Mesothelioma: Stahel RA

Stahel RA, Weder W, Felip E, Anonymous00129. · Clinic and Policlinic of Oncology, University Hospital of Zürich, Switzerland. · Ann Oncol. · Pubmed #18456764 links to  free full text

This publication has no abstract.

Stahel RA, Felley-Bosco E, Opitz I, Weder W. · Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, University Hosptial, CH-8091 Zürich, Switzerland. · Future Oncol. · Pubmed #19374545 No free full text.

Abstract: Malignant pleural mesothelioma continues to be a challenge. The diagnosis and treatment of patients with malignant pleural mesothelioma requires a multidisciplinary approach. The diagnosis is best made by thoracoscopic biopsy and the aid of immunohistochemistry. Molecular studies identified inactivation of the neurofibromatosis-2 gene and INK4alpha/ARF to be key events in tumorigenesis. Based on the results of a Phase III trial, the combination of cisplatin with pemetrexed has become the preferred choice for chemotherapy, although there is suggestive evidence for the activity of other platin combinations based on Phase II studies. The optimal second-line chemotherapy remains to be defined. Surgical interventions ranging from pleurectomy/decortication to extrapleural pneumonectomy are increasingly offered in specialized centers, and the results of multimodality approaches with neoadjuvant or adjuvant chemotherapy and extrapleural pneumonectomy are encouraging. Ongoing investigations are defining the role of postoperative radiotherapy and the clinical activity of tyrosine kinase inhibitors targeting VEGFR2, histone deacetylase inhibitors and proteosome inhibitors.

Stahel RA. · Zürich, Suisse. · Rev Pneumol Clin. · Pubmed #17404533 No free full text.

This publication has no abstract.

Stahel RA. · Clinic and Policlinic for Oncology/Department of Internal Medicine, University Hospital, Zurich, Switzerland. · Lung Cancer. · Pubmed #17059852 No free full text.

Abstract: Malignant pleural mesothelioma (MPM) is an asbestos-associated cancer that occurs most commonly in the pleural cavities and generally has a poor prognosis. A rise in the incidence of this fatal disease, which, in the past has been considered to be relatively refractory to therapy, is predicted over the next decade. The realisation that patients can benefit from systemic chemotherapy and more aggressive multimodal approaches, including extrapleural pneumonectomy (EPP), in earlier stages of disease now provides the opportunity to offer more effective treatment for this disease.

Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, Eberhardt W, Paz-Ares L, Sundstrom S, Liu Y, Ripoche V, Blatter J, Visseren-Grul CM, Manegold C. · Istituto Clinico Humanitas, Rozzano, Italy. · J Thorac Oncol. · Pubmed #18594322 No free full text.

Abstract: INTRODUCTION: Previously published results from a randomized phase III study of pemetrexed plus cisplatin in patients with malignant pleural mesothelioma (MPM) demonstrated a significant survival benefit and higher response rate compared with cisplatin. Although pemetrexed was under review by regulatory agencies, an International Expanded Access Program (EAP) provided more than 3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed in combination with cisplatin or carboplatin in 13 countries. This manuscript reports the safety and efficacy data from the nonrandomized open-label study in chemonaïve patients receiving pemetrexed plus platinum under the EAP. METHODS: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed 500 mg/m in combination with either cisplatin 75 mg/m or carboplatin AUC 5, once every 21 days with standard premedication. Efficacy data were recorded at the end of study participation. RESULTS: A total of 1704 chemonaïve patients received pemetrexed plus cisplatin (n = 843) or pemetrexed plus carboplatin (n = 861) and were evaluated for safety. The efficacy evaluable population consisted of 745 patients in the pemetrexed plus cisplatin group and 752 patients in the pemetrexed plus carboplatin group for whom physician-reported tumor response was available. The pemetrexed plus cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed plus carboplatin group, with similar 1-year survival rates (63.1% versus 64.0%) and median time to progressive disease (7 months versus 6.9 months). The most common grade 3/4 hematologic toxicity was neutropenia in 23.9% of the pemetrexed plus cisplatin group and 36.1% of the pemetrexed plus carboplatin group. CONCLUSION: This large EAP confirmed the activity of pemetrexed plus cisplatin and pemetrexed plus carboplatin in chemonaïve patients with MPM, demonstrating clinically similar time to progressive disease and 1-year survival rates.

Ribi K, Bernhard J, Schuller JC, Weder W, Bodis S, Jörger M, Betticher D, Schmid RA, Stupp R, Ris HB, Stahel RA, Anonymous00017. · Swiss Group for Clinical Cancer Research SAKK Coordinating Center, Bern, Switzerland. · Lung Cancer. · Pubmed #18433927 No free full text.

Abstract: BACKGROUND: In patients with malignant pleural mesothelioma undergoing a multimodality therapy, treatment toxicity may outweigh the benefit of progression-free survival. The subjective experience across different treatment phases is an important clinical outcome. This study compares a standard with an individual quality of life (QoL) measure used in a multi-center phase II trial. PATIENTS AND METHODS: Sixty-one patients with stage I-III technically operable pleural mesothelioma were treated with preoperative chemotherapy, followed by pleuropneumonectomy and subsequent radiotherapy. QoL was assessed at baseline, at day 1 of cycle 3, and 1, 3 and 6 months post-surgery by using the Rotterdam Symptom Checklist (RSCL) and the Schedule for the Evaluation of Quality of Life-Direct Weighting (SEIQoL-DW), a measure that is based on five individually nominated and weighted QoL-domains. RESULTS: Completion rates were 98% (RSCL) and 92% (SEIQoL) at baseline and 98%/89% at cycle 3, respectively. Of the operated patients (N=45) RSCL and SEIQoL were available from 86%/72%, 93%/74%, and 94%/76% at months 1, 3, and 6 post-surgery. Average assessment time for the SEIQoL was 24min compared to 8min needed for the RSCL. Median changes from baseline indicate that both RSCL QoL overall score and SEIQoL index remained stable during chemotherapy with a clinically significant deterioration (change>or=8 points) 1 month after surgery (median change of -66 and -14 for RSCL and SEIQoL, respectively). RSCL QoL overall scores improved thereafter, but remained beneath baseline level until 6 months after surgery. SEIQoL scores improved to baseline-level at month 3 after surgery, but worsened again at month 6. RSCL QoL overall score and SEIQoL index were moderately correlated at baseline (r=.30; p<or=.05) and at 6-month follow-up (r=.42; p<or=.05) but not at the other time points. CONCLUSION: The SEIQoL assessment seems to be feasible within a phase II clinical trial, but may require more effort from staff. More distinctive QoL changes in accordance with clinical changes were measured with the RSCL. Our findings suggest that the two measures are not interchangeable: the RSCL is to favor when mainly information related to the course of disease- and treatment is of interest.

Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, Lardinois D, Betticher D, Schmid R, Stupp R, Ris HB, Jermann M, Mingrone W, Roth AD, Spiliopoulos A, Anonymous00123. · Department of Thoracic Surgery, University Hospital Zurich, Switzerland. · Ann Oncol. · Pubmed #17429100 links to  free full text

Abstract: BACKGROUND: The aim of this multicenter trial was to prospectively evaluate neo-adjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) and radiotherapy, including quality of life as outcome. PATIENTS AND METHODS: Eligible patients had malignant pleural mesothelioma of all histological types, World Health Organization performance status of zero to two and clinical stage T1-T3, N0-2, M0 disease considered completely resectable. Neo-adjuvant chemotherapy consisted of three cycles of cisplatin and gemcitabine followed by EPP. Postoperative radiotherapy was considered for all patients. RESULTS: In all, 58 of 61 patients completed three cycles of neo-adjuvant chemotherapy. Forty-five patients (74%) underwent EPP and in 37 patients (61%) the resection was complete. Postoperative radiotherapy was initiated in 36 patients. The median survival of all patients was 19.8 months [95% confidence interval (CI) 14.6-24.5]. For the 45 patients undergoing EPP, the median survival was 23 months (95% CI 16.6-32.9). Psychological distress showed minor variations over time with distress above the cut-off score indicating no morbidity with 82% (N = 36) at baseline and 76% (N = 26) at 3 months after surgery (P = 0.5). CONCLUSIONS: The observed rate of operability is promising. A median survival of 23 months for patients undergoing EPP compares favourably with the survival reported from single center studies of upfront surgery. This approach was not associated with an increase in psychological distress.

Weder W, Kestenholz P, Taverna C, Bodis S, Lardinois D, Jerman M, Stahel RA. · Division of Thoracic Surgery and Policlinic for Radiation Oncology, University Hospital, Zurich, Switzerland. · J Clin Oncol. · Pubmed #15337794 No free full text.

Abstract: PURPOSE: To investigate neoadjuvant chemotherapy with cisplatin and gemcitabine followed by extrapleural pneumonectomy with or without radiation therapy in patients with potentially resectable malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Eligible patients had MPM with clinical stage T1-3, N0-2, M0 disease considered to be completely resectable and a WHO performance status of 0 to 2. Neoadjuvant chemotherapy consisted of three cycles of cisplatin 80 mg/m2 on day 1 and gemcitabine 1,000 mg/m2 on days 1, 8, and 15, given every 28 days. Surgery had to consist of a complete extrapleural pneumonectomy, including resection of pericardium and diaphragm. Postoperative radiotherapy was to be considered for all patients. RESULTS: Nineteen patients with MPM were included in this pilot study. According to the European Organization for Research and Treatment of Cancer prognostic score, two patients were in the good prognosis group, and 17 patients were in the poor prognosis group. The response rate to neoadjuvant chemotherapy was 32%. The major toxicity was thrombocytopenia. Extrapleural pneumonectomy was performed in 16 patients with no perioperative mortality. Major surgical complications occurred in six patients, and all were treated successfully. Thirteen patients received postoperative radiotherapy. The median survival time was 23 months. Two patients remain alive and free of disease 41 and 38 months after initiation of therapy. CONCLUSION: For patients with potentially operable MPM, the availability of active and well-tolerated chemotherapy regimens, the fact that extrapleural pneumonectomy can be safely performed after neoadjuvant chemotherapy in an experienced center, and the promising results regarding survival in our pilot study warrant further investigation of the role of neoadjuvant chemotherapy in a multimodality strategy.

Stahel RA, Weder W. · Clinic and Policlinic of Oncology and Thoracic Surgery, University Hospital, Zürich CH 8091, Switzerland. · Curr Opin Oncol. · Pubmed #19532013 No free full text.

Abstract: PURPOSE OF REVIEW: The treatment of malignant pleural mesothelioma continues to be a clinical challenge. The question, however, is no longer whether to provide active treatment or not, but how aggressive the treatment should be in view of the limited life expectancy of patients with this disease. RECENT FINDINGS: With platin and pemetrexed-based combination chemotherapy having become the preferred systemic therapy, the major questions now evolve around the identification of a suitable second line therapy and the quest for innovative new approaches. Surgical interventions from pleurectomy and decortication to extrapleural pneumonectomy have increasingly come of use in specialized centres. With neoadjuvant chemotherapy and extrapleural pneumonectomy median survival times of almost 2 years have been reported. Studies on high-dose hemithoracic radiotherapy after extrapleural pneumonectomy suggested a beneficial effect on local recurrence. However, both extrapleural pneumonectomy and high-dose hemithoracic radiotherapy are associated with potential treatment-related mortality and morbidity and cannot yet be recommended outside specialized centres. SUMMARY: More than ever, the diagnosis and treatment of patients with malignant pleural mesothelioma mandate a multidisciplinary approach.

Stahel RA, Weder W, Felip E, Anonymous00170. · Clinic and Policlinic of Oncology, University Hospital of Zürich, Zürich, Switzerland. · Ann Oncol. · Pubmed #19454470 No free full text.

This publication has no abstract.

Thurneysen C, Opitz I, Kurtz S, Weder W, Stahel RA, Felley-Bosco E. · Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, University Hospital of Zürich, Häldeliweg 4, 8044 Zürich, Switzerland. · Lung Cancer. · Pubmed #18835652 No free full text.

Abstract: The tumor suppressor merlin is encoded by the neurofibromatosis type 2 gene (NF2) which is located on chromosome 22q12 and mutations in this gene have been found in 40% of mesothelioma. Mutations including deletions and insertions lead to truncated and inactivated merlin. Experimental animal models indicate that disruption of the NF2 signalling pathway, together with a deficiency in ink4a, is essential for mesothelioma development. Our hypothesis was that in human mesothelioma without detectable NF2 mutations, regulators of NF2/merlin activity such as CPI-17 would be altered. CPI-17 is an oncogene inhibiting the NF2/merlin phosphatase which is necessary to maintain NF2/merlin activity. Samples obtained from 44 mesothelioma, 3 asbestosis patients and 6 normal pleura from non-asbestos related disease patients were analyzed. Truncated NF2 transcripts or presence of isoform II only were observed in 11 mesothelioma samples. In all other mesothelioma samples only NF2 isoform I or isoforms I and II were detected. 18 mesothelioma and 1 normal pleura samples also expressed splicing variant delE2/3. Unexpected variants in addition to wild-type were identified in 24 mesothelioma samples. NF2 protein was either truncated or phosphorylated on Ser 518 in primary cultures derived from 25 tumors. CPI-17 expression was significantly increased in tumor samples without deleted NF2 compared to normal pleura and tumor expressing truncated NF2. Our results support the hypothesis that the disruption of NF2 signalling is essential for the development of human mesothelioma. In tumors where no NF2 truncation can be detected, NF2 is rendered inactive by phosphorylation of Ser 518 and this can be explained at least in part by an increased expression of CPI-17.

Belyanskaya LL, Marti TM, Hopkins-Donaldson S, Kurtz S, Felley-Bosco E, Stahel RA. · Laboratory of Molecular Oncology, Clinic and Policlinic of Oncology, University Hospital of Zürich, Häldeliweg 4, 8044 Zürich, Switzerland. · Mol Cancer. · Pubmed #17953743 links to  free full text

Abstract: BACKGROUND: The incidence of malignant pleural mesothelioma (MPM) is associated with exposure to asbestos, and projections suggest that the yearly number of deaths in Western Europe due to MPM will increase until 2020. Despite progress in chemo- and in multimodality therapy, MPM remains a disease with a poor prognosis. Inducing apoptosis by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or agonistic monoclonal antibodies which target TRAIL-receptor 1 (TRAIL-R1) or TRAIL-R2 has been thought to be a promising cancer therapy. RESULTS: We have compared the sensitivity of 13 MPM cell lines or primary cultures to TRAIL and two fully human agonistic monoclonal antibodies directed to TRAIL-R1 (Mapatumumab) and TRAIL-R2 (Lexatumumab) and examined sensitization of the MPM cell lines to cisplatin-induced by the TRAIL-receptor antibodies. We found that sensitivity of MPM cells to TRAIL, Mapatumumab and Lexatumumab varies largely and is independent of TRAIL-receptor expression. TRAIL-R2 contributes more than TRAIL-R1 to death-receptor mediated apoptosis in MPM cells that express both receptors. The combination of cisplatin with Mapatumumab or Lexatumumab synergistically inhibited the cell growth and enhanced apoptotic death. Furthermore, pre-treatment with cisplatin followed by Mapatumumab or Lexatumumab resulted in significant higher cytotoxic effects as compared to the reverse sequence. Combination-induced cell growth inhibition was significantly abrogated by pre-treatment of the cells with the antioxidant N-acetylcysteine. CONCLUSION: Our results suggest that the sequential administration of cisplatin followed by Mapatumumab or Lexatumumab deserves investigation in the treatment of patients with MPM.

Ziegler A, Seemayer CA, Hinterberger M, Vogt P, Bigosch C, Gautschi O, Tornillo L, Betticher DC, Moch H, Stahel RA. · Clinic and Policlinic of Oncology, Laboratory of Molecular Oncology, University Hospital, Haeldeliweg 4, CH-8044 Zurich, Switzerland. · Lung Cancer. · Pubmed #17513005 No free full text.

Abstract: The association of simian virus 40 (SV40) with malignant pleural mesothelioma is currently under debate. In some malignancies of viral aetiology, viral DNA can be detected in the patients' serum or plasma. To characterize the prevalence of SV40 in Swiss mesothelioma patients, we optimized a real-time PCR for quantitative detection of SV40 DNA in plasma, and used a monoclonal antibody for immunohistochemical detection of SV40 in mesothelioma tissue microarrays. Real-time PCR was linear over five orders of magnitude, and sensitive to a single gene copy. Repeat PCR determinations showed excellent reproducibility. However, SV40 status varied for independent DNA isolates of single samples. We noted that SV40 detection rates by PCR were drastically reduced by the implementation of strict room compartmentalization and decontamination procedures. Therefore, we systematically addressed common sources of contamination and found no cross-reactivity with DNA of other polyomaviruses. Contamination during PCR was rare and plasmid contamination was infrequent. SV40 DNA was reproducibly detected in only 4 of 78 (5.1%) plasma samples. SV40 DNA levels were low and not consistently observed in paired plasma and tumour samples from the same patient. Immunohistochemical analysis revealed a weak but reproducible SV40 staining in 16 of 341 (4.7%) mesotheliomas. Our data support the occurrence of non-reproducible SV40 PCR amplifications and underscore the importance of proper sample handling and analysis. SV40 DNA and protein were found at low prevalence (5%) in plasma and tumour tissue, respectively. This suggests that SV40 does not appear to play a major role in the development of mesothelioma.

Manegold C, Stahel RA, Anonymous00178. · Thoraxklinik Amalienstr. 5, D-69126 Heidelberg, Germany. · Ann Oncol. · Pubmed #15888745 links to  free full text

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Hopkins-Donaldson S, Cathomas R, Simões-Wüst AP, Kurtz S, Belyanskaya L, Stahel RA, Zangemeister-Wittke U, Belyanskya L. · Division of Medical Oncology, Department of Internal Medicine, University Hospital Zürich, Zürich, Switzerland. · Int J Cancer. · Pubmed #12800189 No free full text.

Abstract: Our study was designed to investigate the role of the anti-apoptotic proteins Bcl-2 and Bcl-xL in the chemoresistance of cells derived from malignant pleural mesothelioma. First, we determined the basal expression levels of Bcl-2 and Bcl-xL in mesothelioma cells and examined the effect of their downregulation by antisense oligonucleotides. Bcl-xL mRNA and protein could be readily detected in mesothelioma cell lines, whereas only low levels of Bcl-2 mRNA and protein were found. Preferential downregulation of either Bcl-xL alone or of Bcl-xL and Bcl-2 simultaneously was achieved by treatment with antisense oligonucleotides 4259 and 4625, respectively, whereas the expression of other apoptosis-relevant genes remained unaffected. Treatment with oligonucleotides 4259 or 4625 lowered the apoptosis threshold in ZL34 mesothelioma cells, as indicated by an increase in cell death accompanied by increased caspase-3-like activity, a decrease of the mitochondrial transmembrane potential and the cleavage of procaspase-7 and ICAD. In addition to the direct induction of apoptosis, antisense treatment sensitized ZL34 cells to the cytostatic effect of cisplatin and gemcitabine, with the combination of 4625 and cisplatin being the most effective. Our results demonstrate that Bcl-2 and Bcl-xL antisense treatment facilitates apoptosis in mesothelioma cells and suggest the use of Bcl-2/Bcl-xL bispecific antisense treatment in combination with cisplatin or gemcitabine for therapy of malignant pleural mesothelioma.