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J.P. Van Meerbeeck



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    MTE23 - Screening Tools for a High Risk Population - Can We Screen for Early Mesothelioma? (ID 67)

    • Event: WCLC 2013
    • Type: Meet the Expert (ticketed session)
    • Track: Mesothelioma
    • Presentations: 1
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      MTE23.1 - Screening Tools for a High Risk Population - Can We Screen for Early Mesothelioma? (ID 621)

      07:00 - 08:00  |  Author(s): J.P. Van Meerbeeck

      • Abstract
      • Presentation
      • Slides

      Abstract
      Malignant pleural mesothelioma (MPM) is an asbestos-related disease with a very poor prognosis because of late-stage diagnosis due to unspecific imaging techniques and non-specific symptoms resembling pleural effusions such as chest pain and dyspnea. Early diagnosis could improve the disease’s outcome by reducing the diagnostic delay. Serum tumor biomarkers for early MPM screening are attractive because of their non-invasive and low-cost nature. Nevertheless, MPM is a heterogeneous disease suggesting an ideal biomarker should be capable of capturing all the MPM subtypes and to distinguish MPM from benign or metastatic pleural conditions. To have a clinical impact, biomarkers should predict the development of the disease in which a positive test could enrich the at-risk population eligible for further screening and reduce the economical burden of wild screening. In order rule in MPM, a biomarker should have a positive predictive value of minimally 10%, and the low MPM prevalence urges the need for a high test specificity. Many candidate blood biomarkers have been studied such as hyaluronic acid, carcinoembryonic antigen, CYFRA 21.1 and cancer antigen 125. Nonetheless, their accuracy is insufficient and based upon small-sized retrospective studies without further validation. Hence, they are of little use in clinical practice. More recently, the cell adhesion proteins soluble mesothelin (SM), megakaryocyte potentiating factor (MPF) and osteopontin (OPN) were investigated. OPN functions in cancer progression, bone matrix formation and immunologic responses. Despite 78% sensitivity and 88% specificity found by Pass et al., subsequent validation studies revealed contradictory accuracy findings with AUCs ranging from 0.64 to 0.89. Furthermore, OPN lacks specificity because it is overexpressed in other tumor types, limiting its use as a diagnostic mesothelioma marker. SM has been found the best available serum marker for MPM. It is derived from a mesothelin gene-encoded precursor protein, which is cleaved into a soluble fraction (MPF) and a membrane-bound fraction (mesothelin) involved in cancerous growth, proliferation and migration and present on the pleural, peritoneal and pericardial mesothelial cells. SM enters the circulation by shedding of the membrane-bound mesothelin or frameshift mutations and is highly expressed in mesothelioma and other malignancies. The first determined serum MPF levels differentiated MPM from healthy controls with 91% sensitivity and 100% specificity. Subsequent studies resulted in diagnostic accuracies with AUCs between 0.79 and 0.88. MPF and SM are highly correlated and have equal diagnostic performances. SM was elevated in MPM patients compared to controls and had discriminative power with 84% sensitivity and 100% specificity. A commercial MesoMark[TM] ELISA assay for SM was developed and evaluated by different groups gaining diagnostic accuracies with AUCs from 0.72 to 0.81. The use of SM as diagnostic marker is still under debate because of large intergroup inconsistencies. An individual patient data meta-analysis was performed, yielding an AUC of 0.77 representing the overall SM diagnostic performance. When SM was used to rule in or rule out diagnosis, the specificities and sensitivities were respectively 95% and 32% and 22% and 95%. SM has low specificity and is only selective for epithelioid and biphasic MPM, hampering its use as a stand-alone marker and possible replacement of the current gold standard of invasive histopathologic diagnosis. Hence a combination of several tumor markers might improve the diagnostic performance. However, combining SM, OPN and MPF did not outperform the accuracy of SM alone and it is necessary to take GFR, BMI and age into account as confounding effects because they influence the biomarker levels. New markers like HMGB1 and fibulin-3 were investigated and were found upregulated in patients sera compared to sera from healthy controls. Although both are promising, a long and cumbersome validation process will need to be executed comparing the accuracy of both biomarkers with serum SM. In the past, several programs have been conducted to screen asbestos-exposed individuals for lung disease with annual chest X-rays. Besides demonstrating the presence of benign asbestos-related diseases, these modalities have not proven to be effective at detecting early malignancies. CT has a superior sensitivity, and its use in screening has been examined in several large-scale studies (Table). Results predominantly illustrate the low prevalence of mesothelioma, and the high background noise (non-calcified nodules) in asbestos-exposed populations. In addition, the standardization of reading both chest X-ray and CT has proven to be difficult, while the cost and radiation doses represent other problematic issues. PET and MRI are currently not applied in screening, and their cost is likely to be prohibitive. Altogether, it is now generally accepted that the use of imaging has not made any impact on the early detection of mesothelioma, and their use is not recommended by the different (inter)national guidelines. In the future, the ‘Holy Grail’ could be sniffed out thanks to the innovative field of exhaled breath analysis. Volatile organic compounds (VOCs) arise from the cells’ metabolism and are released in exhaled breath, making these promising diagnostic MPM markers obtained via high-throughput non-invasive techniques. Electronic nose (eNose) analysis has shown promising results for diagnosing MPM with diagnostic accuracies ranging from 80.8% to 95% in discriminating MPM patients from asbestos-exposed and healthy individuals. However, eNoses work as blackboxes and do not identify VOCs as possible biomarkers. GC-MS analysis identified cyclohexane to discriminate MPM patients from asbestos-exposed and healthy persons. Although this research field opens new perspectives for biomarker discovery, a lot of small-sized studies were performed in order to identify new biomarkers for screening, urging the need for large-scale validation studies. Although different routes of discovering biomarkers for early screening have been paved, the way to a validated and clinically useful screening biomarker panel still has to be constructed. Table: Prospective screening studies using chest CT in asbestos-exposed cohorts to detect asbestos-related malignancies.

      Reference Total (n) Lung cancer (n) Mesothelioma (n)
      Tiitola et al. 602 5 1 peritoneal
      Vierikko et al. 633 5 1 pleural
      Fasola et al. 1045 9 -
      Mastrangelo et al. 1119 5 -
      Roberts et al. 516 6 2 pleural/2 peritoneal
      Total 3915 30 (0.7%) 6 (0.2%)

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    O27 - Clinical Trials and Practice (ID 142)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Other Topics
    • Presentations: 1
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      O27.06 - Resistance training in patients with radically treated respiratory cancer: mature results of a multi-centre randomised phase 3 trial (REINFORCE) (ID 678)

      17:10 - 17:20  |  Author(s): J.P. Van Meerbeeck

      • Abstract
      • Presentation
      • Slides

      Background
      There is a lack of data on the effect of conventional resistance training (CRT) on exercise capacity, muscle strenght and quality of life (QoL) in patients with lung cancer. Whole body vibration (WBV) is proposed as an alternative to CRT. We investigated the effect of a radical treatment and of two post-treatment resistance training programmes on the 6-minutes walking distance (6MWD).

      Methods
      Selected patients with clinical stage I-IIIB (non-) small cell lung cancer or I-II mesothelioma were evaluated before (M1) and at completion (M2) of their radical treatment, and thereafter randomised to either control (CON), CRT or WBV. 6MWD was measured at M1, M2 and at least 12 weeks (w) after randomisation (M3) considering a minimal clinically important difference (MCID) of 54 m. Assuming that this MCID would occur in 10% of the CON-group and aiming for an increase to at least 50% in the combined intervention groups (CRT and WBV), a sample size of 25 participants in each arm was required for a power of 90%. Secondary endpoints were estimated by appropriate MCID's for maximal exercise capacity (Wmax), muscle strenght (Quadriceps Force (QF)) and QoL (physical functioning (PF), fatigue (F), pain (P) and dyspnea D)). Multiple imputation was used to correct for patients not finishing the intervention.

      Results
      Of the 86 patients completing radical treatment, 70 were randomised: 24 to CON, 24 to CRT and 22 to WBV. Characteristics at M1 were well balanced. Radical treatment significantly decreased 6MWD, Wmax, QF, PF and increased P, F and D at M2. At M3, 20 of 37 (54%) patients in the combined CRT-WBV-group reached the MCID for 6MWD vs. 5 of 21 CON (24%) patients (p=0·031). 6MWD increased with 95 m (58–132) in CRT (p<0·0001), 37 m (-1–76) in WBV (p=0·06) and 1 m (-33–36) in CON (CRT vs. CON p=0·0006 and WBV vs. CON p=0·16). CRT and WBV patients recovered and exceeded their M16MWD, albeit not significantly. A significant mean increase in Wmax occurred in both CRT and WBV but not in CON, while QF increased only significantly in CRT. The mean score for PF at M3 improved in CON and WBV but only significantly with WBV. The mean score for P and F at M3 did not change significantly, however the MCID for F was reached in 37% of CRT, 44% of WBV and 30% of CON-patients. The mean score for D at M3 decreased significantly after WBV only. Multivariate analysis showed that there was no significant interaction between rehabilitation and surgery with regard to the MCID in 6MWD (p=0.96).

      Conclusion
      Radical treatment significantly impairs exercise capacity, muscle strength and QoL. CRT significantly improves and restores functional exercise capacity, whilst WBV does not fully substitute for CRT. Resistance training by CRT should be offered to radically treated lung cancer and mesothelioma patients. Supported by research grant 070708 of the Belgian Government Agency of Innovation by Science and Technology for applied Biomedical Research (NCT: 00752700)

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    P2.07 - Poster Session 2 - Surgery (ID 190)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P2.07-040 - Is postoperative FEV1 (poFEV1) more accurately estimated by Functional Respiratory Imaging (FRI) than by conventional methods? (ID 3090)

      09:30 - 09:30  |  Author(s): J.P. Van Meerbeeck

      • Abstract

      Background
      Accurate estimation of poFEV1 remains challenging. Underestimation excludes patients with early stage lung cancer from a potential curative resection, overestimation gives more postoperative complications. The anatomic segment method (ASM) and the perfusion scintigraphy (QS) are standard methods, although both underestimate actual poFEV1 (Holvoet 2011). FRI, describing flow characteristics in the lungs, estimates poFEV1 after virtual resection (De Backer 2010). We compared the accuracy of FRI with ASM and QS in the estimation of poFEV1 in patients planned for resection of lung cancer.

      Methods
      23 consecutive patients underwent pre- and postoperative FEV1 measurements by spirometry, ASM, QS and FRI. ASM-poFEV1 was estimated by the product of preop FEV1 with (1-number of resected segments /19). QS-images were obtained following intravenous injection of 175 MBq of [99m]Tc-MAA, using geometric means method to determine left and right sided contribution. QS-poFEV1 was the product of preop FEV1 x (1- number of resected segments/total number of segments in operated lung x perfusion in this lung). Pneumotach controlled CT scan at maximum expiration (RV) and inspiration (TLC) allowed to segment lobar volumes and calculated regional expansion (EXP). Resistances (iRaw before and after virtual resection) were acquired through computational fluid dynamics. FRI-poFEV1 equation: Figure 1

      Results
      Data of 14 patients are available: 8 male, median age 63 y (51-73), median preop FEV1 2490 ml (1660-4070), 10 lobectomy, 2 bilobectomy, 2 pneumonectomy. Median actual poFEV1 was 2100 ml (1210-3210). The Pearson correlation coefficient (R[2]) paired t-test and root mean square error (RMSE) between actual and predicted poFEV1 are shown below. FRI-poFEV1 underestimated fewer cases with respect to the actual- 7% variation corrected-poFEV1 (Oostveen,2013 in press) than the other methods.

      Method Predicted median poFEV1 (ml) (range) Underestimated cases (n) R[2] Slope RMSE (ml) P (paired t-test)
      ASM 1660 (1240-2970) 11/14 0.77 1.06 436 <0.001
      QS 1980 (1320-3040) 7/14 0.84 1.10 309 0.007
      FRI 2050 (1450-3440) 4/14 0.86 0.98 213 0.76

      Conclusion
      FRI seems a superior predictor of actual poFEV1 in resected lung cancer pts than either conventional method, allowing for 20% more functionally operable patients. Confirmation in a larger serie is ongoing.

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-021 - Adjuvant or Induction chemotherapy for Non Small Cell Lung Cancer treated with chemoradiotherapy: An invidual data metaanalysis of phase II trials (ID 1421)

      09:30 - 09:30  |  Author(s): J.P. Van Meerbeeck

      • Abstract

      Background
      it is well known that combining chemotherapy and radiation therapy is beneficial to patients with locally advanced non small cell lung cancer compared to radiation alone or compared to a sequential approach using chemotherapy and radiation therapy. However, it is not obvious what is the best schedule. A few randomized trials assessed chemotherapy as induction before chemoradiotherapy (CT -> CTRT) versus chemotherapy as consolidation, after chemoradiotherapy (CTRT -> CT). Most of those trials are phase II trials with moderate sample sizes and were not designed to demonstrate treatment effect in terms of overall survival.

      Methods
      the study coordinators of those trials (T. Berghmans, H. Choy, P. Fournel, P. Garrido, J. Van Meerbeeck) agreed on a protocol for carrying out a meta-analysis of individual patients data and for sharing the individual patients data that were sent to the coordinating institution. Overall survival was the primary outcome, progression-free survival and toxic death occurrence were among the secondary outcomes. The treatment effect was assessed through the estimation of the hazard ratio of the survival distributions using CTRT -> CT as reference. Combined hazard ratio was obtained through Cox regression models (fixed effects) with a stratification by trial. Preplanned interactions between baseline covariates (age, sex, performance status, stage, histology) and treatment effect were assessed. Toxic death rates were analyzed per trial and odds ratios have been estimated to assess the treatment effect. Combined odds ratio was obtained by the Peto method.

      Results
      the data bases of the 5 eligible identified trials (3 with cisplatin based chemotherapy regimens, 2 with carboplatin based regimens) were shared for a total of 534 patients (CT -> CTRT 271, CTRT -> CT 263). Median ages were 60 and 61 years, stage IIIB represented 69%/70% of the patients and EOCG PS > 1 was rare (3%/2%). Median follow-up ranged from 12 months up to 66 months and rates of events from 44% to 88%. No significant difference was detected either for overall survival with an estimated HR of 0.96 (95% CI : 0.79-1.17) without heterogeneity between the 5 trials (I[2]=0) or for progression-free survival (analysis restricted to 4 out of the 5 trials), HR=0.91 (95% CI : 0.75-1.11) and absence of heterogeneity (I[2]=2%). For both outcomes, no interaction between the above specified covariates and treatment effect was found. Toxic deaths occurred overall in 3% of the patients, no detectable impact of treatment arm was found with a combined odds ratio of 0.40 and a 95 % CI overlapping 1 (0.15-1.06).

      Conclusion
      our results suggest that there is no argument in favour of one of the two therapeutic schedules when looking at overall survival or at progression free survival; however, in the absence of benefit in terms of prognosis, a more detailed evaluation of toxicity is warranted and is ongoing.

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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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      P3.14-003 - Volatile Organic Compounds as diagnostic tool for Malignant Pleural Mesothelioma. (ID 709)

      09:30 - 09:30  |  Author(s): J.P. Van Meerbeeck

      • Abstract

      Background
      Early diagnosis of malignant pleural mesothelioma (MPM) can improve patients’ outcome but is hampered by non-specific symptoms and investigations, which delay diagnosis and result in advanced stage disease [van Meerbeeck JP, 2011]. An accurate non-invasive test allowing early stage diagnosis in asbestos-exposed persons is lacking. Breathomics aims at a non-invasive analysis of volatile organic compounds (VOCs) reflecting the cells’ metabolism. The breathogram obtained by the electronic nose does however, not allow identification of MPM-related VOCs [Chapman EA 2009, Dragonieri S 2011]. Ion mobility spectrometry (IMS) combines the advantages of online direct sampling with the possibility of VOC identification and linking to MPM pathogenesis [Baumbach JI 2009]. We investigated which VOCs could play a role in MPM pathogenesis in order to build a possible diagnostic MPM tool.

      Methods
      10 MPM patients and 10 healthy asbestos-exposed individuals (mean asbestos fiberyear count 14,6 (5,5) fibre.years/cc) were included after refraining from eating, drinking and smoking for at least 2 hours before sampling. They breathed tidally for 3 minutes through a mouthpiece connected to a bacteria filter. Ten ml alveolar air was sampled via a CO~2-~controlled ultrasonic sensor and analyzed using the BioScout Multicapillary Column/Ion Mobility Spectrometer (MCC/IMS, B&S Analytik, Dortmund, Germany) [Westhoff M 2009], by using N~2~ as a carrier gas. Per subject a background sample was taken. Peaks of interest were visually selected and their intensity (V) was analyzed and compared between background and breath samples via on-board VisualNow 3.2 software and SPSS v21 (IBM) using Mann-Whitney-U tests.

      Results
      Out of 41 peaks of interest, three show a significantly higher intensity in the exhaled breath of MPM patients than healthy controls [Table]. The high AUC~ROC~ of resp. P12 (0.877) and P24 (0.863) suggests a possible role of these associated VOCs in MPM pathogenesis and as a diagnostic marker in discriminating MPM patients from asbestos-exposed healthy controls. Figure 1

      Conclusion
      Several VOCs of interest were obtained in the breath of MPM patients. Two peaks were significantly discriminating between both populations. GC-MS analysis and further large cohort studies are ongoing in order to validate the accuracy of IMS as a diagnostic tool for MPM.

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    P3.16 - Poster Session 3 - Other Thoracic Malignancies (ID 188)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P3.16-002 - Outcome and prognostic factors of bronchopulmonary neuroendocrine tumors (BNETS): a single intitutional series (ID 2277)

      09:30 - 09:30  |  Author(s): J.P. Van Meerbeeck

      • Abstract

      Background
      BACKGROUND: BNETs consist of typical carcinoids (TC), atypical carcinoids (AC) and large cell neuroendocrine carcinomas (LCNEC) based on cellular differentiation, mitotic count and the presence or absence of necrosis [Travis 2004]. Since 2009, NETs are included in the TNM-classification for lung cancer [Sobin 2009]. Whilst increasing evidence points towards the prognostic value of the Ki67 index (a measure of the proliferative capacity [Rugge 2008, Grimaldi 2011]), it is unclear which classification method provides the best prognostic stratification. In this series, the prognostic value of clinicopathological characteristics was assessed, including differentiation, stage and proliferation.

      Methods
      METHODS: Medical records of pts with a histologically proven BNET, treated at Ghent University Hospital between January 2001 and June 2012, were retrospectively reviewed for clinical, staging, histopathological and treatment data. Overall and disease-specific survival (DSS) were estimated and correlated to clinicopathological features using uni- and multivariate analysis.

      Results
      RESULTS: Information on differentiation and staging was available in 55 of 57 retrieved pts (96.5%). Tumors were mostly TC (49%) or LCNEC (42%). Twelve pts (22%) presented with stage IV disease, 7 (13%) stage III, 9 (16%) stage II and 27 (49%) stage I. The Ki67 index was assessed in 14 tumors (25%), with a median of 12.5% (2.0 – 95.0%). Ki 67 levels were lowest in TCs and highest in LCNECs (p = 0.014). Forty-one (72%) patients underwent a resection, which was R0/1 in 39. Outcome data are in the table. A strong association was found between differentiation and stage (p <0.001). With a median follow-up of 25 months (0.0 – 132.0), 17 pts (29.8%) died from a tumor-related cause. Male gender (p = 0.025), peripheral tumor (p = 0.04), LCNEC (p < 0.001), higher Ki 67 index (p= 0.03) and stage IV (p < 0.001) were significant predictors of lower DSS in univariate analysis. Ki 67 index was not included in the multivariate analysis, which identified tumor stage as the independent predictor of DSS. Pts with stage IV disease had a 27-fold (95% CI 2.7 – 263.4, p = 0.005), those with stage III disease a 12-fold (1.3 – 113.1, p = 0.026) increased risk of dying from their BNET compared to pts with stage II disease. None of the 27 pts with stage I disease died from a tumor-related cause.

      Median (m) 1y SR (%) 3y SR (%) 5y SR (%) 10y SR (%)
      Disease-specific survival 128 81.5 67.3 67.3 67.3
      Overall survival 128 76.6 63.2 63.2 63.2

      Conclusion
      CONCLUSION: In this series of BNETS, tumor stage is the only independent predictor of prognosis. Further research is needed to assess the prognostic value of Ki67.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-032 - Second opinion for thoracic cancer and its impact on diagnosis and treatment strategy: a single institutional series (ID 1950)

      09:30 - 09:30  |  Author(s): J.P. Van Meerbeeck

      • Abstract

      Background
      Lung cancer patients increasingly seek a second opinion in order to make sure they are receiving an exact diagnosis and an optimal treatment. A second opinion is more likely to be comprehensive when performed in centers with high level of expertise and within a multidisciplinary team.

      Methods
      A dedicated second opinion outpatient clinic was started within the Thoracic Oncology Unit of Ghent University Hospital, in March 2012, aiming at a quick access and evaluating its impact on diagnosis and treatment decisions. Second opinion was defined as a review of the cancer diagnosis and/or the treatment recommendations by another independent oncologist and/or multidisciplinary team. Patients had to be referred by either their general practitioner or the treating specialist. Prior to the consultation relevant investigations (medical history, pathology and imaging) had to be provided.

      Results
      Between March 2012 and June 2013, 79 pts were referred: 31 women and 48 men with a median age of 64 years [17-81 yrs]. Of these, 17 (22%) were never smokers, 18 (23%) smokers and 40 (51%) ex-smokers. Median interval was 3 working days [0-15 days] after first referral. Eighteen percent of patients were referred by their GP’s versus 80% by their treating specialist. Medical information including imaging was available in all pts at the moment of the consultation. Diagnosis included: adenocarcinoma (n=43 - 54%), squamous cell carcinoma (n=8 - 10%), NSCLC, NOS (n=1 large cell neuroendocrine carcinoma (n=3 - 4%), small cell lung cancer (n=4 - 5%), mesothelioma (n=6 - 8%), thymoma (n=2 - 3%), carcinoid tumor (n= 4 - 5%). In 4 patients no diagnosis had been established. Eleven patients were referred for confirmation of diagnosis and treatment, 11 for staging and 57 for treatment advice. Median consultation duration was 35 minutes [15-60 min], median time of multidisciplinary counseling 15 minutes [5-60 min]. In 43% of the referrals, diagnosis and treatment was confirmed, in 21% other diagnostic examinations were advised and in 29% a substantial change in treatment was proposed. Six percent of patients entered into a clinical trial. Almost 50% of patients continued their treatment at our center (26% on request of the referring physician, 23% on patient's request). Patient's satisfaction on waiting time and quality of the advice was high.

      Conclusion
      This dedicated second opinion outpatient clinic confirms the need for an academic second medical advice and provided a quick access. In 50% of cases a substantial change in diagnostic procedure or treatment was proposed.