Malignant Pleural Mesothelioma: Present Status and Future Directions

From 1965 to 1970 mesothelioma was an extreme rarity in the medical wards. It became more common in the 1990s, an increase that was documented by the Health and Safety Executive in the UK. At that time, there were already some published series on extirpative surgery for mesothelioma. However, results were difficult to interpret due to variation in protocols and no control data. The observations and concerns leading to the establishment of the Mesothelioma and Radical Surgery (MARS) trial summarized here reflect a personal experience.

Scholars differ about the date when mesothelioma was discovered as a discrete disease. There is dispute also about when a causal association between mesothelioma and exposure to asbestos dust was established. On balance it appears that the 1960s was the crucial decade in both respects. This was long after asbestos became a mineral of commercial significance in the 1870s. It was also long after the unequivocal discovery, in 1930, that inhalation of asbestos dust could cause the fatal disease of asbestosis. Suggestions of an association between asbestos and mesothelioma emerged in South Africa in the 1950s and by the mid-1960s a causal connection was widely accepted. Protective measures were put in place in the United Kingdom, USA and elsewhere. From the 1970s regulations were progressively tightened. Partial or total bans were enacted and in the west asbestos use declined markedly. But for various reasons mesothelioma remained a significant killer. In America, but not Europe, the peak of the epidemic may have passed in the 1990s. The position is very different in those parts of the world where asbestos is still mined and used but lack of data renders calculation and prediction impossible. Finally, it is noted that mesothelioma may occur in individuals with no exposure to asbestos.

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleural surfaces which is most closely linked to asbestos exposure. The prognosis of MPM is poor; morbidity and mortality results primarily by local extension or invasion of adjacent structures and less commonly by distant metastasis. Death typically results from extensive local involvement from primary lesions due to respiratory failure or infection. Involvement of the heart or of the abdominal viscera may also contribute to mortality. The best-known and commonly used clinical prognostic scoring systems for MPM are based on work performed by European Organization for Research and Treatment of Cancer and Cancer and Leukemia Group B which incorporate a combination of biologic and clinical factors. This chapter will provide an overview of the presenting symptoms and signs, prognostic factors and outcomes of MPM.

Asbestos has been used extensively in Europe for well over 100 years and annual mesothelioma mortality is still increasing. However, the rapid decline in usage led to a substantial reduction in exposures in European worker populations. This effect can be seen in declining death rates in younger age groups in most countries. Projections suggest that peaks will typically occur over the next decade. Although asbestos is now banned in European Union member states, some countries in the east of Europe continue to produce and consume asbestos in large quantities. Even within the EU, however, much asbestos remains in place in older buildings and strict control of abatement work will be required.

Mesothelioma mortality statistics, and to a lesser extent incidence, are reliable for Canada and the United States only over the last two decades. Difficulties still exist, and in the rest of the Americas available statistics are not reliable. A brief history of the recognition, diagnosis, and development of knowledge about mesothelioma in North America is presented. Cohort studies important to mesothelioma epidemiology are discussed, with particular emphasis on Quebec miners and millers, textile workers in the Carolinas, and asbestos insulators in the United States. These studies are highly influential in current risk assessments for asbestos-related disease. Finally, there is a country-by-country selected epidemiological and related investigations of mesothelioma in the countries of North and South America. These emphasize new observations of apparent lack of compensation for registered cases in Canada, and studies of regulatory and public health importance in the United States. Although little work has been published from Latin American countries, some observations of interest include those related to asbestos mining and cement manufacture in Brazil, crocidolite exploitation in Bolivia and the recent identification of naturally occurring erionite causing disease in one locality in Mexico.

The increasing recognition of serious asbestos exposure-induced health issues resulted in the decline and eventual ban of asbestos use in most developed countries. However, the history of asbestos use in East Asian countries is quite different, Japan and South Korea completely banned all forms of asbestos in 2006 and 2009, respectively. In Japan, mesothelioma mortality was low until the early 1990s, with fewer than 200 reported deaths in 1991. The 10th Revision of the International Classification of Diseases, which introduced the category of “malignant mesothelioma,” was adopted in Japan in 1995. Since then, the annual number of deaths from mesothelioma in Japan has been reported. Out of 6030 cases in death certificate in Japan(2003-2008), 929 were pathologically reconfirmed to be mesothelioma; the affected areas were the pleura (85.5%), peritoneum (13.2%), pericardium (0.8%), and tunica vaginalis testis (0.5%). A total of 399 mesothelioma cases were reported in South Korea from 2001 to 2010, revealing a relatively larger proportion of female patients (33.8%). The relatively large proportion of mesothelioma in women in South Korea is likely due to the large proportion of mesothelioma cases in women working in asbestos textile factories in the 1970s–1980s. In summary, the incidence of malignant mesothelioma in Japan and South Korea is rising sharply, and the incidence of mesothelioma is expected to increase dramatically and peak in the near future.

Australia has one of the highest rates of mesothelioma in the world. The burden will continue for many years with an increasing number of subjects at risk of the disease. Earlier detection of the neoplasm may favor a better treatment of the disease. Therefore, development of early markers of disease progression will be useful in better screening or early detection in high-risk groups. However, continued vigilance and awareness of asbestos-induced risks need be maintained.

Although asbestos was produced and consumed by many African countries throughout most of the 20^th century, the only producers of significant amounts were South Africa, Swaziland and Zimbabwe. South Africa mined all three types of commercially viable asbestos, viz. chrysotile, amosite and crocidolite, while the latter two countries mined only chrysotile. South Africa was the global leader in the production of crocidolite asbestos, the fibre most strongly linked with the development of mesothelioma; and it was in this country that the link was first established and reported in 1960. While sporadic case reports of mesothelioma have been published from the continent, they are few and far between, and the only epidemiological studies have been conducted in South Africa, showing that mesothelioma rates in the country are amongst the highest in the world. The disease burden did not dissipate with the closure of the crocidolite and amosite mines in the 1990s. South Africa has a legacy of asbestos contamination in the form of mine tailings dumps and asbestos-containing building materials and other products. As fibre, including South African crocidolite and amosite, was widely exported from the three major asbestos-producing African countries to the rest of Africa, so was the risk of mesothelioma. We can expect many more people to suffer from this debilitating disease in future years.

There is strong scientific evidence demonstrating that exposure to airborne asbestos fibres is considered to be the single major cause of malignant pleural mesothelioma (MPM). There are different aetiological explanations for MPM that remain controversial or unresolved including the role of biological gender differences, genetic risk, as well as the association between maternal asbestos exposure and subsequent mesothelioma in children. Nevertheless, MPM is an important epidemiological marker of asbestos exposure through which it is possible to track a country’s current and prior asbestos consumption and current or future patterns of asbestos-related disease. Quantifying the association between population-level asbestos consumption and MPM disease trends is an important yet challenging task as the morbid effects of asbestos use remain hidden for several decades. This is due to the long latency period between first asbestos exposure and a diagnosis of MPM, with this latency period ranging between 20 and 50 years. There have been significant shifts in global asbestos consumption with the most striking change occurring in the geographical regions in which asbestos is being used. The Asian region has become by far the largest asbestos consumer today. The deleterious human health, social, economic and environmental impacts of asbestos-related disease are preventable. Implementing a universal ban on asbestos and organising comprehensive occupational health and safety programmes are top priorities.

Of the ~400 fibrous minerals that are present in the natural environment, only six were commercially used and regulated under the term “asbestos”. The carcinogenicity of asbestos minerals has been largely demonstrated. Properties associated with mineral fiber toxicity include structure, length/diameter ratio, surface area, and bio-persistence. Unregulated mineral fibers that share similar properties are known or suspected of causing similar hazards to asbestos, and specifically malignant pleural mesothelioma (MPM). For example the fibrous serpentine antigorite in material used to pave roads has been correlated to high MPM rates in New Caledonia. Erionite fibers present in material used for construction has been associated with a MPM epidemic in Central Turkey, and was more potent than asbestos in causing disease in animal experiments. The asbestiform amphiboles winchite and richterite in the vermiculite mined in Libby, Montana, USA, caused an epidemic of asbestos-related disease in workers and the local population. Potential geological sources of fibrous minerals are numerous; they represent a hazard when soil erosion and/or human activities disperse the fibers in places where they may be in contact with population. Environmental exposure to these carcinogens is increasing due to the development of population and human activities in rural areas; geological and environmental investigations should be carried out before any mining, road-making and other dust-producing activities in order to prevent from possible exposure to carcinogenic mineral fibers.

Simian Vacuolating Virus 40 (SV40) was isolated in 1960 from polio vaccines contaminated during the manufacturing process. SV40 is able to induce tumors in animals and is causally associated with human malignant mesothelioma, lymphoma, and bone and brain tumors. SV40 is a co-factor for malignant mesothelioma development in hamsters and mice exposed to asbestos, based on different mechanisms. In addition, SV40 cooperates with asbestos and possibly other mineral fibers, leading to in vitro transformation of primary human mesothelial cells (HM). SV40 induces transformation of HM, rather than cell lysis as occurs in other human cell types, due to the transcription of antisense RNA repressing late viral gene expression. The mechanism of SV40 carcinogenesis relies on the activity of the two SV40 early proteins, large T antigen (Tag) and small t antigen (tag). In SV40-infected mesothelial cells, Tag binds p53 and the resulting complex associates with retinoblastoma protein (Rb), p300, p400 and CREB-binding protein (CBP). This larger complex establishes a potent transcriptional regulator, able to induce IGF-1, Met and Notch-1 expression and the associated downstream signaling pathways. The induction of calretinin expression is also a part of Tag activity in host cells. The interaction of Tag with other binding partners suggests additional mechanisms of interference with cell cycle or survival of the host infected cells.

Malignant pleural mesotheliomais characterised by a large range of complex genetic alterations and peculiarof this disease. The mesothelioma genome contains extensive copy number alterations and aneuploidy which may correlate with response to treatment and survival. The genetics of mesothelioma has increased considerably over the last decade with major advances in whole genome and next generation sequencing. The knowledge of the genomics of mesothelioma is essential for identifying new, effective personalised therapeutic approaches therapies for improving clinical outcomes in patients with mesothelioma.

Although asbestos is banned in several countries, malignant pleural mesothelioma (MPM) incidence is increasing worldwide, and this cancer remains a disease of concern. MPM is a very severe cancer, with no curative treatment despite the development of different kinds of therapeutic approaches. To date the treatments are based on multimodal chemotherapy and surgery. The longest survival data in patients is obtained with the combination of chemotherapy, radical surgery and radiotherapy. The development of targeted therapies offers new strategies to kill cancer cells. To be efficient, they need a precise identification of the critical targets. This objective can be reached by a deep knowledge of the molecular and physiological changes associated with the neoplastic transformation of MPM cells. One approach consists in the identification of gene mutations, epigenetic alterations, study of gene expression profiles and identification of the deregulated signalling pathways in malignant cells, with the goal to select molecules or mechanisms that could kill cancer cells or abolish tumour growth. The present knowledge on the main alterations in genes and signalling pathways indicates that MPM have recurrent mutations in a limited number of tumour suppressor genes, and oncogenic mutation in the promoter of TERT. A number of studies have emphasized the role of receptor tyrosine kinase (RTK) driven signalling, although not related to mutations in RTK. Multiple signalling pathways are altered in MPM. Transcriptomic analyses permitted to classify mesotheliomas in subgroups, according to prognosis. They showed heterogeneity of MPM, not only defined by the histological subtype, but also by molecular features. So far, targeted therapy was unsuccessful, at least partly due to the heterogeneity of MPM. Moreover, the complexity stands in the interconnection between pathways, which is a challenge to choose the most critical target for an efficient therapy. This review summarizes the main alterations identified in genes and signalling pathways in MPM, the impact on therapeutics, and discusses the future of these approaches to improve MPM outcome, especially knowing molecular and physiological characteristics of MPM to define their diversity.

BRCA1-associated protein 1 (BAP1) has recently emerged as a novel important tumor suppressor gene in malignant mesothelioma. BAP1 is a nuclear deubiquitinating enzyme with several critical biological functions, including regulation of gene transcription, DNA damage response and chromosome stability. Somatic BAP1 mutations are found in about 60% of mesotheliomas, and germline BAP1 mutations have been reported to increase the incidence of malignant mesothelioma and to cause a novel hereditary cancer predisposition syndrome characterized also by higher incidence of several other cancers. In this chapter, we reviewed all the current evidences on the biology of BAP1 and on the clinical implications of its somatic and germline mutations in regards to malignant mesothelioma.

Mesothelioma is a rare tumor that derives from the mesothelial cells lining of body cavities. About 90-95% of mesotheliomas originate in the pleura and 5-10% in the peritoneal space. Other sites, such as pericardium and tunica vaginalis are very rare. Generally, mesotheliomas disseminate locally and tend to coat the organs in the different body cavities. The aim of this chapter is to describe the histological, histochemical, and immunohistochemical features of pleural mesotheliomas.

Malignant pleural mesothelioma continues to be a challenging tumor to image and treat. A multimodality multidisciplinary team approach including surgery, oncology, radiology and radiation therapy is required for successful outcomes. Reliable and reproducible methods of assessing treatment response are crucial for guiding management, whether for clinical practice, research, or to meet the requirements of a clinical trial. Computed Tomography is the first line imaging modality due to its superb spatial resolution and volumetric data set, allowing for 3D reconstructions that aid in tumor volume assessment and surgical planning. MRI has the potential to provide qualitative, quantitative, anatomical and functional information without the use of ionizing radiation or intravenous contrast administration. Newer advances and optimization of existing protocols can help identify imaging biomarkers that can serve as surrogates of survival.

The possibility to diagnose malignant pleural mesothelioma (MPM) based on an effusion gives cytology a central role in handling of these patients. Audits have shown that effusion cytology, supported by one or more ancillary techniques, can diagnose a majority of all MPMs. When a definite diagnosis is obtained, this is beneficial for both patient and clinic. The cytological sample is easily accessible with less invasive means. However, the sensitivity for reaching this diagnosis based on cytology is 60-75%, i.e., somewhat lower than for the histopathologic examination of a biopsy, the exact level depending on the extent of ancillary analyses available. The cytological diagnoisis require support from immunohistochemistry and/or electron microscopy, and the sensitivity can be improved by testing soluble biomarkers (hyaluronan and mesothelin).

The interest in identifying circulating soluble biomarkers for malignant pleural mesothelioma is quite high. The studies aim at identifying a tool that could enable early detection of the disease before symptoms develop. Blood-based fibulin-3 and osteopontin studies are currently ongoing. Serum concentrations of YKL-40 had a moderate ability to discriminate between mesothelioma and other clinically relevant controls. Despite a large number of biomarkers being reported for mesothelioma in the literature, mesothelin remains the single-best blood-based biomarker for the cancer and is considered to be the ‘gold standard’.

Despite recent diagnostic and therapeutic advances the prognosis of malignant pleural mesothelioma remains extremely poor. We reviewed the role of some classic (i.e. age, gender, histology, staging) and novel clinical (i.e. occult residual disease, quality of life and fluorodeoxyglucose uptake at positron emission tomography) prognosticators. Many biological and genetic machineries have been lately related with the etiology and the natural history of mesothelioma. These new factors might have a significant function in predicting the prognosis of the disease and in the next future they could reveal an important role for targeted therapies.

Malignant pleural mesothelioma (MPM) kills one person every four hours in the UK and every 12 hours in Australia. The global incidence of MPM continues to rise. MPM has no cure and symptom control is the key. Most MPM patients suffer from a pleural effusion; proficient care of malignant effusions and the associated breathlessness is essential to all MPM programs. MPM has unique characteristics in its pathobiology, clinical presentation and disease course that must be distinguished from those associated with metastatic cancers to the pleura. Recognizing these differences, e.g. the longer survival of MPM patients and higher risk of procedural tract metastases, are important. Patients with MPM-related pleural effusions are more likely to require definitive interventions for pleural fluid control, such as pleurodesis or indwelling pleural catheter (IPC) placement. One-third of MPM patients will fail talc pleurodesis, whether it is delivered by poudrage or slurry. IPC is well accepted as a treatment in patients with a trapped lung or when pleurodesis failed. Increasing evidence support the use of IPC instead of pleurodesis. However, effective use of IPC involves appropriate aftercare and optimal management of potential complications. Breathlessness in MPM is often multi-factorial; optimizing care of concurrent (non-effusion) causes of breathlessness is paramount. MPM cohorts are heterogeneous and disease courses can vary; only ~50% will require definitive therapies for pleural effusion management. Developing a personalized management plan based on predictions of survival, symptomatic response to pleural fluid drainage and effusion recurrence is the goal of contemporary research.

Malignant pleural mesothelioma is usually diagnosed as advanced disease, and treatment is not considered curative. Chemotherapy may palliate symptoms and improve both quality of life and survival for patients with advanced cancer, including those with mesothelioma. For the past decade, the combination of cisplatin with pemetrexed has been the standard of care for first line treatment of mesothelioma. This practice is predicated upon the results of the EMPHACIS trial, a phase III study comparing pemetrexed with cisplatin to cisplatin alone in patients with untreated mesothelioma. Most subsequent studies in cytotoxic chemotherapy have been small, non-randomized phase II studies and have not translated to new developments in the systemic treatment of this disease. Most recent trials use novel targeted therapies rather than cytotoxic chemotherapy, resulting in a paucity of recent data on cytotoxic chemotherapy and no clear advances over this decade, although recent data suggests that the addition of bevacizumab to cisplatin and pemetrexed provides a survival benefit. Herein, we review the current state of the art on chemotherapy in malignant mesothelioma.

The role of radiation therapy in malignant pleural mesothelioma is controversial. It has been used as part of multimodal definitive treatment to ameliorate locoregional control after removal of early disease, as prophylaxis to decrease the probability of recurrence and pain at sites of diagnostic or therapeutic instrument insertion and as symptom palliation in patients with advanced disease. Intensity modulated radiotherapy in the adjuvant mode after extrapleural pneumonectomy achieves good local control with acceptable toxicity. Increasing interest can be seen with radical pleural intensity modulated radiotherapy with intact lung. Prophylactic irradiation can be performed for patients who are in good performance status with a longer life expectancy. So far, pain control seems to be the best evidenced application of radiation therapy.

Malignant pleural mesothelioma (MPM) is an uncommon, but lethal malignancy resistant to most current therapies. It represents a good field of investigation for gene therapy because the disease remains confined for a long time during its growth and the neoplasm is quite accessible through the chest wall. Translational mechanisms for the treatment of this disease are emerging from the novel high-throughput molecular techniques, but a therapeutic gene capable of inhibiting the disease progression through specific gene therapy has not yet been identified. Several trials on gene therapy have been conducted in the last two decades showing safety but limited efficacy. Recent progress in the field has provided optimism for successful molecular strategies in the future.

This chapter will review the utilization of therapeutic viruses for the treatment of mesothelioma. For a variety of reasons, certain viruses can preferentially infect mesothelioma cells and through natural replication cycle result in cancer cell lysis and spread of virus to surrounding cancer cells. Since the host antiviral response is a major limitation to clinical application of virotherapy, viruses have mainly been employed in tumor types that are directly injectable. Because mesothelioma is predominantly localized to the pleural or peritoneal cavity and is hallmarked by local progression rather than distant metastasis, it has been seen as an ideal candidate tumor for treatment with virus therapy. Thus far several viruses have demonstrated preclinical activity in mesothelioma models. These data have led to the first clinical trial testing oncolytic measles virus specifically in patients with mesothelioma. The rationale and available data for the potential efficacy of oncolytic viruses for mesothelioma will be reviewed in this chapter.

After a wide review of the role of palliative chemotherapy in non-resectable malignant pleural mesothelioma, this chapter illustrates promising future research directions. The role of thymidylate synthase and of excision repair crosscomplementation group 1 expression has been found to significantly correlate with prognosis. Several approaches to improve the efficacy of platinum salts are being explored. The search for novel antifolates (i.e. pralaxate and GW1843) as well as thymidilate synthase (i.e. plevitrexed and BGC 945) is ongoing. The platinum-based regimens could benefit from the addition of bevacizumab and amatuximab, monoclonal antibody against the vascular endothelial growth factor and mesothelin, respectively.

The earliest documented staging system for malignant pleural mesothelioma was proposed by Dr. Eric Butchart in 1976, who defined four stages of disease using clinical and pathological data from 29 patients who underwent extrapleural pneumonectomy. In the 1990s, Dr. David Sugarbaker from Brigham and Women’s Hospital proposed a new ‘functional’ staging system that aimed to predict resectability and extended survival, with particular attention given to nodal involvement. Not long after, a separate staging system was proposed by the International Mesothelioma Interest Group, led by Dr.Valerie Rusch from the Memorial Sloan-Kettering Cancer Center. For the first time, a collaborative effort was made to define T and N descriptors according to anatomic definitions consistent with the traditional TNM staging system. More recently, the International Association for the Study of Lung Cancer Staging Committee developed an international database to revise the TNM staging system. The implications of staging criteria on clinical research are discussed, and a brief summary of existing international Guidelines is presented.

In malignant pleural mesothelioma (MPM) diagnostic success of noninvasive procedures is generally reported to be unsatisfactory. Both medical and surgical thoracoscopy seem to be ideal tools causing little discomfort, with very low risk of complication and short hospital stay. Both procedures therefore represent the diagnostic gold standard whilst also offering effective palliation at the same time. In this chapter all these aspects as well as anesthesiological patterns, technical tricks, conditions for associating pleurodesis, role of partial thoracoscopic pleurectomy are discussed.

Although there is lack of consensus regarding the “standard of care” for malignant pleural mesothelioma, surgery-based multimodality therapy has demonstrated long-term survivors in multiple retrospective and prospective trials. The authors advocate radical or extended pleurectomy/decortication when possible, but for patients with adequate cardiopulmonary function in whom disease is resectable only by extrapleural pneumonectomy, this operation now has a long track record of safety and serves a critical role in the treatment of this aggressive disease.

Malignant pleural mesothelioma is a diffuse tumor that does not easily lend itself to surgical resection. However, there are several observations that seemingly support the use of surgery in this disease. A variety of surgical procedures have been utilized in an attempt to provide the maximum therapeutic benefit to patients with malignant pleural mesothelioma. They vary from a small thorascopic pleurodesis procedure to a radical extrapleural pneumonectomy. Pleurectomy/decortication (P/D) and partial pleurectomy, have been used in many centers as an alternative procedure in patients who cannot undergo extrapleural pneumonectomy (EPP). Mortality of partial pleurectomy and P/D ranges between 0% and 8%. Survival statistics showed a slight trend for longer disease-free survival in extended P/D versus P/D, but there were no differences in median overall survival. Partial pleurectomy appeared to be inferior, with an overall median survival ranging from 7.1 to 14 months. Overall, current evidence supports the claim that P/D produces similar or better outcomes than EPP. The results of the Mesothelioma And Radical Surgery 2 trial will hopefully provide a stronger evidence on these topics.

alignant Pleural Mesothelioma (MPM) is a diagnosis that implies a poor prognosis and lack of effective treatment options. As a consequence of the lag time between exposure to asbestos and onset of disease, the incidence of MPM is expected to keep rising in the coming years. Although many treatment algorithms have been tried in the past, mortality is still very high due to both high local recurrence rates and development of distant disease. A new protocol was thus developed in an attempt to improve overall survival from this disease - Surgery for Mesothelioma After Radiation Therapy (SMART). The SMART involves a fractionated administration of 25 Gy over seven days to the whole chest by intensity modulated radiation therapy (IMRT). A concomitant boost of 5 Gy is also delivered to high risk volumes - based on imaging findings (CT and PET). Within 15 days of the completion of the radiation treatment, therapy, extra-pleural pneumonectomy is performed. This protocol may yield satisfactory results in case of epithelial-type MPM.

Management of malignant pleural mesothelioma is still a clinical challenge. Currently, the best survival figures are described after multimodality regimen including macroscopic complete resection achieved by either extrapleural pneumonectomy or extended pleurectomy/decortication in patients selected for tumor biology, stage, and risk factors. One particular approach is to perform neoadjuvant chemotherapy followed by macroscopic complete resection, which will be discussed in the following chapter.

Malignant pleural mesothelioma (MPM) is a virulent disease that is essentially incurable. Although surgery cannot currently be considered standard of care, there is general agreement that a certain subset of patients appear to benefit from surgery-based multimodal treatments beyond what would be expected with the current standard of care, pemetrexed-based chemotherapy alone. Exactly who those patients are remains to be defined. One intuitively appealing aspect of surgery-based therapies is that they allow for the employment of an intraoperative adjuvant therapy. There are multiple intraoperative adjuvant therapies, each with their own advantages and disadvantages. This chapter is a review of these treatments.

Malignant pleural mesothelioma prognosis is still dire. Since results are not optimal via single modality protocols, combined treatments have been proposed with more encouraging results. However, the likelihood of severe complications should be taken into the account. In this chapter, we will discuss complications due to the surgical treatment. In particular, cardiovascular complications are frequently encountered after mesothelioma surgery. Atrial fibrillation may occur in more than 50% of patients after extrapleural pneumonectomy. Myocardial infarction and serious ventricular arrhythmias are seen more rarely. Respiratory complications may include prolonged air-leak, ARDS and pneumonia. Meticulous surgical technique, proper anesthetic management with preoperative fluid restriction, and early mobilization are of paramount importance to decrease postoperative morbidity.

The prognosis of malignant pleural mesothelioma remains very poor. The role of the two intentionally-curative surgical procedures, extra-pleural pneumonectomy and radical pleurectomy/decortication, is widely debated and mainly focused on the impact on survival, which is not significantly improved whatever the operation may be.

On these bases the clinical impact of these procedures may assume a relevant importance on immunology, symptoms and quality of life.

Despite the unsatisfactory results on survival these two procedures proved effective in ameliorating symptoms and quality of life. In the early-postoperative period, greater improvements are detected after pleurectomy/decortication, whereas extrapleural pneumonectomy produced better symptom-relief later. Conversely this procedure may have a negative impact on immunological conditions thus producing a significantly greater risk of postoperative infection implying a higher morbidity rate.

Evaluating the benefit of therapies for malignant mesothelioma is a quite difficult task. The difficulty lies in identifying patients who might have benefited from a given treatment but knowingly did not receive it. Unless these 'suitable' patients have been identified in advance of any treatment and the process of allocation to one treatment or another is without bias. This is best achieved by randomization and in our view, for relatively small trials with heterogeneous patients, that is best done with the additional step of minimization.