important for the regulation of the cell epigenome, via modulation of histone H2A ubiquitination and thus chromatin accessibility. In complex with other proteins (e.g. HCF-1, OGT, and YY1), BAP1 is also important in the transcriptional regulation of several genes and in the stability of target proteins such as PGC-1α. Recent reports also suggest a possible involvement of BAP1 in DNA repair pathways. However, the relevance of BAP1 to the biology of normal and cancer cells remains largely unexplained, in fact manipulation of BAP1 in cancer cells has often yielded unexpected or even contradictory results. For example, silencing of BAP1 in MM and uveal melanoma cell lines resulted in reduced cell growth (Bott et al; Matatall et al). We discovered that germline BAP1 mutations cause a novel cancer syndrome characterized by a significant excess of both pleural and peritoneal MM, uveal and cutaneous melanoma and possibly other tumors. In the same study, we reported that 22% sporadic MM tumors harbored somatic BAP1 mutations (Testa et al). In a separate study using 53 primary pleural MM collected in the USA, 42% of tumors harbored either BAP1 loss, BAP1 somatic mutations (detected in 23% of the samples), or both. Moreover, another 25% of tumors showed no BAP1 staining by immunohistochemistry (IHC) despite apparently normal BAP1 status, raising the possibility of post-translational deregulation of BAP1 in a subset of cases. In this MM cohort, there was a significant association between BAP1 status and patients’ age (66.7 years in mutant BAP1 compared to 58.6 years in wild-type BAP1), but there was no significant correlation with other variables such as sex, overall survival, histological subtype or asbestos exposure (Bott et al). In a recent meeting, using a bigger sample size, the same group confirmed that somatic BAP1 mutations occur in about 20% of pleural MM. They reported that the only clinical variable significantly different among those with and without BAP1 mutations was smoking (former or current), with BAP1 mutations more prevalent among smokers (75% vs. 42%). A Japanese study reported BAP1 gene alterations (either deletions or sequence-level mutations) in 61% of their 23 MM samples (Yoshikawa et al). Their data, but not those reported by Bott et al, also suggested an association between BAP1 mutations and the epithelioid histological MM subtype. Whether this discrepancy results from the different methodologies in sample preparation and detection of BAP1 mutations or it is an intrinsic difference between the two populations (e.g. due to ethnicity) has still to be determined. A third recent study, with a separate cohort of 52 pleural MM, reported absence of BAP1 IHC staining in 60% of pleural MM, confirming previous results (Arzt et al). The Authors also confirmed the absence of a correlation between BAP1 expression and asbestos exposure, and suggested that expression of BAP1 in tumor samples is inversely correlated to survival. The discovery of BAP1 germline and somatic mutations has renewed after decades the interest in MM genetics. Because germline BAP1 mutations predispose to multiple cancers and because BAP1 loss of heterozygosity is frequent in different tumor types, BAP1 would appear to act as a classical tumor suppressor. However, this definition is unsatisfactory because manipulation in vitro of BAP1 expression has often given unexpected and paradoxical results, complicating our understanding of its mechanisms of action. BAP1 absence (due to genetic, genomic, epigenomic or post-translational causes) was reported in about 60% of pleural MM. No studies so far have thoroughly investigated BAP1 expression in MMs arising from other sites. BAP1 expression is not associated to asbestos exposure, suggesting that its role in MM pathogenesis may be independent from the known asbestos-related pathways. Other clinicopathological associations are at this moment too weak to be conclusive, possibly due to limited tumor sample sizes, methodological differences in the studies or finally ethical differences of the analyzed populations. It appears, but remains unproven, that patients with germline BAP1 mutations have less aggressive MMs compared to sporadic MMs in which BAP1 mutations do not appear to influence prognosis. More experiments are urgently required to see whether BAP1 expression could be use in diagnostic, prognostic, or therapeutic settings. In fact, defining a therapeutically accessible synthetic lethal target in the setting of BAP1 loss could eventually benefit the approximately 40-60% of patients with BAP1 negative MMs. Even more speculatively, the same synthetic lethal target could be studied as chemoprevention drug targets in individuals with germline BAP1 mutations. The impact of this work obviously extends to other cancers with BAP1 mutations.

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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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      MS04.3 - New Molecular Targets in Mesothelioma (ID 473)

      14:45 - 15:05  |  Author(s): R. Stahel

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS04.4 - Current Clinical Trials of Targeted Therapies (ID 474)

      15:05 - 15:25  |  Author(s): P. Baas

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 2
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      MO09.05 - DISCUSSANT (ID 3966)

      16:35 - 16:45  |  Author(s): A.K. Nowak

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO09.10 - Volumetric Response Classification Criteria in Mesothelioma (ID 3302)

      17:10 - 17:15  |  Author(s): A.K. Nowak

      • Abstract
      • Presentation
      • Slides

      Background
      Tumor response criteria provide a framework for therapeutic decisions and clinical trials management in oncology. The standard response classification categories (partial response (PR), stable disease (SD), and progressive disease (PD)) were defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines based on relative changes in linear measurements of tumor diameter on computed tomography (CT) scans. An increase in linear dimension of at least 20% is categorized as PD, a decrease in linear dimension of at least 30% is categorized as PR, and a change in linear dimension not great enough to exceed either of these thresholds is categorized as SD. With improvements in imaging technology and enhancements in computer algorithms, the extraction of tumor volume from CT scans has become more practical. The possibility that tumor volume may eventually become the preferred tumor measurement metric rather than linear dimension necessitates the development of volumetric response criteria. Although extrapolation of the RECIST response criteria to volume is straightforward for spherical nodules, tumors as non-spherical as mesothelioma likely will require unique volumetric response criteria.

      Methods
      A semi-automated computerized method was used to determine the mesothelioma tumor volume from CT scans (baseline and all available follow-up scans) retrospectively collected from 70 patients undergoing standard-of-care chemotherapy. Relative changes in tumor volume from baseline were categorized as PR, SD, or PD based on different combinations of percent change thresholds. Overall patient survival was correlated with best response using Harrell’s C statistic. The response criteria for PD and PR were each varied in 1% increments to obtain optimized classification criteria.

      Results
      The process that systematically evaluated various combinations of response criteria identified an increase in tumor volume of at least 58% and a decrease in tumor volume of at least 17% for PD and PR, respectively, as the criteria that were best correlated with patient survival. These criteria yielded a C statistic of 0.76, where a C statistic value of 1.0 would indicate perfect separation of response groups with respect to subsequent survival times. This result may be compared with the C statistic value of 0.61 obtained when volumetric response criteria extrapolated directly from the RECIST criteria (+73% for PD and -66% for PR) were applied to this cohort.

      Conclusion
      The evolution toward volumetric assessment of tumor burden and response to therapy necessitates the derivation and validation of volume-specific tumor response criteria to distinguish among PR, SD, and PD. The present study motivates such response criteria for mesothelioma and indicates that mesothelioma volumetric response criteria differ substantively from a simplistic extension of the RECIST criteria to three dimensions. Future prospective studies will be required to validate these criteria.

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    MO19 - Lung Cancer Immunobiology (ID 91)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO19.03 - The effects of epidermal growth factor (EGFR) receptor inhibitors on the immune system in patients with advanced non-small cell lung cancer (NSCLC) (ID 3152)

      10:40 - 10:45  |  Author(s): A.K. Nowak

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR tyrosine kinase inhibitors (TKIs) have an important role in the treatment of NSCLC, particularly in the context of activating mutations, but resistance invariably develops. Recently, the immune checkpoint blockers anti-PD1 and anti-PDL1 were the first immunotherapies to demonstrate activity in advanced lung cancer. As immunotherapies such as anti-CTLA4, anti-PD1 and anti-PD-L1 antibodies enter clinical practice, there is potential to combine immunotherapies with TKIs to improve patient outcomes. The immune effects of EGFR-TKIs have not been elucidated, and the aim of this study is to examine the effect of TKIs on the immune response in patients with NSCLC, to provide a rationale and pilot data to underpin future clinical development of combinations of TKIs and immunotherapy.

      Methods
      Patients with advanced NSCLC who were commencing an EGFR-TKI were included in this prospective study. Eligible patients had a confirmed diagnosis of NSCLC, were treated with a single-agent EGFR-TKI , had no concurrent autoimmune disease and received no chemotherapy within 21 days, or corticosteroid therapy within 3 days of study entry. Peripheral blood samples were collected before commencing a TKI and 7 days, 21 days and 8 weeks after start of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and immediately frozen for subsequent analysis by 8-colour flow cytometry for relevant surface and intracellular marker expression. 4 panels were developed to examine the activation and proliferation status of effector CD8[+] T and CD4[+] T-regulatory cells (Tregs), enumeration of dendritic cells and B-cells, as well as the inhibitory pathway programmed death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 on T cells and antigen-presenting cells. Changes in immune parameters will be correlated with overall survival (OS) and radiological response (RECIST 1.1 criteria) at 8 weeks post-treatment.

      Results
      33 eligible patients were prospectively enrolled. Histopathology was adenocarcinoma (n=23), squamous cell carcinoma (n=7) and NSCLC not otherwise specified (NOS, n=3)). 12 patients had an activating EGFR mutation, 11 were EGFR wild type, and mutation-status was unknown in 10. 6 patients received the TKI gefitinib and 4 received erlotinib as first-line treatment for EGFR-mutation positive disease. 22 patients received erlotinib and 1 patient received afatinib as second or subsequent line therapy. At time of this report, 22/33 patients were deceased. Median OS from study entry was: all patients (7.7 months); mutation-positive (11.1 months); and mutation negative (4.4 months). Samples for 13 patients (2 were mutation-positive) have been analysed for effector T cell and Treg panels and no significant changes were seen between baseline and subsequent time points. Data will be presented for all samples.

      Conclusion
      This is the first study to explore to the immune effects of EGFR-TKIs. Initial results have not revealed a significant effect on peripheral T-cells, and analysis of remaining patient samples and other panels is in progress. An understanding of the immune effects of targeted therapies will be crucial in the rational development of strategies for incorporating immunotherapy into the anti-EGFR treatment paradigm, in an era of promising immunotherapy and checkpoint blockade approaches.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-041 - Optimising regulatory T cell (Treg) depletion in combination with chemotherapy for enhanced anti-tumour immunity (ID 2576)

      09:30 - 09:30  |  Author(s): A.K. Nowak

      • Abstract

      Background
      Cytotoxic chemotherapy is widely used to palliate malignant pleural mesothelioma (MM) and non small cell lung cancer (NSCLC). While originally considered detrimental to the immune system, there is now abundant preclinical data showing that chemotherapy can enhance anti-cancer immunotherapy. Tregs are immunosuppressive CD4[+] T cells thought to inhibit anti-tumour immune responses; murine data suggests that Treg eradication may augment existing anti-tumour immunity. Cyclophosphamide (CTX) is immunostimulatory and at low doses selectively depletes Tregs in mice and humans. The primary objective of this study is to identify an optimum dose and schedule of iterative low dose oral CTX for Treg depletion in the context of pemetrexed-based chemotherapy, and to determine how treatment affects the function and phenotype of the cellular immune response.

      Methods
      In this single centre phase 1b study we investigate an optimum dose and schedule of iterative low dose oral CTX for Treg depletion, in the context of pemetrexed-based chemotherapy, and how treatment affects the function and phenotype of the cellular immune response. Thirty-one patients with advanced malignant pleural mesothelioma (MM) or non-small cell lung cancer (NSCLC) received standard doses of pemetrexed ± cisplatin or carboplatin on a 21 day schedule (6 cycles max.). From the second cycle, escalating doses of oral CTX were administered, initially with 50 mg daily. Weekly peripheral blood samples were collected, and the proportion of Tregs within the CD4[+] population (Treg%) determined by flow cytometry, amongst other immunological parameters.

      Results
      31 participants enrolled on the study (27 MM, 4 NSCLC). The mean number of treatment cycles completed was 4.2 from a potential total of 6 cycles, with 20 participants on-study for at least 4 cycles, and the combination was safe and feasible. Contrary to our initial hypothesis, CTX treatment did not reduce the Treg proportion of CD4[+] T cells in peripheral blood, with baseline Treg (CD127[lo]CD25[+]Foxp3[+]) proportion of CD4+ T cells at 4.44±1.56% and no significant change observed when comparing values from the end of each treatment cycle. Doses above 50/100 mg did not improve depletion. However, analysis of the T-effector cell population has demonstrated an increased frequency of CD38[hi]HLA-DR[hi] cells within the total CD8[+] T cell pool. From the perspective of biological relevance, the ratio of activated T-effector cells to Tregs changes minimally during the first cycle of standard care chemotherapy (baseline = 0.21±0.15 T-effectors per Treg); however, from mid-way through cycle 2 (when CTX treatment begins) onward a notable and variable increase in the proportion of activated T-effector cells is observed (end of cycle 3 = 2.21±3.83 T-effectors per Treg). Detailed immunological data will be presented.

      Conclusion
      These data suggests that CTX with chemotherapy can increase the proportion of activated T-effector cells, an observation that has the potential to improve anti-tumour immunity or chemo-immunotherapy efficacy. We postulate that CTX may affect the function rather than numbers of Treg cells, decreasing their ability to suppress the proliferation of CD8+ effector T cells.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 2
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      P2.14-004 - EORTC and CALGB prognostic models, but not neutrophil-to-lymphocyte ratio, are prognostic in unselected patients with newly diagnosed malignant mesothelioma (ID 1259)

      09:30 - 09:30  |  Author(s): A.K. Nowak

      • Abstract

      Background
      Neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, was proposed as a prognostic biomarker in a number of malignancies, including malignant pleural mesothelioma (MPM). We examined baseline variables predictive of overall survival (OS) in patients with newly diagnosed MPM, including NLR and the established EORTC and CALGB prognostic models.

      Methods
      Consecutive patients with newly diagnosed MPM between 1[st] January 2005 and 31[st] December 2010 at Sir Charles Gairdner Hospital, Western Australia were included in this retrospective study. Eligible patients had a confirmed diagnosis of MPM, neutrophil and lymphocyte count within 90 days of diagnosis, no concurrent haematological malignancy, and follow-up more than 90 days from diagnosis. Any subsequent treatment, including supportive care alone, was allowed. Variables to be analysed and cut-off determination was predetermined according to previous reports. Multiple imputation was performed for missing values, and univariate analyses and multivariate Cox models were calculated for OS.

      Results
      274 of 369 patients screened met the eligibility criteria and were included in this retrospective study. 159 received systemic chemotherapy, 10 underwent tri-modality therapy; 2 underwent surgery only, and 103 received supportive care alone. Prognostic factors predictive of shorter survival in univariate analysis were: age ≥ 65 years, non-epithelioid histology, sarcomatous histology, AJCC stage III-IV, ECOG performance status (PS) 2-3, weight loss, chest pain, low haemoglobin and high platelet count. An NLR ≥ 5 at diagnosis did not predict for shorter OS (hazard ratio (HR) 1.25; p=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain, and platelet count remained significant. The EORTC and CALGB prognostic groups were highly statistically significant as predictors for OS (HR 1.62; p<0.001 and HR 1.65; p<0.001, respectively). On preplanned subgroup analyses, baseline NLR was not prognostic in chemotherapy-treated or non-chemotherapy treated patients.

      Univariate and multivariate analyses of association of prognostic factors with overall survival
      Univariate analysis Multivariate analysis
      Baseline prognostic factor HR (95% CI) P-value HR (95% CI) P-value
      Baseline NLR <5* vs. ≥5 1.25 (0.94-1.66) 0.122 1.02 (0.76-1.37) 0.893
      Age <65* vs. ≥65 years 1.64 (1.24-2.17) <0.001 1.41 (1.05-1.90) 0.023
      Female* vs. Male 1.23 (0.86-1.77) 0.262 1.24 (0.85-1.81) 0.269
      Epithelioid* vs. non-epilthelioid 1.40 (1.08-1.80) 0.009 1.38 (1.05-1.82) 0.023
      Non-sarcomatous* vs. sarc. 2.37 (1.62-3.48) <0.001 1.86 (1.22-2.84) 0.004
      AJCC Stage I-II* vs. III-IV 1.52 (1.17-1.97) 0.002 1.27 (0.97-1.66) 0.087
      ECOG PS 0-1* vs. 2-3 2.35 (1.59-3.46) <0.001 1.81 (1.21-2.70) 0.004
      Weight loss absent* vs. present 2.11 (1.62-2.74) <0.001 1.62 (1.22-2.15) <0.001
      Chest pain absent* vs. present 1.58 (1.21-2.07) <0.001 1.34 (1.02-1.76) 0.038
      Hb difference <10* vs. >10 1.87 (1.41-2.49) <0.001 1.32 (0.96-1.80) 0.087
      WCC (x 10[9]/L) ≤8.30* vs. >8.30 1.22 (0.96-1.57) 0.110 0.95 (0.73-1.25) 0.745
      PLT (x 10[9]/L) ≤400* vs. >400 1.96 (1.49-2.58) <0.001 1.71 (1.26-2.33) <0.001
      Abbreviations: *=referent; AJCC=American Joint Committee on Cancer Staging System; ECOG= Eastern Cooperative Oncology Group, WCC=White cell count; NLR=Neutrophil-to-lymphocyte ratio

      Conclusion
      Our findings validate established baseline prognostic variables as well as the EORTC and CALGB models, but not baseline NLR in unselected patients with newly diagnosed MPM. In guiding treatment decisions for patients at time of diagnosis, multiple variables should be considered that jointly predict survival

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      P2.14-014 - A Phase 2 Randomized, Double-blind, Placebo-Controlled, Multicenter Study of VS-6063 as Maintenance Therapy in Subjects with Malignant Pleural Mesothelioma which has Not Progressed on at least 4 Cycles of Pemetrexed/Platinum therapy (ID 3375)

      09:30 - 09:30  |  Author(s): A.K. Nowak

      • Abstract

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive tumor in the pleural lining of the lung usually caused by asbestos exposure. Median OS following frontline chemotherapy with pemetrexed/cisplatin is ~12 months. There is no established second line therapy. Approximately 50% of MPM patients exhibit homozygous disruption of the NF2 tumor suppressor gene by mutation and/or deletion resulting in lack of expression of functional merlin protein. Preclinical data have indicated that mesothelioma cell lines that lack NF2/Merlin are especially sensitive to focal adhesion kinase (FAK) inhibition in both cellular and animal models. Interestingly, pemetrexed and cisplatin increase cancer stem cells (CSCs), while FAK inhibitors have been found to decrease CSCs in mesothelioma models. Given the sensitivity of mesothelioma cells lacking NF2/Merlin and the effect on CSCs, the use of a FAK inhibitor in a maintenance setting after first line chemotherapy may be an attractive strategy to extend survival of MPM patients. VS-6063 is an orally bioavailable selective inhibitor of FAK. In a phase 1 trial VS-6063 was generally well tolerated, with grade 1/2 nausea, vomiting and fatigue as the most frequent adverse events (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002).

      Methods
      A multinational, randomized, double-blind, placebo controlled, phase 2 clinical trial was designed to determine if VS-6063 provides superior clinical benefit compared with placebo as a maintenance treatment in patients with MPM following frontline therapy with pemetrexed/platinum therapy. The study aims to assess whether VS-6063 improves median OS and median PFS over placebo. Randomization will be stratified by Merlin status (high versus low) and patients will receive either VS-6063 400mg BID continuously or matched placebo (1:1). The study follows an adaptive enrichment design where, pending results from an interim analysis, sampling may be restricted to patients with low Merlin protein expression if promising results are observed among the subpopulation. Approximately 370 eligible patients with pathologically confirmed MPM, who have PR or SD following at least 4 cycles of pemetrexed with either cisplatin or carboplatin, Karnofsky PS ≥70%, will be enrolled. Patients will continue treatment until disease progression. Archival tumor tissue will be used for the analysis of Merlin status and is therefore required for participation. Secondary endpoints include patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms utilizing the LCSS-meso scale, objective response and safety and tolerability. Clinical trial information: NCT01870609.

      Results
      not applicable

      Conclusion
      not applicable

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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-020 - Strategies for the prevention of mesothelioma in MexTAg mice (ID 3205)

      09:30 - 09:30  |  Author(s): A.K. Nowak

      • Abstract

      Background
      Current treatments for mesothelioma typically increase median survival by a matter of months. Progress in treatment has been hampered by lack of a suitable small animal model, which could guide clinical advances, given limited numbers of patients eligible for clinical trials. To this end we recently developed a transgenic mouse model of mesothelioma in which the viral oncogene, SV40TAg (TAg) is directed to mesothelial cells by use of the cell type specific mesothelin promoter. MexTAg mice develop mesothelioma rapidly and uniformly, but only following exposure to the natural carcinogen, asbestos. The model closely mimics the human disease and is thus ideal for both rapid analysis of novel therapeutic studies and for investigating factors that might act synergistically with asbestos to cause disease. Since all MexTAg mice develop mesothelioma following asbestos exposure the model is highly suitable for early intervention and cancer prevention studies. An effective cancer prevention strategy for the millions of people who have been exposed to asbestos could have enormous benefit worldwide. Epidemiological evidence indicates that supplementation with some dietary factors or use of common drugs such as statins and non-steroidal anti-inflammatory drugs is associated with a lower incidence of cancer.

      Methods
      not applicable

      Results
      We previously reported that dietary supplementation with a number of antioxidants did not alter the time to develop disease nor overall survival, despite the widely accepted hypothesis that asbestos catalyzed production of reactive oxygen and nitrogen species contribute to the development of this cancer. We have extended these studies to test whether vitamin D, non-steroidal anti-inflammatories, statins and some other candidate diets could alter the pattern of disease in the MexTAg model. Supplemented diets were provided at levels based on published data and began 2 weeks prior to asbestos exposure in order to maximize our chance of detecting a benefit. Preliminary data suggests a single agent or nutraceutical may not be enough to prevent the multiple pathways involved in tumorigenesis. This is somewhat supported by epidemiological data from the Wittenoom cohort of asbestos exposed workers and residents.

      Conclusion
      In conclusion, we think it is unlikely that antioxidants, anti-inflammatories or other nutrient-specific dietary supplements will moderate the rate of mesothelioma in asbestos exposed populations.

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    P3.14 - Poster Session 3 - Mesothelioma (ID 197)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P3.14-010 - Evaluation of Mesothelioma Tumor Thickness Measurement Variability (ID 2522)

      09:30 - 09:30  |  Author(s): A.K. Nowak

      • Abstract

      Background
      Single time-point unidimensional tumor thickness measurements define measurable disease for clinical trial inclusion and also constitute a field in the IASLC prospective mesothelioma staging database. The modified RECIST guidelines for mesothelioma did not alter the 10mm minimum tumor measurement recommendation. It is unclear at what minimum thickness interobserver variability exceeds 20% of tumor thickness and how morphology, and location affect interobserver variability in a single baseline measurement.

      Methods
      105 thoracic CT scans were collected retrospectively from 50 mesothelioma patients. Each scan was reviewed by a medical oncologist, who identified 170 discrete sites of mesothelioma tumor across all scans that represented a range of thickness. Lesion morphology (concave rind, convex rind, convex mass, fusiform mass), and anatomic location (chest wall, mediastinum, anterior angle, or posterior angle; craniocaudal location; bone/soft tissue) were categorized. Using a custom computer interface (Abras), reference tumor thickness measurements were obtained by creating a line segment that spanned the tumor from the parietal tumor margin along the chest wall or mediastinal structures to the inner tumor margin. Measurements were selected to capture a range of tumor thicknesses and morphologies, rather than the most clinically relevant measurement sites. An observer study was conducted in which each of five other physicians was presented with the individual CT sections and the same digitally fixed location of the outer tumor margin at each of the 170 pre-defined tumor measurement sites. Each observer then independently created a line segment to capture tumor thickness at all measurement sites. Relative differences among the tumor thickness measurements of observers were estimated using a random-effects analysis of variance model (ANOVA) to identify the smallest tumor thickness at which linear measurements could be made reliably. Comparisons were made with the RECIST tumor response criterion of 20% for progression.

      Results
      The median mean measurement across all sites was 9.68mm, reflecting the study’s aim to investigate measurement variability as a function of tumor thickness, given that the current standard minimum is set at 10mm. The mean range of observer measurements across all sites was 15.1% of the mean per-site measurement (SD 9.1%). Measurements acquired at tumor sites with reference thickness less than 7.5 mm demonstrated inter-observer variability (as defined by the difference between the maximum and minimum measurements of the observers at each site) with a 75th percentile that included 20% of the tumor thickness, while measurements acquired at sites with mean tumor thickness >7.5mm showed inter-observer variability with a 75[th] percentile <20% of tumor thickness. Inter-observer variability tended to be lower for convex mass lesions relative to that associated with the other three tumor morphologies.

      Conclusion
      The results of this study have implications for the definition of minimum measurable tumor adopted by clinical trial and staging protocols.