Mesothelioma: van Meerbeeck JP

van Meerbeeck JP, Hillerdal G. · No affiliation provided · Am J Respir Crit Care Med. · Pubmed #18832552 No free full text.

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van Meerbeeck JP. · No affiliation provided · J Thorac Oncol. · Pubmed #17409869 No free full text.

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Goeminne H, van Meerbeeck JP. · Department of Pulmonary Diseases, University Hospital, Ghent, Belgium. · Expert Opin Pharmacother. · Pubmed #16634714 No free full text.

Abstract: Both lung cancer and mesothelioma are malignancies with increasing incidence, and both are primarily due to inhalation of an external carcinogen. The occurence of both diseases is expected to rise worldwide, although a stabilisation and/or decrease may be anticipated in some developed countries. There are other common similarities to both cancers, including the median age of their patients, the advanced stage at presentation, the outcome and the treatments given. This review focuses on the available evidence of a novel antifolate agent, pemetrexed, in the treatment of both of these thoracic malignancies. Current status, persisting controversies and future developments are discussed.

van Meerbeeck JP, Boyer M. · University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. · Lung Cancer. · Pubmed #15950792 No free full text.

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Kindler HL, van Meerbeeck JP. · Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. · Semin Oncol. · Pubmed #11836671 No free full text.

Abstract: Gemcitabine is broadly active in a variety of solid tumors, including malignant mesothelioma. In vitro, gemcitabine demonstrates activity against mesothelioma cell lines. The role of single-agent gemcitabine in patients with mesothelioma is unclear, since three phase II trials treated a total of 60 patients and achieved response rates of 0%, 7%, and 31%. The combination of gemcitabine and cisplatin is synergistic against mesothelioma cell lines in vitro. Gemcitabine in combination with cisplatin or carboplatin shows definite activity in phase II trials. The trial by Byrne and colleagues that demonstrated a response rate of 48% established the combination of gemcitabine plus cisplatin as a standard therapy for this disease in the United States. Subsequent multicenter trials have achieved lower response rates of 26% and 16% for this combination. Gemcitabine plus carboplatin also has activity. Future roles for gemcitabine in malignant mesothelioma patients include incorporating a gemcitabine/platinum regimen for neoadjuvant or adjuvant therapy, combining it with other cytotoxic chemotherapy agents such as pemetrexed or vinorelbine, or adding novel cytostatic agents such as the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, to the gemcitabine and platinating agent combination.

Bottomley A, Coens C, Efficace F, Gaafar R, Manegold C, Burgers S, Vincent M, Legrand C, van Meerbeeck JP, Anonymous00124. · EORTC Data Center, Quality of Life Unit, Avenue E. Mounier, 83, 1200 Brussels, Belgium. · J Clin Oncol. · Pubmed #18089874 No free full text.

Abstract: PURPOSE: Malignant pleural mesothelioma (MPM) is a rare disease. Unlike other advanced cancer types, little is known about patient-reported symptoms or health-related quality of life (HRQOL) and their possible prognostic value. This study reports an evaluation of the prognostic value of these factors using data gathered from a recent randomized controlled trial. PATIENTS AND METHODS: Patients were entered onto this trial if they had a histologically proven unresectable MPM, not pretreated with chemotherapy, WHO performance status < or = 2, and adequate hematologic, renal, and hepatic function. Patients were randomly assigned to receive cisplatin 80 mg/m2 intravenously on day 1, without or with preceding infusion of raltitrexed 3 mg/m2. HRQOL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30/Lung Cancer 13 tool. The Cox proportional hazards regression model was used for the univariate and multivariate analyses of survival, along with a bootstrap validation technique. Included were the EORTC prognostic index (PI) composed of stage of disease, histology type, time since diagnosis, and WBC, and, in addition, 10 selected key symptoms and HRQOL scales. RESULTS: Two hundred fifty patients were randomly assigned (80% male; median age, 58 years; WHO performance status 0, 1, 2 in 25%, 62%, and 13% of cases, respectively). Two hundred twenty-nine patients (91.6%) had a valid HRQOL assessment. The final multivariate model retained the PI, pain (P < .0001), and appetite loss (P = .0100) as independent prognostic indicators of survival. CONCLUSION: Results suggest that the PI, pain, and appetite loss may be independent prognostic factors in patients with advanced MPM.

van Meerbeeck JP, Gaafar R, Manegold C, Van Klaveren RJ, Van Marck EA, Vincent M, Legrand C, Bottomley A, Debruyne C, Giaccone G, Anonymous00121, Anonymous00122. · Thoracic Oncology Unit, University Hospital -7K12IE, De Pintelaan 185, B 9000 Ghent, Belgium. · J Clin Oncol. · Pubmed #16192580 No free full text.

Abstract: PURPOSE: We conducted a phase III trial to determine whether first-line treatment with raltitrexed, a thymidine synthase inhibitor, and cisplatin results in superior outcome compared with cisplatin alone in patients with malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B). In patients with measurable disease, response was monitored using the Response Evaluation Criteria in Solid Tumors criteria. Health related quality of life (HRQOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Lung Module (QLQ-LC13). RESULTS: Two hundred fifty patients were randomized: 80% male; median age, 58 years; and WHO PS, 0, 1, 2 in 25, 62, and 13% of cases, respectively. There were no toxic deaths. The main grade 3 or 4 toxicities observed were neutropenia and emesis, reported twice as often in the combination arm. Among 213 patients with measurable disease, response rate was 13.6% (arm A) versus 23.6% (arm B; P = .056). No difference in HRQOL was observed on any of the scales. Median overall and 1-year survival in arms A and B were 8.8 (95% CI, 7.8 to 10.8) v 11.4 months (95% CI, 10.1 to 15), respectively, and 40% v 46%, respectively (P = .048). CONCLUSION: A combination of raltitrexed and cisplatin improves overall survival compared with cisplatin alone. This study confirms that a combination of cisplatin and an antifolate is superior to cisplatin alone in patients with MPM, without harmful effect on HRQOL.

van Meerbeeck JP, Baas P, Debruyne C, Smit EF, van Klaveren RJ, Galdermans D, Lentz MA, Manegold C, Giaccone G, Anonymous00225. · Erasmus MC-Department of Pulmonology, PO Box 5201, NL-3008 AE, Rotterdam, The Netherlands. · Eur J Cancer. · Pubmed #11937311 No free full text.

Abstract: The aim of this study was to investigate the anti-tumour activity of temozolomide in patients with malignant pleural mesothelioma. 27 chemotherapy-naïve patients with histologically-proven malignant mesothelioma were treated with temozolomide 200 mg/m2/day, given orally on days 1-5 of each 28-day cycle. Therapy continued up to 10 cycles unless disease progression or excessive toxicity mandated discontinuation. Toxicity, symptom improvement and pain intensity were regularly assessed. With a median relative dose intensity of 97%, toxicity was moderate with grade 3 or more nausea, vomiting, thrombocytopenia, leucocytopenia, neutropenia, febrile leucocytopenia, arthralgia, infection and fever with infection occurring in 13, 13, 10, 3, 7 and 3% of patients for the remaining events, respectively. Overall, 1 objective response was observed (response rate 4%, 95% Confidence Interval (CI): 0.1-19). Median survival was 8.2 months. Symptom assessment showed no improvement and an increase of pain was observed during the study. Thus, oral temozolomide is an inactive agent in malignant mesothelioma.

van Haarst JM, Baas P, Manegold Ch, Schouwink JH, Burgers JA, de Bruin HG, Mooi WJ, van Klaveren RJ, de Jonge MJ, van Meerbeeck JP. · Rotterdam Oncological Thoracic Studygroup (ROTS), Department of Pulmonology, University Hospital Rotterdam, PO Box 5201, 3008 AE Rotterdam, The Netherlands. · Br J Cancer. · Pubmed #11875695 links to  free full text

Abstract: Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. METHOD: Gemcitabine 1250 mg m(-2) was administered on day 1 and day 8 and cisplatin 80 mg m(-2) was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1-31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5-7 months) with a median survival from registration of 9.6 months (95% CI 8-12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.

van Meerbeeck JP, Baas P, Debruyne C, Groen HJ, Manegold C, Ardizzoni A, Gridelli C, van Marck EA, Lentz M, Giaccone G. · Department of Pulmonology, University Hospital, Rotterdam, The Netherlands. · Cancer. · Pubmed #10375105 links to  free full text

Abstract: BACKGROUND: Gemcitabine has shown activity in patients with less chemosensitive solid tumors. Phase II screening of novel drugs is an accepted method with which to investigate new therapies in malignant mesothelioma. The European Organization for Research and Treatment of Cancer-Lung Cancer Cooperative Group has performed several sequential Phase II trials of new agents for the treatment of mesothelioma over the last 10 years. METHODS: Twenty-seven chemotherapy-naive patients with histologically proven malignant mesothelioma were treated with gemcitabine as a 30-minute intravenous administration of 1250 mg/m2 on Days 1, 8, and 15 of a 28-day cycle. Therapy continued for up to ten cycles unless disease progression or excessive toxicity mandated discontinuation. RESULTS: With a median relative dose intensity of 96%, toxicity was mild and neutropenia of > or = Grade 3 (according to National Cancer Institute criteria) occurred in 30% of patients, without episodes of febrile neutropenia. One case of hemolytic-uremic syndrome, most likely related to gemcitabine use, was observed. Overall, 2 objective responses were observed (response rate of 7%; 95% confidence interval, 1-24%). The median survival was 8 months. CONCLUSIONS: At the prescribed dosage and schedule, single agent gemcitabine appears to have limited activity in chemotherapy-naive patients with malignant pleural mesothelioma.

Tournoy KG, Burgers SA, Annema JT, Vermassen F, Praet M, Smits M, Klomp HM, van Meerbeeck JP, Baas P. · Department of Respiratory Medicine and Lung Oncology Network, Ghent University Hospital, De Pintelaan 185, Ghent, Belgium. · Clin Cancer Res. · Pubmed #18829506 No free full text.

Abstract: PURPOSE: Surgical resection as part of a multimodality approach in malignant pleural mesothelioma (MPM) has a high morbidity and mortality. Because mediastinal lymph node (MLN) metastases are a negative prognostic factor, preoperative staging is of paramount importance. Transesophageal endoscopic ultrasound with real-time guided fine needle aspiration (EUS-FNA) enables accurate MLN staging in lung cancer. EXPERIMENTAL DESIGN: The feasibility and yield of EUS-FNA in MLN staging were prospectively analyzed in patients with presumed early-stage MPM considered for multimodality therapy. MLN reference pathology was defined by either pathologic staging or the formal demonstration of malignant cells by either EUS-FNA or mediastinoscopy. RESULTS: Thirty-two consecutive patients (81% males; median age, 61 years) with proven MPM underwent EUS-FNA. In 11 (34%) patients, a negative EUS-FNA or mediastinoscopy was not confirmed by surgical MLN dissection because of clinical deterioration or disease progression. In 21 (66%) patients, a formal pathology of the MLN was obtained and staging with EUS-FNA was positive in 4 (19%). Mediastinoscopy did not result in a greater yield of MLN metastasis as compared with EUS-FNA. Thoracotomy with complete lymph node dissection was done in 17 (81%). The overall prevalence of MLN metastasis was 24%, and the sensitivity of EUS-FNA was 80% (95% confidence interval, 28-99%) with a specificity of 100% (95% confidence interval, 79-100%). One patient had esophageal perforation related to EUS-FNA. CONCLUSIONS: EUS-FNA is feasible and sensitive for MLN staging in patients with MPM who are candidate for multimodality treatment. These data warrant further evaluation.

Taylor P, Castagneto B, Dark G, Marangolo M, Scagliotti GV, van Klaveren RJ, Labianca R, Serke M, Schuette W, van Meerbeeck JP, Heigener D, Liu Y, Adachi S, Blatter J, von Pawel J. · University Hospital of South Manchester, Manchester, United Kingdom. · J Thorac Oncol. · Pubmed #18594323 No free full text.

Abstract: INTRODUCTION: Pemetrexed has established efficacy, and is the backbone for chemotherapy in patients with malignant pleural mesothelioma (MPM). An International Expanded Access Program provided >3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed plus platinum analogs (cisplatin or carboplatin) in 13 countries. In this article, we report the safety and efficacy data of MPM patients who were treated with single-agent pemetrexed (n = 812). METHODS: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed (500 mg/m) once (day 1) every 21 days with standard premedication and vitamin supplementation. Investigator-determined response and survival data were recorded at the end of study participation. Myelosuppression data were also collected. RESULTS: All 812 MPM patients (319 chemonaïve; 493 pretreated) received single-agent pemetrexed (>or=1 dose) and were evaluated for safety. A total of 643 patients (247 chemonaïve, 396 pretreated) were evaluated for efficacy. Of the chemonaïve patients evaluated for efficacy (n = 247), the overall response rate was 10.5%, median time to progressive disease (TTPD) was 6.0 months, and median survival was 14.1 month. Of the pretreated patients evaluated for efficacy (n = 396), the overall response rate was 12.1%, median TTPD was 4.9 months, and the median survival was not estimable due to high censoring. Common terminology criteria grade 3/4 hematologic toxicity was mild in both groups, with neutropenia (<18%) as the main toxicity. CONCLUSIONS: In the present expanded access program, single-agent pemetrexed demonstrated promising activity in MPM in both chemonaïve and pretreated patients, with TTPD of 6.0 and 4.9 months, respectively, 1-year survival >or=54.7%, and mild hematologic toxicity.

Aerts JG, Delahaye M, van der Kwast TH, Davidson B, Hoogsteden HC, van Meerbeeck JP. · Department of Pulmonary Diseases, Erasmus MC, Rotterdam, the Netherlands. · Diagn Cytopathol. · Pubmed #16850492 No free full text.

Abstract: The aim of the study was to establish in a prospective and blinded manner the diagnostic yield of morphology, immunocytochemistry (ICH) and electron microscopy (EM) in the cytological analysis of malignant pleural mesothelioma (MPM). Pleural fluid from consecutive patients, 14 with a histologically proven MPM, 12 with a malignant pleuritis due to adenocarcinoma (AC), and 13 with a reactive pleural effusion (RM), was separately analyzed. Smears were incubated with monoclonal antibodies (Tag72, Ber-Ep4, anti-CEA, EMA). These were considered suggestive for MPM when only EMA stained positive, for AC when three out of four markers stained positive, and for RM when no marker stained positive. The post-test probability of the morphological, ICH, and EM analysis were 92, 100, 92% or MPM, 91, 100, 86% for AC, and 88, 88, 90% for RM, respectively. We concluded that the high post-test probability of a combined morphological and ICH diagnosis of MPM warrants to cease further diagnostic procedures in these patients. Electron microscopy did not add to accuracy of diagnosis.

Francart J, Legrand C, Sylvester R, Van Glabbeke M, van Meerbeeck JP, Robert A. · European Organisation for Research and Treatment of Cancer. · J Clin Oncol. · Pubmed #16809726 No free full text.

Abstract: PURPOSE: Phase II cancer clinical trials play a key role in the development of new drugs. These trials should be designed to accurately determine if the drug should be abandoned or if it is sufficiently promising for further investigation in phase III trials. With new cytostatic agents or when the response assessment is difficult, using the progression-free survival rate (PFSR) at a fixed time point, such as 3, 4, 5, or 6 months, instead of the response rate (RR) as the primary end point is an alternative approach. To design future phase II trials, reference values for PFSRs that correspond to drugs with insufficient (P0) and sufficient (P1) clinical activity (CA) are necessary. This article provides these values in mesothelioma. MATERIALS AND METHODS: The European Organisation for Research and Treatment of Cancer database registered ten closed mesothelioma trials (nine phase II trials and one phase III trial) with 523 total patients. Trials were grouped into three categories according to the published RR: significant (n = 259), moderate (n = 142), and insufficient (n = 122) CA. RESULTS: The PFSRs at 3, 4, 5, and 6 months, respectively, were as follows: 72%, 67%, 51%, and 43% in the group with significant CA; 59%, 51%, 42%, and 35% with moderate CA; and 52%, 40%, 34%, and 28% with insufficient CA. CONCLUSION: These values may be used to define relevant P0 and P1 values in future phase II mesothelioma trials that use PFSR as the primary end point.

Bard MP, Hegmans JP, Hemmes A, Luider TM, Willemsen R, Severijnen LA, van Meerbeeck JP, Burgers SA, Hoogsteden HC, Lambrecht BN. · Department of Pulmonary Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. · Am J Respir Cell Mol Biol. · Pubmed #14975938 links to  free full text

Abstract: Exosomes are membrane vesicles from endosomal origin secreted by various cells such as hematopoietic, epithelial, and tumor cells. Exosomes secreted by tumor cells contain specific antigens potentially useful for immunotherapeutic purposes. Our aim was to determine if exosomes are present in human cancerous pleural effusions and to identify their proteomic content. Exosomes were purified by sucrose gradient ultracentrifugation, and electron microscopy was used to check both concentration and purity of exosomes. Proteins were separated by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and protein bands were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry and Western blotting. Exosomes were present in pleural fluid obtained from patients suffering from mesothelioma (n = 4), lung cancer (n = 2), breast cancer (n = 2), and ovarian cancer (n = 1). As previously reported by others, antigen-presenting molecules, cytoskeletal proteins, and signal transduction-involved proteins were present. Proteins not previously reported were identified (SNX25, BTG1, PEDF, thrombospondin 2). Different types of immunoglobulins and complement factors were abundantly present in the sucrose fractions containing exosomes. Exosome-directed specificity of these immunoglobulins was not observed. In conclusion, sucrose gradient ultracentrifugation allows isolation of exosomes from malignant pleural effusions. However, pleural fluid proteins and especially immunoglobulins are coisolated and may hamper the use of exosomes isolated from malignant effusion for immunotherapy programs.

van Klaveren RJ, Aerts JG, de Bruin H, Giaccone G, Manegold C, van Meerbeeck JP. · Department of Pulmonology, Erasmus University Medical Center, Rotterdam, Netherlands. · Lung Cancer. · Pubmed #14698538 No free full text.

Abstract: The newly introduced Response Evaluation Criteria in Solid Tumors (RECIST), which relies on a single largest dimension of tumor rather than on the product of perpendicular diameters World Health Organisation (WHO) is intended to simplify the assessment of tumor response. PURPOSE: Is to evaluate the performance and validity of the RECIST compared to the WHO criteria. DESIGN: Thirty-four consecutive patients with bidimensionally measurable malignant pleural mesothelioma (MPM) were evaluated prospectively. RESULTS: In 27% (9/34) a discrepancy was found between the WHO and RECIST response evaluation 9% (3/34) concerned best responses and 18% (6/34) objective confirmed responses. In 24% (8/34) disease progression was missed by RECIST. The percentage of patients in whom one or more discordance's between WHO and RECIST were detected was 47, 88% due to underscoring by RECIST. In a subgroup of 24 MPM patients with bidimensionally measurable pleural lesions only, the discrepancy rate was 29%, always due to underscoring by RECIST. However, when in the same subgroup the modified RECIST response evaluation was used the discrepancy rate was 21% and in all cases due to underscoring by WHO. CONCLUSION: For MPM bidimensional WHO response evaluation cannot automatically be replaced by RECIST because MPM has a non-spherical growth pattern. Our recommendation is to use the WHO criteria for bidimensional measurable lesions, RECIST for unidimensional measurable lesions and a modified RECIST response evaluation, in which the short axis perpendicular to the chest wall is used, for thickened pleural rind disease, according to the method used in the recently completed pemetrexed (Alimta) trial for MPM.