Elsevier

The Lancet Oncology

Volume 19, Issue 3, March 2018, Pages e161-e172
The Lancet Oncology

Review
Novel therapies for malignant pleural mesothelioma

https://doi.org/10.1016/S1470-2045(18)30100-1Get rights and content

Summary

Malignant pleural mesothelioma is a rare cancer that is typically associated with exposure to asbestos. Patients with malignant pleural mesothelioma have poor outcomes with suboptimal therapeutic options and currently no treatment is curative. The standard frontline treatment, cisplatin plus pemetrexed chemotherapy, has only short and insufficient efficacy, and no validated treatment beyond first-line therapy is available. New therapeutic strategies are therefore needed. The addition of bevacizumab (an anti-VEGF antibody) combined with cisplatin plus pemetrexed has shown some promise. However, immunotherapy, especially immune checkpoint inhibitors, has generated a lot of excitement because of data suggesting the potential value of immune checkpoint inhibitors for patients who have failed chemotherapy. In this Review, we describe immune checkpoint inhibitors, other immunotherapies, targeted therapies, or combinations of novel drugs being investigated in malignant pleural mesothelioma, as well as the issues surrounding the selection of the best candidates for these treatments.

Introduction

Malignant pleural mesothelioma is an aggressive cancer that develops from pleural mesothelial cells and is usually associated with previous asbestos exposure (occupational, or more rarely environmental or domestic exposure). Although malignant pleural mesothelioma is a rare cancer, the annual incidence varies from ten cases per million people (in the USA) to 29 cases per million people (in Australia and in the UK),1 according to national registries in some countries. Although incidence of mesothelioma seems to have reached a plateau for some countries such as the USA (approximately 3200 per year),2 incidence for many European countries is not expected to peak before the 2020s because of the long latency period between asbestos exposure and diagnosis (up to 30–50 years), and the extensive use of asbestos up until the 1970s in most high-income countries.3 Sadly, asbestos is still not banned worldwide, and its extraction and use is still ongoing in many countries (eg, China, India, Kazakhstan, Russia). According to 2013 WHO predictions,4 this continued use is likely to lead to an epidemic of asbestos-related diseases, such as malignant pleural mesothelioma, in the next decades.

After inhalation, asbestos fibres can enter the lung periphery and the pleura inducing local chronic inflammation and other carcinogenic processes. Abnormalities observed include overexpression of growth factors (eg, VEGF), as well as genetic and epigenetic alterations and mutations of mesothelial cells, such as BRCA-associated protein 1 (BAP-1), neurofibromatosis type 2 (NF-2), and p16 INK4A or CDKN2A. These factors leading to cell proliferation and resistance to apoptosis, and local immunosuppression induced by the tumour,5, 6 provide the rationale for some new treatment targets.

The management of malignant pleural mesothelioma is complex and the outcomes can be disheartening. Often tumour cells resist chemotherapy treatment and patients are usually diagnosed at an advanced stage of the disease because of late and non-specific symptoms. To date, two main frontline therapeutic strategies in this cancer are used in addition to best supportive care: surgery with curative intent, or palliative cytotoxic chemotherapy.

Unfortunately, few patients are candidates for surgery. Depending on the cancer centre, patients are selected on the basis of tumour stage, performance status, histology (only the epithelioid subtype is usually operated on), nutritional status, and the usual functional parameters for thoracic surgery eligibility. Moreover, most international guidelines on the management of patients with malignant pleural mesothelioma recommend that surgery (either extrapleural pneumonectomy, or pleurectomy or decortication), should be part of a multimodal treatment regimen (ie, surgery combined with chemotherapy, radiotherapy, or both) and should be done only in highly specialised centres with multi-disciplinary expert teams or within a clinical trial.7

First-line chemotherapy combining pemetrexed and cisplatin or pemetrexed and carboplatin has been the international standard of care for the past 15 years.6, 7, 8, 9 Raltitrexed could be an alternative to pemetrexed, in combination with cisplatin, as first-line chemotherapy in malignant pleural mesothelioma.10 Based on data from a phase 3 randomised trial11 and further results from control groups in other trials,7, 12, 13 the median overall survival with pemetrexed plus platinum does not exceed 13–16 months, with the best outcome in patients with the epithelioid malignant pleural mesothelioma subtype.

The use of radiotherapy is rare in the treatment of patients with malignant pleural mesothelioma and is generally reserved for pain relief induced by the infiltration of the chest wall, new modalities of radiotherapy, such as intensity modulated radiotherapy, protontherapy, or stereotaxic radiotherapy, are under investigation in this form of cancer.7, 8, 9, 14 Prophylactic radiotherapy of chest wall tracts after surgery to prevent tumour parietal seeding, a highly controversial procedure,15 is no longer recommended in the 2018 American Society of Clinical Oncology guidelines,16 after the results of the SMART and PIT trials were reported.16, 17

No therapy has been approved or officially recommended beyond first-line treatment with malignant pleural mesothelioma, except to consider a repeat course of pemetrexed-based chemotherapy if a patient has had a long progression-free survival after standard front-line treatment.7, 8, 9 In fact, all other routinely used drugs, such as vinorelbine or gemcitabine, which have been tested in previous malignant pleural mesothelioma trials,18, 19, 20, 21 did poorly, with less than 30% of patients with disease control after 12 weeks of treatment, and a median overall survival not exceeding 6 months.7, 20, 21

On the basis of these data, new treatments are urgently needed for malignant pleural mesothelioma. Given recent successes in other thoracic tumours, such as lung cancer, strategies such as targeted therapies and anti-tumour immunotherapy have attracted great interest in managing this disease.

Section snippets

Targeted therapiesAnti-angiogenic drugs

Based on the known role of angiogenic processes in tumorigenesis, and the high expression of angiogenic growth factors and their receptors in malignant pleural mesothelioma, several anti-angiogenic drugs have been investigated over the past decade, either alone or in combination with standard chemotherapy (cisplatin plus pemetrexed), or as maintenance treatment, or both (table 1).

Until recently, no significantly improved efficacy was observed with anti-angiogenic drugs in the treatment of

Anti-tumour immunotherapy

The immune system plays a major role in the pathogenesis of malignant pleural mesothelioma as shown by chronic inflammation and local tumour immunosuppression.46 Rare cases of spontaneous malignant pleural mesothelioma regression have been reported, likely mediated by an immune response.47 It has been reported48 that survival of patients with malignant pleural mesothelioma is better when there is a high intra-tumour infiltration by cytotoxic CD8 T cells (tumour-infiltrating lymphocytes).

Conclusion

After a long and frustrating era with suboptimal medical treatment, patients with malignant pleural mesothelioma might soon benefit from more long-lasting disease control and a better quality of life due to new targeted therapies and immunotherapies. Based on the success in melanoma, non-small-cell lung cancer, and other solid tumours, expectations are high that immune checkpoint inhibitors will change the standard of care for these patients. However, it must be emphasised that current

Search strategy and selection criteria

References for this Review were selected through searches of PubMed and proceedings of major (thoracic) oncology international meetings using the search terms “malignant pleural mesothelioma”, “chemotherapy”, “targeted therapy”, “immunotherapy”, and “mesothelin” from Jan 1, 2000, until Sept 27, 2017. Only papers published in English were included. A search of all clinical trials for patients with malignant pleural mesothelioma was also done in ClinicalTrials.gov. However, this Review cannot be

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