Document a4XKDn01yMa0Q04Ep4k73D6gM

Kospidon Thematic Review Series 2008 Respiration 2008;76:1-15 DOI: 10.1159/000127577 Mesothelioma and Asbestos-Related Pleural Diseases Laurent Greillier Philippe Astoul Service d'Oncologie Thoracique, Assistance Publique - Hopitaux de Marseille, Faculte de Medecine, Universite de la Mediterranee, Marseille, France Key Words Asbestos Mesothelioma Plaque Pleural effusion Pleural cancer Rounded atelectasis Pleural fibrosis Abstract At present, the use of asbestos is not regulated at a world wide scale. Moreover, there is a latency period between as bestos exposure and the manifestations of asbestos-related diseases. Consequently, pulmonologists are still dealing with consequences of asbestos exposure, which mainly oc cur at the pleural surface. The aim of this review is to provide an overview of asbestos-related pleural diseases. We sum marized the most relevant data for the diagnosis and the management of benign asbestos pleural effusions, pleural plaques, diffuse pleural thickening and rounded atelectasis. Special attention is dedicated to malignant pleural mesothe lioma, given the challenging issues of this disease, the recent advances in its management and the dynamism of research in this area. Copyright 2008 S. Karger AG, Basel Previous articles in this series: 1. Froudarakis ME: Diagnos tic work-upof pleural effusions. Respiration 2008;75:4-13. 2. Jantz MA, Antony VB: Pathophysiology of the pleura. Respiration 2008;75: 121-133. 3. Koegelenberg CFN, Diacon AH, Bolliger CT: Parapneu monic pleural effusion and empyema. Respiration 2008;75:241-250. 4. Bouros D, Pneumatikos I, Tzouvelekis A: Pleural involvement in sys temic autoimmune disorders. Respiration 2008;75:361-371. Introduction Asbestos is the name given to a group of naturally oc curring silicate minerals, whose fire-resistant properties have been known for thousands ofyears. Asbestos depos its are widely distributed throughout the world, most of them in mountain-forming regions. Techniques for spin ning and weaving the fibers were developed in the 19th century and led to a rapid increase in their use. Asbestos is a good thermal and electrical isolator and is durable, strong and flexible. That is the reason why asbestos was extensively used in different commercial settings, such as insulation materials, brake pads and linings, house hold products, floor tiles, electric wiring, paints and cements. Asbestos fibers can be categorized into 2 main groups, the serpentines and the amphiboles [1]. Serpentine fibers are curly, pliable, easily shred into finer particles and sub ject to dissolution in tissues. The most important serpen tine fiber is chrysotile (white asbestos). Amphiboles are rigid fibers, sharp and highly resistant to chemical and biological dissolution. There are 5 members: 2 which can be used commercially, i.e. crocidolite (blue asbestos) and amosite (brown asbestos), and 3 non-commercial fibers that can be found as contaminants in other mining op erations, i.e. tremolite (a common contaminant of chrysotile), anthophyllite (a common contaminant of indus trial talc) and actinolite. KAI\GEK Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com 2008 S. Karger AG, Basel 0025-7931/08/0761-0001$24.50/0 Accessible online at: www.karger.com/res Philippe Astoul Service d'Oncologie Thoracique, Hopital Sainte-Marguerite 270, Bd de Sainte-Marguerite FR-13274 Marseille Cedex 09 (France) Tel. +33 4 91 74 47 36, Fax +33 4 91 74 55 24, E-Mail philippe.astoul@mail.ap-hm.fr Thus, the incidence of MPM is increasing throughout most developed countries and is expected to rise in the next 15 years in Europe [74] and to reach a peak in the United States in 2010 [75]. Although the incidence of MPM should then decrease in the developed countries, it will still increase in the developing countries, in which the use of asbestos is regulated poorly or not at all [76]. Consequently, MPM will remain a major health problem for many years on a worldwide scale. Diagnosis Clinical Presentation. Most patients with MPM are males and 50-70 years old [77]. Their initial clinical pre sentations are usually unilateral chest pain and dyspnea [78]. Constitutional symptoms such as fatigue and weight loss can occur [79], but generally, these appear later in the course of the disease. Occasionally, patients have no symptoms and their pleural disease is fortuitously found on a chest X-ray. Physical examination findings are most often consistent with a pleural effusion. A fixed hemithorax is suggestive ofMPM, but is a relatively late sign. Signs of locoregional invasion, such as chest wall mass, pericar dial effusion, superior vena cava obstruction, Horner's syndrome, spinal cord compression, phrenic nerve com pression and esophageal compression are rare at presen tation [80] . Imaging. The radiographic manifestation of MPM is usually unilateral pleural effusion [81]. Occasionally, MPM can present as a pleural mass or with DPT with in volvement of the interlobar fissures in the absence of pleural effusion. Pleural plaques, which are the witnesses of asbestos exposure, may be observed on chest X-ray. In later stages of the disease, an ipsilateral mediastinal shift may be seen secondary to encompassment of the lung by a thick rind of tumor and resultant significant unilateral loss of lung volume [82]. Patients with advanced MPM may have radiographic findings of mediastinal widening due to direct tumor invasion or lymph node involvement, enlargement ofthe cardiac margins secondary to pericar dial invasion with effusion, and evidence of rib destruc tion or soft tissue masses extending from the chest wall. A chest CT scan is the key imaging modality used for MPM evaluation and follow-up. Preliminary removal of fluid improves the visualization of pleural abnormalities. Unilateral pleural effusion, nodular pleural thickening and interlobar fissure thickening are the most frequent features observed [83, 84]. It is not rare to see a contrac tion of the affected hemithorax with associated medias tinal shift, narrowed intercostal spaces and elevation of ipsilateral diaphragm [83]. However, the accuracy of the CT scan is suboptimal for correctly appreciating the in volvement of mediastinal lymph nodes, chest wall and diaphragm [83]. These issues may potentially be im proved by using multidetector row CT with multiplanar reformatting capacity. The use of MRI can improve the detection of tumor extension, especially to the chest wall and diaphragm, and better predicts the resectability of the tumor [83]. Positron-emission tomography (PET) can be used to dis tinguish benign from malignant pleural masses and to increase the detection of occult distant metastases [85 87]. Integrated CT-PET, providing a better spatial resolu tion than PET alone, seems to be a sensitive technique for MPM staging [88]. Additionally, recent findings suggest that PET or PET-CT can provide prognostic [87, 89] and predictive (early detection of chemotherapy efficacy) in formation [90-92] . Thoracentesis, Percutaneous Pleural Biopsy, Thoracos copy. Effusions associated with MPM are usually exuda tive with a lymphocytic predominance. If thoracentesis can diagnose a malignant pleural effusion, it only seldom leads to a precise diagnosis ofMPM [93]. Concerning per cutaneous pleural biopsy, it generally brings back little of the tissue material, which remains essential to confirm the diagnosis ofMPM. Consequently, the diagnostic yield of these techniques is poor [94]. Thus, an invasive ap proach such as a thoracoscopy is very often mandatory to obtain a diagnosis of certainty. Thoracoscopy is indicated in any patient without pre cise histopathological diagnosis in whom clinical and laboratory findings raise suspicion of MPM [95]. MPM gross appearance is a firm, grayish tumor coalescing on the visceral and parietal pleural surfaces into discrete plaques and nodules. The lung can be completely covered with a thick ring of tumor. Adjacent structures are in volved at an advanced stage, with invasion of the chest wall, pericardium, diaphragm and interlobar fissures. In most patients, nodules and masses are associated with parietal pleural thickening up to several millimeters. Thoracoscopy allows performing large biopsies of the parietal (and visceral) pleura under visual control. Thus, with a diagnostic yield >90% in MPM patients [94, 95], thoracoscopy is regarded as the standard diagnostic pro cedure for MPM (fig. 2). However, recent studies showed that thoracoscopy is less efficient in diagnosing the his tologic subtype of MPM [96, 97], Histology. MPM is typically classified into 4 histologic subtypes: epithelioid, sarcomatoid, desmoplastic and biphasic [98]. The epithelioid variant is the most common, comprising 50-60% of all mesotheliomas. Sarcomatoid Asbestos and the Pleura Respiration 2008;76:1-15 5 Fig. 2. Early- (a) and advanced-stage (b) malignant pleural mesothelioma. Endoscopic features are important prognostic parameters, in particular the invasion of visceral pleura and diaphragmatic muscle. mesothelioma is composed of malignant spindled cells which may mimic malignant mesenchymal tumors such as fibrosarcoma or leiomyosarcomas. Biphasic or mixed mesothelioma has epithelioid and sarcomatoid features, and desmoplastic MPM is a rare variant of the disease. Even with large pleural biopsies, histological diagnosis of MPM is difficult, because MPM can show various mis leading histopathological pitfalls, and the pleura is a common site for metastatic disease. Visual similarities are particularly frequent between adenocarcinoma and epithelial MPM. Diagnostic problems also occur with be nign inflammatory or reactive lesions ofthe pleura. These very frequent lesions occur often in patients of the same age group as MPM (pleural effusion during cardiac fail ure, collagen disease, pneumonia or cirrhosis). They may lead to atypical mesothelial hyperplasia which can result in diagnostic error [99]. Immunohistochemical staining of the biopsy tissue, using a panel of antibodies, is often necessary for the de finitive diagnosis of MPM. Typically, MPM is character ized by the presence of staining for epithelial membrane antigen, calretinin, WT1, cytokeratin 5/6 and mesothelin, and the absence of staining for carcinoembryonic an tigen, as well as the tumor glycoproteins B72.3, MOC-31 and Ber-EP4 and the epithelial glycoprotein BG8 [100]. Diagnostic Biomarkers. Because the diagnostic proce dure of MPM is particularly hard, it is not rare that sev eral months separate the first signs of the disease and the diagnosis of MPM [101]. Thus, it would be helpful to have methods to speed up the diagnosis process and identify patients who require invasive procedures at an early time. The ideal diagnostic biomarker for MPM should be as sessable using a blood or a pleural fluid sample and should be able to detect high-risk subjects developing the dis ease, to differentiate MPM from benign pleural diseases and metastatic pleural malignancies, and to reflect the disease severity or the tumor load. Many candidate biomarkers have been studied for MPM, notably hyaluronic acid [102-104], Cyfra 21.1 [103, 105], carcinoembryonic antigen [103, 105, 106] andCA153 [105]. However, none were accurate enough to be used in clinical practice. Recently, new diagnostic biomarkers were proposed in serum, plasma and/or pleural fluid, no tably soluble mesothelin-related peptides (or C-Erc mesothelin) [107-111], N-Erc mesothelin [112, 113] and osteopontin [114, 115]. In addition, global gene profiling us ing microarray technologies was used in tumor samples [116] and in pleural fluid [117, 118] to differentiate MPM from other diagnoses. These recent findings sound very promising, but the validation of diagnostic biomarkers in large and independent samples of patients remains a ma jor challenge before their use in clinical practice. Staging and Prognosis MPM usually has a poor prognosis, with a median overall survival ranging from 4 to 12 months without treatment [71, 119]. In 1995, the International Mesothe lioma Interest Group developed a new staging system for 6 Respiration 2008;76:1-15 Greillier/Astoul MPM [120] (table 1). Although their staging system par allels prognosis, it is difficult to use it in daily practice, because it is based on surgical findings [120]. In a large retrospective series of phase II trials, the Eu ropean Organization for Research and Treatment of Can cer (EORTC) found important prognostic factors: histo logical subtype, certainty of histologic diagnosis, perfor mance status, white blood cell count and gender [121]. The Cancer and Leukemia Group B reviewed 337 patients treated for MPM and found that pleural involvement, lac tate dehydrogenase >500 IU/l, poor performance status, chest pain, platelet count >400,000/ml, non-epithelial histology and increasing age >75 years jointly predicted poor survival [122] [ Both EORtC and the Cancer and Leukemia Group B prognosis scores were validated in in dependent sets of patients [123, 124]. Recently, Bottomley et al. [125] demonstrated that some items of the EORTCQLQ-C30/Lung Cancer 13 questionnaire were correlated with patient survival. Additionally, a very large number of biomarkers were assessed in a prognostic intent [110, 115, 126-130], but have not been validated in large and independent samples of patients at the present time. Treatment In the past decade, there have been several major de velopments in the management of MPM, especially thanks to the emergence of new therapies. Chemotherapy. Until recently, chemotherapy for MPM was only assessed in small non-comparative phase II studies. With low median survival and objective response rates ranging from 10 to 26% for monotherapy [131-133], MPM was considered to be widely chemoresistant. A meta-analysis, using a systematic review of the literature including 88 studies, was published in 2002 and showed cisplatin as the most active single drug [134]. Due to the lack of efficacy of single agents, several combination reg imens have been studied, with best results for combina tions including antifolates and platinum compounds. To date, only 2 phase III randomized trials have been published in the setting of first-line chemotherapy for MPM. First, Vogelzang et al. [135] randomized 222 MPM patients to cisplatin alone and 226 patients to a combina tion of pemetrexed and cisplatin. Pemetrexed is a multi target antifolate agent that acts by blocking 4 different enzymes involved in folate metabolism and essential for cell replication (glycinamide ribonucleotide formyltransferase, thymidylate synthase, dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) [136]. Combination therapy was asso ciated with an improved response rate (41.3 vs. 16.7%; p < 0.001) and a significantly better median survival (12.1 vs. 9.3 months; p = 0.02) and 1-year survival rate (50.3 vs. 38.0%; p = 0.012) compared with cisplatin alone [135]. In 2005, the results of a second phase III trial were published [137], This trial, conducted by the EORTC Lung Cancer Group and the National Cancer Institute of Canada, compared a chemotherapy doublet with cisplatin and raltitrexed, another inhibitor of the antifolate pathway, with a monotherapy with cisplatin. The combi nation arm compared with the monotherapy arm showed a response rate of 23.6 versus 13.6% (p = 0.056), an overall median survival of 11.4 months (95% confidence interval, 10.1-15) versus 8.8 months (95% confidence interval, 7.8 10.8) and a 1-year survival rate of 46.2 versus 39.6% (p = 0.048) [137], Taken together, these results led to the combination of cisplatin and an antifolate (pemetrexed or raltitrexed) as the standard therapy for MPM patients. As suggested by a phase II study [138], cisplatin could be replaced by carboplatin in the case of a contraindication to cisplatin. To answer the question of whether chemotherapy should be given immediately after diagnosis or whether there is time to wait, O'Brien et al. [139] compared freedom from symptom progression and overall survival in MPM pa tients with no or stable symptoms who received early che motherapy (mitomycin C, vinblastine, and cisplatin [or carboplatin]) or late chemotherapy. Median time to symptom progression was longer with early compared with late chemotherapy (25 vs. 11 weeks; p = 0.1) [139]. Although not statistically significant, these findings sup port the use of early chemotherapy immediately after di agnosis of MPM. After failure of first-line chemotherapy, no standard treatment has been defined. Few data are available in the literature concerning second-line chemotherapy. In a ret rospective analysis of patients enrolled in the phase III trial of cisplatin plus pemetrexed versus cisplatin alone, Manegold et al. [140] observed a significantly prolonged survival in the groups treated with post-study chemo therapy (PSC). However, as PSC was not randomized, it is not possible to know whether the reduced risk of death was associated with PSC or whether patients who had prolonged survival tended to receive more PSC. In addi tion, some phase II trials on second-line chemotherapy have recently been published [141-143], with sometimes conflicting results [144, 145] (table 2). Thus, no standard treatment can be defined after failure of first-line chemo therapy. Radiotherapy. Radiotherapy with an attempt to treat the entire involved pleural surface is technically difficult Asbestos and the Pleura Respiration 2008;76:1-15 7 Table 1. Staging system for MPM developed by the International Mesothelioma Interest Group a Tumor descriptions Descriptor Characteristics Primary tumor T1a Tumor limited to the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura; no involvement of the visceral pleura Tib Tumor involving the ipsilateral parietal pleura, including mediastinal and diaphragmatic pleura; scattered foci of the tumor also involving the visceral pleura T2 Tumor involving each of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral pleura) with a least 1 of the following features: Involvement of diaphragmatic muscle Confluent visceral pleural tumor (including the fissures) or extension of the tumor from vis ceral pleura into the underlying pulmonary parenchyma T3 Locally advanced but potentially resectable tumor; the tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with a least 1 of the following features: Involvement of the endothoracic fascia Extension into the mediastinal fat Solitary, completely resectable focus of the tumor extending into the soft tissues of the chest wall Nontransmural involvement of the pericardium T4 Locally advanced technically unresectable tumor; the tumor involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic, and visceral pleura) with at least 1 of the following features: Diffuse extension or multifocal masses of the tumor in the chest wall, with or without associated rib destruction Direct transdiaphragmatic extension of the tumor to the peritoneum Direct extension of the tumor to the contralateral pleura Direct extension of the tumor to one or more mediastinal organs Direct extension of the tumor into the spine Tumor extending through to the internal surface of the pericardium with or without a pericar dial effusion, or the tumor involving the myocardium Lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases N1 Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes N2 Metastases in the subcarinal or the ipsilateral mediastinal lymph nodes, including the ipsilateral internal mammary nodes N3 Metastases in the contralateral mediastinal, contralateral internal mammary, ipsilateral, or contra lateral supraclavicular lymph nodes Metastases MX M0 M1 Presence of distant metastases cannot be assessed No distant metastasis Distant metastasis present b Staging Stage Ia Ib II III IV Tumor T1a T1b T2 Any T3 Any T4 Node N0 N0 N0 Any N1 or N2 Any N3 Metastasis M0 M0 M0 M0 Any M1 8 Respiration 2008;76:1-15 Greillier/Astoul MPM is often associated with pain, which is initially due to excessive nociception [152, 180]. Much later in the disease process, neurogenic pain (neuropathological) may arise due to invasion of nervous structures or as a side effect of therapy [152, 180]. Pain related to MPM should be managed as cancer pain in general, especially with opiates, non-steroidal anti-inflammatory drugs and anticonvulsants for the neurogenic part of the pain. Pain related to MPM can be controlled in around 90% of cases by oral treatments [152, 180]. However, neurosurgical techniques can be performed, but decisions should be taken solely by a multidisciplinary team experienced in pain management in general and in these techniques in particular and after careful evaluation of the benefit/risk ratio for each indication [152, 180]. Psychological and emotional factors are important in the palliation ofMPM symptoms and should be managed attentively [181]. Future Directions. The use of agents that specifically target the biochemical and molecular changes underly ing tumorigenesis could facilitate the combination of therapies to treat cancer on multiple fronts, offering the potential to significantly enhance tumor responses and improve survival. At present, several targeted therapies are under evaluation for MPM. Inhibition of angiogene sis is probably the most studied pathway. At least 5 anti angiogenesis inhibitors, bevacizumab, semaxanib, sunitinib, pazopanib and thalidomide, have been or are used in clinical trials for the treatment ofMPM. However, first reports did not show major improvement in outcomes [182, 183]. Several other pathways are suspected to play an im portant role in MPM pathogenesis. Platelet-derived growth factor is explored as a potential target for MPM treatment, particularly with ongoing studies using imatinib mesylate and dasatinib. The apoptotic pathway is also targeted by several new agents, such as bortezomib (a proteasome inhibitor that is under evaluation in com bination with cisplatin in a phase II EORTC study) [184, 185], and TRAIL agonists [186]. Mesothelin, a cell surface glycoprotein, is another attractive candidate for targeted cancer therapy given its limited expression on normal mesothelial cells and its high expression in several hu man cancers including mesothelioma, ovarian and pan creatic cancer [107]. The results of a phase I study with recombinant anti-mesothelin immunotoxin, SSP-1, were reported at the last ASCO meeting [187], and a phase II study is now ongoing. At last, the deacetylase inhibitor suberoylanilide hydroxamic acid (or vorinostat), which demonstrated some activity in phase I study [188, 189], is now assessed as single agent in second-line treatment and in combination with standard frontline chemotherapy. Conclusion As long as the use of asbestos is not regulated on a worldwide scale, asbestos-related pleural diseases will continue to affect populations. Benign asbestos-related pleural diseases are now well known and generally do not require specific treatments. Conversely, MPM is a poor prognosis disease with increasing incidence in many countries. In the last decade, some therapeutic progress has been obtained with the use of cisplatin combined with an antifolate. Moreover, several additional drugs or strategies provided preliminary promising results and are now under evaluation. However, research efforts for MPM must continue in numerous ways. Indeed, the ear ly detection of MPM patients among asbestos-exposed subjects remains a real challenge. Moreover, tools for se lecting MPM patients who will benefit from a specific therapy are needed. 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