Malignant pleural mesothelioma: The standard of care and challenges for future management

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Abstract

This review addresses the management of MPM. In an introductory section, the etiology, epidemiology, presentation, diagnosis and staging of MPM will be reviewed. The evidence was collected by a systematic analysis of the literature (2000–2009) 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: pleura, cancer, mesothelioma, guidelines, treatment, surgery, chemotherapy, radiotherapy, palliation, supportive care, pleurodesis, review.

Introduction

Mesothelioma is a rare malignant tumour originating from the cells lining the mesothelial surface of the coelomic cavities of the body: pleura, peritoneum, pericard and tunica vaginalis. Malignant pleural mesothelioma (MPM) is the commonest presentation, followed by the peritoneal localisation. Only rare pure cases of other origin have been reported. This manuscript will only address MPM. The etiology and epidemiology of MPM have recently been reviewed [1].

The background incidence of MPM is very low. Asbestos is the principal etiological agent of MPM. The first studies on the association between asbestos and MPM were published in the 1960s. Since most asbestos exposure is work-related, mesothelioma is an occupational disease in the majority of cases. This has obvious compensatory and medico-legal implications which differ among countries. Because past exposure to asbestos was more common in occupations with a predominantly male workforce, the current incidence of MPM is higher among men than among women. The risk fraction attributable to occupational asbestos exposure is higher than 80% in men, and lower than 40% in women. Over the last decades, a shift has been observed in the exposure history of mesothelioma cases, from primary asbestos workers (handling raw asbestos material) to end-users often exposed when installing asbestos products or handling asbestos materials still in place (construction workers, electricians, plumbers, heating workers, etc.). Even if the occupations with the highest risk of mesothelioma belong to the first group, the number of subjects at risk of MPM is presently much larger in the latter. Environmental mesotheliomas are linked either with a “natural” exposure in areas of the world where asbestos (generally tremolite) exists as a geological component of the soil or with neighbourhood exposures in people living close to asbestos mines or factories. Para-occupational cases are described in households of asbestos workers, mainly because of domestic exposure via clothes used at work. A dose–effect relationship has been demonstrated, but it is impossible to define a threshold of cumulative exposure below which there is no increased risk. Therefore, all individuals who have been exposed to asbestos are considered as a population at risk. The mean latency of MPM after exposure to asbestos is around 40 years (range 15–67 years). The median age at diagnosis in Western countries is 69 years with an increasing fraction of elderly patients with co-morbidities.

There are prominent differences in incidence of MPM reported from different countries worldwide varying from to 7 per million (Japan) to 40 per million (Australia) inhabitants per year. In Europe the incidence is around 20 per million with large intercountry variation. It is reasonable to accept that these differences are mainly due to differences in historical asbestos import and consumption. For the future, epidemiologists expect peak incidences in the very next decades. Because of the long latency of MPM and of national differences in the timing of reduction or ban of asbestos use, the timing of the peak incidence of MPM cannot be predicted precisely and may vary from one country to another. The peak is expected between 2015 and 2020 in Europe and may already have been reached in some countries (USA, Sweden). In countries which continue to use asbestos in the 21st century, the incidence of MPM is expected to increase in the next decades. Patient distribution will be younger and more female than in the Western countries. Due to a lack of accurate tools and of a curative treatment, screening for MPM – even in populations at risk – is currently not recommended [2].

MPM typically originates from the lower parietal pleura and the costodiaphragmatic sinus. Presenting clinical symptoms are most often dyspnea and chest pain, each present in 60% of patients [3]. Pneumothorax and paraneoplastic features are classical other presenting features. The average interval between onset of symptoms and diagnosis is 2–3 months. Dyspnea is due to the accumulation of pleural fluid in the thoracic cavity with atelectasis of the underlying lung and impaired diaphragmatic movement, grafted on pulmonary co-morbidity as COPD or asbestosis. Natural history of MPM is further characterised by progressive local expansion and invasion explaining much of the symptoms and signs. Invasion of the thoracic wall with its intercostal nervous structures causes chest pain and the development of chest wall lumps. The pain is pleuritic, lateralised, dull or diffuse with nociceptive, inflammatory and neuropathic components due to entrapment of intercostal thoracic, autonomic, or brachial plexus nerves and irradiating to upper abdomen, shoulder, or arm. This pain pattern has been called the costo-pleural syndrome. Encasement of the lung results in pneumonia, dyspnea and rarely, hemoptysis. Invasion of the mediastinal structures leads to superior vena cava syndrome, hoarseness, Pancoast or Horner's syndrome by nervous invasion, or dysphagia by compression of the esophagus. Invasion of the pericard and heart results in hemi-diaphragmatic paralysis, tamponade and arrhythmias. Spreading to the abdomen in ascites, constipation or even bowel obstruction; spreading to the contralateral hemithorax results in pleural effusion. Clinical lymphatic and hematogenous dissemination occurs only late in natural history but is fairly common in autopsy series. All organs can be involved, leading to case reports of unusual metastatic presentation, more often now that active treatments are applied and demise from local causes is postponed. Constitutional symptoms as fatigue, hyperhydrosis and weight loss are usually late symptoms.

MPM has a dismal prognosis: median survival of untreated cases is 6–9 months with less than 5% 5-year survivors. Essential prognostic factors associated with better outcome are earlier stage and epithelioid histologic type [4]. Additional prognostic factors are the presence of symptoms, performance status, age, gender and weight loss. The prognostic value of asbestos exposure is controversial.

The clinical manifestations of MPM are usually non-specific and insidious and cannot be used alone as diagnostic criteria, even in case of previous asbestos exposure. Chest X-ray usually shows a unilateral pleural effusion or thickening. Chest X-ray alone should not be used for the diagnosis of MPM. Chest CT scan is unsuitable for definitive diagnosis of MPM, but a rind-like tumour along the pleural cavity together with diffuse or nodular pleural thickening are suggestive of the disease [5], [6] (Fig. 1). It is not recommended to make a diagnosis of mesothelioma based on cytology alone because of the high risk of diagnostic error. In view of the medico-legal aspects, a formal tissue diagnosis on a biopsy specimen of MPM is required to obtain compensation. The recommended way is thoracoscopy, except in cases with pleural symphysis or contraindication to thoracoscopy, when either a surgical or transthoracic needle biopsy can be substituted, albeit with a lower sensitivity. Besides light microscopy, appropriate immunohistochemistry is necessary to make the diagnosis and allow subtyping in either the epithelioid or non-epithelioid or sarcomatoid-subtype. Mixed forms occur, besides the rare desmoplastic and other variants [7].

In the absence of a uniform, robust and validated staging system, the experts advocate the use of the most recent TNM-based UICC-classification [8], [9] (Table 1). Its main drawback is the inaccuracy in describing the actual T- and N-extent by the current imaging techniques with CT scan and MRI [10]. In clinical series, most patients present with locally advanced stage (stage III, 40%), followed by advanced (stage IV, 35%) and local (stages I–II, 25%), respectively [11].

A three step pre-treatment staging assessment is recommended based on empirical observation, good clinical practice and the fact that the treatment intent differs between patients [1], [12]. Whether a patient goes through all three steps depends strongly on the results of the procedures and the consequences for the choice of treatment with radical or palliative intent only.

Step I is to be considered in all patients at presentation or diagnosis (Table 2A). Step II is to be considered in patients being candidate for any kind of active treatment (Table 2B). Step III is the final process of patient selection for combined modality or any radical loco-regional treatment (Table 2C). This last situation will be only the case in a minority of patients with pleural mesothelioma. Among the investigations to be considered in these patients are mediastinoscopy, MRI of the chest, video assisted thoracoscopy (VATS), E(B)US-FNA, FDG-PET-scan and laparoscopy. In the absence of comparative data no formal advice regarding their respective staging performance can be given. Further research should be done with regard to the comparative efficacy of different intra-thoracic techniques (mediastinoscopy, VATS, EUS-FNA) and the value of the newer ones (PET-CT, EBUS-FNA). In patients proceeding to step II or higher: (a) a diagnosis of mesothelioma should be confidently established; (b) the interval within which the pre-treatment assessment has to be finalised should be as short as possible; (c) recent (less than 1 month old) imaging studies should be available prior to invasive procedures or start of any treatment.

Section snippets

Management of MPM

Early reports of outcome in MPM have suffered from one or several of the following biases:

  • (1)

    Inclusion of variable number of unproven cases of MPM, due to a lack of expertise of the pathologist with the disease. This has been addressed by a greater awareness among pathologists and the installation of central pathology panels.

  • (2)

    A small sample size spread over many years of inclusion due to the rarity of the disease, restricted to a limited number of cities and institutions. With the increasing

Radical treatment

a: The use of radiation therapy to the full hemithorax is limited by critical organs such as the lung, the liver and heart most particularly, but also the spinal cord and the esophagus. Therefore it is difficult to administer a total dose more than 54 Gy to such a large volume, so that sophisticated treatment techniques, oriented by surgeon's and pathologist's findings, are needed [97], [98]. As radical radiotherapy has never been compared to chemotherapy or surgery or to best supportive care

Guidelines

Several international cancer organisations have issued guidelines and recommendations for the management of MPM: the British Thoracic Society [116], the Société de Pneumologie de Langue Française (SPLF) [117], the provincial Lung Cancer Disease Site Group of Ontario (CDN) [118], the European Society of Medical Oncology (ESMO) [119], and the European Respiratory Society (ERS) with the European Society of Thoracic Surgeons (ESTS) [1]. These recommendations are summarised in Table 4. The

Advanced and inoperable/unresectable locally advanced early stage MPM

There are historical analogies between the management of MPM and advanced NSCLC. Defeatism has long surrounded their treatment as the disease was considered refractory to chemo- and radiotherapy. The low incidence and difficult diagnosis of MPM further precluded the conduct of large clinical trials.

Platinum-based combination chemotherapy with 3rd generation drugs became the standard of 1st line care in advanced NSCLC after the publication of a meta-analysis of randomised trials of chemotherapy

Conclusions

The last decade has seen some important changes in the management of mesothelioma, driven by an increasing incidence and awareness among the public and physicians and the extrapolation from treatments approaches and drugs from other cancer types. Therapeutic nihilism and defeatism are not anymore sensible, as we now have active chemotherapy available, which, albeit palliative, will not only moderately increase life expectancy but will also help in relieving symptoms. Coping with the latter

Reviewer

Laurent Greillier, M.D., Hôpital Saint Marguerite, Pôle Cardiovasculaire et Thoracique, Service d’Oncologie Thoracique, 270 Blvd de Sainte-Marguerite, F-13274 Marseille, France.

Dr. Van Meerbeeck is a board certified chest physician, professor in Thoracic Oncology at Ghent University, chair of the Thoracic Oncology Programme and divisional head at the University Hospital Ghent. His scientific interests are the molecular diagnosis, minimally invasive staging and multimodality treatment of mesothelioma and lung cancer. He is and has been the study coordinator and principal investigator for numerous international phase 2 and 3 studies. He has served the EORTC Lung Cancer

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    Dr. Van Meerbeeck is a board certified chest physician, professor in Thoracic Oncology at Ghent University, chair of the Thoracic Oncology Programme and divisional head at the University Hospital Ghent. His scientific interests are the molecular diagnosis, minimally invasive staging and multimodality treatment of mesothelioma and lung cancer. He is and has been the study coordinator and principal investigator for numerous international phase 2 and 3 studies. He has served the EORTC Lung Cancer Group as secretary from 1994 to 2000, chairman from 2003 to 2006, past chair and General Assembly member since. He has been co-promotor of several PhD's in Belgium and the Netherlands. He has published more than 100 peer-reviewed articles in oncology and pulmonology journals and textbooks. He is on the review and editorial board of several international journals. He has (co-)organised several national and international scientific meetings on thoracic oncology. He is grant reviewer for the Flemish Foundation of Scientific Research (FWO) and the Dutch Cancer Foundation (KWF).

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