Current Mesothelioma Treatment and Future Perspectives

The established treatments in malignant mesothelioma are based on trimodality approach including surgery, radiation and chemotherapy. Such approach has proved to clinically benefit mesothelioma patients, however the current treatments seem to have reached a limit regarding the survival and disease control. One approach to overcome the limitations of current treatments is focused on finding appropriate serum or genetic biomarkers that could support personalized medicine and improve outcomes with established treatment modalities in mesothelioma patients. The other approach is exploiting better understanding of molecular and genetic characteristics of mesothelioma to search for new treatment modalities. Immunotherapy with anti PD-1, PD-L1 and CTLA-4 agents is a new frontier in mesothelioma treatment. As in many solid tumors, CAR-T cell therapy is emerging from the field of hematological malignancies. Immunomodulatory approaches seem to be a new perspective in treatment of malignant mesothelioma. This chapter aims to explore possible new therapeutic approaches in mesothelioma.

Peritoneal Mesothelioma: Clinical and Therapeutic Aspects

Mesothelioma is a very rare malignant disease that originates from mesothelial cells that line the serosa: pleura, peritoneum, pericardium, or testicular vaginal tunic. Peritoneal mesothelioma accounts for 7–10% of all mesotheliomas diagnosed, and ranks second after pleural localization of mesothelioma. The incidence of peritoneal mesothelioma is 0.5–3 cases per million in men and 0.2–2 cases per million in women. Diagnosis of peritoneal mesothelioma is difficult due to nonspecific symptoms and because of this patients present in advanced stages of the disease. Histologically there are three major categories of malignant peritoneal mesothelioma: epithelioid, sarcomatoid, and biphasic. The differential diagnosis of peritoneal mesothelioma is made with peritoneal pseudomyxoma, ovarian tumors, and peritoneal metastases from colorectal cancer. An important role in differential diagnosis, in addition to immunohistochemistry, is played by various tumor markers and genetic tests. The treatment of peritoneal mesothelioma is performed by cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), with good results for patients in the early stages of the disease. For patients with advanced disease, a new treatment has been proposed: pressurized intraperitoneal aerosol chemotherapy (PIPAC). For patients who cannot use CRS and HIPEC, the only therapeutic option remains chemotherapy (systemic + intraperitoneal).

Genetic Alterations of Malignant Pleural Mesothelima

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that arises from the mesothelial cells lining the pleural cavity. Asbestos is considered the major factor in the pathogenesis of this malignancy, with more than 80% of patients with a history of asbestos exposure. MPM is characterized by a long latency period, typically 20–40 years from the time of asbestos exposure to diagnosis, suggesting that multiple somatic genetic alterations are required for the tumorigenic conversion of a mesothelial cell. In the last few years, advancements in next-generation sequencing and “–omics” technologies have revolutionized the field of genomics and medical diagnosis. The focus of this chapter is to summarize recent studies which explore the molecular mechanisms underlying this disease and identify potential therapeutic targets in MPM.

Biomarkers Progress and Therapeutic Implications in Malignant Mesothelioma

We are witnessing enormous efforts to identify prognostic and predictive biomarkers to inform treatment decisions in malignant mesothelioma. In this chapter, we will review and discuss the current literature and supportive evidence for the progress in development and use of biomarkers in malignant mesothelioma. There are currently several clinical trials evaluating treatment options in mesothelioma, and this will be an up-to-date review of these trials from published literature.

Mesothelioma, a Review of Current Guidelines

Mesothelioma is considered as a rare tumor originating in the mesothelial surfaces of pleura or, more rarely, in other sites such as peritoneum, which harbors a very poor prognosis. Despite clinical research efforts, lack of available therapies remains clear. Standard of care treatments and guidelines have not been evolved much along recent years. In this chapter, main guidelines will be reviewed, besides a systematic Pubmed review, with a focus on epidemiology, diagnosis tests, and approved local and systemic treatments, including most important advances. Searched terms included “mesothelioma,” “ESMO and NCCN guidelines,” “diagnosis,” “surgery,” “targeted therapy,” “clinical trials,” “palliative treatment,” and “meta-analysis.” First-line regimen recommendations have not evolved since the phase III pivotal study of cisplatin-pemetrexed was published, and this combination became the standard of care. Targeted therapies have brought disappointing results. However, recent clinical trial data with immunotherapies are bringing some light and may become a new paradigm in the following years.

Predictive and Prognosis Factors of Clinical Utility in Mesothelioma

The constant research in therapeutics for mesothelioma has been improving their tumor response and overall survival, generating the need to propose markers that guide the doctor’s therapeutic approach in a more precise way. Recently, different predictive factors have been proposed, such as mesothelin-related peptides, fibulin-3, and osteopontin associated with an image giving information about the probability of tumor response to a therapeutic agent or a combination of agents. As is well known, the importance of prognostic markers of utility lies in providing prospective information on the evolution of the patient and thus their ability to guide therapeutic decisions. Although the clinical stage and histology are currently the most described prognostic factors, recent studies have shown interest in the expression of estrogen receptor beta and calretinin, among other promising factors. Given the heterogeneity of this broad field of research in mesothelioma, it is necessary to objectively present the prognostic and predictive factors of greater clinical utility.

Emerging Drug Therapies for Mesothelioma

The systemic chemotherapy combination of cisplatin and pemetrexed has been the mesothelioma standard of care for well over a decade. This regimen has only achieved a disappointing overall median survival of about 1 year. Improved survival has been reported when systemic chemotherapy is combined with surgery and radiotherapy, and for using localized chemotherapy in some cases. The choice of mesothelioma treatment often depends on the anatomical location, histologic subtype, and disease progression. Several experimental drugs have also been investigated in mesothelioma, often with limited positive results that maintain the reputation of mesothelioma as a graveyard for drug development. This chapter will review the use of drug treatment in mesothelioma and highlight emerging experimental drug therapies in clinical trials. Experimental drugs for mesothelioma include inhibitors for checkpoints, epidermal growth factor, AXL, focal adhesion kinase, vascular endothelial growth factor, poly-ADP-ribose-polymerase, and hippo signaling.