The extensive utilization of asbestos in the previous century in industrialized countries, the rapid surge of asbestos use in developing countries and the omnipresence of asbestos containing materials in most man-made environments continue to contribute to the constantly increasing epidemic of malignant pleural mesothelioma (MPM) (1-3). Chronic inflammation elicited by inhaled asbestos fibers is considered the principal etiologic factor for this almost universally lethal malignancy originating in the pleura. It is assumed that 20-60 years (median around 40 years) of chronic inflammation is needed before this disease manifests itself (4). The direct consequence of this long latency period is that MPM is most frequently diagnosed at an older age (5). MPM is usually confined to one hemithorax at the time of diagnosis, but the disease has a strong tendency to spread and involve the entire pleura and interlobular space. Infiltration into adjacent structures is characteristic of advanced MPM and despite attempts to completely resect the affected pleura, MPM will recur in most cases.
Notwithstanding the dismal overall prognosis of MPM, there is a subgroup of MPM patients in whom the disease shows a less aggressive course and prolonged survival. An early report revealing that radical surgical treatment for MPM may be followed by prolonged survival appeared in 1959 (6). A 43 year-old female, who underwent a right pleuropneumonectomy for what was finally diagnosed as MPM, survived for more than 6 years. Butchart and colleagues reported the first series of MPM patients who underwent pleuropneumonectomy, a procedure currently referred to as extrapleural pneumonectomy (EPP) (7). Observations from this series, consisting of 29 MPM patients who underwent radical surgical treatment (EPP) and 17 MPM patients who received non-surgical treatment, were sufficient to suggest a potentially curative role for EPP. These observations further led to the proposal of an algorithm for individualization of treatment of MPM on the basis of age, performance status, stage and histological subtype, as well as a staging system. Moreover, a number of contentious issues concerning surgery in MPM were discussed in this paper, including the impediments to achieving complete tumour clearance, the risk of seeding tumour in the chest wall and the high (hospital) mortality associated with EPP. The hospital mortality in Butchart’s series was around 30% and this high figure and the difficulties in achieving complete tumour clearance led to a fierce debate.
In an overview article published 13 years later Butchart lists a number of factors that complicate the interpretation of surgical reports on MPM, including a frequent lack of information about preoperative performance status, lack of staging information, selection bias, lack of precise histological subtyping, varied surgical techniques and the lack of information concerning use of (neo)-adjuvant therapy (8). It seems reasonable to add the expertise of the surgeon and his team to this list, as data from retro- and prospective studies reveal that certain institutions were able to limit the surgical morbidity and mortality of EPP (9). Mortality rates of 6% or less were documented in a number of reports in which EPP formed a part of multimodality treatment (10-16). Multivariate analyses suggested that EPP was associated with prolonged survival, especially when the radical surgery was part of a multimodality treatment program (17). While it could be argued that the studies mentioned above might have suffered from selection bias, it is worth noting that results obtained in one center were reproducible in another. During the last 10 years, the surgical oncological community has devoted considerable time to discussions concerning the role of radical surgery in the treatment of MPM, including, the use of uniform definitions of surgical techniques (18), comparisons between EPP and pleurectomy and decortication (P/D) (19), the lack of randomized controlled clinical trials (20,21) and the need to include quality of life measures in in surgical trials for MPM (22).
A study to test the feasibility of randomizing MPM patients between EPP and no EPP following induction chemotherapy was initiated in 2005 (23). Recruiting patients for this study was considered difficult and a feasibility study with the objective of randomizing 50 patients in one year to gauge the potential recruitment rate was organized. Patient accrual indeed turned out to be difficult and 2 years were needed to randomly assign 50 patients from 12 participating centers to the two study arms (23). The interpretation of the results of this multicenter feasibility study is complicated by the facts that the induction was not standardized and that protocol deviations occurred in a significant percentage of patients. The perioperative mortality in the EPP arm amounted to 18% and contributed to the poor overall survival in the EPP arm, which turned out to be inferior to the survival in the no-EPP arm. The authors concluded that radical surgery in the form of EPP within trimodality therapy might have harmed patients. It is obvious that the teams involved in this multicentre study were unable to equal the standards set by other single or multicenter teams (12,15,16,21), making it difficult to generalize their conclusion - that EPP is potentially harmful - to centres outside those participating in the UK study (24).
In recent years, several studies have pointed to a relationship between surgical volume/expertise and the outcomes of surgical treatment. This relationship is prominent in the surgical treatment of lung cancer (25) and it is tempting to use this relation as an explanation for the better outcomes of surgery and combined modality therapy for MPM in experienced (high-volume) centers. A recent retrospective single institution study describing 18 years of EPP practice confirmed that more experience (higher patient numbers) and better outcomes (perioperative morbidity and overall survival) were associated and provides support for this explanation (17). The assumption that experienced surgeons, in high volume centres, might be in a better position to adequately select patients for multimodality therapy (on the basis of prognostic factors and co-morbidity) may be used as an additional argument.
Prognostic factors and patient selection
The prognostic value of histologic subtype became apparent in one of the first MPM cohorts published and this finding has been consistently confirmed in later studies (26,27). As well tumor grade has been proposed as a prognostic factor for MPM and recent studies exploring calretinin and aquaporin 1 suggest that tumour differentiation is associated with survival (28-30). The importance of mediastinal lymph node involvement for the prognosis of MPM was recognized in the 1990s and has been used to propose a modification of the Butchart staging system (27). Shortly thereafter a new staging system was proposed by the International Mesothelioma Interest Group (IMIG) (31). A staging project (IMIG/IASLC) is underway to collect a (surgical) dataset of sufficient size to validate the TNM elements of this system. The progress in staging of MPM has been negatively influenced by the low incidence of the disease and also by the fact that the IMIG staging system is based on post-resection parameters. The debate about the value of staging in MPM is ongoing and some discrepancies have been noticed between the clinical and pathologic staging, emphasizing the importance of the ongoing project activities of IMIG and IASLC (32-34).
Mediastinoscopy has been advocated as a valuable staging procedure for patients eligible for radical treatment approaches. A thorough preoperative staging approach with bilateral thoracoscopy, mediastinoscopy and laparoscopy revealed that a significant proportion (26%) of MPM patients were ineligible for radical treatment (35,36).
Other factors with prognostic importance were identified by retrospective pooling of data from European Organization for Research and Treatment of Cancer (EORTC) studies in MPM patients and included poor performance status, high white blood cell count, an uncertain histologic diagnosis and male gender (37). A similar exercise carried out by the Cancer and Leukemia Group B (CALGB) revealed that elevated platelet counts, elevated serum LDH levels and the presence of chest pain were all associated with poor prognosis and further confirmed that younger age, good performance status and epithelial histology were associated with a more favorable prognosis (38). Scoring systems based on EORTC and CALGB data were independently validated and multivariate analyses showed that histologic subtype, hemoglobin level, leukocytosis and thrombocytosis remained independent prognostic factors.
The Neutrophil-to-Lymphocyte Ratio (NLR), a measure of systemic inflammation, was found to provide more accurate prognostic information than elevated leukocyte and thrombocyte counts and was able to separate MPM patients who underwent EPP or received standard chemotherapy into different prognostic categories (29). In one study, normalization of NLR in patients receiving chemotherapy was found to be clearly associated with prognosis (39). It is interesting to speculate whether NLR is purely host related as MPM cells produce significant amounts of myeloid cell stimulating factors. Numbers of tumor-infiltrating myeloid cells and monocytes have also been found to be associated with survival of MPM patients (40), pointing to an important host-tumour interaction. The NLR may be described as an ‘inflammatory performance status’ and, after recent independent validations, this simple and inexpensive test is well on its way to becoming a valuable tool to select MPM patients (41-43). In addition PET scanning has been recognized as a potential tool to separate MPM patients into categories of poor and more favorable prognosis. A study from Western Australia suggested that total glycolytic volume in non-sarcomatous mesothelioma provided more important prognostic information than the anatomic extent of the tumor (44). Considering the limited number of established prognostic factors for MPM the real challenge will be to prospectively validate the prognostic value of NLR and PET in MPM.
The way forward
Before discussing the future, it seems appropriate to repeat the carefully drafted conclusion in Van Schil’s paper on trimodality therapy for MPM:
Although a trimodality treatment consisting of induction chemotherapy followed by extrapleural resection and postoperative radiotherapy seems feasible in selected patients with early stage mesothelioma, the results of the present study do not warrant its use outside selected institutions with high level of expertise and, preferably, in prospective clinical trials exploring ways to improve its acceptance rate and overall success (21).
It is clear that multimodality therapy for MPM should be offered only to carefully selected patients and it might be prudent to add that individual modalities should be weighted for their efficacy and morbidity. For example the proposed use of P/D as an alternative to EPP must take into account that the efficacy of the induction regimen, in combination with a less radical surgical procedure, is critical and it seems justified that radical P/D only be considered after a significant response to chemotherapy. Assessing the response to chemotherapy is notoriously difficult and as this is considered an important element in judging a patient’s eligibility for EPP, it seems appropriate to include PET scans and serial measurements of soluble mesothelin in the pre-operative work-up (45).
Locoregional (intracavitary) administration of chemotherapy remains an attractive approach for MPM as higher doses of chemotherapy can be delivered with less systemic toxicity (46-48). While results of pilot studies that combined intracavitary chemotherapy with surgery in MPM were not encouraging (49), promising results obtained with this combination in peritoneal mesothelioma justify further research in MPM (50).
The place of radical surgery in MPM and especially the morbidity and mortality associated with EPP continue to be subjects of controversy (51-54). Before expressing an opinion for or against EPP, it is important to remember how multimodality therapy for MPM has developed (55) and to accept that the debate about EPP will not be solved by renewed efforts to get an answer from a randomized study. In a time in which the oncological community is confronted with increasing numbers of subgroups within malignant diseases it is now becoming a challenge to explore alternatives (surrogates) to randomization. One of the reasons for randomization is to balance host-related and tumour related prognostic factors. If it were possible to select a specific subgroup of patients using (a set of) excellent prognostic factors, and to reproduce treatment outcomes in independent groups of patients selected by the use of the same factors, might be in better position to compare treatment options.
A dominant factor in the multimodality therapy for MPM remains the expertise of the surgeon and his or her team. The collective literature on expertise and treatment outcome allows no other conclusion other than that it is reasonable to encourage referral of MPM patients to centres with expertise. Another step forward could be made by the prospective collection of data from patients undergoing radical multimodality treatment as is being done for patients with peritoneal mesothelioma (56). The IMIG/ IASLC staging project would greatly benefit from such an exercise and when combined with high-quality biobanking it would assist in collecting the materials necessary to sequence the MPM genome, a project of the TCGA/ICGC (cancergenome.nih.gov).
Disclosure: The authors declare no conflict of interest.
- Linton A, Vardy J, Clarke S, et al. The ticking timebomb of asbestos: Its insidious role in the development of malignant mesothelioma. Crit Rev Oncol Hematol 2012;84:200-12.
- Lin RT, Takahashi K, Karjalainen A, et al. Ecological association between asbestos-related diseases and historical asbestos consumption: an international analysis. Lancet 2007;369:844-9.
- Olsen NJ, Franklin PJ, Reid A, et al. Increasing incidence of malignant mesothelioma after exposure to asbestos during home maintenance and renovation. Med J Aust 2011;195:271-4.
- Kamp DW. Asbestos-induced lung diseases: an update. Transl Res 2009;153:143-52.
- Delgermaa V, Takahashi K, Park EK, et al. Global mesothelioma deaths reported to the World Health Organization between 1994 and 2008. Bull World Health Organ 2011;89:716-24, 724A-724C.
- Harris MS, Maurice MH, Nevius DS. A resectable form of multiple mesothelioma. Dis Chest 1959;35:127-33.
- Butchart EG, Ashcroft T, Barnsley WC, et al. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax 1976;31:15-24.
- Butchart EG. Contemporary management of malignant pleural mesothelioma. Oncologist 1999;4:488-500.
- Sugarbaker DJ, Jaklitsch MT, Bueno R, et al. Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 2004;128:138-46.
- Weder W, Kestenholz P, Taverna C, et al. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 2004;22:3451-7.
- Flores RM, Krug LM, Rosenzweig KE, et al. Induction chemotherapy, extrapleural pneumonectomy, and postoperative high-dose radiotherapy for locally advanced malignant pleural mesothelioma: a phase II trial. J Thorac Oncol 2006;1:289-95.
- Weder W, Stahel RA, Bernhard J, et al. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18:1196-202.
- Rea F, Marulli G, Bortolotti L, et al. Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic radiation in malignant pleural mesothelioma (MPM): Feasibility and results. Lung Cancer 2007;57:89-95.
- Opitz I, Kestenholz P, Lardinois D, et al. Incidence and management of complications after neoadjuvant chemotherapy followed by extrapleural pneumonectomy for malignant pleural mesothelioma. Eur J Cardiothorac Surg 2006;29:579-84.
- de Perrot M, Feld R, Cho BC, et al. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27:1413-8.
- Krug LM, Pass HI, Rusch VW, et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27:3007-13.
- Yan TD, Cao CQ, Boyer M, et al. Improving survival results after surgical management of malignant pleural mesothelioma: an Australian institution experience. Ann Thorac Cardiovasc Surg 2011;17:243-9.
- Rice D, Rusch V, Pass H, et al. Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group. J Thorac Oncol 2011;6:1304-12.
- Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135:620-6,626.
- Treasure T, Sedrakyan A. Pleural mesothelioma: little evidence, still time to do trials. Lancet 2004;364:1183-5.
- Van Schil PE, Baas P, Gaafar R, et al. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J 2010;36:1362-9.
- Maziak DE, Gagliardi A, Haynes AE, et al. Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary. Lung Cancer 2005;48:157-69.
- Treasure T, Lang-Lazdunski L, Waller D, et al. Extrapleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 2011;12:763-72.
- Weder W, Stahel RA, Baas P, et al. The MARS feasibility trial: conclusions not supported by data. Lancet Oncol 2011;12:1093-4; author reply 1094-5.
- von Meyenfeldt EM, Gooiker GA, van Gijn W, et al. The relationship between volume or surgeon specialty and outcome in the surgical treatment of lung cancer: a systematic review and meta-analysis. J Thorac Oncol 2012;7:1170-8.
- Antman KH. Asbestos-related malignancy. Crit Rev Oncol Hematol 1986;6:287-309.
- Sugarbaker DJ, Strauss GM, Lynch TJ, et al. Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 1993;11:1172-8.
- Milano MT, Zhang H. Malignant pleural mesothelioma: a population-based study of survival. J Thorac Oncol 2010;5:1841-8.
- Kao SC, Klebe S, Henderson DW, et al. Low calretinin expression and high neutrophil-to-lymphocyte ratio are poor prognostic factors in patients with malignant mesothelioma undergoing extrapleural pneumonectomy. J Thorac Oncol 2011;6:1923-9.
- Kao SC, Armstrong N, Condon B, et al. Aquaporin 1 is an independent prognostic factor in pleural malignant mesothelioma. Cancer 2012;118:2952-61.
- Rusch VW. A proposed new international TNM staging system for malignant pleural mesothelioma from the International Mesothelioma Interest Group. Lung Cancer 1996;14:1-12.
- Patz EF Jr, Rusch VW, Heelan R. The proposed new international TNM staging system for malignant pleural mesothelioma: application to imaging. AJR Am J Roentgenol 1996;166:323-7.
- Rusch VW, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1996;111:815- 25; discussion 825-6.
- Nakas A, Black E, Entwisle J, et al. Surgical assessment of malignant pleural mesothelioma: have we reached a critical stage? Eur J Cardiothorac Surg 2010;37:1457-63.
- Schouwink JH, Kool LS, Rutgers EJ, et al. The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thorac Surg 2003;75:1715-8; discussion 1718-9.
- Alvarez JM, Hasani A, Segal A, et al. Bilateral thoracoscopy, mediastinoscopy and laparoscopy, in addition to CT, MRI and PET imaging, are essential to correctly stage and treat patients with mesothelioma prior to trimodality therapy. ANZ J Surg 2009;79:734-8.
- Curran D, Sahmoud T, Therasse P, et al. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 1998;16:145-52.
- Herndon JE, Green MR, Chahinian AP, et al. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest 1998;113:723-31.
- Kao SC, Pavlakis N, Harvie R, et al. High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res 2010;16:5805-13.
- Burt BM, Rodig SJ, Tilleman TR, et al. Circulating and tumor-infiltrating myeloid cells predict survival in human pleural mesothelioma. Cancer 2011;117:5234-44.
- Kao SC, Vardy J, Chatfield M, et al. Validation of prognostic factors in malignant pleural mesothelioma: a retrospective analysis of data from patients seeking compensation from the New South Wales Dust Diseases Board. Clin Lung Cancer 2012. [Epub ahead of print].
- Cedrés S, Montero MA, Martinez P, et al. Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM). Lung Cancer 2012;77:192-8.
- Pinato DJ, Mauri FA, Ramakrishnan R, et al. Inflammation-based prognostic indices in malignant pleural mesothelioma. J Thorac Oncol 2012;7:587-94.
- Nowak AK, Francis RJ, Phillips MJ, et al. A novel prognostic model for malignant mesothelioma incorporating quantitative FDG-PET imaging with clinical parameters. Clin Cancer Res 2010;16:2409-17.
- Hollevoet K, Nackaerts K, Gosselin R, et al. Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in mesothelioma. J Thorac Oncol 2011;6:1930-7.
- Rusch V, Saltz L, Venkatraman E, et al. A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol 1994;12:1156-63.
- van Ruth S, Baas P, Haas RL, et al. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann Surg Oncol 2003;10:176-82.
- van Ruth S, van Tellingen O, Korse CM, et al. Pharmacokinetics of doxorubicin and cisplatin used in intraoperative hyperthermic intrathoracic chemotherapy after cytoreductive surgery for malignant pleural mesothelioma and pleural thymoma. Anticancer Drugs 2003;14:57-65.
- van Sandick JW, Kappers I, Baas P, et al. Surgical treatment in the management of malignant pleural mesothelioma: a single institution’s experience. Ann Surg Oncol 2008;15:1757-64.
- Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol 2009;27:6237-42.
- Flores RM. Surgical options in malignant pleural mesothelioma: extrapleural pneumonectomy or pleurectomy/decortication. Semin Thorac Cardiovasc Surg 2009;21:149-53.
- Sharif S, Zahid I, Routledge T, et al. Extrapleural pneumonectomy or supportive care: treatment of malignant pleural mesothelioma? Interact Cardiovasc Thorac Surg 2011;12:1040-5.
- Rena O, Casadio C. Extrapleural pneumonectomy for early stage malignant pleural mesothelioma: a harmful procedure. Lung Cancer 2012;77:151-5.
- Baas P. Primum non nocere? Does this also apply to mesothelioma? Lung Cancer 2012;77:1.
- Zauderer MG, Krug LM. The evolution of multimodality therapy for malignant pleural mesothelioma. Curr Treat Options Oncol 2011;12:163-72.
- Cao C, Yan TD, Morris DL, et al. Prospective Registry On Mesothelioma Peritonei Treatment (PROMPT): study design and rationale. Tumori 2012;98:166-71.