Malignant Pleural Mesothelioma Patients Research Articles

MS 06.05 The Use of Adjuvant IMRT after Pleurectomy/Decortication

MS 06.05 The Use of Adjuvant IMRT after Pleurectomy/Decortication

P3.09-003 Heart Radiation Dose as a Risk Factor for Dyspnea Worsening After Multimodality Treatment for NSCLC and MPM: An Exploratory Analysis

The purpose of our study was to quantify the influence of heart dose on the early and late onset of dyspnea in a cohort of non-small cancer (NSCLC) and malignant pleural mesothelioma (MPM) patients having multimodality treatment including radiotherapy (RT).

MS 08.04 Immunotherapy in MPM

MS 08.04 Immunotherapy in MPM

P3.09-007 Thoracic Asymmetry and Its Impact on Survival after Radiation and Surgery for Malignant Pleural Mesothelioma

Staging for malignant pleural mesothelioma (MPM) remains a challenge due to poor prognostic utility. Other clinical factors may improve and refine the staging system. We investigate the impact thoracic asymmetry at time of initial presentation prior to therapy on survival in MPM patients treated with multimodal therapy. We reviewed 93 consecutive treatment naïve MPM patients treated with Surgery for Mesothelioma after Radiation Therapy (SMART protocol) from Sep 2008 to Jul 2015. The right and left axial thoracic areas (defined as the product of the ant-post and med-lat extent of hemithoraces at the level of carina) were used to calculate the asymmetric thoracic ratio (ATR, where 1 is more symmetric, Fig 1). Significant factors were determined using univariate (log rank), multivariate (Cox proportional hazards) as well as recursive partition analysis (RPA). Continuous variables were discretized into binary categories split by its median value. After a median follow-up of 15.6 months, 63 (68%) patients recurred, 56 (60%) died. The median ATR was 0.85, ranging from 0.52 to 1.00. On univariate analysis, histology (p=0.003 and 0.0002), gross tumor volume (GTV, p=0.004 and 0.001), and ATR (p=0.00001 and 0.0000002) all significantly impacted both overall and disease free survival, respectively, while mediastinal nodal involvement (p=0.03) was significantly associated with DFS only. On multivariate analysis, histology (p=0.01 and 0.005) and GTV (p=0.02 and 0.016) significantly impacted both overall and disease free survival, respectively. ATR significantly impacted disease free survival (p=0.02, HR=0.06 95% CI 0.02-0.20) and was suggestive of a trend for overall survival (p=0.07). On RPA, ATR<0.848 was significantly (p<0.001) associated with poorer DFS. A low asymmetric ratio (ATR<0.848) is significantly associated with poorer outcomes, specifically disease free survival, and is independent of histology and tumor volume. Further study is needed to validate this parameter.

MA 19.01 A Phase II Study of Nivolumab: A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma (MERIT)

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy with poor prognosis and limited treatment options beyond progression after platinum-based combination with pemetrexed chemotherapy. Nivolumab (anti-PD-1, ONO-4538, BMS-936558), a humanized monoclonal antibody, PD-1 immune-checkpoint inhibitor, has demonstrated antitumor activity and a manageable safety profile in several advanced malignancies. Here, we report the preliminary results of a phase II study to evaluate the efficacy and safety of Nivolumab in previously treated Japanese MPM patients (pts): ONO-4538-41/JapicCTI-No.163247.

P2.09-002 Prevalence and Survival of Malignant Pleural Mesothelioma Patients Treated in a Single Brazilian Cancer Center

P2.09-002 Prevalence and Survival of Malignant Pleural Mesothelioma Patients Treated in a Single Brazilian Cancer Center

Soluble Mesothelin-Related Peptides to Monitor Recurrence After Resection of Pleural Mesothelioma

Most patients undergoing surgical resection of malignant pleural mesothelioma (MPM) will experience recurrence, and radiographic diagnosis of recurrence can be difficult in the postoperative chest. Our objective was to determine the utility of the serum biomarker soluble mesothelin-related peptide (SMRP; or mesothelin) in monitoring of the postoperative MPM patient. We retrospectively evaluated a prospectively maintained single institution clinical database. SMRP levels were evaluated preoperatively and postoperatively in patients undergoing surgical resection of MPM. One hundred two patients underwent pleurectomy/decortication (58%), extrapleural pneumonectomy (20%), chest wall resection (2%), or exploratory thoracotomy (20%) for MPM of 81% epithelial histology. Sixty percent received heated intraoperative chemotherapy and 57% received perioperative systemic chemotherapy. Patients with epithelial histology had substantially greater mean (± SD) preoperative SMRP levels (4.5 ± 7.3 nmol/L) than did patients with biphasic (1.9 ± 2.5 nmol/L) or sarcomatoid (1.2 ± 1.0 nmol/L) histology. Radiologic 3-dimensional tumor volume and tumor mesothelin gene (MSLN) expression correlated with preoperative SMRP. In patients with epithelial histology undergoing complete resection (n= 66), preoperative SMRP (3.4 ± 4.9 nmol/L) dramatically decreased immediately after operation (0.8 ± 0.5 nmol/L), and preoperative SMRP was independently associated with poor disease-free survival. Percentage of change in serial postoperative SMRP values at the best statistical cutoff at 48% revealed high predictive capability of disease recurrence with 90% sensitivity and 93% specificity (area under the curve= 0.96, p < 0.001). SMRP is a promising serum biomarker for the detection of recurrence after resection of epithelial MPM that may have value in clinical practice and should be studied in a prospective cohort.

Fast, Low-Dose Megavoltage-Topogram Localization in a Helical IGRT Unit: Initial Clinical Experience with Mesothelioma Patients

To present our initial clinical experience with malignant pleural mesothelioma (MPM) patients in Megavoltage (MV)-Topogram trial, for evaluating the potential of MV-Topogram-based alignment as an alternative to Megavoltage Computed Tomography (MVCT) in reducing imaging time and dose. Four mesothelioma patients were enrolled in an on-going Institutional Review Board (IRB)-approved MV-Topograms clinical trial at our institute. Patients were set up using the clinical protocol employing red lasers. Anterior-Posterior (AP) and lateral (LAT) MV-Topograms were acquired using gantry angles of 0°/90° with 1 mm collimator opening, all MLC leafs open, 4 cm/s couch speed, and 12.5 s scanning time. Routine MVCT scans were performed immediately afterwards. MV-Topograms were reconstructed and enhanced using contrast-limited adaptive histogram equalization (CLAHE). AP and LAT kilo voltage (kV) digital reconstructed topograms (DRT) images were reconstructed based on TomoTherapy geometry from CT simulation scans. Registrations between MV-Topograms and kV-DRT images were performed by a physicist manually. Due to image contrast limitations, the registration primarily involved aligning the carina. To be consistent with MV-Topograms, the same physicist re-aligned MVCTs to planning CT based on carina as well. Results were compared between MV-Topograms based shifts and the corresponding MVCT shifts. MV-Topogram and MVCT doses were measured using an ion-chamber in a 28 cm diameter cylindrical water-equivalent phantom at depths between 1-14 cm. The mean and standard deviation of shift discrepancies between MV-Topogram and MVCT were -0.52±1.35 mm, 2.51±2.40 mm, -0.24±4.09 mm in lateral, longitudinal and vertical directions for manual registrations. The dose ratio between MVCT and MV-Topogram ranged from 14.7 to 26.9 for depths between 1 cm and 14 cm, respectively. On average, the time required to acquire 38 cm long MVCT scans were five times more than a pair of 50 cm long MV-Topograms. Lateral and vertical shifts from MV-Topograms showed equivalent alignment results with MVCT. The greatest discrepancy between the MV Topograms and MVCT was in the longitudinal direction. This could be due to the breathing motion of the carina, which has been shown to be approximately 5 mm in the longitudinal direction. Substantial reductions of dose and acquisition time were observed for MV-Topogram. Challenges of employing bony anatomy for Topogram alignment were the relatively poor contrast and image artifacts caused by small dose rate fluctuations. Improving the linear accelerator dose stability would improve the ability to employ MV Topograms for patient alignment.

External validation of prognostic indices for overall survival of malignant pleural mesothelioma

ObjectiveThere are several prognostic indices (PIs) to predict overall survival (OS) in malignant pleural mesothelioma (MPM) patients. Before using a clinical prediction model in the actual clinical setting, empiric evaluation of its performance based on datasets that were not used to develop the model (i.e., external validation) is essential. The purpose of this study was to conduct an external validation of the PIs for MPM. Materials and methodsA retrospective cohort study was performed on MPM patients treated at 2 tertiary hospitals in Japan between 2007 and 2015. The primary outcome was OS. Harrell’s c-index, and was calculated to examine the discrimination of three models. The bootstrapping technique was used to evaluate optimism. ResultsThe participants comprised 183 patients who underwent surgical treatment (n=61), chemotherapy (n=101), and best supportive care (BSC, n=21). The median OS rates were 1014days for surgery, 690days for chemotherapy, and 545days for best supportive care (BSC). The respective discriminations (95% confidence interval) of the Eastern Cooperative Oncology Group Performance Status, the European Organisation for Research and Treatment of Cancer index, regimen, PS, histology or stage (rPHS) index, and Tagawa index for the OS of MPM patients were 0.532 (0.444–0.620), 0.560 (0.472–0.648), 0.584 (0.452–0.716), and 0.525 (0.453–0.596) for surgery; 0.632 (0.539-0.724), 0.622 (0.548–0.696), 0.677 (0.587–0.766), and 0.545 (0.436–0.653) for chemotherapy; and 0.504 (0.365–0.644), 0.583 (0.456-–0.710), 0.704 (0.508–0.899), and 0.583 (0.436–0.730) for BSC. ConclusionsEach PI showed poor discrimination for MPM patients who underwent surgical treatment. The rPHS index showed moderate discrimination for patients given chemotherapy and BSC.

Prognostic and predictive role of [18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with unresectable malignant pleural mesothelioma (MPM) treated with up-front pemetrexed-based chemotherapy.

The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG‐PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed‐based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first‐line pemetrexed‐based chemotherapy, and evaluated by FDG‐PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression‐free survival (PFS) and overall survival (OS) were correlated with FDG‐PET parameters, such as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), and percentage changes in SUVmax (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUVmax and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUVmax reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG‐PET in a large series of MPM patients treated with first‐line pemetrexed‐based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut‐off values to define early metabolic response supported the role of FDG‐PET in predicting disease outcome and treatment response in patients not receiving pleurodesis.

Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with an increasing incidence, poor prognosis and limited effective treatment options. Hence, new treatment strategies are warranted which include immune checkpoint blockade approaches with encouraging preliminary data. Research on the immunological aspects of the easily accessible mesothelioma microenvironment could identify prognostic and/or predictive biomarkers and provide useful insights for developing effective immunotherapy.In this context, we investigated the immune cell composition of effusions (pleural and ascites fluids) from 11 different chemotherapy-treated MPM patients. We used multicolor flow cytometry to describe different subsets of immune cells and their expression of immune checkpoint molecules TIM-3, LAG-3, PD-1 and PD-L1. We demonstrate a patient-dependent inter- and intraspecific variation comparing pleural and ascites fluids in immune cell composition and immune checkpoint expression. We found CD4+ and CD8+ T cells, B cells, macrophages, natural killer cells, dendritic cells and tumor cells in the fluids. To the best of our knowledge, we are the first to report TIM-3 and LAG-3 expression and we confirm PD-1 and PD-L1 expression on different MPM effusion-resident immune cells. Moreover, we identified two MPM effusion-related factors with clinical value: CD4+ T cells were significantly correlated with better response to chemotherapy, while the percentage of PD-L1+ podoplanin (PDPN)+ tumor cells is a significant prognostic factor for worse outcome. Our data provide a basis for more elaborate research on MPM effusion material in the context of treatment follow-up and prognostic biomarkers and the development of immune checkpoint-targeted immunotherapy.

LBA58_PR - Second or 3rd line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Updated results of the IFCT-1501 MAPS2 randomized phase 2 trial

LBA58_PR - Second or 3rd line nivolumab (Nivo) versus nivo plus ipilimumab (Ipi) in malignant pleural mesothelioma (MPM) patients: Updated results of the IFCT-1501 MAPS2 randomized phase 2 trial

1620P - Outcomes of malignant pleural mesothelioma (MPM) patients (p) treated with immune-oncology drugs (IO) in clinical trials

1620P - Outcomes of malignant pleural mesothelioma (MPM) patients (p) treated with immune-oncology drugs (IO) in clinical trials

A Prospective Randomized Study of Prophylactic Irradiation of Tracts in Patients with Malignant Pleural Mesothelioma

Background: Procedure tract metastasis (PTM) may complicate pleural procedures in malignant pleural mesothelioma (MPM) patients and cause significant morbidity.Aim: To evaluate the effectiveness of prophylactic radiotherapy (RTH) in preventing PTM and reducing pain.Methods: Forty patients with MPM, who had a pleural invasive procedure within the preceding 15 days, were randomized in a 1:1 ratio to receive prophylactic RTH to the procedure site (21 Gy in three consecutive daily fractions using 9MeV) vs. no RTH. During a 12-month follow up period, patients were examined monthly for PTM, toxicities and pain at the procedure site.Results: Patients receiving RTH had lower incidence of PTM than the control group (2/20, 10% vs. 5/20, 25%); however, this difference was not statistically significant. The proportion of patients who experienced pain at the pleural procedure site was significantly less in the RTH group compared with the control group (2/20, 10% vs. 12/20, 60%; p=0.001). Pain scores were significantly less in the RTH group compared with the control group (mean pain score 1.6 vs. 2.8, respectively; p=0.014).Conclusion: Prophylactic RTH to the pleural procedure site in MPM was not significantly effective in preventing or delaying PTM. However, prophylactic RTH reduced significantly the rate and severity of pain at the procedure site. Future studies may be needed to assess the effect of prophylactic RTH timing and its technique on preventing PTM.

Downregulation of miR-99a/let-7c/miR-125b miRNA cluster predicts clinical outcome in patients with unresected malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal overall survival (OS) and to date no molecular markers are available to guide patient management. This study aimed to identify a prognostic miRNA signature in MPM patients who did not undergo tumor resection. Whole miRNA profiling using a microarray platform was performed using biopsies on 27 unresected MPM patients with distinct clinical outcome: 15 patients had short survival (OS<12 months) and 12 patients had long survival (OS>36 months). Three prognostic miRNAs (mir-99a, let-7c, and miR-125b) encoded at the same cluster (21q21) were selected for further validation and tested on publicly available miRNA sequencing data from 72 MPM patients with survival data. A risk model was built based on these 3 miRNAs that was validated by quantitative PCR in an independent set of 30 MPM patients. High-risk patients had shorter median OS (7.6 months) as compared with low-risk patients (median not reached). In the multivariate Cox model, a high-risk score was independently associated with shorter OS (HR=3.14; 95% CI, 1.18–8.34; P=0.022). Our study identified that the downregulation of the miR-99a/let-7/miR-125b miRNA cluster predicts poor outcome in unresected MPM.

The value of delayed phase enhanced imaging in malignant pleural mesothelioma.

Cross-sectional imaging of malignant pleural mesothelioma (MPM) can underestimate the presence of local tumor invasion. Since accurate staging is vital optimal choice of therapy, techniques that optimize pleural imaging are needed. Here we estimate the optimal timing of MPM enhancement on magnetic resonance imaging (MRI). All MPM patients with intravenous (IV) contrast enhanced staging MRI between 2000-2016 at our institution were retrospectively selected for image analysis. Patients with incomplete imaging protocol and maximum pleural tumor thickness <1 cm were excluded. Quantitative measurements of tumor signal intensity were obtained on pre-contrast and post-contrast phases where MRI acquisition parameters were fixed. Using best-fit model curves, predicted maximum time points of enhancement were determined using a simulation of predicted values. Additionally, a qualitative assessment of tumor conspicuity was performed at all IV contrast time delays imaged. A statistical analysis assessed for correlation between qualitative lesion conspicuity and quantitative tumor enhancement. Of the 42 MPM patients who had undergone staging MRI during the study period, 12 patients met the study criteria. Peak tumor enhancement was between 150 and 300 sec following IV contrast administration. Within this time window, 80% of patients are projected to have reached >80%, >85%, and >90% peak tumor enhancement. There was a statistically significant correlation between increasing tumor enhancement and subjective lesion conspicuity. Optimal MPM enhancement on MRI likely occurs at a time delay between 2.5-5 min following IV contrast administration. Further study of delayed phase enhancement of MPM with dynamic contrast enhanced MRI is warranted.

Pathological complete response in malignant pleural mesothelioma patients following induction chemotherapy: Predictive factors and outcomes

A small proportion of patients with malignant pleural mesothelioma (MPM) achieve pathological complete response (CR) following treatment with current practice induction chemotherapy. Our analysis of 58 patients with MPM treated with platinum-based chemotherapy showed 4 patients (7%) attained pathological CR at subsequent extrapleural pneumonectomy (EPP). Patient and tumour factors such as age, gender, smoking habit, histological subtype, and clinical stage were not found to be associated with pathological CR. Patients with pathological CR had longer disease-free survival (29.2 vs. 13.8 months; p=0.08) and overall survival (76.4 vs. 23.4 months; p=0.06) but this did not reach statistical significance. Our study suggests that patients who achieve pathological CR after chemotherapy may have improved survival in MPM.

Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer caused by asbestos exposure. An inherited predisposition has been suggested to explain multiple cases in the same family and the observation that not all individuals highly exposed to asbestos develop the tumor. Germline mutations in BAP1 are responsible for a rare cancer predisposition syndrome that includes predisposition to mesothelioma. We hypothesized that other genes involved in hereditary cancer syndromes could be responsible for the inherited mesothelioma predisposition. We investigated the prevalence of germline variants in 94 cancer-predisposing genes in 93 MPM patients with a quantified asbestos exposure. Ten pathogenic truncating variants (PTVs) were identified in PALB2, BRCA1, FANCI, ATM, SLX4, BRCA2, FANCC, FANCF, PMS1 and XPC. All these genes are involved in DNA repair pathways, mostly in homologous recombination repair. Patients carrying PTVs represented 9.7% of the panel and showed lower asbestos exposure than did all the other patients (p = 0.0015). This suggests that they did not efficiently repair the DNA damage induced by asbestos and leading to carcinogenesis.This study shows that germline variants in several genes may increase MPM susceptibility in the presence of asbestos exposure and may be important for specific treatment.

Abstract 204: In vitro metabolomics of mesothelioma: Challenges and outcomes

Abstract Introduction Early detection of malignant pleural mesothelioma (MPM) is likely to improve outcome in affected patients. From our previous studies (MesoBreath 1 &amp; 2) we developed a screening tool in which volatile organic compounds (VOCs) in breath allowed discrimination of MPM patients from at risk controls. However it is not yet clear which VOCs arise from the neoplastic cells themselves or from the host response. Identifying the cancer cell-specific compounds should increase the specificity of our breathomic signature model. Therefore, we set up an in vitro experimental setup model for VOC analysis from the headspace of mesothelioma cell lines. Methods Standard polystyrene culture flasks (NunclonTM Delta Surface, Thermo Scientific) were mounted with an adapted cap accommodating teflon inlet and outlet tubes. The inlet tube provides environmental air while an external pump (Gilian GilAir Plus, Sensidyne) draws headspace air from the outlet tube over an adsorption column (Tenax GR, Markes International, UK). The adsorption columns were further processed on a GC-MS platform (GC: Focus GC, Thermo Finnigan, Milan, Italy; DSQII Single Quadrupole MS, Thermo Finnigan, Austin, TX, USA). VOC profiles were processed using supervised clustering algorithms and principal component analysis. Results Using this setup, we have investigated the impact of flow and total sampled volume on the concentration and range of VOCs detected. For a constant flow, VOCs were detected in higher concentrations with increasing sample volume. For a constant volume, a lower sampling flow yielded a higher concentration of detected VOCs. Most of the VOCs obtained were alkanes and ketones. We will show data illustrating the differential VOC profiles of container plastic, cell culture medium and growing mesothelioma cancer cells, as well as the differential VOC output of epithelioid vs sarcomatoid mesothelioma cell lines. Conclusions We have succesfully developed an in vitro experimental setup allowing collection and analysis of VOCs emanating from mesothelioma cancer cell line cultures. This platform will allow us to investigate how VOC profiles are impacted in different experimental conditions (e.g. hypoxia, nutrient deprivation, cytostatics, co-culture with leukocytes). The data collected will help us to pinpoint the cancer cell-derived VOCs from patient exhaled breath, and increase the robustness of our mesothelioma breathomic signature. Note: This abstract was not presented at the meeting. Citation Format: Sabrina Lagniau, Kevin Lamote, Lore Vandermeersch, Herman Van Langenhove, Jan P. van Meerbeeck, Karim Y. Vermaelen. In vitro metabolomics of mesothelioma: Challenges and outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 204. doi:10.1158/1538-7445.AM2017-204

Novel immunotherapy clinical trials in malignant pleural mesothelioma.

In this article, we review ongoing novel clinical trials currently investigating immunotherapeutic approaches for patients with malignant pleural mesothelioma (MPM). There is a dearth of effective therapeutic options for patients diagnosed with MPM and metastatic cancers of the pleura; these diseases have an estimated annual incidence of 150,000. Modulating the immune microenvironment to promote antitumor immune responses by systemically and regionally delivered therapeutic agents is an active area of investigation. We have conducted a review of the clinical trials database for clinical trials actively recruiting MPM patients. We focused on novel therapeutic agents administered either systemically or intrapleurally to modulate the tumor immune microenvironment. Herein, we have summarized the published results of early phase clinical trials. A total of 43 clinical trials met our inclusion criteria. These trials are investigating immunologic agents (n=20) and antibody directed therapies (n=23). The regional intrapleural delivery technique (6 trials) is used to administer chemotherapy agents (3 of 6 trials) and immunotherapy agents (3 of 6 trials), including chimeric antigen receptor T cells (1 of 6 trials). Current clinical trials modulating the MPM immune microenvironment and the combination of these novel agents with standard of care therapy provide a promising area of investigation for MPM therapy.