Elsevier

Cancer Treatment Reviews

Volume 39, Issue 6, October 2013, Pages 584-591
Cancer Treatment Reviews

Anti-Tumour Treatment
Malignant mesothelioma: New insights into a rare disease

https://doi.org/10.1016/j.ctrv.2012.12.005Get rights and content

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy of the pleura associated with exposure to asbestos. Its incidence is anticipated to increase over the next 10 years in both Europe and the developing nations. In advanced disease, chemotherapy is the cornerstone of treatment, especially platinum-containing regimens. Most efforts are directed toward improving standard first-line therapy or developing effective second-line therapy, which is still not yet standardized 10 years after the first-line standard of care was established.

This review focuses on the systemic management of MPM in patients who are not considered suitable for surgical approaches, and it discusses some questions that remain open such as the benefits of administering a maintenance treatment, whether it is better to give cisplatin or carboplatin as first-line therapy, the role of new drugs as second-line therapy, and the treatment of the elderly population. It also summarizes the results from clinical trials that have evaluated new treatments as first- or second-line therapy, which are based on the understanding of mesothelioma biology, such as antiangiogenic drugs, immunotherapies and growth factors agents.

Introduction

Malignant pleural mesothelioma (MPM) is a rare malignancy that is mainly localized to the pleura. The epithelial histologic subtype is the most common. Asbestos exposure is the dominant etiologic agent, with a latency period of 20–40 years. The global incidence of malignant mesothelioma is poorly reported, but it is likely to continue to increase due to ongoing use of asbestos in the developing world. In Spain, deaths from mesothelioma are expected to continue to increase until at least 2016, as the use of asbestos was banned in 2001.1

MPM is more common in men than in women, and 75% of patients are older than 65 years. The median overall survival (OS) of locally advanced or metastatic disease without treatment is 6–9 months. The vast majority of treatments are palliative. Poor prognosis factors of this disease are non-epithelial histologic subtype, a poor performance status (PS), anaemia, high white blood cells and thrombocytosis.2, 3

In the suspicious diagnosis of MPM, a positive blood test for mesothelin, which is a high specificity test, strongly suggests further diagnostic tests. However, the poor sensitivity of mesothelin limits its use as a screening marker.4 Given the biologic and phenotypic tumor heterogeneity of MPM, immunohistochemistry helps in the differential diagnosis between MPM and metastatic carcinoma.5

Therapeutic options depend mainly on Tumor, Node, Metastasis (TNM) stage,6 but it should be noted that positron emission tomography/computed tomography (PET/CT) can detect 15% of occult metastases and is a new tool in not advanced MPM.7 Pleurectomy/decortication (P/D) and extrapleural pneumonectomy (EPP) are the two main cytoreduction surgeries in MPM. Optimal therapy remains controversial, mainly because it is disputed whether surgery increases survival and whether survival benefit is best achieved with EPP or P/D within a multimodal regimen. In the MARS trial, EPP compared with no-EPP within trimodal therapy did not offer any benefits, and possibly harmed patients, but the low accrual and the mortality rate in the surgery arm did not allow final conclusions to be drawn about the role of surgery in MPM.8

There are no randomized trials directly comparing EPP with P/D, however in one trial patients who underwent to P/D had a better survival with lower operative mortality, compared to EPP, which may be explained by subject selection.9, 10 The International Association for the Study of Lung Cancer (IASLC) MPM database with 3101 patients showed a better survival with EPP than with P/D in stages I–II MPM.11 At present, the choice of resection depends on the extent of disease, patient comorbidities, and type of multimodality treatment; and the main goal of surgery should not only be complete resection if possible, but more realistically, the resection of all macroscopic disease as an adjunct to delivery of chemotherapy and radiotherapy.

This review focuses on systemic management of MPM in patients not considered suitable for surgical approaches.

Section snippets

First-line treatment of patients with MPM

MPM is considered a rare and heterogeneous malignant disease (different prognostic factors and three different histologic subtypes), and it is difficult to evaluate the response rate (RR) to the treatment by classical RECIST criteria (modified RECIST is recommended),12 and to stage the disease. These facts make it more difficult to perform double-blinded randomized clinical trials, which is the gold-standard of clinical research. Thus, patients with MPM have not yet benefited from the

Maintenance treatment for patients with MPM

In NSCLC, maintenance strategy with a single agent is effective,33 especially with pemetrexed,34, 35 even after an induction treatment with a platinum–pemetrexed schedule. The role of pemetrexed as maintenance therapy in responding or stable patients with MPM after ending first-line treatment with a combination schedule has not been answered through a large randomized trial. However, results from several small prospective trials have been reported. In a small trial with 27 patients, maintenance

Individualized treatment for patients with MPM

Nowadays, the pemetrexed–platinum combination represents the standard of care as first-line treatment for patients with MPM. However, approximately one half of patients will not respond to this schedule and there are no established indicators of responsiveness that can be used to improve these results.

In advanced NSCLC, a subgroup analysis showed that the antitumor efficacy of pemetrexed in patients with non-squamous histologic types was better than in squamous carcinomas, suggesting that low

Second-line treatment for patients with MPM

In a retrospective analysis, second-line chemotherapy in MPM showed an increase in OS (HR: 0.56; 95% CI: 0.44–0.72; p < 0.001). This fact illustrates that some patients with MPM, who are fit after first-line treatment, are suitable for receiving subsequent treatments. However, it is not known whether the reduced risk of death is associated with the treatment or whether patients who have prolonged survival tend to receive more treatment.55

Nowadays, second-line therapies are being increasingly used

New treatments for patients with MPM

The resistance of MPM to conventional treatment and poor clinical outcome has prompted basic research to identify possible new molecular targets. Randomized phase II trials, with or without new drugs, may be able to give a better signal activity than single arm phase II trials. Table 2 shows the results obtained from most important clinical trials carried out with new drugs in patients with MPM.

Conclusion

Modest improvements in the treatment of patients with advanced or unresectable MPM with chemotherapy have been made in the last decade and MPM remains a therapeutic challenge. Nowadays, the combination of platinum with antifolate is the standard of care. Other approaches such as the administration of maintenance therapy, the benefits of second-line treatment, the outcome of newer drugs such as antiangiogenic and immunotherapeutics agents, and the possibility of administering personalized

Conflicts of interest

The authors declare that they do not have any conflicts of interest that could inappropriately influence their work.

Acknowledgment

Editorial assistance in the preparation of this manuscript was provided by Dr. Fernando Sánchez Barbero of HealthCo (Madrid, Spain).

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