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S. Kao



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    MO09 - Mesothelioma I (ID 120)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track:
    • Presentations: 1
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      MO09.07 - Disease and Patient Characteristics related to Survival in a large population-based cohort of patients with Malignant Pleural Mesothelioma (MPM) (ID 3184)

      16:50 - 16:55  |  Author(s): S. Kao

      • Abstract
      • Presentation
      • Slides

      Background
      Despite advances in therapy, the prognosis of MPM remains poor (median overall survival (OS) of 9-12 months). Nevertheless, as described in surgical series, a small proportion of patients survive far longer. Previously identified prognostic factors in patients undergoing extra-pleural pneumonectomy (EPP) include histological subtype, gender and neutrophil-lymphocyte ratio (NLR). Similar factors including stage and performance status have also been shown to be prognostic in chemotherapy studies. We aim to assess in the general MPM patient population, what factors predict for better prognosis independent of the treatment path chosen.

      Methods
      We reviewed records of patients registered (2002 -2009) with the NSW Dust Diseases Board; a government compensation body for NSW workers with occupational asbestos exposure. We evaluated a priori prognostic factors including age, gender, histological subtype, staging on CT imaging and NLR using Kaplan Meier and Cox regression analysis, and by treatment interventions, smoking and asbestos exposure history. Exploratory subgroup analyses compared these factors in long-term (>20 months) survivors versus the remainder of the study population.

      Results
      We identified 913 patients: 90% male; median age 71.9 years; histological subtype (epithelioid 54%; biphasic 11%; sarcomatoid 16.3%; unknown 19%); stage on CT imaging (Tx-I-II 49%; III-IV 51%). 51% of patients received chemotherapy and 6% underwent EPP (of which 67% received chemotherapy. Median age of first occupational asbestos exposure was 18 years, cumulative duration of exposure, 24 years and latency from exposure to diagnosis, 50 years. Median OS was 10.0 months, 15.0 months (range(1-120) in patients receiving chemotherapy and/or EPP and 5.8 months (range 0-125) in patients receiving neither. On univariate analysis, younger age (<70 vs. >70yrs at diagnosis; 13.1 vs. 8.5 months; p<0.001); female gender (12.0 vs. 9.8months; p<0.001); epithelioid subtype (11.8 vs. 7.2 months ;p>0.001); and NLR <5 (12.9 vs. 7.5months; p<0.001) were associated with prolonged OS. Patients who underwent chemotherapy (13.6 vs. 7.2 months; p<0.001) and EPP (17.9 vs. 9.6 months; p<0.001) also had an improved survival. Smoking history (current/ex vs. never) and cumulative asbestos exposure did not affect survival. A trend to improved survival was noted with early stage disease (11.2 vs. 9.1 months; p=0.284) and younger age at first exposure (<18 vs. >18 years of age; 10.9 vs. 9.4 months; p=0.091). On multivariate analysis, age, gender, histological subtype, NLR, EPP and chemotherapy administration remained significant. 24% of patients demonstrated survival over 20 months. Of those, 14% underwent EPP, and 63% received chemotherapy. On multivariate analysis, epithelioid histology (p<0.001), chemotherapy use(p=0.002), undergoing EPP(p=0.01) and NLR<5(p=0.007) were independently associated with survival over 20 months.

      Conclusion
      In this large, population based cohort of MPM patients, we have validated age, gender, histological subtype and NLR as significant prognostic factors. Patients undergoing interventions such as EPP or chemotherapy demonstrated more favourable survival, however it is important to note that 86% of long survivors did not receive radical surgery, and 37% did not receive chemotherapy. As such, we hypothesise that apart from active treatment and inherent selection criteria, there are additional factors, such as favourable tumour biology, that seem to positively influence survival of MPM patients.

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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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      MO14.07 - Elevated tumour expression of miR-210 is associated with short survival in malignant pleural mesothelioma patients undergoing extrapleural pneumonectomy (ID 1491)

      11:10 - 11:15  |  Author(s): S. Kao

      • Abstract
      • Presentation
      • Slides

      Background
      Malignant pleural mesothelioma (MPM) is an aggressive cancer with a median survival of around one year and a 5 year survival rate of less than 10%. A selected group of patients with a potentially resectable tumour mass and good performance status may be considered for extrapleural pneumonectomy (EPP). However the results of this form of treatment are variable. Several prognostic markers have been explored to assist with patient selection including histological subtype, neutrophil-to-lymphocyte ratio (NLR), calretinin and microRNA miR-29c* expression in tumour tissue. In the present study we used microarray profiling to identify other microRNAs which might have the potential to serve as a prognostic biomarker.

      Methods
      The study used 60 formalin-fixed paraffin embedded (FFPE) tumour tissues from MPM patients who underwent EPP and had sufficient tumour for RNA extraction, a series which had been previously used to assess the prognostic value of the NLR. MicroRNA microarray profiling was performed on RNA from the 8 patients with longest (median: 53.7 months) and the 8 patients with shortest (median: 6.4 months) survival. Candidate microRNAs were selected on a basis of biological (>2-fold difference) and statistical (p<0.05) significance, and selected candidates were independently validated in the initial profiling samples using TaqMan assay-based microRNA-specific RT-qPCR. Levels of validated candidates were then assessed by RT-qPCR in 44 additional tumour samples. Overall survival (OS) was calculated from date of EPP and date of death or last follow-up, with patients still alive at last follow-up censored. The median relative expression level of each candidate was used as cut-off to determine high and low expression for examination using the Kaplan-Meier method. Individually significant (p<0.05) variables were entered into a multivariate model together with the established risk factors age, gender, histological subtype, NLR.

      Results
      Microarray profiling identified 12 microRNAs with lower expression in long-term survivors and 4 microRNAs with higher expression in long-term survivors. None of the microRNAs with higher expression in long-term survivors could be validated using RT-qPCR. Of the microRNAs with lower expression in long-term survivors, miRs-30e, -93, -106b, -210, and -222 were validated by RT-qPCR in the same samples used for the profiling and found to be significantly different between long-term and short-term survivors. The expression levels of miR-30e and miR-210 showed a significant association with survival. MiR-30e: median OS of 24.2 months for low expression vs 13.3 months for high expression (p=0.03); miR-210: median OS of 24.2 months for low expression vs 13.7 months for high expression (p=0.008). In addition, both gender and histological subtype were significant prognostic factors using a univariate model. Multivariate analysis with age, gender, histological subtype, NLR and microRNA expression included as variables revealed that miR-210 was the only factor remaining significant (p= 0.006; hazard ratio: 0.41; 95% CI: 0.2-0.85).

      Conclusion
      This study has identified expression of miR-210 as a potential new prognostic factor for patients undergoing EPP. Further validation is needed, but this marker has the potential to assist in better selection of patients considered for radical surgery of MPM.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 2
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      P1.14-001 - Estimates of expected years of life lost and lifetime direct medical costs for malignant pleural mesothelioma patients: data from Taiwan and New South Wales, Australia (ID 108)

      09:30 - 09:30  |  Author(s): S. Kao

      • Abstract

      Background
      Quantifying the burden of malignant pleural mesothelioma (MPM) is an important yet challenging task. Little is understood about the societal and economic costs following a diagnosis of MPM. We investigated survival, years of life lost, and direct medical costs associated with MPM using data from Australia and Taiwan.

      Methods
      159 and 136 MPM patients from New South Wales (NSW) Disease Dust Board data and Taiwanese Cancer Registry (TCR) data respectively were included in: (i) survival function analyses and (ii) analyses to estimate the years of life lost associated with a MPM diagnosis. Further, data on 428 patients from the Taiwanese National Health Insurance Research Database, and the NSW data linked to Medicare data, were also used to (iii) estimate lifetime healthcare expenditure following a MPM diagnosis.

      Results
      (i) The mean age at MPM diagnosis in NSW was 71 and 60 in Taiwan. Median survival in months for NSW MPM patients was 11.7 (95% CI 9.3, 13.5) and 6.0 (95% CI 5.1, 7.8) for TCR patients. Four and eight percent of patients in NSW and Taiwan respectively were estimated to survive up to five years following a MPM diagnosis. (ii) The lifetime survival difference between the MPM patient cohort and a comparable population free of the disease was estimated to be 13.6 (95% CI 13.4, 13.8) years in the NSW cohort and 18.8 (95% CI 18.5, 19.1) years in the TCR cohort. (iii) Using national health insurance data in Taiwan, we estimated that the direct heath care costs following a MPM diagnosis to be USD$18,812. In NSW, this cost was estimated to be USD$20,573.

      Conclusion
      We analysed MPM cohort data from Taiwan and Australia to estimate survival and expected life years lost, with possible differences in the age at diagnosis and median survival. We also analysed Taiwan and Australian data to estimate direct medical costs following a MPM diagnosis. The impact of selection bias in this study cannot be ruled out as there is likely under-ascertainment of MPM cases in the Taiwanese Cancer Registry and the NSW data is a subset of all MPM cases diagnosed in NSW. However, these estimates provide useful data to contribute to evidence-based clinical and policy decision-making in the area of MPM prevention and care services.

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      P1.14-010 - Estimation of an optimal chemotherapy utilisation rate for malignant pleural mesothelioma: An evidence-based benchmark for patient care (ID 2535)

      09:30 - 09:30  |  Author(s): S. Kao

      • Abstract

      Background
      Chemotherapy has been shown to provide a survival benefit in malignant pleural mesothelioma (MPM). There are wide ranging chemotherapy utilisation rates internationally (18 – 61%). This study aims to determine the optimal proportion of patients with MPM that should receive chemotherapy at least once during the course of their illness, based on the best available evidence, so that it can be determined whether chemotherapy is under-utilised in MPM.

      Methods
      An optimal chemotherapy utilisation tree was constructed using indications for chemotherapy identified from evidence-based treatment guidelines. Epidemiological data on the proportion of patient and tumour-related attributes for which chemotherapy was indicated (resectability of the tumour, degree of comorbidities and patient performance status) were obtained and merged with the treatment indications to calculate an optimal chemotherapy utilisation rate, using the decision analysis software (TreeAge Pro 2007). Sensitivity analyses were performed to assess the impact of major variations in the epidemiological data on the overall utilisation rate. This optimal rate was compared with reported actual rates of chemotherapy utilisation in the literature.

      Results
      Chemotherapy is recommended at least once in 65% of all MPM patients. Sensitivity analyses indicate an optimal utilisation rate ranging from 50 to 65% for at least once during the course of their illness. The optimal utilisation rate is consistently higher than the reported actual chemotherapy utilisation rates in United Kingdom (18%), Netherlands (36%), United States (37%), and Australia (54%).

      Conclusion
      An evidence-based model provided an optimal chemotherapy utilisation rate for patients with MPM of 65%. It can serve as a feasible measure of the quality of cancer care. Chemotherapy appears to be under-utilised in the management of MPM in a number of high-income countries.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-015 - Novel plasma proteins associated with prognosis in malignant pleural mesothelioma (ID 1337)

      09:30 - 09:30  |  Author(s): S. Kao

      • Abstract

      Background
      The search for novel biomarkers to define more successful and individual treatment approaches represent an important challenge for those involved in the care for patients with malignant pleural mesothelioma (MPM). In this exploratory study, we have systematically investigated the proteins present in plasma of MPM patients and correlated their levels with disease outcomes.

      Methods
      Plasma samples from twelve MPM patients (6 ‘short-’ and 6 ‘long-term’ survivors from parallel phase II studies investigating thalidomide) were used for proteomic analyses. Our series included samples from 9 patients with epithelial MPM and 3 patients with biphasic MPM. Plasma samples were immuno-depleted of the 14 most abundant proteins prior to labelling for isobaric tag for relative and absolute quantitation (iTRAQ) analysis using mass spectrometry. The most promising candidates and mesothelin were chosen for selected reaction monitoring mass spectroscopy (SRM-MS) quantification and enzyme-linked immunosorbent assay (ELISA) validation. Statistical analyses using T-Test of peak areas were used to identify proteins that were differentially expressed between the short- and long-term survivor groups.

      Results
      Median survival of short- and long-term survivors (1.2 and 38.3 months, respectively) differed significantly (p = 0.001). This was also the case for the neutrophil-to-lymphocyte ratio (NLR) that was significantly higher in the group of short-term survivors (p=0.03). Other baseline characteristics did not reveal major differences between the short- and long-term survivors. The total number of proteins identified was 226 (1% false discovery rate) in iTRAQ. A number of those were found to be differentially expressed between short- and long-term survivors (≥1.2-fold change; p≤0.05) by iTRAQ: selenoprotein P; tetranectin; insulin-like growth factor-binding protein 2 (IBP2); osteonectin (SPARC); platelet basic protein (CXCL7); and attractin. Mesothelin was assessed to validate the proteomic methodology: SRM-MS quantification was highly correlated with the MESOMARK ELISA values with a Pearson correlation of 0.82 (p=0.001). SRM-MS quantification revealed that the concentrations of attractin (p=0.02), tetranectin (p=0.003) and selenoprotein P (p=0.001) were higher in long-term survivors. In contrast, there was a trend for an increase in the concentration of SPARC (p=0.32), IBP2 (p=0.12) and CXCL7 (p=0.19) to be correlated with shorter survival. Furthermore, quantification by ELISA demonstrated an association between long survival and low concentration of SPARC (p=0.07) as well as high tetranectin (p=0.13).

      Conclusion
      We have demonstrated the feasibility of using the iTRAQ and SRM-MS proteomic techniques to investigate potential prognostic protein markers in plasma of MPM patients. Potential prognostic biomarkers worthy of further studies include SPARC and tetranectin and we plan to validate these in a larger clinical cohort.

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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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      P2.10-030 - Eastern Cooperative Oncology Group (ECOG) score: Agreement between non-small-cell lung cancer (NSCLC) patients and their oncologists and clinical implications (ID 1792)

      09:30 - 09:30  |  Author(s): S. Kao

      • Abstract

      Background
      Oncologists use ECOG score to assess patients’ performance status (PS) and guide treatment decisions, but patients and doctors do not necessarily agree on their score. We compared ECOG scores assessed by NSCLC patients and their oncologists to determine if this has implications on treatment and survival prediction.

      Methods
      NSCLC patients who underwent chemotherapy in prospective inter-ethnic difference and nutrition studies at Concord Hospital were included. Patients self-assessed their ECOG score as part of the Patient-Generated Subjective Global Assessment questionnaire prior to chemotherapy. Kappa was used to assess agreement of ECOG score between patients and oncologists. Survival was calculated from date of chemotherapy, using Kaplan Meier method.

      Results
      79 patients (median age 63 years, 86% Stages IIIB/IV, median survival of 15.5 months) were included. ECOG scores differed in 34 (43%) cases (Table).The interrater reliability between patients and their oncologists was Kappa = 0.35 (p <0.001). Figure 1 If patient ECOG scores were used, 11 patients (14%) would be deemed unfit for chemotherapy (ECOG≥3) and 21 patients (27%) would be excluded from clinical trials (ECOG≥2). ECOG status (0 versus >0) irrespective of assessor was predictive of overall survival (18.7 vs. 12.1 months with p=0.023 and 17.4 vs. 11.1 months with p=0.017 for patient and oncologist-assessed ECOG respectively). In patients whose ECOG score was assessed to be 0 by their oncologist (n=39), a worse survival was associated with a poorer patient assessed PS (median survival 16.7 vs. 18.2 months for patient assessed ECOG >0 vs. ECOG=0 respectively; p=0.31).

      Conclusion
      Both physician and patient-assessed ECOG scores are predictive of overall survival. In this study, there was only fair agreement in ECOG assessed by NSCLC patients and their oncologists, with patient scores usually poorer. A number of patients would have excluded themselves from therapeutic interventions including clinical trials based on their ECOG PS rating. Patient-assessed ECOG scores of > 0 may be associated with worse survival despite their oncologist’s more optimistic scoring, a finding which may be incorporated to benefit clinical decision-making.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 2
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      P3.14-012 - Pathological complete response after platinum-based chemotherapy in malignant pleural mesothelioma (ID 3072)

      09:30 - 09:30  |  Author(s): S. Kao

      • Abstract

      Background
      Prior to the demonstration of the efficacy of cisplatin/pemetrexed chemotherapy, Malignant pleural mesothelioma (MPM) was previously considered a chemotherapy-resistant tumour. In order to assess the efficacy of chemotherapy in the pre-operative setting, we aimed to: (1) determine the radiological and pathological complete response (CR) rate; (2) evaluate any potential association between pathological CR and patient characteristics; and (3) assess if pathological CR is associated with a longer disease free survival (DFS) and overall survival (OS) in MPM patients.

      Methods
      A retrospective review of a prospectively collected database of MPM patients treated with induction chemotherapy followed by extrapleural pneumonectomy (EPP) at our institutions since 2003 were performed. Radiological response was determined by CT/PET scans while pathological response was assessed by examination of the EPP specimen. OS and DFS from the day of EPP was determined by the Kaplan Meier method and comparison was made by log rank test. Chi square tests were used to determine potential association between pathological CR and patient characteristics.

      Results
      Forty-two patients are included: median age 63 years; 81% male. Pathology was 91% epithelial and 9% biphasic subtype. A median of 3 cycles of induction chemotherapy was administered with either 67% cisplatin-based and 31% carboplatin-based treatment. The regimen in the remaining 2% of patients was unknown. All patients proceeded to EPP and 86% of patients received adjuvant radiotherapy. The median OS was 30.6 months (95% CI: 2.9 – 58.2 months), while the median DFS was 19.6 months (95% CI: 11.0 – 28.2 months). No-one achieved a radiological CR. Four patients (9.5%) had pathological CR and all were male (p=0.31) and had epithelial subtype (p=0.50). No association was found between pathological CR and the type of chemotherapy (cisplatin vs. carboplatin; p=0.76) or the number of cycles administered (≤3 vs. >3; p=0.64). Median OS was 30.6 months vs. median not reached (p=0.31), while median DFS was 19.4 vs. 36 months (p=0.34), for those without pathological CR and those with pathological CR respectively.

      Conclusion
      A 9.5% pathological CR rate was demonstrated after induction chemotherapy, indicative of chemo-sensitivity in a subgroup of MPM patients. There was a trend for longer OS and DFS in MPM patients achieving a pathological CR.

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      P3.14-013 - Longitudinal Observation of Health Related Quality of Life following Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma (ID 3159)

      09:30 - 09:30  |  Author(s): S. Kao

      • Abstract

      Background
      The aim of this study was to describe the longitudinal picture of Health Related Quality of Life (HQOL) in people with Malignant Pleural Mesothelioma (MPM) post Extrapleural Pneumonectomy (EPP).

      Methods
      Participants receiving EPP from 2011- 2013 were assessed pre-operatively, pre and post adjuvant radiotherapy (Rt), and at 8, 12 and 24 months following surgery. Here we report Global HQOL and HQOL Domain Scores of the EORTC QLQ-C30, and Fatigue Scores from FACT-F. Least squares means were obtained from a mixed models analysis with time as a fixed effect, the pre-op assessment as a covariate and a random subject effect.

      Results
      Twelve men with a mean age of 65 years (range 48-78) completed pre-op and at least one post op assessment. Table 1 and Figure 1 report the mean HQOL domain scores, global HQOL and fatigue at baseline as well as the least squares mean and 95% confidence intervals at each follow up assessment. Table 1. Health related quality of life over time Figure 1 Figure 2 Figure 1: Health related quality of life over time These results suggest that people who elect to have EPP have baseline levels of HQOL comparable to the general population. As expected, HQOL declines after surgery and during adjuvant radiotherapy. Emotional functioning changes least, while physical and social functioning closely mirror each other. Role functioning is the domain most affected and remains low out to 24 months. Global HQOL is relatively stable over time, with an apparent increase at 24 months. Fatigue is worst at the conclusion of radiotherapy and gradually improves.

      Conclusion
      People electing to have EPP report a sudden decline in HQOL, with the nadir around the end of adjuvant radiotherapy. This gradually improves over time, returning to slightly below baseline in many domains.