Therapeutic Surgery for Nonepithelioid Malignant Pleural Mesothelioma: Is it Really Worthwhile?

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1 Therapeutic Surgery for Nonepithelioid Malignant Pleural Mesothelioma: Is it Really Worthwhile? Bram Balduyck, MD, Delphine Trousse, MD, Apostolos Nakas, MD, Antonio E. Martin-Ucar, MD, John Edwards, MD, PhD, and David A. Waller, MD Department of Thoracic Surgery, Glenfield Hospital, Leicester, United Kingdom Background. Debate remains about the relative prognostic importance of the histologic subtype of malignant pleural mesothelioma. Methods. From a prospective database, the details of 312 malignant pleural mesothelioma surgical patients were reviewed. A comparison was made of the survival from the three major cell types. Results. One hundred ninety-five patients underwent radical surgery, and 117 underwent nonradical surgery. Final histologic subtype was epithelioid in 218 patients, biphasic in 66 patients, and sarcomatoid in 28 patients. The median survival was 15.3 months in the epithelioid group, 10.1 months in the biphasic group, and 5.0 months in the sarcomatoid group. On univariate analysis in the epithelioid group, age (p 0.005), International Mesothelioma Interest Group stage (p 0.001), radicality of the procedure (p 0.001), leukocytosis (p 0.016), and preoperative or postoperative chemotherapy (p 0.012) were significant prognostic factors influencing postoperative survival. In the biphasic group, preoperative anemia was the only significant factor (p 0.007). In sarcomatoid patients, International Mesothelioma Interest Group stage and radicality of the surgical procedure were significant prognostic variables (p and p 0.015, respectively). Multivariate analysis in the epithelioid group identified International Mesothelioma Interest Group stage (p 0.001), radicality of the procedure (p 0.008), and preoperative or postoperative chemotherapy (p 0.007) as significant prognostic factors, whereas in the sarcomatoid group, only the International Mesothelioma Interest Group stage (p 0.012) was significant and the radicality of surgery had no effect. Conclusions. The extremely poor prognosis of sarcomatoid malignant pleural mesothelioma is independent of the extent of surgery unlike other cell types. Patients with sarcomatoid histology should therefore be considered separately in trials evaluating radical procedures and adjuvant treatment. The treatment of biphasic pleural mesothelioma remains debatable. (Ann Thorac Surg 2010;89:907 11) 2010 by The Society of Thoracic Surgeons Malignant pleural mesothelioma (MPM), although relatively rare, is increasing in incidence in Western Europe [1]. Debate remains about the relative prognostic importance of the histologic subtype of MPM. In a palliative setting alone, patients with epithelioid MPM tumors fare much better than those with a biphasic or sarcomatoid cell type [2]. Publications concerning surgery for nonepithelioid MPM are rare, but some authors have reported median survival between 4.5 and 11.1 months [3 5]. At present there is no consensus concerning the management of nonepithelioid MPM because some argue that early stage is more important than histologic subtype. The objective of the present study was to analyze our surgical experience in nonepithelioid MPM compared with epithelioid MPM to formulate a coherent, evidence-based strategy. Material and Methods Accepted for publication Dec 17, Address correspondence to Dr Waller, Department of Thoracic Surgery, Glenfield Hospital, Groby Rd, LE3 9QP Leicester, United Kingdom; david.waller@uhl-tr.nhs.uk. From a prospective database, the details of 329 consecutive MPM patients who underwent surgery in a single institution in an 11-year period (January 1998 to December 2008) were reviewed. A comparison was made of the survival from the three major cell types of mesothelioma: epithelioid, biphasic, and sarcomatoid. To analyze the effect of histology on long-term survival, patients who died within 30 days of surgery were excluded from the analysis. The assumption was made that mortality in the first 30 days after surgery is procedure-related rather than histology-related. In the prospective database, 17 patients of 329 (5.2%) had a 30-day mortality. There were no statistical significant differences in patient characteristics and histologic subtype between the 17 patients who died in the first 30 days after surgery and the study population of 312 patients. Histologic subtype in the 30-day mortality group was epithelioid in 10 patients, biphasic in 6 patients, and sarcomatoid in 1 patient. The causes of 30-day mortality were all surgery-related: bleeding (n 2), pulmonary embolus (n 2), chest infection (n 3), cardiac failure n 7), bronchial pleural fistula (n 10), patch disruption (n 1), and esophagopleural fistula (n 1). Three hundred twelve MPM patients were included in the study. There were 273 men and 39 women with a median age of 61.0 years (range, 14.0 to 80.0 years). All patients provided written informed consent, and the local ethics committee approved the data collection and analysis of MPM archives by The Society of Thoracic Surgeons /10/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 908 BALDUYCK ET AL Ann Thorac Surg NONEPITHELIOID MALIGNANT PLEURAL MESOTHELIOMA 2010;89: Preoperative Workup The diagnosis of malignant mesothelioma was made by video-assisted thoracoscopic pleural biopsy, confirmed with an appropriate panel of immunohistochemical stains. Concurrent talc pleurodesis was performed in 74 patients (23.7%). All patients underwent contrast enhanced computed tomography of chest and abdomen. Routine video-assisted cervical mediastinoscopy was performed since 2004 on 82 patients, of whom 8 were positive for N2 disease. All patients underwent full lung function tests, and echocardiography and quantitative radionuclide scintigraphy were used selectively in those considered for extrapleural pneumonectomy. Computed tomography positronemission tomography was not used routinely in preoperative staging nor was laparoscopy. Extrapleural pneumonectomy was offered to patients who were deemed resectable and medically operable. Radical pleurectomy or decortication was offered to patients deemed unfit for pneumonectomy or in whom mediastinoscopy revealed mediastinal lymph node metastases. We deemed extrapleural pneumonectomy to be inappropriate for patients with limited survival by virtue of mediastinal nodal metastases. Mediastinoscopy was not performed in those patients who were not considered fit enough for extrapleural pneumonectomy. Surgical Technique Nonradical and radical procedures were included in the study. Nonradical procedures, including video-assisted thoracoscopic surgery pleurectomy or decortication [6] and open simple decortication, were reserved for palliative intent and symptom control. The surgical objective was to remove the bulk of the tumor including both visceral and parietal pleura, to reexpand the trapped lung, and achieve effusion control. Open simple decortication was more frequently performed earlier in the series. The surgical objective of the radical procedures was to achieve complete macroscopic clearance of the tumor and thereby prolong survival. Extrapleural pneumonectomy was performed using the standard technique [7] with removal of all visible tumor by an en bloc excision of lung, pericardium, and hemidiaphragm. Radical pleurectomy or decortication constituted a complete macroscopic resection of the tumor with removal of both parietal and visceral pleura, pericardium, and hemidiaphragm but preserving the underlying lung [8]. In both procedures, the excision was followed by prosthetic reconstruction of the hemidiaphragm and pericardium. A systematic mediastinal lymph node dissection was performed. The resected specimen was evaluated by specialized pulmonary pathologists with experience in MPM. Postoperatively, patients were followed up in an outpatient clinic until death. Statistical Analysis Data were obtained from a prospective database held in our institution. Medical notes were reviewed retrospectively to retrieve data that were not directly entered in the database. Age at diagnosis, sex, side of procedure, International Mesothelioma Interest Group (IMIG) stage [9], radicality of the procedure, preoperative hemoglobin levels higher than 14 g/dl, white cell count, platelet count, preoperative or postoperative chemotherapy, and postoperative radiotherapy were evaluated in a histologic subtype specific univariate analysis. Statistical analysis was performed using statistical software (version 15.0; SPSS, Chicago, IL). Quantitative variables were expressed as mean standard deviation. Differences between groups were tested with the Mann Whitney U test. The probability value was considered statistically significant if lower than or equal to Actuarial survival was calculated according to the Kaplan-Meier method. Differences in survival were tested for significance by the log-rank test. A Cox proportional hazards regression model was used to identify statistically significant differences in survival and to estimate 95% confidence intervals. Prognostic variables identified by univariate analysis were analyzed in a multivariate Cox model. A forward, stepwise selection procedure was used, with variables being added to the model according to a partial likelihood ratio test, using an entry criterion of p Results Patient Characteristics The characteristics of the three histologic groups are shown in Table 1. The groups were comparable with the exception of age, which was significantly higher in the sarcomatoid group (p 0.008). Radical surgery was performed in 195 patients, and 117 patients underwent a nonradical procedure. Radical surgery was performed more often in the epithelioid and biphasic groups (p 0.001), and as a consequence, the total length of hospitalization and the incidence of major complications were Table 1. Patient Characteristics Variable Epithelial (n 218) Biphasic (n 66) Sarcomatoid (n 28) Male/female 189/29 58/8 26/2 Median age (y) Procedure: radical/nonradical 142/76 44/22 9/19 Side: right/left 99/119 30/36 11/17 Median length of hospitalization (days) Postoperative complications (%) 17.0% 18.2% 0%

3 Ann Thorac Surg BALDUYCK ET AL 2010;89: NONEPITHELIOID MALIGNANT PLEURAL MESOTHELIOMA 909 Table 2. Median, 1-Year, and 2-Year According to Stage for Each Histology Subgroup Histology Subtype IMIG Stage n Median (months) 1-Year 2-Year 3-Year 4-Year 5-Year Epithelial I % 62.5% 37.5% 37.5% 37.5% II % 61.5% 23.1% 7.7% 0% III % 32.9% 13.9% 7.6% 3.8% IV % 31.4% 14.3% 5.7% 0% X % 22.9% 7.2% 2.4% 0% Biphasic I % 0% 0% 0% 0% II % 0% 0% 0% 0% III % 4.3% 4.3% 0% 0% IV % 6.7% 6.7% 6.7% 6.7% X % 13.0% 0% 0% 0% Sarcomatoid I II % 0% 0% 0% 0% III % 0% 0% 0% 0% IV % 0% 0% 0% 0% X % 0% 0% 0% 0% IMIG International Mesothelioma Interest Group. significantly higher in the epithelioid and biphasic groups (p and p 0.017, respectively). Pathologic Diagnosis Final histologic subtype was epithelioid in 218 patients, biphasic in 66 patients, and sarcomatoid in 28 patients. The groups had similar pathologic staging at the time of surgery (Table 2). Accurate assessment of staging and resection margin was not feasible for 117 patients undergoing a nonradical resection. In 10 patients undergoing a radical pleurectomy or decortication, no systematic lymph node dissection was performed and an accurate IMIG staging was therefore not feasible; these patients were not included in univariate and multivariate analysis. Resection margins were R0 in 42.0% of cases. histology was 15.3 months, with a 1- and 2-year survival rate of 63.3% and 31.7%, respectively. The median survival in 66 biphasic patients was 10.1 months, with 1- and 2-year overall survival rates of 40.9% and 7.6%, respectively. Median survival and 1-year survival were 5.0 months and 3.6%, respectively, in the 28 sarcomatoid patients. No patient with the sarcomatoid histologic subtype had a survival of more than 2 years (Fig 1). The differences in survival among the MPM histologic groups were highly significant (p 0.001). In patients who underwent a radical procedure, significant differ- Additional Nonsurgical Therapy Chemotherapy or radiotherapy was given according to the preference of the referring oncologist, who also decided on the timing of the therapy and regimen. Forty-four patients received preoperative chemotherapy, and 111 were treated with postoperative chemotherapy. Regimens varied between the units offering the treatment. In the 155 patients who received chemotherapy, cisplatin/pemetrexed was used in 39.2%, cisplatin/ gemcitabine in 22.6%, mitomycin-vinblastine-cisplatin (MVP) in 19.0%, vinorelbine in 8.3%, and others in 10.7%. Most patients received a mean of three cycles. Postoperative radiotherapy was given to 157 patients of whom 44 patients (60.7%) received radical hemithorax radiotherapy. The histologic diagnosis did not influence the use of preoperative or postoperative chemotherapy or postoperative radiotherapy. Median follow-up after surgery was 12.5 months. The median survival in the 218 patients with epithelioid Fig 1. Kaplan Meier survival curve for each histologic subtype (days).

4 910 BALDUYCK ET AL Ann Thorac Surg NONEPITHELIOID MALIGNANT PLEURAL MESOTHELIOMA 2010;89: ences were seen in survival between epithelioid versus biphasic (p 0.001) and sarcomatoid (p 0.001), but not between biphasic and sarcomatoid. After a nonradical procedure no significant difference was seen in survival between epithelioid and biphasic groups, but survival in the sarcomatoid group was significant lower after a nonradical procedure compared with those with biphasic histology. Univariate analysis showed that in the epithelioid group, age (p 0.005), IMIG stage (p 0.001), radicality of the procedure (p 0.001), leukocytosis (p 0.016), and preoperative or postoperative chemotherapy (p 0.012) were significant prognostic factors influencing postoperative survival. In the biphasic group, preoperative anemia was the only significant factor (p 0.007). In sarcomatoid patients, IMIG stage and radicality of the surgical procedure were significant prognostic variables (p and p 0.015, respectively). Multivariate analysis in the epithelioid group identified IMIG stage (p 0.001), radicality of the procedure (p 0.008) and preoperative or postoperative chemotherapy (p 0.007) as significant prognostic factors, whereas in the sarcomatoid group, only the IMIG stage (p 0.012) was significant (Table 3) and the radicality of surgery had no effect. Comment Malignant pleural mesothelioma is associated with poor outcome. Currently, no consensus exists on the indications for surgical management. Selection bias remains one of the explanations of the apparently favorable published surgical results. Nonepithelioid MPM is one of the predetermined bad prognostic factors used in operative selection. Many reports have indicated that patients with epithelioid MPM have a better prognosis than those with sarcomatoid type [2, 4, 10 13]. The prognosis of biphasic MPM has also been compared with the epithelioid [14, 15] and sarcomatoid types [2, 13]. However, Van Gelder and colleagues [16] question the prognostic difference of biphasic histologic subtype because biphasic MPM is more frequently diagnosed at thoracotomy or autopsy specimen in contrast to smaller preoperative biopsies. The present paper reports the results of a retrospective analysis of 312 MPM patients during a 10-year period. Patients with epithelioid histology have a median survival of 15.1 months, which is comparable to that of previous publications [3, 4]. In contrast, the median survival after biphasic and sarcomatoid MPM is only 10.1 and 5.0 months, respectively. Therefore, surgery in sarcomatoid disease does not appear to give any survival benefit when compared with reports of best supportive care with a median survival of 7 months [14]. A significant difference in survival for biphasic compared with sarcomatoid MPM is seen after nonradical surgery but not after radical surgery. This observation, combined with disparate clinical behavior, leaves the impression that epithelioid and sarcomatoid MPM variants represent distinct disease entities. We agree with the assertion [15] that sarcomatoid MPM should be considered as the equivalent of small cell lung cancer in surgical terms. The diagnosis of sarcomatoid histology on biopsy should preclude radical surgery, and therapy should be aimed at symptom control and preservation of quality of life. The situation with biphasic pleural mesothelioma is more debatable. In some cases of biphasic MPM with other favorable prognostic indicators (young age, N0 disease), radical excision should be discussed considering the operative risk and benefit of either extrapleural pneumonectomy and radical pleurectomy or decortication. However, because of incomplete sampling, it is often not possible to exclude biphasic from the epithelioid histologic subtype, and therefore biphasic is often a postoperative diagnosis. There is evidence of differences in the molecular biology of epithelioid and nonepithelioid MPM, which may contribute to differences in their clinical behavior. We have previously noted a significantly higher expression of epidermal growth factor receptor in epithelioid compared with sarcomatoid MPM [17]. Other workers have identified epidermal growth factor receptor expression to be associated with a favorable outcome in mesothelioma [18]. This study has several limitations. First, the analysis was retrospective, and second, it had an extended period of data collection, during which treatment evolved with experience and was not uniformly established. The group of patients selected for radical surgery may have been destined to have a good prognosis even without treatment. Also, none of the present patients were treated as part of a prospective protocol. Finally, the decision to operate may have been biased by a preconceived belief in the poor outlook of sarcomatoid disease. In conclusion, this study confirmed the extremely poor prognosis of sarcomatoid MPM, which is independent of Table 3. Multivariate Analysis Histology Subtype Variables p Value Confidence Interval Epithelial IMIG stage Radical surgical procedure Preoperative or postoperative chemotherapy Biphasic Preoperative hemoglobin levels Sarcomatoid IMIG stage IMIG International Mesothelioma Interest Group.

5 Ann Thorac Surg BALDUYCK ET AL 2010;89: NONEPITHELIOID MALIGNANT PLEURAL MESOTHELIOMA 911 the extent of surgery unlike other cell types. The present study has implications for future trials in mesothelioma surgery and adjuvant treatment. We believe that patients with sarcomatoid histology should be considered in exclusive trials evaluating different radical procedures or adjuvant treatment. The treatment of biphasic pleural mesothelioma is debatable. The decision to operate in these cases should involve patients health status, stage of the disease, and patients preference. Considering the relatively low benefit on survival and the high operative risk, extrapleural pneumonectomy should be avoided in nonepithelioid MPM in favor of radical pleurectomy or decortication or palliative debulking surgery. The results of future studies to evaluate the potential role of surgery for epithelioid MPM are awaited. References 1. Pelucchi C, Malvezzi M, La Vecchia C, Levi F, Decarti A, Negri E. The mesothelioma epidemic in Western Europe: an update. Br J Cancer 2004;90: Van Gelder T, Damhuis RA, Hoogstede HC. Prognostic factors and survival in malignant pleural mesothelioma. Eur Respir J 1994;7: 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: Borasio P, Berruti A, Billé A, et al. Malignant pleural mesothelioma: clinicopathologic and survival characteristics in a consecutive series of 394 patients. Eur J Cardiothorac Surg 2008;33: 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: Nakas A, Martin-Ucar AE, Edwards JG, Waller DA. The role of video assisted thoracoscopic pleurectomy/decortication in the therapeutic management of malignant pleural mesothelioma. Eur J Cardiothorac Surg 2008;33: Edwards JG, Martin-Ucar AE, Stewart DJ, Waller DA. Right extrapleural pneumonectomy for malignant mesothelioma via median sternotomy or thoracotomy? Short- and longterm results. Eur J Cardiothorac Surg 2007;31: Martin-Ucar AE, Nakas A, Edwards JG, Waller DA. Casecontrol study between extrapleural pneumonectomy and radical pleurectomy/decortication for pathological N2 malignant pleural mesothelioma. Eur J Cardiothorac Surg 2007; 31: Rusch VW, The International Mesothelioma Interest Group. A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 1995;108: Antman K, Shemin R, Ryan L, et al. Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women s Hospital experience over two decades, J Clin Oncol 1988;6: Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organisation for Research and Treatment of Cancer experience. J Clin Oncol 1998;16: Schildge J, Kaiser D, Henss H, Fiebig H, Ortlieb H. Prognostic factors in diffuse malignant mesothelioma of the pleura. Pneumologie 1989;43: Johansson L, Lindén CJ. Aspects of histopathologic subtype as a prognostic factor in 85 pleural mesotheliomas. Chest 1996;109: Merritt N, Blewett CJ, Miller JD, Bennett WF, Young JE, Urschel JD. after conservative management of pleural mesothelioma. J Surg Oncol 2001;78: Sugarbaker DJ. Editorial comment made on Martin-Ucar AE, Nakas A, Edwards JG, Waller DA. Case control study between extrapleural pneumonectomy and radical pleurectomy/decortication for pathological N2 malignant pleural mesothelioma. Eur J Cardiothorac Surg 2007;31: Van Gelder T, Hoogsteden HC, Vandenbroucke JP, van der Kwast TH, Planteydt HT. The influence of the diagnostic technique on the histopathological diagnosis of malignant mesotheliomas. Virchows Arch A Pathol Anat Histopathol 1991;418: Edwards JG, Swinson DEB, Jones JL, Waller DA, O Byrne KJ. EGFR expression: associations with outcome and clinicopathological variables in malignant pleural mesothelioma. Lung Cancer 2006;54: Dazzi H, Hasleton PS, Thatcher N, Wilkes S, Swindel R, Chatterjee AK. Malignant pleural mesothelioma and epidermal growth factor receptor (EGFR). Relationship of EGFR with histology and survival using fixed paraffin embedded tissue and the F4 monoclonal antibody. Br J Cancer 1990;61: