Document LpxqxxNzzyZQRKY5Lj80yYNqb

,, ur Respi? J 1998; 12:972-981 Printed in UK all rights reserved ' . Copyrighl ERS Journals Ud 1998 European Respiratory Journal! ISSN 0903 - 1936 SERIES 'THE PLEURA' Edited by H. Hamm and R.W. Light Number 13 and last in series Malignant pleural mesothelioma C. Boutin**, M. Schlesser*, C. Frenay*, Ph. Astoul** Malignant pleural mesothelioma. C. Boutin, M. Schlesser, C. Frenay, Ph. Astoul. ERS Journals Ltd 1998. ABSTRACT: The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak between 2010 and 2020. Up to now, no single treatment has been proven to be effective and death usually occurs within about 1217 months after diagnosis. Perhaps because of this poor prognosis, early screening has incited little interest However, certain forms may have a better prognosis when diagnosed early and treated by multimodal therapy or intrapleural Immunotherapy. Diagnosis depends foremost on histological analysts of samples obtained by thoracos copy. This procedure allows the best staging of the pleural cavity with an attempt to detect visceral pleural involvement, which is one of the most important prognostic factors. Although radiotherapy seems necessary and is efficient in preventing the malignant seeding after diagnostic procedures In patients, there has been no random, zed phase III study showing the-superiority of any treatment compared with another. However, for the early-stage disease (stage I) a logical therapeutic approach seehts to be neoadjuvant intrapleural treatment, using cytokines. For more advanrod disease (stages n and HI) resectability should be discussed with' thetboracic surgeons and a multimodal treatment combining surgery, radiotherapy and chemotherapy should be proposed-for a randomized controlled study. Palliative treatment is indicated for stage IV. In any case, each patient should be enrolled in a clinical trial. Eur Respir J 1998; 12: 972-981. *Dept of Pulmonary Diseases,' Hdpiici tie La Conception,.Marseille, Franoe; *Ui%S 2050 (Bnviroeraental Pulmonary ancous Diseases),-.L>niyet;sity of the (4e4itenranean, Maiseiils/Fianpe. rPOnespondence: Cyjoutin Hdpisal <fc U Conception 147 Bd Bailie. 13385 Marse-lfc- ' V . : Cede5 " ' France ' ' . Fax: 33 491383659' '. Keywords: Asbestos nrabgnapt.... pleura':' ;V "" .-. . thoracoscopy ' '. Received; Aprii:.t7VlM7 The term "mesothelioma" was first used in 1921 by Eastwood and Martin (1) to describe primary tumours of the pleura. At that time, the primary, nature of these pair), and surgery (even when petfornjfeid^at'aiBfettively pgdy stage) is controversial (6-iOJ. The: vjadiip pf 'tiw cunyiit staging system is quesUonabre:--afteFtti^i^-e^j^i^c^i^.v tumours was controversial without confirmation by au by BuTCHARTefa/. (8j the number dfsucb^iyib'chBsiifiiW topsy. Today, the histological diagnosis of mesothelioma tions provides evidence for the difficulty'in distinguisiurig remains problematic and differential diagnosis against ad between-the various stages of the disfcasfe.fl 1-13. enocarcinoma is difficult in 10-15% of cases despite the Recent studies have reported ^ routine use of histochemistry. ... . . .. ... t^ejf^y^n^unaavgn^^^ The firet evideride iniplicaxing asbestos esis of mesbffielf6ina%asfpfeseiite<l in i9(5&! byWarner''''%irpS [2] in South African miners. The incidence dfmalignajit pleural mesothelioma (MPM) has risen for snoimne decades ' and is expected to peak sometime between 2010 and 2020 P, 4J. This increase has been attributed to the widespread Bpide use of asbestos in the period from World War II until the end. of the 1970s. J5J. Pleural mesothelioma is more.fea..... - - -'.faf- quent than peritoneal mesothelioma, possibly because in- used from the end bf W0fWw;' halation is die usual route of the pathogenic fibres. No single treatment has been proven to be effective for malignant mesothelioma.. Chemotherapy alone has no ef fect, radiation therapy simply provides palliation against 1970s', t*h' e incidence pefyeaf* 2 pis.c rrtiliiori'ln feyririiS [5], Geographical . gional differences, riit^tidiis^fj'i m Previous articles in this series: No. t:G. Miserocchi. Physiology and pathophysiology of pleural fluid tiiraoyifV'EiLr^ 2: R.W. Light Diagnostic principles in pleural disease. Eur Respir / 1997; 10:47(5-481. No.3:G,T. KniscwitzV?&! 1997; 10: 714-718. No. 4: J. Ferrer. Pleural tuberculosis; EurJRespirJ. 1997; 10:942-947.. Np.S: ! empyema. Eur RespirJ 1997;'I0: 1150-1156. No. $: Q. ffiiierdal. Chylothorai and ps4udochy(iMiiSraiii: F.M.N.H. Schramcl, PjE. Postmus. R.GJ.RA. Vandersctiueren. Current aspects ofspontaneous pneum6tta^?'$ 8: F. Rodriguez-Panadero, V.B. Antoay. Pieurodesis: state of the tut. EurRespirj 1997; Mfc. 1648-1654. No.Wsr astatic malignancies. Eur RespirJ 1997; 10: 1907-1913. No. 10: G. Kroeget VJ)'. Antony. Irairmnpkigy.o.fji^n for pathogenesis, diagnosis and therapy. Eur Respir J 1997; 10: 2411-2418. No. II: R.W. Light, H. Haitira; Ptatriih ciency syndrome. Eur Respir J 1997; 10: 2638-2643. No. ,12: R^Loddenkemper: Thoracoscopy - state of the ait t#r Rcspil J-ftl M I JL .'v.yv.v y;. 'i HWBUIQ0Q8925 MANAGEMENT OF MALIGNANT PLEURAL MESOTHELIOMA 973 upyards are at particularly high risk [16]. Another factor Jftifluenping.incidence is the type of fibre used, the inci- Vdtence.being higher with crocidolite and amosite than with Adhiyst^Ue f1-7-19]. Details on occupational risks have been ;^In Frahoe,"e'exact incidence of mesothelioma is not (spQW.n since there is- no national register for the disease. According .to a recent review by the National French In stitute for Medical Research (INSERM) (191 950 new cases per year pre, probably observed. In the authors reg ion (sputh-easfFrhnce, which has a large number of ship yards) a study petfomied between 1989 and 1993 indicated ah annual incidence of 14.2 per million in males and I per millionin lentaies iiLthe.Provence .'region and 1 per mil- - ifottiin- per imllion in males in Corsica incidence rate is 75 per per nutlion for females. In die XlSA the highest published annual rate per million is 13.3 [23,24] 'for males and 25 for females and in Australia the Canada; AuMi3fa',riife Netherlands) die annual incidence increased 3-5rfold for males and 1.4-fold for females from the end.of the 1960$ to the beginning of the 1980s [2628]. In the UK the epidemic will peak at about 2,700 deaths per year and will disappear rapidly after 2020 [4], The USA epidemic has. already reached its peak [29]: since 1980 USA rates have declined in both sexes. - /.Despite .thelrrupreliability these data, seem to indicate a ._ major increase in the annual incidence of mesothelioma in files';anda-smaller increase in females. This trend will {ui>biat>Iy cwntirjiie ki.many countries until the second dec ade .-of.the `Tlie long, latency period for the development ofn&sqtheiioriia accounts for the rising inci.d^;oftrp^|i'gijpmTor up to 3CMP yrs after appiicattflri'ofsS^|i^/i5'b|i'the'.ii5e of asbestos. jprevaieiice for males in .niost countries is strong evidence Tpfi.occupational exposure to- asbestos, since females ffle .less likeiy to have worked in contami- natedafeas, Mesothelioma due to- rionoccupalional envirorwnental exposure has been reported in various places IncludingCb'rsica[21|,.New Caledonia [30],Cyprus [31], Qre^"I32] ^d;^h^;ey, p3]. Cases due to exposure in .buildings *vith"asb6jiios` insulation seem to be extremely iaie.t34,35].: ' the parietal or diaphragmatic pleura. Malignant pleural mesothelioma probably also originates from the parietal pleura. Up to now, however, very few studies have de tected significant amounts of asbestos fibres in the parietal pleura (18). Experiments by Stanton et at. [41] demon strated that the risk for mesothelioma is related to the con centration of long (>8 pm) amphibole fibres. Other animal experiments using intracavitary injections of asbestos con firmed that the most carcinogenic fibres were those meas uring >5 nun in length and <0.25 mm in diameter [42, 43]. In sharp contrast to these data, all previous mineralogicai studies have shown that short chrysolite fibres are the most common type of asbestos present in the parietal pleura [44] . where amphibole fibres meeting the criteria of Stanton for carcinogenicity are uncommon or absent [45]. A possible explanation forthis paradox could be that fibres are heterogeneously distributed in the parietal pleura. This would explain why random sampling in unselected areas yields poor concentrations. Indeed, when samples were taken from pathological zones such as pleural plaques or tumours' [46], more fibres' were found. Several findings led to the speculation that these asbes tos fibres could accumulate in certain areas of the parietal pleura. In mice, subcutaneously injected fibres are known to concentrate in the milky spots of the parietal pleura [47], In humans, milky spots are almost invisible in the healthy pleura. However* thoracoscopy sometimes visualizes foci of parietal anthracosis near lymphatic vessels of parietal pleura [48], which have been called "black spots". Indeed, these black spots could correspond to the milky spots des cribed by Kanazawa et at. [47] in mice and be rendered visible by trapped coal dust. Thoracoscopic biopsy samples were collected from these black spots [18] and from normal areas of the pari etal pleura and lung from 14 subjects (eight with and six without asbestos exposure). Asbestos content was deter mined by transmission electron microscopy. In exposed subjects mean fibre concentrations were 12.4+9.8. x lO fibres-g of dry tissue-' in lung, 4.11.9 in black spots and 0-50.2 in normal pleura. In unexposed patients, these con centrations were0,030.1 and 0, respectively. Amphiboles outnumbered chrysotile in all samples. A total of 225% of the fibres were >5 mm in length in black spots. These findings could explain why the parietal pleura is the target organ for mesothelioma and plaques. ,tfipigeiilcI%.oEasb(Kto&'fibres - . .'7 . AsMstos fibres, that reach the respiratory bronchioles jril^^^aibJ^cblp^^ijBferent fates. Chrysotile fibres .acids,.and progres`l|^^P^pb^f^|l^^:'a^Sjbiole'iibres;irtay remain un:<^|ng^.fpVd^iiM [36). High concentrations of asbestos .;ps;in;thetMng1w--ats'sociated with asbestosis and bron6mal carcinoma '(37]:..' fn patients with these conditions, ^bfestos bodies, rhpstly1 formed on amphibole fibres, are .Usually found in lung sections and bronchpalveolar lavage ;|jmt{38).. Fibres may also migrate towards the periphery ;lung, e&pipially the lower lobes [39], into mediastl'fi jymph nodes [40] and the pleura. Afiiewgn ptattstplaques are the most common*manifes^tTdn'of asbestos exposure [26]. They usually develop on Clinical manifestations The mean age of patients is approximately 60 yrs. A few cases have been described before the fourth decade of life in patients exposed to asbestos during childhood. The tumour can occur rarely in children [49] and a number of these cases probably has no relation to asbestos. The pre viously mentioned strong male predominance is due to the fact that exposure to asbestos is less common in females. Clinical manifestations depend on the stage of the dis ease. Recently, an international staging system was pro posed by the International Mesothelioma Interest Group (IMIG) on a new tumour, node, metastasis (TNM) basis [12] (table I). In early-stage disease general symptoms such as fatigue, weakness and weight loss are rare (15%) [50]. The pain which is extremely frequent in advanced 974 C. BOUTIN ET AL. ' **> Table 1. - New international staging system for diffuse malignant pleural mesothelioma Stage Description .. .V^.* T1 rta: Tumour limited to the ipsilatera! parietal pleura including mediastinal and diaphragmatic pleura. No involvement visceral pleura ' Tib: Tumour involving the ipsilatera! parietal pleura, including mediastinal and diaphragmatic pleura. Scattered foci of tuntour also involving the visceral pleura : T2 Tumour involving each of the ipsilateral surfaces (parietal, mediastinal,diaphragmatic and visceral pleura) with at least one of the following features: Involvement of diaphragmatic muscle ' Confluent visceral pleural tumour (including the fissure) or extension of the tumour from visceral pleura into the under lying pulmonary parenchyma .. -v- T3 Locally advanced but potentially resectable tumour . . .....; Tumour involving all of the ipsilatera! pleural surfaces (parietal, mediastinal, diaphragmatic and.visceral pleural) with at least one of the following features: Involvement of the thoracic fascia Extension to the mediastinal fat Solitary, completely resectable focus of the tumour extending into the soft tissues of the chest wall Nontransmural involvement of the pericardium T4 Locally advanced technically unresectable tumour " ; v Tumour involving all of the ipsilateral pleural surfaces (parietal, mediastinal, diaphragmatic and visceral pleura) with at least one of the following features: .. Diffuse extension or multifocal masses of tumour in the chest wall, with or without associated rib destruction Direct transdiaphragmatic extension of the tumour in the peritoneum Direct extension of the tumour to the contralateral pleura Direct extension of the tumour to one or more mediastinal organs Direct extension of the tumour into the spine (From International Mesothelioma Interest Group [12].) stages is less common in stage la. In contradiction to descriptions given in manuals pleurisy may.'be unremar kable and often occurs without radiologicaily detectable tumour. Massive effusion at the time of presentation is possible, but moderate effusion is more likely. The fact that pleurisy may not recur for weeks or months after ini tial drainage can lead to a delay in diagnosis. Moderate tightness followed by progressive pain, cough and short ness of breath are the most common, presenting signs. Since the symptoms are nonspecific, practitioners in reg ions exposed to industrial or environmental asbestos fibres should keep mesothelioma in mind and not rule out the possibility even if the initial cytological or histological findings are negative. In oyr series the initial thoracic radiographleading to ?; diagnbsis of mesothelioma showed a pleiirai emision In 92% of cases, where the thoracentesis showed a clear or haemorrhagic fluid {50J. In 0.5% thoracentesis revealed an empyema. Radiography showed in 0.5% a spontaneous pneumothorax and in 7% multinodular, pleural tumdur without fluid. Three patients had a history of radiation ther apy for lymphoma. An association between irradiation' of the thorax and mesothelioma has been reported previously {51]. In another series [27] only 1% of diagnoses were made coincidentally on routine radiographic images with no thoracic symptoms. The pleural fluid is an exudate with little evidence of in flammation: cell counts reveal a high number of mesothelial cells [52] without a significant increase in neutrophils or lymphocytes. Cytological examination of pleural effu sions, which is one of the first diagnostic techniques at tempted in patients with MPM, is usually positive in only 30% of the cases [53]. At stage I, pleural effusion is the prominent feature seen on radiography and computed tomographic (CT) scan. This is not specific. Removal of fluid>iriijproyes'the'fecognitiqii. of more specific signs: 'ifEe^^Ut^pr $dM^utar entng is the more . [54] (fig. 1). Spread of the staging or evaluation of treatment'risjlbii^ih.'the-'lollpw^ ing sites: diaphragmatic pleura', chest Wafli pencaidilsm' ' mediastinum and lymph ricktes'[55-57] Thoracoscopy allows assessment .Of -:the -parieiiii:>arid visceral pleura and is the most reliable method by wliith to achieve early diagnosis. GT scan.arid;fhbracosc0g^'arc sis [56], Magnetic resonance:irhagiitg.^MRI) seemsitobe HWBUI0008927 MANAGEMENT OF. MALIGNANT PLEURAL MESOTHELIOMA 975 ( ^ . * 'Diagnosis .diagnosis was achieved by cytolby closed pieutal biopsy in &Ms <n 38.7%. to those obtained in '.:.. p|e|iQ,^st^es. .wifli.Uie Cope.'needie [60]. A recent trial . .niattfcers were used in an . eff6j^i8;aisBpi*i'Kh ;4he. results tif blind biopsy was disap- ..poiHjtagiCSitvvii.. ;', ;.:..;.,, V- indieated in any sfe lifefepatly)16gical diagnosis in whom ..... . . Jtoiy findiiigSraisetheSuspicionofme- phaiactenstics are age between 55 - asbestos,pleural effusion df iifSges showing-irregular and nodular lesiMti^^f^^.j^etsd.;p!^ura,'dSpefeially. in the posterior and - ihra^'^dtt'.of4fie eostoyertebral gutter. . Macnjsidpically, the iesiOns range from 1-3 mm to 1 cm^ip.diartteter.Or .eyen fcugjsj;, depending on the stage. In ?% aall .(i-^S'mih iff diameters). A typi cal aspect of inesothhlioma is the grape-like aspect, which consists!of a patch Of closely spaced, smooth, translucid, poorly vascularized nodules 5--10 nun in diameter with a clear or yellowish appearance. Upon biopsy these lesions niaiy other be friable and filled with sticky fluid or hard aikidUfiasltto remove. The grape-like aspect is typical of n&^'theUoina, generallyat the advanced stage, but it is 'tprisjpecuic sitice if is also encountered in patients with jet^ia||c:cancer,.of die pleura.'Unlike benign inflammaihihltemitg of the pleura associated with tt^dmp|fo'fnafs: hand and (inelastic. When biopsy samples the .cut edge, is' clear and there is little or no1 1 of ksi cases' and in 50% of stage la cases [Sf^i'dtelStdhs'obsefved during thoracosdopy are macroscqii&ll|'','ti6ris|)ecific: benign inflammation of the pari etal or .diaphragmatic pleura with lymphangitis in some ca^i'ln ffofc cases a more discrete sign is irregular thickemhgldcatM'niainly in thepoSterior and inferior region of me-perietal pleura, where lymphatic vessels are most ffuiigii&tiir.. The' more. nonspecific the lesions, the more biop&'sBoilil tife akfch (tip tp 15 or 20). An impcutinf diagnostic finding is the involvement of thri.Visceral ffleuf' add lung [59]. These structures can be . .^ng thoiacoscopy. The visceral pleura Blfflwajgit^'ihv 'y^d fhtin'the parietal.pleurarwidthQd'- ules being not only less numerous but also smaller. In many cases the visceral pleura appears macroscopically normal but routine biopsy should be performed to confirm or exclude the diagnosis. Histolbgical diagnosis is problematic because of stiuctural variability between different turnouts and even with in the same tumour. Furthermore, differential diagnosis with adenocarcinoma is often difficult. Mesothelioma is classified into various major histological types, t. epithe lial, sarcomatous, mixed and desmoplastic. The cell pat tern ofepithelial-tumours can be tubular, papillary or more complex and differential diagnosis with reactive mesothelial cells can require histochemical or immunohistochemical techniques and even election microscopy [61-64]. Diagnosis is further complicated by the fact that involve ment of the pleura is. patchy. and histological findings can vary from one place to another. In this regard sampling must be extensive, focusing on the most suspicious areas, especially for the desmoplastic type. In our series medical thoracoscopy allowed diagnosis in 185 of I&8 discs (98.4%) [50J. The three failuresficcuned when artificial pneumothorax was impossible to realize, precluding the access to the pleural cavity. Thoracoscopy is .currently (he technique of choice for the diagnosis of mesothelioma and thoracotomy should be resorted to only when medical thoracoscopy is unfeasible or inadequate. Thoracoscopy is- a safe technique [65]. Mortality is 1: 8,000 and complications are uncommon and usually min or (subcutaneous emphysema, localized pleural infection and minor bleeding, <100 mL). The only major problem associated with medical thoracoscopy in patients with me sothelioma is seeding of the chest wall along the path of insertion of the trocar. Seeding, which has also been ob served after.thoracenteses Or blind pleural biopsies, can be prevented by performing prophylactic radiotherapy after healing of the point of entry [66]. Prognosis and classification Median survival ranges from 12 to 17 months depend ing on the series [67,68], while 5-yr survival is less than 5%. Several large studies involving multivariate analysis have identified several factors for a more favourable prog nosis (table 2). More recently, an absence of weight loss at the time of diagnosis, absence of involvement of the vis ceral pleura, stage I and epithelial histopathologicai type were found to be the most favourable factors in an analy sis according to a Cox model [59]. The absence of symptoms-in general-andpaiir in particulardepends Oft the stage. hjjuBifeicaorial Analysis of prognostic factors for malignant pleural mesothelioma: data from the literature y\ >;? y- - ** Chamman - 168] Alberts HO] Hist author [ref.] Antman [67] RUFFlfe P7] Kusch [6] Boutin [59] l^faisurvival months . Endurable: factors. >" ' ' ' 1982 57 . 13 Epithelial Age <65 yrs PS Surgery Response CT 1988 262 9.6 PS Treatment White race Sdg >6 months Stage 1 1988 136 15 PS Epithelial No chest pain Sdg >6 months Surgery 1989 170 9 Stage I Platelets No weight loss mi 83 10 None 1993 188 16. Epithelial Stage la PS Lesions <5 mm :.-K$rPterf6iinance status; Sdg: interval between first symptom and diagnosis; CT: computed tomography. HWBUI0008928 976 C. BOUTIN T AL. The first published classification by Bittchart et al. (8) is frequently used owing to its simplicity. However the early stage of malignant pleural mesothelioma is not part of this classification. Thus, different types of stage I are mixed in that classification. Spontaneous survival is long er if the visceral pleura and the lung are not invaded (stage fa) and careful examination of visceral pleura must be conducted during thoracoscopy [12]. Several classification systems have been proposed for mesothelioma [11], The most recent system is the TNM classification of the IMIG [12], This TNM classification is close to the one pro posed by Chahinian [69] and includes a full range of stages from an isolated lesion of the parietal pleura or diaphragm (stage la, as previously mentioned) to advanced-stage mes othelioma. The main advantage of this classification is to provide clinicians with a standard allowing comparison of study data and results. Although this TNM system still requires further refinement, it constitutes a solid founda tion. However, several remarks may be made concerning this system. One point of discussion is the importance of node status. In the series of Sugarbaker et al. [70] the long survival of patients without node involvement (NO) could have been due to the fact that these patients had ear lier stage disease. Since metastasis is an uncommon late occurrence, it is not an important criterion in the class ification. It must also be determined whether the TNM classification should be clinical.'made on the basis of en doscopic and radiological findings, or postoperative, made on the basis of surgical findings. It should also be said that the distinction between T2 and T3 is of little practical value since the difference in survival is minimal.'as shown in .a recent series [13]. Evolution As previously mentioned, the possible disappearance of the initial effusion after drainage is a special feature of early mesothelioma. Owing to this misleading develop ment the disease may be wrongly diagnosed as benign pleurisy and allowed to progress untreated' for up to 1 yr or more. Thus, caution is always necessary with regard to the diagnosis of benign pleurisy in subjects between the ages of $0 and 60 yts with a histojy. of^x^fi^^lisbgsli.1: - tos and?fbt these patieitts Mesothelioma develops locally, sometimes, for.a long time, before invading surrounding organs. Diaphragm and lung involvement usually occur first, with progressive re traction of the hemithorax and development of'trapped lung. Involvement of the liver occurs later. The periton eum is infiltrated either through the diaphragm or through , its-posterioro^rangs with s^ondary'ascites; ;Wtart6(>!- ' plastic syndrome is uncommon; this involves migrating phlebitis, thrombocytosis, haemolytic .anaemia, faypqgty- caemia, hypercalcaemia and pulmonary hypettrophic ristep-. arthropathy. " ... Spreading to the endothoracic fascia (T2) and intercos tal spaces (T3) is frequent and has been noted in 30-30% - of patients who have undergone invasive surgical of diag nostic procedures (e.g. thoracentesis and biopSy).^Parietal involvement can bc massive and painful and parietal pain is extremely frequent. '' Clinically detectable secondary-lesions in bone, subcm taneous and brain sites are uncommon, as is involvement of the contralateral pleura or lung. However, it should be noted that metastasis is more frequent after surgery, more often after pleuropneumonectomy than after p!eurectomy;fs| [71, 72]. According to the authors.-tills could reflect disease stage and prevalence of nodal stages..HoWeverV.iiffl can also be hypothesized that during :thd^bofomy:h^i-Al dling of tumour tissue releases isolated cells liitti blood and perhaps lymphatic circulationIChir palhdiogiSts fottfid a large number of isolated cells in the washing of theplett-.- ^ ral cavity after pleurectomy or pleuropneuiiidnectbmy! To reduce the risk of metastasis the, sfirgedn.miist^ca^^py wash the operative cavity after friSoitidin ' :4 static spread has' ben pbirerved' Death is usually due to'pro^ssive dysphoea iid tjeMra- tory insufficiency with extensive weight loss and wasting... Surgery Treatment _i it should be emphasized tMt'fe^(^h'RuiS:i)idl^;|^riip!ma - (in stage la) and cases the ffiaptfihgm,;peric5^u&^and:ipSjiik'`'^~'t'^ irralf rfrt/lai.tkaea, Worn [74] repd'f|^?'s6ri^p^^ survival was.the sam^after-liSpi^ Probst et al: '[75J7dK^ril^..^ which -medliah^iilStSd^l^iK monectbmy only 1.4 montte.-S|tKi pperatiy|'^I.__,,:(5,r^. rents must' be-Selected selection I mediastinal lymph' node'ihv6lveiri^E']HQwey&5 suh;Msr, es are uncommon and most resectioiisv.renr-*&=*--cis-j's. a-Mi-jcst. . 'sraligt^f moiiecidpy/wij study-jis'lieed^d'JOT"' Radiation therapy . Although jaMfadn-lhetjiij^. sollthftpelliifoirnnitai .#cve1l!l ..tfllirtierpsVv.{f777.71! -'if'-Ti'tao' mi ,, ^ r.- HWBUI0008929 MANAGEMENT OF MALIGNANT PLEURAL MESOTHELIOMA 977 mesothelioma patients and poor results have been des cribed.Ln seyeial series [78,79]. One of the major probleins irt perfottning radiation therapy is determining the >, VoUmje.Qif the target area, .which includes the diaphragm, ,chest wii] and excludes the lung. . therapy is also performed palUatively [80} to controK p^^.lfaitliation is effective when pain is due to a . dSract .ex^ij^ion qf the tumour, into the chest wall arid ribs. r.^oyei^jC it isriot effective and may even be harmful if "paira.prigiitiries from.compression of the intercostal nerve a$;.-a ijestijt of retritijtion of the. chest wall. Postradiation fibtos&cmi aggravate pain in these cases. Piriphylactlq local radiation therapy to prevent parietal cffagmgtic pxaipijialipns.has been shown to 81jlAffei, thoracoscopy we wait for 10- i^'d^^j^Mpw'the.po.int _pf entty to .heal and then apply i;6^`:iR',flSdB'se^i6iis''0?t:/'.iC3y' each over 48 h. Target fields of 4-^12 cm on each side are selected around the illusion; drainage and previous puncture scars. A random ized trial,of. this .technique was carried put .in 40 patients any V':^^^^|^^tp?Md>;ii5lR^rit.pfqjhy|actic:radiati0n Whereas sfedlbg was observed in eight of the 20 patients who did n^t undergo prophylactic radiation ther apy. Based on thesefindings we now perform prophylactic radiation therapy routinely after thoracoscopy and have not observed any seeding at entry or drainage sites. Chemotherapy Chemotherapy has also been disappointing in patients )Dvigi .mesothelioma. In the best series, objective responses aMoriingleragent treatment were achieved in 20-30% of casesyfiufthere was' no significant impact on overall sur vival. ' . . .Despite their good 'reputation, doxorubicin mid other aftffirskyriiiries achieve responses in no more than 15% of <^^;f$2];^imUmly,..ctsplatin alone achieves a response rate of only' 14% of cases'at standard dosage .and up to 33% at high dosage [83-87] , High doses of methotrexate albneobtain responses in 37% of rases [88]. . Several groups began using ciSpIatin-mitotnycin after a randomized study showing that it was more effective than doxombicm-cisplatin [89]. A response rate of 44% was repotted with' mUturiycitribleomycin-cysplatin-doxonibicin combined wifli systemic and intrapleural hyaluronidase [90]. A res inse rate of 66% was obtained using high-dose . tpeffit r^ate and foMc acid with vincristine oc.cisplatin fli; &inbitedlpn4toa)l involving platinum-nutomycin- S-flubtodfifcil and etoposide (PMFE) was tested and res ponses were obtained ini 33% of cases [92]. s,umtria^zes Ae complete and partial response 'ffe oroliried rising single-agent chemotherapy protocols studieS'lii which response rates of :^5.% orjnore were achieved using combined-agent proto- jcrils.lnifc overall results of chemotherapy alone have been 'disappointing since it has had no clear-cut effect on sur- .viwd. '-^trapleural treatment (immunotherapy) Y;:Intrapleura! immunotherapy is a new weapon in the ar-4enai against mesothelioma [93] .-The antitumoural-aetioh Wf.immunotherapy is complex and remains poorly under- Table 3. - Response rates (complete or partial) after single-agent chemotherapy Class Agent Response rate % Anthracyelines Antimetabolites Alkylants Alkaloids Doxorubicin Piranibicin Detombicin Epirubicin Mitoxantrone Methotrexate hd 5-Fluorouracil Edatrexate Trimetrexafe Cisplatin.. Cisplatin hd Carboplatin -Cyclophosphamide Ifosphamide Mitomycin Vincristine Vindesine - Etoposide. 0-40 ' 22 26 5-15 3 37 5 25 12 14 13-33 7-16 0 3-24 21 0 0-65 j 0-41 hd: high dose. stood. Two cytokines, interferon-gamma (IFN-y) and interleukin-2 (IL-2), have been tested in patients with malignant mesothelioma and have shown several objective antitumoural responses-[!5,94J. One property of interferon is its ability to facilitate cell differentiation [95], This mechanism could explain the efficacy of interferon on pleural mesothelial cell cultures [96]. Moreover, several studies have shown a possible dir ect cytotoxic effect on mesothelial cells [97-99] and stim ulation of the activity of natural killer lymphocytes and macrophages [100-102], .... The rationale for using IL-2 is based on the fact that it activates lymphokine-activated killer (LAR) cells and induces a cytolytic response [103]. In vitro studies have shown that human-natural killer (NK) cell activity, is sup pressed by asbestos fibres, but restored by IL-2 [104], and human, malignant mesothelioma cells lines were reported to be lysed by NK and LAK cells [105]. The intrapleural route of administration has several advantages. The pleural cavity acts as a reservoir where the injected drugs remain concentrated for several days or weeks [106]. This limits side-effects and ensures that the drug is applied to the tumour site. Table 4. -- Response rates 225% after combined che motherapy...................... Combined-agent protocol Doxonibicin-dacarbazine Doxocubicin-cisplatin Doxonibicin-cyclophosphamide-cisplatin Doxorubicin-cyclophosphamide-vincristine Doxorubicin-cydophosphamide-vincristine-dacarbazme Doxorabiciti-ifosphaoude Doxonibicin-vincristine-methotrexate Mitomycin-cisplatin CycIophosphamide-vmcristine-5-fluorouracil-raethotrexate Cisplatin-R-fluorouracil-mitomycin-etoposide Mitomycin-bleomycui-cisplatin-doxorubicm+hyaluronidase Methotrexate hd-vincristine Methotrexate hd-cisplatin Doxorubicin-vincristine-methotrexate 978 C. BOUTIN ET AL. Since 1987, more than 150 patients have been treated via the intrapleural route with either IL-2 [107J or IFN-y [15]. No data are available showing that one of these drugs is superior to the other and that the combination allows an increasing number ofobjective responses. INF-y was infused at a dose of 40x10s IU for 6 h twice a week for 8 weeks [15]. IL-2 was infused continuously for 5 days at a mean dose of 21x10s Ill-day1 for 5 days [107]. Infusion was performed through an implantable port to avoid multiple punctures and infection [108]. The predictive factors for a good outcome of intrapleu ral immunotherapy appear to be as follows. 1) Stage: the overall percentage of complete or partial responses'for the patients treated with IFN-y was 19.1%, but the response rate varied greatly depending on disease stage; 44;8% of patients with stage I disease and 6% of patients with stage II disease achieved responses. The mean duration of par tial responses was 19 months. For-22 patients treated with IL-2, one complete response and 11 partial responses (two with stage I and nine with stage U) were seen. The mediaittSE survival time of responders differed significantly from that of nonresponders: 2812.12 and 85.07 months, respectively (fxO.Oi). The 24- and 36-month surviyal rates of responders were 58% and 41%, respectively [109]. 2) Tutttour. size: the best results have been achieved in pat ients with nodiules <5 mm in diameter. 3) Epithelial histo logical type: immunotherapy failed quickly in two patients with fibrosarcomatous mesothelioma. 4) Absence of weight loss at the time of diagnosis. Gene therapy Recently, trials have been carried out in mesothelioma patients to evaluate gene therapy consisting of transfer of the thymidine kinase gene from herpes virus using adeno virus [110, 111]. It is too early to judge the outcome of these trials. Multimodal treatment - In view of the poor results obtained with thedifferent treatments used individually, Antman et al. [U2] prop osed a^ulrijnddd.appnjachat the beginftifigibf^fe.i98(fei.;: lit their series of 180 pafieitS' tf& tained by combining extrapleural pneumonectomy with chemotherapy and radiation therapy. Survival,was longer in patients with early-stage epithelial turnouts. The best results reported so far were by Sugarbaker et al. (14,72], who obtained a 5-yr survival rate of 45% in a group of patients with epithelial mesothelioma without mediastinal ' lymph node involvement. Rtractt and;VEHKATRXM/tir[i-3] also repotted excellent local control in six of 13 patients treated by pleuropneumonectomy followed by radiation therapy. However, it should be noted that in The-series of Rusch and Venicatraman [13] distant recurrences were observed in 11 patients, indicating that after surgery me sothelioma may become a generalized disease that re quires systemic treatment. Conclusions Early-stage disease appears to be the most important factor for the success of treatment. The only way to ach ieve early diagnosis in industrialized countries'and'geo graphically exposed areastisto bear in mindthc possibility of mesothelioma in any patient with pleural fluid who was exposed to asbestos 30 yrs earlier. This possibility should not be ruled out even if the patient does not present with fibrohyalin or calcified pleural plaques. After diagnostic procedures, prophylactic local radia tion therapy is always recommended to prevent spreading to the wall or secondary sites. In stage 1 and especially stage la, the disease is-still intrapleural and thus can be treated by neoadjuvaht-irftta- pleural treatment. Pilot studies are still underway.but pharmacological assays have consistently shovrii tmt^fii' trapleural concentrations arfe up to 1,000times-Wghferthfn serum concentrations. This enhancement of drug rrohdenV tration greatly increases the chance of.obtaining -a reSpi onse. Both IFN-y and IL-2 have shown pn nising; results in prospective phase I-H trials. The best re jdnse'Ts'-^n' 45* in epithelial type mesothelioma' with nodi s or thiCkgh-- ing not >5 mm, in patients whose general status is still good. However, such results must:be confirmed in com parative studies with surgery. ' `V The role of adjuvant-surgery performed after intrapleu ral treatment to improvelocal control (pleurecfomy brex- tended pleuiopneumonecfomy) or adjuvant cheiriotheirapy to prevent distaik-ifetastasis is 'stfll utft^wn'MdJfuiSher studies are'needed. In patients with stage H and in m^ffiefiiMiiffl:no.;.ran- domized study has shown over another; thus, the a mnltftnoda! approach includihgj^^.^'uigecy;;t^dMon therapy, and chemotherapy. The result.depfehcls ottjhejwc- pertise oftfte surgeons tality (range 4-8%); and talc pteuiodesis if necessary -[113], paflia^e r^Stibiiiher- apy and combined chemoferapy-. tsikiinglihtdi account that no regimen has shown a superiority: f v.,.-, , ,' In patients with stage IV disease qfly <aWsewatiye;'pal- liative treatment to control pain is indicated-.*' . - . Mesothelioma Is . difficult to detedt ai'in'early ,stage. Nevertheless, early detection is lhef key.,ito prolonged Re vival. All possible diagnosticto acjuqve-.this^nd. 1. -Eastwood pleuira,- "l. 3. Walker'AM;;Ltiughiiii DreyerNA,Prej^ofepf' <i:'. 'Peto'J, Hod|gdfrjJT,'^ 5. McDotiaM .^McDonald hint tnesothelioiha-'/ni Antman ibs-related Malignancy \.Orl 1987; pp. 31-^55. . ..... 6. Rucsft VW, Piaritadosi S, Hbln$3? pleural pneumonectomy m .ioma: A lung cancerstudy ."Surg -199l-;`.lp'2v-l-=9::r i- .- HWBUI0008931 * MANAGEMENT OF MALIGNANT PLEURAL MESOTHELIOMA 979 -v Brenner 1/Soriitto PP, MagilS GB, Golbey RB. 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