Malignant pleural mesothelioma (MPM) is a rare, aggressive tumor with a poor prognosis. In view of the poor survival benefit from first-line chemotherapy and the lack of subsequent effective treatment options, there is a strong need for the development of more effective treatment approaches for patients with MPM. This review will provide a comprehensive state of the art of new investigational approaches for mesothelioma. In an introductory section, the etiology, epidemiology, natural history, and standard of care treatment for MPM will be discussed. This review provide an update of the major clinical trials that impact mesothelioma treatment, discuss the impact of novel therapeutics, and provide perspective on where the clinical research in mesothelioma is moving. The evidence was collected by a systematic analysis of the literature (2000-2011) using the databases Medline (National Library of Medicine, USA), Embase (Elsevier, Netherlands), Cochrane Library (Great Britain), National Guideline Clearinghouse (USA), HTA Database (International Network of Agencies for Health Technology Assessment - INAHTA), NIH database (USA), International Pleural Mesothelioma Program - WHOLIS (WHO Database), with the following keywords and filters: mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, review, investigational, drugs. Currently different targeted therapies and biologicals are under investigation for MPM. It is important that the molecular biologic research should first focus on mesothelioma-specific pathways and biomarkers in order to have more effective treatment options for this disease. The use of array technology will be certainly an implicit gain in the identification of new potential prognostic or biomarkers or important pathways in the MPM pathogenesis. Probably a central mesothelioma virtual tissue bank may contribute to the ultimate goal to identify druggable targets and to develop personalized treatment for the MPM patients.

BACKGROUND:

Malignant pleural mesothelioma is a relatively uncommon disease, but the incidence is increasing and is expected to peak in many developed countries in the next two decades. The management of patients with malignant mesothelioma is controversial. Very few patients are suitable for any potentially curative treatment and the effectiveness of radical therapy with surgery, radiotherapy and/or chemotherapy in curing patients or prolonging survival is uncertain. The role of radiotherapy is controversial although it has been used as part of multimodal therapy. The present review will try to clarify these uncertainties.

OBJECTIVES:

To assess the effectiveness and safety of radiotherapy on patients with malignant pleural mesothelioma in any stage of the disease.

SEARCH METHODS:

We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2008), MEDLINE (1966 to January 2009) and EMBASE (1974 to January 2009). We performed handsearches aimed at the identification of evidence by reviewing journals not indexed in databases, conference proceedings and/or scientific meetings.

SELECTION CRITERIA:

We included all randomised controlled clinical trials using radiotherapy for malignant pleural mesothelioma in any stage, alone or combined with other therapies in patients of either sex and any age. We excluded studies without a control group.

DATA COLLECTION AND ANALYSIS:

No studies fulfilled the inclusion criteria.

MAIN RESULTS:

We found no reports of randomised comparisons of radiotherapy alone or combined for patients with malignant pleural mesothelioma.

AUTHORS' CONCLUSIONS:

As radiotherapy has never been compared to chemotherapy or surgery or to best supportive care (as part of combination therapy) in a prospective, randomised trial, there are no data to support one or the other treatment as a better option for patients with malignant pleural mesothelioma. There is a need for multicentre controlled randomised trials assessing the role of radiotherapy in the radical treatment of malignant pleural mesothelioma. The studies should be limited to patients with malignant pleural mesothelioma, classified by stage, cytology and type of radiotherapy. The type of radiotherapy should be defined in advance and variables of radiotherapy dose definition and delivery should be carefully controlled.

BACKGROUND:

Numerous markers have been evaluated to facilitate the non-invasive diagnostic work-up of mesothelioma. The purpose of this study was to conduct a structured review of the diagnostic performance of non-invasive marker tests for the detection of mesothelioma in patients with suspected mesothelioma.

METHODS:

Studies on the diagnostic accuracy of serum and cytological markers published till 31 December 2009, available in either PUBMED or Embase, to detect or exclude the presence of mesothelioma were extracted. Study quality was assessed with use of the Quadas criteria.

RESULTS:

In total, 82 articles were included in this systemic review. Overall, quality of the incorporated studies to address our objective was poor. The most frequently studied immunohistochemical markers for cytological analysis were EMA, Ber-Ep4, CEA, and calretinin. The most frequently investigated serum marker was soluble mesothelin-related protein (SMRP). The markers CEA, Ber-EP4, and calretinin were most valuable in discriminating mesothelioma from other malignant diseases. Markers EMA and SMRP were most valuable in discriminating mesothelioma from non-malignant diseases. No marker performed well in discriminating between mesothelioma and all other diseases.

CONCLUSION:

Currently, there is only limited evidence to properly assess the value of non-invasive marker tests in the diagnosis of mesothelioma. Studies were of limited value to address our objective and results showed considerable unexplained study heterogeneity.

OBJECTIVE:

A review of the evidence supporting the use of radiotherapy in patients with mesothelioma was performed.

METHODS:

Relevant publications were searched for on Medline.

RESULTS:

In a Medline search on radiotherapy and mesothelioma, 611 hits were obtained. A limited number of prospective phase II trials of radiotherapy as part of trimodality protocols for early disease and in the palliation of pain were found, along with three small randomized controlled trials of port-site prophylaxis.

CONCLUSION:

No randomized data exist to support the use of radiotherapy after radical surgery, although there are a large number of publications describing its use as an integral part of therapy, including seven phase II studies. One ongoing trial is randomizing patients to radiotherapy or not after extrapleural pneumonectomy. None of these studies provided any assessment of radiotherapy independent of the other modalities investigated, nor did any formally assess intensity-modulated radiotherapy. There have been several reports of excessive toxicity with this technique, and its use should be limited to phase I studies until the basis of this toxicity is better understood. Three trials have looked at port-site prophylaxis, one supporting its use and two showing no evidence of benefit. Two studies addressed pain control prospectively, one showing definite but short-lived benefits. Implications. Radiotherapy is widely used in treating mesothelioma with little supporting evidence. More randomized trials are required to justify this use in all three common settings for its use.

BACKGROUND:

Cordotomy can be effective in relieving pain for patients with mesothelioma, but the evidence to support continued provision is limited. This review forms part of the Invasive Neurodestructive Procedures in Cancer Pain pilot study: The role of cordotomy in mesothelioma-related pain in the UK.

AIM/DESIGN:

We report on the results of the first comprehensive systematic review of the use of cordotomy in mesothelioma-related pain, with specific reference to effectiveness in relieving pain and safety. The review was conducted according to guidelines reported in the NHS Centre for Reviews and Dissemination and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses.

DATA SOURCES:

14 databases from inception to March 2012 were searched, with no limitations on language or publication type.

RESULTS:

Nine studies met the inclusion criteria, all of which were case series of percutaneous cervical cordotomy (PCC) involving 160 patients. All studies demonstrated good pain relief in the majority of patients. Initial post-procedure measurements showed the greatest reduction in pain. Some side effects (headache, mirror pain, motor weakness) occurred relatively frequently but were mostly transient. Respiratory dysfunction post-PCC was rare. No deaths were directly ascribed to cordotomy.

CONCLUSIONS:

The available evidence is significantly limited in quantity and quality. Although it seems to suggest that cordotomy might be safe and effective in this setting, more reliable evidence is needed to aid decision making on continued provision. A national registry for cordotomy would be a valuable first step in this process.

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The results of radiation therapy in the management of 27 patients with malignant mesothelioma were reviewed. Eight patients were treated with a curative intent combining attempted surgical excision of tumor (thoracic in 6 and peritoneal in 2), aggressive radiation therapy, and combination chemotherapy using an adriamycin-containing regimen. One patient achieved a 2-year disease-free interval followed by recurrence of tumor above the thoracic irradiation field. This patient was retreated with localized irradiation and is disease-free after 5 years of initial diagnosis. One patient has persistent abdominal disease at 18 months; the other 6 patients suffered local recurrence within 8-13 months of initiation of treatment. Radiation therapy was used in 19 other patients who received 29 courses for palliation of dyspnea, superior vena cava syndrome, dysphagia, or neurological symptoms of brain metastasis. A palliation index was used to determine the effectiveness of irradiation and revealed that relief of symptoms was complete or substantial in 5 treatment courses, moderately effective in 6 courses and inadequate in 18 treatment courses. Adequate palliation strongly correlated with a dose at or above 4,000 rad in 4 weeks. The management of patients with mesothelioma requires new and innovative approaches to increase the effectiveness of radiation therapy and minimize the significant potential combined toxicity of pulmonary irradiation and adriamycin.

Introducción: El mesotelioma pleural maligno es un cáncer raro, agresivo y que presenta expectativa de aumento en la incidencia hasta 2030. Objetivo: Sintetizar las evidencias de eficacia y seguridad de los diferentes esquemas quimioterápicos de primera línea disponibles para el tratamiento del mesotelioma pleural maligno. Método: Se utilizaron las bases bibliográficas LILACS, MEDLINE, Scopus, Cochrane Controlled Trials Register y Web of Science. Se buscó estudios en la literatura gris. Los criterios de elegibilidad incluyeron ensayos aleatorizados de fase II o III, de pacientes con mesotelioma pleural vírgenes de tratamiento quimioterápico, sometidos a cualquier régimen terapéutico, teniendo como control otros esquemas quimioterápicos o control activo de síntomas, y presentando tiempo de supervivencia global, tiempo libre de progresión, respuesta tumoral y toxicidad como resultados. Todas las etapas fueron realizadas por dos revisores, de forma independiente. El protocolo de la revisión se registró en el International Prospective Register of Systematic Reviews (PROSPERO 2014: CRD42014014388). Resultados: Se incluyeron trece estudios de catorce esquemas terapéuticos. El único esquema uimioterápico que se presentó superior al comparador con significancia estadística en los tres resultados de eficacia fue cisplatino + pemetrexede. Cisplatino + pemetrexed y cisplatino + gemcitabina presentaron más casos de toxicidad grados 3 y 4. Conclusion: Existen buenas evidencias para recomendar combinaciones de derivado de platino y antifolato como opción de primera elección en el tratamiento quimioterápico del mesotelioma pleural. Más estudios clínicos son necesarios para basar decisiones de incorporación de los antifolatos en el tratamiento rutinario de esa neoplasia en Brasil.

CITATION:

National Institute for Health and Clinical Excellence. Pemetrexed disodium for the treatment of mesothelioma. London: National Institute for Health and Clinical Excellence (NICE). Technology Appraisal Guidance 135. 2008

BACKGROUND:

Malignant mesothelioma is a rare but aggressive tumor, with a high misdiagnosis rate and overall bleak prognosis. In 0.7% of all cases, the origin is the pericardium.

METHODS:

The present study is a review of the literature published in recent decades focusing on the advances in clinical manifestations, radiological findings, diagnosis, differential diagnosis, and treatment of malignant pericardial mesothelioma (MPM).

RESULTS:

No clear relationship has been established between the etiologies and the development of MPM. Clinical symptoms and signs are nonspecific when present. The main presentations are chest pain and dyspnea. Imaging plays an important role in the detection, characterization, staging, and posttreatment follow-up. The definitive diagnosis is made on the basis of pathological findings. Chest radiography and echocardiography are common techniques used initially, but their roles are limited. Computed tomography and magnetic resonance imaging have an advantage in depicting the thickened pericardium, mediastinal lymph node, tumor, and the extension of adjacent structures. Surgery is the most important treatment modality and remains palliative in most cases, while the roles of chemo- and radiotherapy are unsatisfactory.

CONCLUSION:

Clinical trials of malignant pleural and peritoneal mesothelioma remain important for MPM management. Multimodality treatment of surgery, chemotherapy, radiotherapy, and immunotherapy is expected to have a role in the treatment of MPM.