Mesothelioma is a malignant condition arising from the pleura and peritoneum that is closely related to asbestos exposure. Due to the prolonged time needed for one to fully develop mesothelioma, difficulty in diagnosing this condition early, its quick progression once manifested, and the limited treatment options, the prognosis for this condition has traditionally been poor. This review will briefly reflect on what we know about mesothelioma so far and relate it to the novel therapeutic strategies that have been developed over recent years. These include immunotherapy or immune checkpoint inhibitors (ICIs), molecular targeted therapies, and the use of cell-based therapy (such as CAR-T cells or dendritic cells), among others. Mechanistic rationales and clinical evidence will be provided, and prospective therapies will also be discussed.
While the exact mechanism that causes the carcinogenesis of mesothelioma is unknown, the exposure to and inhalation of asbestos fiber is a definite trigger. Around 85% of mesothelioma cases are attributable to occupational asbestos exposure, although only around 10% of those exposed to asbestos actually develop mesothelioma. Moreover, mesothelioma has a long latency period (20–50 years). Thus, even with stringent regulations and bans on asbestos usage, new cases of mesothelioma are still being diagnosed. Chronic and repeating cycles of inflammation and healing in the mesothelium have been linked to the molecular mechanism of mesothelioma. Indeed, prolonged exposure to asbestos causes multiple changes in mesothelial cells, including DNA damage and cell cycle arrest, apoptosis defects, and the release of reactive oxygen species and reactive nitrogen species, among others. Asbestos also induces mast cells to release inflammatory mediators such as tumor necrosis factor α (TNF-α), which together can trigger the activation of the central inflammation response protein in nuclear factor-kB (NF-kB). All of these processes lead to genotoxicity and may cause mutations in mesothelial cells. Prolonged, repeated exposure to asbestos and the subsequent triggering of the above process are currently thought to be the mechanisms behind mesothelioma.
The treatment options have traditionally been limited. For instance, surgery for pleural mesothelioma is controversial because until recently no phase 3 trials had addressed its efficacy. Selecting patients who may benefit from surgery is a key component, as is determining the appropriate surgical approach and whether any pre-/post-surgical radiotherapy or other adjuvant/neoadjuvant therapies are needed around the time of surgery. Notably, the MARS set of clinical trials tried to determine whether surgery is beneficial in mesothelioma. In the first MARS trial, the authors found that extrapleural pneumonectomy (EPP) did not benefit the patients and may have been harmful due to its high morbidity. Moreover, in MARS 2, a different surgical approach of extended pleurectomy decortication (EPD) in combination with chemotherapy led to worse survival rates, increased adverse events, and reduced quality of life, discouraging clinicians from performing surgery in mesothelioma patients. Still, more clinical data are needed to conclude that surgery is not a viable option for this condition. The addition of hyperthermic intraoperative chemotherapy (HITHOC) to the surgical approach has been observed in various prospective and retrospective studies, but no large clinical trials have been conducted for this strategy. HITHOC combines several therapeutic options, including surgery, intraoperative and topical administration of chemotherapeutic drugs, and simultaneous warming of the thoracic cavity, to treat cancer cells that spread to the pleural spaces. The adverse events reported for HITHOC include local pain from the procedure; nausea and vomiting; anemia and thrombocytopenia; and even hemodynamic and respiratory instability, in rare cases. However, the variability in the actual indications and technical applications of HITHOC currently limits its clinical usage. Palliative systemic therapy via chemotherapy is the treatment of choice for most patients, with the combination of cisplatin and pemetrexed being preferred. Radiotherapy can also be used in palliative settings to manage symptoms that are not manageable with drugs. Until relatively recently, clinicians utilized the options mentioned above to treat mesothelioma patients, which contributed to their poor prognosis. As discussed below, the evolution of our understanding of how malignancies such as mesothelioma function has enabled various breakthroughs and innovations related to therapeutic options. In the next section, we discuss the novel therapies that are approved, being examined, or being considered for mesothelioma treatment. A relatively recent development in the usage of immunotherapy has changed the landscape of mesothelioma treatment. Significant improvements could be seen after its administration in several large clinical trials. Beyond immunotherapy, many other novel therapeutic strategies are being developed to combat mesothelioma. Below, we discuss in detail the current evidence for these strategies. It must be noted, however, that the only novel treatment options currently approved for clinical use are nivolumab/ipilimumab combination immunotherapy, nivolumab monotherapy (in Japan), and tumor-treating fields (TTFields). Table 1 summarizes the novel therapeutic modalities for mesothelioma that are discussed below. [Footnotes omitted.] [Article continues at original source]
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