Resectable Malignant Pleural Mesothelioma Research Articles

A Feasibility Study of Induction Pemetrexed Plus Cisplatin Followed by Pleurectomy/Decortication Aimed at Macroscopic Complete Resection for Malignant Pleural Mesothelioma

A prospective multi-institutional study has been initiated in Japan to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by pleurectomy/decortication aimed at macroscopic complete resection in patients with resectable malignant pleural mesothelioma. The study was initiated on September 2012, for which 24 patients will be recruited over a period of 2 years. The primary endpoint is the macroscopic complete resection rate, regardless of the surgical technique employed (i.e. pleurectomy/decortication or extrapleural pneumonectomy). The secondary endpoints are the pleurectomy/decortication rate, macroscopic complete resection rate by pleurectomy/decortication, pulmonary function at 3 months after surgery, adverse events, treatment-related mortality, response rate to chemotherapy and 3-year overall survival rate.

Treatment for recurrence after extrapleural pneumonectomy for malignant pleural mesothelioma: A single institution experience.

Malignant pleural mesothelioma (MPM) is a relatively rare, aggressive neoplasm associated with asbestos exposure. Extrapleural pneumonectomy (EPP) is often performed for resectable MPM as part of a multidisciplinary treatment; however, available data on treatments for recurrence after EPP are limited. The clinical records of consecutive MPM patients who underwent EPP at our institution from 2001 to 2010 were retrospectively reviewed. There were 10 patients who underwent EPP with or without perioperative chemotherapy; of these, recurrence was observed in eight patients. The overall median survival time and time to recurrence were 49.6 months and 15.4 months, respectively, after EPP. The first recurrence occurred within the ipsilateral thorax in four patients. These patients all underwent local treatments for their recurrence, including surgery or radiotherapy and with or without systemic chemotherapy. Other first recurrences were seen in the peritoneal space of two patients and in the contralateral lung of two patients. These patients received platinum-based systemic chemotherapy for their recurrence. The median survival time after the first recurrence was 17.8 months, and the 2-year survival rate was 23.4%. Most patients who underwent EPP developed tumor recurrences. Direct tumor extension may be a major mechanism of recurrence. Aggressive treatment for recurrent MPM after EPP, including locoregional control and/or systemic chemotherapy, was important for achieving long-term survival.

Long term survival after trimodal therapy in malignant pleural mesothelioma

Trimodal therapy results in long term survival in a small fraction of patients with malignant pleural mesothelioma, particularly in patients having epithelial histology, R0-resection and no nodal involvement. This study analyses the outcome after trimodal therapy including extrapleural pneumonectomy. From 2000 to 2005 41 patients with histologically verified malignant pleural mesothelioma were included. Diagnosis and nodal status were confirmed by surgery. 21 patients (51%) underwent trimodal therapy with 655 days (63-2,567 days) of median follow-up. Postoperative complications, mortality, long term survival and recurrence rates were analysed retrospectively. Neoadjuvant chemotherapy consisted of a combination of platinum based agents (n = 19) with gemcitabine (n = 15) or pemetrexed (n = 4). Extrapleural pneumonectomy was the standard procedure for surgery. 13 patients (62%) had postoperative complications. 16 patients (76%) received postoperative adjuvant radiotherapy. There was a 30-day mortality of 4.8% in the trimodal group. Survival rates in the trimodal group were 71% after one, 28% after two and 10% after five years. There were no significant differences regarding age, tumour stage, cell type or lymph node involvement. Tumour recurrence occurred after one and two years in 44% and in 83% respectively. The majority of patients considered for surgical resection of malignant pleural mesothelioma have regionally advanced disease. In those receiving trimodal therapy long term survival is achieved only in a minority of patients. In view of the time consuming and intensive treatment it should be offered only in carefully selected patients as new surgical approaches such as pleurectomy/decortication have shown high efficacy rates regarding patients' survival.

Comparison of prognostic impact between metabolic and radiologic response after induction chemotherapy for resectable malignant pleural mesothelioma: A multicenter study.

7031 Background: Induction chemotherapy followed by extrapleural pneumonectomy (EPP) for resectable malignant pleural mesothelioma (MPM) is controversial. To select optimal candidates for EPP, we evaluates the usefulness of metabolic response on fluorodeoxyglucose-positron emission tomography (FDG-PET) compared with radiologic response on high-resolution computed tomography (HRCT) after induction chemotherapy to predict prognosis for patients with resectable MPM who underwent EPP in the setting of multicenter study. Methods: We performed HRCT and FDG-PET before and after induction platinum-based chemotherapy on 50 patients with clinical T1-3 N0-2 M0 MPM who underwent EPP ± postoperative hemithoracic radiation. A decrease of more than 30% in tumor maximum standardized uptake value (SUVmax) was defined as a metabolic responder. Radiologic response using modified RECIST or metabolic response and surgical results were analyzed. Results: In all cohort patients, median overall survival (OS) from diagnosis was 20.5 month (95% confidence interval [CI], 15.0-26.0 month). Fourteen patients were classified as metabolic responders (28%) and 36 as non-responders (72%). Metabolic responders significantly correlated to OS with median OS for metabolic responders of not reached (3-year OS of 60.0%) versus 18.7 month (95% CI, 13.3-24.2 month, 3-year OS of 26.5%) for non-responders (P = .025). No correlation was observed between OS and radiologic response with median OS for radiologic responders of 25.7 month (n = 20, 95% CI, 14.5-37.0 month, 3-year OS of 35.8%) versus 17.7 month (n = 30, 95% CI, 12.8-22.6 month, 3-year OS of 35.1%) for non-responder (p = .216). Based on the multivariate Cox analyses, decreased SUVmax (%) (p = .010) was a significantly independent factor for OS as well as epithelioid subtype (p = .044). Conclusions: Metabolic response on FDG-PET has higher predictive value of prognosis than radiologic response on HRCT after induction chemotherapy for patients with resectable MPM. Patients with metabolic responder and/or epithelioid subtype can be good candidates for EPP after induction chemotherapy.

Elevated PDGFRB gene copy number gain as prognostic in resected malignant pleural mesothelioma.

7078 Background: PDGF/PDGFR pathway has been implicated in malignant pleural mesothelioma (MPM) carcinogenesis. We sought to evaluate the incidence of PDGFRB gene copy number gain (CNG) and PDGFR pathway protein expression by immunohistochemistry (IHC) in the tumor cell cytoplasm, membrane, nucleus, and stroma, and correlate it to patient clinical outcome. Methods: 88 archived tumor blocks from resected MPM with full clinical information were used to perform the analyses. IHC biomarkers for PDGFRα,β and p-PDGFRβ, and fluorescence in situ hybridization were performed for analysis of PDGFRB gene CNG. Spearman’s rank correlation, Wilcoxon rank-sum test or Kruskal-Wallis test, BLiP plots, and Kaplan-Meier method were used to assess the biomarkers and their correlation to clinical outcome. Results: There were several correlations identified between the IHC biomarkers; however, none associated with patient demographics or histology subtype, with the exception of high cytoplasmic PDGFRα occurring in patients with no prior known asbestos exposure (p=0.029). In the CNG analysis, PDGFRB gene CNG in > 10% of tumor cells had lower cytoplasmic p-PDGFRβ (p=0.029), while PDGFRB gene CNG in > 40% of tumor cells had a higher cytoplasmic PDGFRβ (p=0.04). PDGFRB gene CNG status did not associate with patient demographics or tumor characteristics. Patients with PDGFRB CNG > 40% of tumor cells had an improved relapse-free survival (RFS) [HR 0.25 (95% CI 0.09, 0.72), p=0.0096]. In the patients with PDGFRB CNG > 40% of cells, the addition of chemotherapy appeared to also improve RFS (p=0.017). In the multi-covariate analyses for RFS, there was no association with any IHC biomarker. In the overall survival (OS) analysis, having PDGFRB gene CNG > 40% of tumor cells correlated with an improved OS [HR 0.32 (95% CI 0.11, 0.89), p=0.029] and the addition of peri-operative chemotherapy led to a trend towards improved OS (p=0.089). Conclusions: PDGFRB CNG > 40% of tumor cells is a potential prognostic biomarker in surgically resected MPM tumors. Adding chemotherapy to patients with PDGFRB CNG > 40% of cells improved RFS and led to a trend towards improved OS. Future validation of this biomarker in prospective trials is needed.

Three-Dimensional Stereoscopic Volume Rendering of Malignant Pleural Mesothelioma

Our objective was to investigate the application of three-dimensional (3D) stereoscopic volume rendering with perceptual colorization on preoperative imaging for malignant pleural mesothelioma. At present, we have prospectively enrolled 6 patients being considered for resection of malignant pleural mesothelioma that have undergone a multidetector-row computed tomography (CT) scan of the chest. The CT data sets were volume rendered without preprocessing. The resultant 3D rendering was displayed stereoscopically and used to provide information regarding tumor extent, morphology, and anatomic involvement. To demonstrate this technique, this information was compared with the corresponding two-dimensional CT grayscale axial images from two of these patients. Three-dimensional stereoscopic reconstructions of the CT data sets provided detailed information regarding the local extent of tumor that could be used for preoperative surgical planning. Three-dimensional stereoscopic volume rendering for malignant pleural mesothelioma is a novel approach. Combined with our innovative perceptual colorization algorithm, stereoscopic volumetric analysis potentially allows for the accurate determination of the extent of pleural mesothelioma with results difficult to duplicate using grayscale, multiplanar CT images.

Hemithoracic Intensity-modulated Radiotherapy Using Helical Tomotherapy for Patients after Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma

Postoperative hemithoracic irradiation is regarded as an important part of the curative treatment for resectable malignant pleural mesothelioma (MPM). Because the clinical target volume in postoperative MPM is irregular and surrounded by dose-limiting critical structures, intensity-modulated radiation therapy (IMRT) is thought to be suitable. However, postoperative hemithoracic IMRT remains experimental due to a high incidence of fatal pneumonitis. Therefore, a Phase I dose escalation study for hemithoracic IMRT using helical tomotherapy was planned, and the results of the first three patients are herein reported because this technique may provide benefits to such patients. For 3 patients with postoperative MPM, who were treated by extrapleural pneumonectomy (EPP), a radiation dose of 45.0 Gy in 25 fractions was given to cover 95% of the PTV. The lung V5s of the three patients were 14.3%, 10.0%, and 31.3%, respectively. The V5s of the present plans was smaller than that of the recent IMRT planning studies. The lung V20s of these patients were 2.4%, 2.2%, and 4.3%, respectively. Their MLDs were 4.3 Gy, 3.4 Gy, and 5.8 Gy, respectively. The follow-up periods of the patients were 26, 14 and 9 months from initiation of IMRT, respectively. All patients were alive, although local and contralateral recurrences had developed in 1 patient. Only 1 patient had Grade 2 acute esophagitis and nausea. There was no treatment-related pneumonitis. Hemithoracic IMRT using helical tomotherapy may play a crucial role in adjuvant treatment for MPM after EPP.

Medical Treatment of Mesothelioma: Anything New?

In the present report, we review the current standard and investigational treatments of malignant pleural mesothelioma (MPM). Several studies have reported the use of gemcitabine and cisplatin as an induction chemotherapy in combination with extrapleural pneumonectomy (EPP) and thoracic radiation in a combined-modality approach for resectable MPM. Since the combination of cisplatin with pemetrexed was applied as the standard first-line regimen for unresectable MPM, the combination as an induction chemotherapy regimen has been proven effective in phase 2 trials. In addition, intensity-modulated radiation therapy and proton therapy have been introduced as new radiation methods into the combined modality. Hyperthermic intraoperative chemotherapy following EPP appears effective with acceptable toxicity. In addition, clinical studies that include molecular targeting agents, immunotherapy, and gene therapy have all been conducted. Thus, although there are numerous hopeful treatments for MPM, the benefits of these regimens remain to be proven in a randomized clinical setting.

Abstract 4121: Folate pathway in malignant pleural mesothelioma (MPM): Novel therapeutic opportunities due to folate receptor alpha overexpression

Abstract Background. The folate pathway is active in several cancers including malignant pleural mesothelioma (MPM). Membrane receptors folate receptor alpha (FRα), reduced folate carrier 1 (RFC1), proton coupled folate transporter (PCFT) and the enzyme thymidylate synthase (TS) regulate intra-cellular uptake of folate molecules and antifolate drugs. Due to the documented overexpression of folate markers in MPM they arise as potential targets for novel specific therapies with humanized monoclonal anti-FRα antibody and also to antifolate chemotherapy with pemetrexed. Material and Methods. We studied 79 surgically resected MPM (43 epithelioid, 28 biphasic and 13 sarcomatoid histology types). Protein expression of FRα, RFC1, PCFT and TS was examined by immunohistochemistry (IHC) in FFPE tissues placed in tissue microarray platform and results correlated to clinical-pathologic characteristics. Gene expression and DNA copy number changes of the FRα gene (FOLR1) were examined in 53 mesothelioma tumors using Affymetrix U133 Plus 2.0 microarray's and Illumina HumanOmni1-Quad v1.0 chips, respectively. The expression microarray data was analyzed in the GeneSpring GX 11 software (Agilent technologies Inc.) while DNA copy number changes were detected using the Nexus 5.0 software (BioDiscovery Inc.). Results. MPM frequently showed protein over-expression of FRα, RFC1 and PCFT. Nuclear TS expression positively correlated (P<0.043) with cytoplasmic TS and membrane RFC1. Patients with T1/T2 tumor had significantly (P=0.038) higher levels of membrane FRα, compared to patients with T3/T4 tumors. Epitheloid MPM had the highest level of cytoplasmic PCFT (P=0.005) among the three histological types, while patients with sarcomatoid histology had the lowest. In the multivariate analysis, with adjustment of gender, N and M stage, Patients who expressed any nuclear TS (score >0) had a lower hazard ratio than those who did not (HR=0.309; 95%CI 0.159, 0.601; P=0.0005). Patients with any level (score >0) of cytoplasmic PCFT had lower hazard ratio than those with absence of the marker (HR=0.539; 95%CI 0.306, 0.952; P=0.0332). Our gene expression data analysis on 53 mesothelioma tumors showed greater than 2-fold increase in the FOLR1 and 3-fold increase in the TYMS messenger RNA levels compared to paired normal tissue. Additionally, at least 7 of these tumors show increased gene copy number at the FOLR1 locus (Ch11q 13.4). Conclusions. Folate membrane transporters (FRα, RFC1, PCFT) and the enzyme TS are frequently over expressed in MPM tumor tissues, and PCFT and TS are associated with tumors’ clinico-pathological features. The high level of expression of FRα in MPM supports the rational use of potential utilization of humanized monoclonal anti-FRα antibody and also standard antifolate chemotherapy in this disease. Supported by grant US DoD W81XWH-07-1-0306, ASCO CDA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4121. doi:10.1158/1538-7445.AM2011-4121

Current Status and Future Direction of Japan's Clinical Trial for Malignant Pleural Mesothelioma

The feasibility and efficacy of trimodality therapy for malignant pleural mesothelioma (MPM) are still controversial mainly due to the lack of clinical evidence. Although three major clinical trials on this therapy have been recently reported from North America and Europe, it remains unclear whether results in Caucasian populations may be directly applicable to Asian populations. In this context, as a project of the "Comprehensive approach on asbestos-related diseases" supported by the "Special Coordination Fund for Promoting Science and Technology of MEXT, Japan", a prospective multi-institutional study has been planned to evaluate the feasibility of induction chemotherapy using pemetrexed plus cisplatin, followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation in patients with resectable MPM. Primary endpoints are macroscopic complete resection rate by EPP and treatment-related mortality for trimodality therapy. The study was initiated in May 2008 and patient enrollment was finished in November 2010.

Evaluation of Src Tyr419 as a predictive biomarker in a neoadjuvant trial using dasatinib in resectable malignant pleural mesothelioma.

7042 Background: Preclinical studies in malignant pleural mesothelioma (MPM) have shown that dasatinib, a multitargeted Src kinase/PDGFR inhibitor, has antitumor activity. We designed a novel biomarker-based neoadjuvant trial using dasatinib in resectable MPM. Methods: Untreated MPM patients undergo extended surgical staging (ESS) with multiple biopsies along the future surgical incision line to account for tumor heterogeneity. If deemed a surgical candidate for either P/D or EPP, patients receive 4 weeks of oral dasatinib (70 mg BID) followed by P/D or EPP. If a radiographic response is seen, an additional 2 years of dasatinib maintenance after adjuvant radiotherapy and chemotherapy is given. Serum/blood/platelets/pleural effusion are collected for exploratory analysis of peripheral surrogate biomarkers. Primary endpoint is biomarker modulation of Src Tyr419 in tumor tissue. Secondary endpoints: response, survival, safety/toxicity, and peripheral biomarker modulation. Results: 15 patients enrolled on the trial (4/08–1/10) have successfully completed ESS, neoadjuvant dasatinib, and P/D (n=10) or EPP (n=5). 13 epitheliod and 2 biphasic histology, 12 men: 3 women. The dasatinib main side effects were grade 1-2: anemia, nausea, vomiting, anorexia, fatigue, and anxiety. Grade 3 toxicities included fluid retention, infection (pneumonia), and hypoxia. There are no grade 4-5 toxicities. Post-surgical grade 3 toxicity included anemia, arrhythmia, HTN, and pleural effusion; 1 grade 4 episode of hyperglycemia. After 4 weeks of neoadjuvant dasatinib therapy, there was 1 PD, 12 SD and 2 minor responses. In the initial analysis of Src Tyr419 in 13 patients, higher baseline levels of p-Src Tyr419 predicted for an improved PFS with dasatinib therapy (p=0.008). Also, patients who had significant modulation of p-Src Tyr419 after dasatinib therapy had improved PFS (p=0.008). Conclusions: There is preliminary evidence that a subgroup of MPM patients gain clinical benefit from dasatinib therapy and that baseline p-Src Tyr419 levels in MPM tumor tissue may be predictive of PFS. This is the first targeted therapy neoadjuvant trial to potentially identify a predictive biomarker in MPM. No significant financial relationships to disclose.

Survival and relapse pattern after trimodality therapy for malignant pleural mesothelioma

Multimodality therapy has been applied to resectable malignant pleural mesothelioma, but the tolerability of the treatment and relapse pattern in detail remain unknown. We reviewed our experience of trimodality therapy as a single-institution study in Japan. A total of 16 patients with resectable malignant pleural mesothelioma were intended to treat with extra-pleural pneumonectomy followed by platinum-based chemotherapy and external beam radiation therapy. The histology of the tumors was epithelioid in 10, sarcomatoid in 4, and biphasic in 2. International Mesothelioma Interest Group staging was stage II in 1, stage III in 11, and stage IV in 4. The tolerability to the combined treatment, the survival, and the relapse pattern were examined. All patients underwent a macroscopic complete resection. In all, 14 patients received chemotherapy, and subsequently 13 underwent radiotherapy, indicating a tolerability of 81%. The overall median survival was 28.1 months; and the 2-year and 5-year survival rates were 53.3% and 26.7%, respectively. In patients with stage III or lower disease, the median survival was 37.9 months. Recurrence was seen in eight patients; the first relapse site was local in seven and distant in two. The local recurrences occurred within 24 months, mostly around 12 months, after the extrapleural pneumonectomy, whereas the distant metastases occurred later. Trimodality therapy showed a survival benefit in patients with stage III or lower malignant pleural mesothelioma. Most of the recurrences were local. Therefore, better local control is required to improve the prognosis of the disease.

O6 Cytoreductive surgery for malignant pleural mesothelioma in the elderly: a single-center experience in 227 patients

Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis. Surgical treatments of MPM with a curative intent include extrapleural pneumonectomy and extended pleurectomy/decortication (P/D). This meta-analysis aimed to compare the perioperative and long-term outcomes of EPP and extended P/D for selected surgical candidates.A systematic review of the literature was performed on six electronic databases to identify all relevant data on comparative outcomes of extended P/D and EPP in a multimodality setting. Endpoints included perioperative mortality and morbidity, as well as long-term overall survival.Seven relevant studies with comparative data on EPP (n = 632) versus extended P/D (n = 513) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (2.9% vs 6.8%, p = 0.02) and morbidity (27.9% vs 62.0%, p < 0.0001) for patients who underwent extended P/D compared to EPP. Median overall survival ranged between 13–29 months for extended P/D and 12–22 months for EPP, with a trend favouring extended P/D.Although it must be emphasized that patient selection and treatment strategies differ between EPP and extended P/D, a number of comparative studies have recently been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that selected patients who underwent extended P/D had lower perioperative morbidity and mortality with similar, if not superior, long-term survival compared to EPP, in the context of multi-modality therapy. This may represent an important paradigm shift in the surgical management of MPM.

9125 Can the modified RECIST criteria and EORTC PET criteria predict the postoperative pathologic findings for resectable malignant pleural mesothelioma following neoadjuvant chemotherapy?

9125 Can the modified RECIST criteria and EORTC PET criteria predict the postoperative pathologic findings for resectable malignant pleural mesothelioma following neoadjuvant chemotherapy?

Malignant pleural mesothelioma: current treatments and emerging drugs

Background: Malignant pleural mesothelioma (MPM) is an uncommon disease whose incidence is increasing worldwide over the past 30 years. Surgical resection and radiotherapy represent the standard treatment in patient with resectable MPM. Chemotherapy is also necessary to reduce incidence of distant metastases, but the optimal setting of treatment (neoadjuvant, adjuvant and intrapleural) is not clarified. For the patients with unresectable MPM, the combination cisplatin and pemetrexed or ralitrexed is the standard treatment as supported by a Phase III study. Better understanding of molecular pathways involved in MPM has enabled inclusion of new drugs targeted against pathways responsible for proliferation, cell survival and angiogenesis. Objective: This review discusses the current treatment option, the specific signal pathways activated in MPM and the novel agents under evaluation in clinical trials. Methods: We use for this article abstracts, papers, oral presentations from ASCO and the website http://www.clinical-trials.gov. Results/ conclusion: This review summarizes the activity of chemotherapy and of new agents under evaluation in clinical trials. The better understanding of molecular pathways activated in MPM will hopefully provide new therapeutic options for these patients in the future.

Photodynamic Therapy as an Innovative Treatment for Malignant Pleural Mesothelioma

Photodynamic therapy (PDT) of the pleura is an experimental treatment aimed at eradicating residual microscopic disease after macroscopic complete resection of malignant pleural mesothelioma (MPM) by means of intracavitary administration. A light-based treatment, PDT consists of 3 components: a nontoxic photosensitizing compound, oxygen, and visible light. The treatment is FDA-approved for several oncological targets, but remains experimental for MPM. PDT can be combined with lung-sparing pleurectomy and decortication and does not preclude other treatments such as adjuvant chemotherapy and/or radiation therapy. Additionally, PDT appears to bolster an immunologic effect by rendering the cancer cells that have been destroyed by the light-activated photosensitizer more presentable to the immune system. Local control and survival rates have been sufficiently rewarding to merit ongoing development of this combination of surgical technique and PDT.

Phase II trial of extrapleural pneumonectomy followed by adjuvant radiotherapy in malignant pleural mesothelioma

7579 Background: This phase II clinical study was conducted to evaluate the effectiveness of the association of extrapleural pneumonectomy followed by radiation therapy in patients with potentially resectable malignant pleural mesothelioma (MPM). Methods: Eligible patients had histologically proven epithelial or mixed MPM with clinical stage T1–3, N0–2, M0 disease considered to be completely resectable and a WHO performance status of 0 or 1. Surgery had to consist of a complete extrapleural pneumonectomy including resection of pericardium and diaphragm. Postoperative radiotherapy (40 Gy) was delivered through anterior and posterior fields, with a 10 to 20 Gy boost dose if necessary. Results: Thirty seven patients were included in this study. Extrapleural pneumonectomy was completed in 35 patients. Overall hospital mortality was 5,7 %. Major post operative complications were: 3 acute lung injury, 1 bronchopleural fistula, 1 stroke, 1 chylothorax and one diaphragmatic patch dehiscence. IMIG post-operative staging was: stage II = 5 patients; stage III = 25 patients; stage IV = 5 patients. Adjuvant radiation was administered to 29 patients. Survival for the 35 patients with complete resection was 47 ± 8 % at 2 years. Median overall survival time was 22 months. Survival without recurrence was 37 ± 8 % at 2 years. Median time to progression was 15 months. Locoregional recurrence is the most common form of relapse. Conclusions: In the era of surgical neoadjuvant therapy in MPM treatment, extrapleural pneumonectomy followed by radiation therapy in patients with resectable epithelial or mixed MPM can achieve acceptable results. No significant financial relationships to disclose.

Validity of the modified RECIST criteria and EORTC PET criteria evaluated based on the pathologic findings for patients with resectable malignant pleural mesothelioma

e11639 Background: The unique growth pattern of malignant pleural mesothelioma (MPM) presents challenges for clinical investigators evaluating the responses to chemotherapy, which is an important surrogate endpoint for patient benefit, particularly in clinical trials. In patients with resectable MPM, multicenter clinical trials of neoadjuvant chemotherapy followed by extrapleral pneumonectomy (EPP) and subsequent radiotherapy have been attempted around the world. The applicability of modified RECIST based on the findings on CT images and EORTC (European Organization for Research and Treatment of Cancer) criteria based on the findings on FDG-PET images to resectable MPM would be challenging and significant, but their validity has never been examined. Methods: Between May 2006 and November 2008, 13 consecutive patients with resectable pathologically proven MPM were included in this study. All were initially treated with combination chemotherapy including cisplatin. EPP was successfully performed in all the patients. In addition to modified RECIST (CR vs PR vs SD vs PD), FDG uptake by the tumor on PET was also evaluated according to the EORTC PET criteria (CMR vs PMR vs SMD vs PMD). Also, pathologic findings (NT; no viable tumor vs MR; minimal residual vs GR; gross residual) were reviewed. Results: According to modified RECIST, in which the definition of measurable lesions is ≥10mm in diameter, 7 of the 13 patients investigated had no measurable lesion. Even when the definition of measurable lesions was changed to ≥5mm, 2 patients had no measurable lesion and 4 had only one lesion. In regard to the response, 4 of 11 patients with any measurable lesions were classified as PR, and 7 were classified as SD, while 8 patients were classified as PMR and 3 were classified as SMD according to the PET findings. Eight patients were classified as GR and 5 as MR. Kappa statistics suggested potential variation between the CT response and the pathologic findings (κ=0.214, 95% CI=-0.377 ∼ 0.806) and between the PET response and the pathologic findings (κ=0.286, 95% CI=-0.049 ∼ 0.620). Conclusions: Our data raise doubts about the validity of applying the modified RECIST criteria as well as EORTC PET criteria to resectable MPM. No significant financial relationships to disclose.

Integrating microRNA and mRNA expression profiling using a novel algorithm identified a small set of unique genes upregulated in malignant pleural mesothelioma (MPM)

e22111 Background: We employed a global profiling strategy using miRNA microarrays in MPM cell lines and archival tumor tissue. Methods: We isolated total RNA from 4 MPM cell lines, 2 control cell lines, and 16 tissue specimens from patients with resected MPM (n=8) and normal counterpart (n=8) patients as controls. Total RNA was labeled with Cyanine 3, then hybridized with Agilent human miRNA microarray v1 slides. Results: Preliminary miRNA profiles show up-regulation of 44 versus down-regulation of 29 miRNA's in MSTO-211H cancer cells compared to HCT-4012 (pleural telomerase-transformed control). Profiling of 16 tissue specimens (8 normal vs 8 MPM) revealed down-regulation of 11 miRNA's in MPM tumor tissue. To focus on relevant miRNA that regulate genes involved in carcinogenesis and progression, we identified &gt; 1000 unique genes using the online targetscan 4.2 program ( http://www.targetscan.org ), which predicts biological targets of miRNAs by identifying the presence of conserved 8-mer and 7-mer sites that match the seed region of each miRNA. We then explored a novel screening strategy, which combines mRNA expression dataset with the miRNA dataset, to narrow the list of relevant miRNA's. We conducted gene expression profiling on the cell lines and MPM tissue samples with Affymetrix U133 plus 2.0 chips. Bioinformatic analysis was conducted with MeV: MultiExperiment Viewer software, data reduction techniques (Correspondance Analysis), hierarchical clustering methods, and Serial Analysis for Microarray (SAM), and showed up-regulation of ∼300 genes in MPM compared to normal tissues. We then computed of the ∼300 mRNA's up-regulated in MPM only 32 are recognized by the 11 down-regulated miRNA's using the targetscan 4.2 algorithm. Most of the miRNA's regulate single messages while ∼20 % of the messages are regulated by more than 1 miRNA's. Some of these targets include Ets variant 1 and Protein kinase C - epsilon. Conclusions: This innovative approach of selecting highly relevant miRNA is feasible and enables discovery of novel genes based on their ability to be bound by single or multiple miRNA's. Validation of our profiling studies using real-time PCR and protein analysis methods will be presented. No significant financial relationships to disclose.

Phase I trial of neoadjuvant dasatinib in patients with resectable malignant pleural mesothelioma

7580 Background: The optimal multi-modality treatment for resectable malignant pleural mesothelioma (MPM) remains unknown. We designed a biomarker-based neoadjuvant trial from our preclinical studies showing that dasatinib, a multi-targeted Src kinase inhibitor, has activity against MPM and target specificity to Src Tyr419. Methods: Untreated MPM patients underwent extended surgical staging (ESS) with multiple biopsies to account for tumor heterogeneity, lymph node status and to rule out sarcomatoid features. If deemed a surgical candidate for either pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP), patients received 4 weeks of oral dasatinib (70 mg BID) followed by P/D or EPP. If either a radiographic or molecular response (de-phosphorylation of Src Tyr419 in tumor) is achieved, an additional 2 years of dasatinib maintenance after adjuvant radiotherapy and systemic chemotherapy is given. The primary endpoint of this trial was biomarker modulation of Src Tyr419. Secondary endpoints included response, survival, safety/toxicity, and biomarker modulation in tumor/serum/platelets/pleural effusion. The total planned sample size is 24 to detect a 50% reduction in positive p-Src Tyr419 expression with 80% power, one-sided 10% type I error rate, and 10% inevaluable rate. Results: To date, ten patients have registered on the trial (4/08 - 12/08); six have successfully completed the ESS, neoadjuvant dasatinib, and P/D (n=3) or EPP (n=3). Two patients are still receiving neoadjuvant dasatinib; and 2 patients were deemed to not be surgical candidates due to a rapid decline in PS and one was found to have bilateral mesothelioma. The main side effects to dasatinib were grade 1–2: anemia, nausea, vomiting, anorexia, electrolyte abnormalities, fatigue, and anxiety. Grade 3 toxicities included hyperkalemia (1), infection - pneumonia (1), and hypoxia (1). There were no grade 4–5 toxicities. Post-surgical grade 3 toxicity included anemia, electrolyte abnormalities, arrhythmia, HTN, and pleural effusion; one grade 4 episode of hyperglycemia was seen. Conclusions: This study demonstrates that biomarker-based neoadjuvant MPM trials with novel agents are feasible. Updated clinical and translational correlative results will be presented. No significant financial relationships to disclose.