From the Section of Hematology/Oncology, University of Chicago, Chicago, IL; Division of Thoracic Surgery, Brigham and Women's Hospital; Boston, MA; and the Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA
Authors' disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Hedy Lee Kindler, MD, Associate Professor of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Ave, MC 2115, Chicago, IL 60637; E-mail: hkindler{at}medicine.bsd.uchicago.edu
Overview: Mesotheliomas typically exhibit numerous clonal chromosome alterations. Tumor suppressor genes at the sites of recurrent chromosome loss include CDKN2A/ARF and CDKN2B at 9p21 and NF2 at 22q12. A mouse model using asbestos-treated, heterozygous (+/–) Nf2 knockout mice recapitulates many molecular features of human mesothelioma and may be useful for testing novel therapies. Preclinical data suggest that inhibitors of the PI3K/AKT, PAK, or ERK signaling pathways may have efficacy in mesothelioma. Prospective studies will determine the utility of the new serum markers — soluble mesothelin/megakaryocyte–potentiating factor-related protein and ostepontin — for early detection of mesothelioma in asbestos-exposed individuals and for monitoring disease outcomes. There is no consensus on the best staging system or on the preoperative testing required for potentially resectable mesothelioma. The optimal surgical approach — extrapleural pneumonectomy or pleurectomy/decortication — also is controversial. Surgery alone yields a high incidence of local recurrence, and as such, multimodal therapy is usually recommended; whether chemotherapy should be given before, during, or after the operation is debated. A prospective clinical trial has demonstrated the efficacy of a gene expression-based test to identify patients likely to benefit from surgery. For most patients with mesothelioma, systemic therapy is the only treatment option because age, comorbidity, non-epithelial histology, and advanced disease often preclude resection. Several cytotoxic agents generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, gemcitabine, and vinorelbine. Pemetrexed plus cisplatin is the standard front-line regimen for this disease, although there are several other active combinations. Agents targeted against the vascular endothelial growth factor, src kinase, histone deacetylase, proteasome, and mesothelin are in clinical trials.
