Anti-Tumour TreatmentMalignant mesothelioma: New insights into a rare disease
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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Cited by (32)
Analysis of angiogenic and stromal biomarkers in a large malignant mesothelioma cohort
2020, Lung CancerCitation Excerpt :High VEGF and FGFR expression were present in 68% and 40% of the mesothelioma cohort respectively, but no correlation between prognosis and immune expression of VEGF or FGFR was present. The interaction between mesothelioma cells and angiogenic factors such as VEGF/ VEGFR, PDGF/ PDGFR and FGFR have been known to be of significance in the pathogenesis and progression of MM.23,39 Our data builds on this knowledge but also suggests that targeting these pathways may also have prognostic impact.
Trophoblast Glycoprotein is Associated With a Favorable Outcome for Mesothelioma and a Target for Antibody Drug Conjugates
2018, Journal of Thoracic OncologyCitation Excerpt :Malignant pleural mesothelioma (MPM) is an aggressive tumor from mesothelial cells covering the pleural cavity. The prognosis for MPM is poor and most patients die within 2 years after diagnosis.1-4 Standard of care chemotherapy, consisting of a platinum-based drug and anti-folate combination, gives a modest median survival benefit of at least 3 months.5,6
Targeting BAP1: a new paradigm for mesothelioma
2017, Lung CancerResponse evaluation in mesothelioma: Beyond RECIST
2015, Lung CancerCitation Excerpt :In the UK, the incidence of MPM is reportedly 41 per million in 2011, of which males are 4.5 times more affected than females [4]. The pathogenesis of malignant pleural mesothelioma is related to asbestos exposure [1], and the use of asbestos in the developing countries may result in further increase in the global incidence of MPM [5]. There are three major histological subtypes of MPM: epithelioid, sarcomatoid, and mixed or biphasic, among which the sarcomatoid type has the worst prognosis [6].
Surgical cytoreduction restores the antitumor efficacy of a Listeria monocytogenes vaccine in malignant pleural mesothelioma
2015, Immunology LettersCitation Excerpt :Mesothelioma is an insidious neoplasm arising in the pleura, pericardium, peritoneum, or tunica vaginalis, with approximately 80% of cases originating in the thorax. Asbestos exposure is the predominant cause of malignant pleural mesothelioma (MPM), which has a latency period of approximately 30 years [1,2]. Though modest improvements in the treatment of MPM have been made in the past decade, the disease remains a therapeutic challenge and the median survival of MPM patients is between 12 and 18 months [3,4].
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