Biological and Clinical Aspects of Malignant Pleural Mesothelioma: Past, Present and Future Treatment Strategies

Flavio Colaut, Luisa Delsedime, Alberto Oliaro

Flavio Colaut, Thoracic Surgery, City Hospital, Montebelluna, Italy
Luisa Delsedime, Department of Pathology, University of Turin, Italy
Alberto Oliaro, Chief of Thoracic Surgery, University of Turin, Italy

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Correspondence to: Flavio Colaut, Thoracic Surgery, City Hospital, Montebelluna (Treviso), Italy.
Email: flavio.colaut@outlook.it
Telephone: +390499367643
Fax: +393496039619

Received: July 23, 2016
Revised: September 15, 2016
Accepted: September 18, 2016
Published online: December 28, 2016


Pleural mesothelioma is still increasing and its prognosis remains dismal. Trimodality theraphy (surgery, chemo and radiotheraphy) is the treatment that seems work better, even if there is no evidence if extrapleural pneumonectomy is more curative than pleurectomy/decortication so far. Chemotherapy will probably play a fundamental role in the next future and further randomized studies are necessary, but patients should see the benefits of participating in randomized and controlled trials.

Key words: Mesothelioma; Surgery; Chemotherapy

© 2016 The Author(s). Published by ACT Publishing Group Ltd. This is an open access article under the CC BY-NC-ND license (http: //creativecommons.org/licenses/by-nc-nd/4.

Colaut F, Delsedime L, Oliaro A. Biological and Clinical Aspects of Malignant Pleural Mesothelioma: Past, Present and Future Treatment Strategies. Journal of Respiratory Research 2016; 2(4): 85-91 Available from: URL: http: //www.ghrnet.org/index.php/jrr/article/view/1798


At present, we are witnessing an ever-increasing number of cases of malignant pleural mesothelioma (MPM), with poor prognoses. Asbestos is the principal carcinogen associated with MPM. Malignant mesotheliomas initially occur on the parietal pleural surface of the pleural mesothelium, and one possibility is that the asbestos fibers stick out from the surface of the lung and cause repeated cycles of scratching damage, inflammation and repair in the adjacent parietal pleura. Mesothelial cells normally facilitate the free movement of the pleural surfaces during respiration by enmeshing lubricating glycoproteins. These cells readily proliferate in response to injury and growth factors. Sequences of Simian Virus 40, a DNA virus, have been found in atypical mesothelial proliferations and there is some evidence that SV 40 may have been inadvertently transmitted to humans via injectable poliomyelitis vaccines 35 to 50 years ago. It's role remains unclear and unproven so far. In the initial phase of MPM, its symptoms generally go unnoticed, but as its dimensions increase, its symptomatology is typically that of a mass progressively occupying more and more space within the pleural cavity. In some cases the clinical presentation may worsen to the point of developing Tobias syndrome – a condition characterized by scoliosis and a retraction of the accordant hemithorax; or, alternatively, Pancoast syndrome, with an involvement of the brachial plexus and cervical sympathetic nerves. A pleural effusion occurs at the outset of nearly all cases (Figures 1, 2), while in a small percentage of cases (1%) the disease manifests itself with a spontaneous pneumothorax (Figure 3).

No matter how carefully selected the patients or how succesfully they’ve undergone multimodal treatment (surgery, chemo and radiation therapy), controlling the disease remains a problem to be solved. Even when patients undergo a pleurectomy/decortication (P/D) or an extrapleural pneumonectomy (EPP), a progression of the disease remains inevitable.

The most significant histological subtypes are epithelioid (Figure 4), biphasic (Figure 5), sarcomatoid (Figure 6) and desmoplastic (Figure 7).

Figure 1 Rx T: MPM pleural effusion (left).

Figure 2 Rx T: pleural mass (right) of MPM with effusion.

Figure 3 Rx T: MPM pneumothorax (left), 0.1% of cases.

Figure 4 Hematoxylin – Eosin: Epithelioid Mesothelioma (by courtesy of Dr L. Delsedime Pathology, Univeristy of Turin, Italy).

Figure 5 Hematoxylin - Eosin: Biphasic Mesothelioma (by courtesy of Dr L. Delsedime Pathology, University of Turin, Italy).

Figure 6 Hematoxylin – Eosin: Sarcomatoid Mesothelioma (by courtesy of Dr L. Delsedime Pathology, University of Turin, Italy).

Figure 7 Hematoxylin-Eosin: Desmoid Mesothelioma, Calretinin right low (by courtesy of Dr L. Delsedime, Pathology, University of Turin, Italy).


Mesothelioma surgery has evolved in order to obtain an ever-increasing oncological radicality, as, from the beginning, the surgical debulking of the disease has proven to be extremely difficult. For this reason, from the point of view of a resective strategy, two surgical methods have developped: the pleurectomy/decortication (Figures 8, 9), conceptually derived from pleural empyema surgery; and the pleuropneumonectomy or so-called extrapleural pneumonectomy (Figures 10, 11), to which there are various associated protocols of CT and RT. Surgeons in favor of EPP believe it makes possible a complete macroscopic removal of the disease with acceptable risk of morbidity and mortality and facilitates the administration of postoperative RT at high doses with excellent local control.

Figure 8 Pleurectomy/Decortication.

Figure 9 Pleurectomy/Decortication.

Figure 10 Pleuropneumonectomy.

Figure 11 Pleuropneumonectomy.

From Journal of Thoracic Oncology, volume 6, Number 5, May 2011.

Supporters of P/D believe that it provides adequate cytoreduction, particularly in patients at early stages of MPM (I and II), without the risk of morbidity and mortality that characterize EPP. They also believe that P/D plays an important role in the multimodal treatment when combined with intrapleural and/or systemic CT and intensity modulated radiation therapy (IMRT). Because the surgery, utilized singularly, whether P/D or EPP, has given disappointing results, in the same ways as CT and RT, the multimodal treatment strategy was developped. The innovation of multimodal treatment as a cure for MPM has been to adopt a combination of surgical resection and adjuvant therapy (chemo, radiation or both), as such a strategy represents a better therapeutic option for patients, even if only for a select group[1,2]. There are two fundamental studies regarding multimodal treatment of MPM, one combining surgery with RT, the other with adjuvant CT.

Memorial Sloan Kettering Cancer Center has conducted a prospective study in which patients have undergone EPP (n = 54) followed by RT at high doses (54 Gy) at the ipsilateral hemithorax. The adjuvant RT has been studied to improve local control after EPP, particularly for high doses of radiation which can be applied without risk of pneumonia. This therapeutic strategy has resulted in a dramatic reduction in local recurrence prolonging survival in patients at advanced stages of the disease. The median survival has been 33.8 months for stages I and II, and 10 months for stages III and IV.

The intervention of EPP followed by adjuvant CT has been studied at Brigham and Women’s Hospital in 183 patients with MPM. The perioperative mortality equaled 3.8%. Among the remaining 176 patients, 38% survived 2 years, 15% survived 5 years, and the median survival was 19 months.

Infact, at the moment the most appropriate treatment for MPM is considered to be the trimodality protocol, which consists of surgery following chemotherapy and radiation therapy. Regarding this it must be noted that in a study by Sugarbaker published in 1999, it was made clear that patients with MPM who had undergone EPP followed by CT and RT could survive for a longer period. In particular, among the stage I subgroup with the epithelial histotype, negative margins of resection and lack of lymph node involvement registered a survival rate of 68% for 2 years, and 46% for 5 years[3,4].

However, the decision to select between an EPP or P/D is still mostly based on the preference of the surgeon rather than conclusive scientific evidence, since there is not enough significant statistical data for either regarding survival rates[5-8].

In fact, to justify the choice of surgical procedure, some studies focus on the importance of two “end points”, which are the rate of progression and the type of relapse. However, these “end points” have not always proven to be very accurate parameters for carrying out follow ups, because definitions regarding the “progression of diseases” aren’t always clear, and relapses haven’t always been studied in homogenous ways. Therefore, estimations of how the disease will progress tend to differ considerably from estimations related to 5-year survival.

Rush and Pass (2008) showed that patients with MPM at stages I and II presented a survival of 19 months when having undergone an EPP and of 23 months with a P/D: the study in question, like other analogous studies, emphasized the similitudes of the outcome after an EPP or P/D for MPM in a multicentre trial, and doesn’t allow for a clear understanding of which of the two procedures are preferable, as the typically diffuse spread of MPM throughout the chest renders debulking particularly difficult in either cases.

More recently the general concept of trimodality therapy for mesothelioma has generated the idea of neoadjuvant CT as a strategy for treatment. This new concept of neoadjuvant CT in MPM has been extrapolated by results obtained in patients with stage IIIA NSCLC. In fact, the use of neoadjuvant CT in stage IIIA NSCLC has made major pulmonary resections possible with acceptable risk of morbidity and mortality[9].

This strategy has been evaluated in at least 6 studies:

1. In 2002, the French group for thoracic pathology reported a median survival of 23 months for patients with MPM treated with neoadjuvant CT with cisplatin and gemcitabine, EPP and postoperative RT. These results were much superior to the group of patients with MPM treated with EPP followed by adjuvant CT and RT, where the median survival was only 13 months[10].

2. In 2003, De Perrot, Ginsberg and Payne presented a study in which it was reported a median survival of 74% during a year with an operative mortality of 6% for MPM patients treated with neoadjuvant CT followed by surgery (EPP) and postoperative RT[11].

3. In 2009, De Perrot, Feld, et al reported the experience of a single center with neoadjuvant CT followed by EPP and postoperative RT at high doses: the median survival for patients was 59 months using trimodality therapy, completed without mediastinal lymph node involvement. It has once again been confirmed how the N2 disease remains an important negative prognostic factor for survival[12].

4. In 2007, Lucchi, Chella, et al presented a phase II study of a single centre centered on the following treatment: preoperative intracavitary IL-2, P/D, epidoxorubicin + post-operative intracavitary IL-2, adjuvant radiation therapy, cisplatin+gemcitabine for systemic therapy and s.c. longterm IL-2.

The median survival was 26 months (31 and 21 months for stages II and III respectively)[13].

5. In 2009, Krug, Pass and Rush reported their experience with pemetrexed + cisplatin + EPP + adjuvant RT on 77 patients affected by MPM. The survival median was 29.1 months, and at 2 years they recorded a survival rate equaling 61.2%. The univariate analysis for subgroups of patients showed that the radiological response, and no other factor, was associated to an increase in survival. It was therefore once again confirmed what previous studies had already shown, which is that even when treatment is homogenous, only a subgroup of patients benefit with a long survival[14].

6. From October 2005 to November 2008 in the MARS study 112 patients with MPM were registered. Out of them 50 were randomly assigned to EPP (24 pts) or to no EPP (26 pts). 83 out of 112 pts received CT before intervention. The findings were that there is no significative difference between the survival of the EPP group (median survival of 14.4 months) and the no EPP group (median survival of 19.5 months) and that there is no benefit to EPP within trimodality therapy over chemotherapy alone for survival or quality of life[15].

However it is a well-established fact that in the treatment of MPM the most encouraging results have been obtained with the improvement of CT protocols, more than with surgery. In fact, EPP or P/D have only proved to be useful in the macroscopic removal of the disease. In regard to chemotherapy in MPM, only since 2000 have new molecules been used that are capable of working efficaciously with this disease. The results of a large, randomized trial presented in 2002 at the meeting of the American Society of Clinical Oncology and later published (Vogelzang, Rusthoven) brought into consideration the idea of combining pemetrexed (folate antimetabolites) + cisplatin, whereas initially that of gemcitabine + cisplatin was considered to be the most effective combination for MPM. In fact, the response in MPM to cisplatin and gemcitabine had been estimated between 16 and 47 %[16-18]. However, based on the most recent findings[19,20], pemetrexed + cisplatin have since become the standard regimen for the first-line treatment of MPM. In fact, using this protocol, large clinical studies of phase III have shown a response rate of 41%, a median survival of 12.1 months and a rate of progression of 5.7 months. Regarding the cardiopulmonary function, the spread of the disease, and the possibility of macroscopically performing a radical resection, the fundamental importance of an accurate selection of patients has also been reconfirmed[21]. To improve patient selection and to individuate high-response patients to chemotherapy, studies into gene expression profiling have also been undertaken[22], tough their findings are not yet conclusive.

The crucial point in MPM treatment, however, seems to be in the selection of patients, so much so that it can delineate the idea of a prognostic score of long-term survival for MPM patients who’ve undergone surgery. In fact, out of a recent multicenter analysis[23] there emerged proof that a young age, a lack of exposure to asbestos, an epithelioid histology, and a low number of metastatic lymph nodes from all removed lymph nodes are all factors associated to better survival after EPP. Moreover multivariate analysis showed that nuclear atypia and mitotic count were independent prognostic factors so that it has been reported that nuclear grading is a strong predictor of survival in epithelioid diffuse malignant pleural mesothelioma[24].

Knowledge about the biology of MPM, however, is not yet conclusive, and the estimation that a spike in illnesses will occur after 2015[25,26], will favor a concentration of new cases of MPM at highly specialized centers. Only then can large case studies be evaluated and advancements in the necessary randomized studies be made.

Patient with MPM need to receive all the necessary information about their disease, so that they can decide which treatment on a clinical-evidence basis, and hopefully see the benefits of participating in randomized and controlled trials[27,28].


Special thanks for translation in English to Prof. Tobin James Stewart (tobin.stewart@gmail.com) and Greta Riondato (greta.riondato@gmail.com).


1 Maggi G, Casadio C, Cianci R, Rena O, Ruffini E. Trimodality management of malignant pleural mesothelioma. Eur J Cardiothorac Surg 2001; 19: 346-506

2 Rusch VW, Rosenzweig K, Venkatraman E, Leon L, Raben A, Harrison L, Manjit SB, Downey RJ, Ginsberg RJ. A phase II trial of surgical resection and adjuvant high – dose radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001; 122: 788-795

3 Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, De Camp MM Jr, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ. Resection margins, extrapleural nodal status and cell type determine post-operative long – term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999; 117: 54-63

4 Rena O, Oliaro A. Mesotelioma pleurico maligno. Minerva Chir 2001; 56: 611-41

5 Allen KB, Faber LP, Warren WH. Malignant pleural mesothelioma. Extrapleural pneumonectomy and pleurectomy. Chest Surg Clin N Am. 1994; 4: 113

6 Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomyin malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 1991; 102: 1-9

7 Stewart DJ, Martini – Ucar A, Pilling JE, Edwards JG, O' Byrne KJ, Waller DA. The effect of extent of local resection on patterns of disease progression in malignant pleural mesothelioma. Ann Thorac Surg 2004; 78: 245-52

8 Batirel HF, Metintas M, Caglar HB, Ak G, Yumuk PF, Yildizeli B, Yuksel M. Adoption of pleurectomy and decortication for malignant mesothelioma leadsto similar survival as extrapleural pneumonectomy. J Thorac Cardiovasc Surg. 2016 Feb; 151(2): 478-84

9 French Thoracic Cooperative Group. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non -small-cell lung cancer. J Clin Oncol 2002; 20: 247-53

10 Walter Weder, Peter Kestenholtz, Christian Taverna, Stefan Bodis, Didier Lardinois, Monika Jerman, and Rolf A. Stahel. J Clin Oncol 2004; 22: 3451-3457

11 De Perrot M, Ginsberg R, Payne D. A phase II trial of induction chemotherapy followed by extrapleural pneumonectomy and high - dose hemiothoracic radiation for malignant pleural mesothelioma. Lung Cancer 2003; 41: S59 (abstract)

12 Marc De Perrot, Ronald Feld, B.C. John Cho, Andrea Bezjak, Masaji Anraku, Ronald Burkes, Heidi Roberts, Ming S. Tsao, Natasha Leighl, Shaf Keshavjee, and Michael R. Johnson. Trimodality Theraphy With Induction Chemotherapy Followed by Extrapleural Pneumonectomy and Adiuvant High – Dose Hemitoracic Radiation for Malignant Pleural Mesothelioma. J Clin Oncol 2009; 27: 1413-1418

13 Marco Lucchi, Antonio Chella, Franca Melfi, Paolo Dini, Marcello Ambrogi. Leonardo Fino, Gabriella Fontanini, Alfredo Mussi. A phase II study of intrapleural immuno – chemotherapy, pleurectomy/decortication, radiotherapy, systemic chemotherapy and long term sub – cutaneous IL – 2 in stage II – III pleural mesothelioma. Eur J Cardiothorac S 2007; 31: 529-535

14 Lee M. Krug, Harvey I. Pass, Valerie W. Rusch, Hedy L. Kindler, David J. Sugarbaker, Kenneth E. Rosenzweig, Raja Flores, Joseph S. Friedberg, katherine Pisters, Matthew Monberg, Coleman K. Obasaju, and Nicholas J. Vogelzang. Multicenter Phase II Trial of Neoadiuvant Pemetrexed Plus Cisplatin Followed by Extrapleural Pneumonectomy and Radiation for Malignat Pleural Mesothelioma. J Clin Oncol 2009; 27(18): 3007-3013

15 Tom Treasure, Loic Lang-Ladzunski, David Waller, Judit M. Bliss, Carol Tan, James Entwistle, Michael Snee, Mary O'Brien, Gill Thomas, Suresh Senan, Ken O'Byrne, Lucky S. Kilburn, James Spicer, David Landau, John Edwards, Gill Coombes, Liz Darlison, Julian Peto. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibibility study. Lancet Oncol 2011 Aug. 12(8): 763-772

16 Byrne MJ, Davidson JA, Musk AW, Dewar J, van Hazel G, Buck M, de Klerk NH, Robinson BW. Cisplatin and Gemcitabine treatment for malignant mesothelioma: a phase II study. J Clin Oncol 1999; 17(81): 25-30

17 Nowak AK, Byrne MJ, Williamson R, Ryan G, Segal A, Fielding D, Mitchell P, Musk AW, Robinson BW. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma. Br J Cancer 2002; 87(5): 491-496

18 Van Haarst JM, Baas P, Manegold C, Schouwink JH,Burgers JA, de Bruin HG, Mooi WJ, van Klaveren RJ, de Jonge MJ, van Meerbeeck JP. Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma. Br J Cancer 2002: 86(3): 342-345

19 Vogelzang NJ, Rusthoven JJ, Symanowsky J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niykiza C, Paoletti P. Phase III study study of pemetrexed in combination with cisplatin versus cisplatin alonein patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636-2644

20 Ellis P, Davies AM, Evans WK, Haynes AE, Loyd NS and the Lung Cancer Disease Site Group of Cancer Care Ontario's program in Evidence – based care. The Use of Chemotherapy in Patients with Advanced Malignant Pleural Mesothelioma; A Systematic Review and Practice Guideline. J Thorac Oncol 2006; 1(6): 591-1601

21 Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignat pleural mesothelioma: Results in 663 patients. J Thorac Cardiovasc Surg. 2008; 135(3): 620 - 626

22 Sugarbaker DJ, Richards WG, Gordon GJ, Dong LS, Rienzo AD, Maulik G, Glickman JN, Chirieac L, Hartman ML, Taillon BE, Du L, Bouffard P, Kingsmore SF, Miller NA, Farmer AD, Jensen R, Gullans SR, Bueno R. Transcriptome sequencing of malignant pleural mesothelioma tumors. Proc Nati Acad Sci USA 2008; 105: 3521-3526

23 Leuzzi G, Rea F, Spaggiari L, Marulli G, Sperduti I, Alessandrini G, Casiraghi M, Bovolato P, Pariscenti G, Alloisio M, Infante M, Pagan V, Fontana P, Oliaro A, Ruffini E, Ratto GB, Leoncini G, Sacco R, Mucilli F and Facciolo F. Prognostic Score of Long – Term Survival After Surgery for Malignant Pleural mesothelioma: A Multicenter Analysis. Ann Thorac Surg 2015; 100: 890-7

24 Kadota K, Suzuki K, Colovos C, Sima CS, Rusch VW, Travis WD, Adusumilli PS. A nuclear grading system is a strong predictor of survival in epithelioid diffuse malignant pleural mesothelioma. Modern Pathology 2012; 25: 260-271

25 Walzer AM, Loughlin JE, Friedlander ER, Rothman KJ, Dreyer NA. Projections of asbestos-related disease 1980-2009. J Occup Med 1983; 25: 409-25

26 Peto J, Hodgson JT, Matthews FE, Jones JR. Continuing increase in mesothelioma mortality in Britain. Lancet 1995; 343: 535 - 539

27 Tom Treasure. What is the best approach for surgery of malignant pleural mesothelioma? It is to put our efforts into obtaining trustworthy evidence for practice. J Thorac Cardiovasc Surg 2016; 151: 307-309

28 H M Evans. Should patients be allowed to veto their participation in clinical research? J Med Ethics 2004; 30: 198-203

Peer reviewer: Mariano García-Yuste


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