Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy,

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1 European Journal of Cardio-thoracic Surgery 40 (2011) Clinical and pathological features of three-year survivors of malignant pleural mesothelioma following extrapleural pneumonectomy, David J. Sugarbaker *, Andrea S. Wolf, Lucian R. Chirieac, John J. Godleski, Tamara R. Tilleman, Michael T. Jaklitsch, Raphael Bueno, William G. Richards Division of Thoracic Surgery and Department of Pathology, Brigham and Women s Hospital, Boston, MA, USA Received 21 June 2010; received in revised form 15 December 2010; accepted 18 December 2010; Available online 9 February 2011 Abstract Objective: Surgery-based multimodality therapy is associated with long-term survival in a significant number of pleural mesothelioma patients. We explored factors associated with 3-year survival in patients with malignant pleural mesothelioma, who underwent extrapleural pneumonectomy, to help refine patient selection criteria for surgery and other therapies. Methods: With Institutional Review Board approval, we reviewed records in the International Mesothelioma Program Patient Data Registry to identify all patients, who underwent extrapleural pneumonectomy for malignant pleural mesothelioma between 1 January 1988 and 31 May Vital status as of 31 May 2010 was confirmed. Fisher s exact test was used to compare dichotomous variables for patients who survived at least 3 years with those who did not. Kaplan Meier analysis was used to estimate the cumulative survival probability for all 3-year survivors. Results: Among 636 patients who underwent extrapleural pneumonectomy, 117 (18%) survived at least 3 years following surgery, including 26 remaining alive and four lost to follow-up. Of the 3-year survivors, 39 (33%) were female, 61 (52%) had left-sided disease, and the median age was 56 years (range 27 77). Relatively more 3-year survivors were younger than, or at the median age ( p = ), or female ( p = ), had epithelial tumor histology ( p < ) and/or had normal white blood cell count ( p = ), hemoglobin ( p < ), or platelet count ( p < ) preoperatively. The median survival of the 117 patients who survived 3-years was 59 months. Among these patients, a significant association between age and survival was found only for women. Conclusions: A significant proportion of patients undergoing extrapleural pneumonectomy for pleural mesothelioma experienced extended survival. Although favorable prognostic features were more common, the cohort of 3-year survivors included a substantial number of patients with late-stage disease. The longest survival (median greater than 7 years) was experienced by women under the median age of 56 years. These data support the role of macroscopic cytoreduction through extrapleural pneumonectomy in the context of multimodality therapy to extend survival for malignant pleural mesothelioma. Further efforts to treat micrometastatic disease and improve patient selection are warranted. # 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. Keywords: Extrapleural pneumonectomy; Mesothelioma; Staging; Survival 1. Introduction Malignant pleural mesothelioma (MPM) is a thoracic tumor that originates in pleural mesothelial cells and is associated with inhalation exposure to asbestos. MPM progresses primarily by local extension to involve the ipsilateral lung and mediastinal structures, and is refractory to most conventional therapies [1]. Patient survival with supportive care is nearly 7 months [2], and with chemotherapy is generally 1 year [3]. Presented at the 18th European Conference on General Thoracic Surgery, Valladolid, Spain, 30 May 2nd June, Funded by the Division of Thoracic Surgery and the International Mesothelioma Program, Brigham and Women s Hospital, Boston, MA, USA. * Corresponding author. Address: Division of Thoracic Surgery, Brigham and Woman s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02215, USA. Tel.: ; fax: address: dsugarbaker@partners.org (D.J. Sugarbaker). The current treatment paradigm for non-metastatic solid tumors is first to remove all macroscopic disease with surgical resection and then to eradicate residual microscopic disease or prevent the development of micrometastatic recurrence with additional local and systemic treatment. Successful application of this treatment strategy depends on selection of patients with appropriate fitness and technically favorable conditions for resection and on the efficacy of additional modalities used to control microscopic disease. Commonly, tumor stage has been used as an additional criterion to guide patient selection for primary surgery. Extrapleural pneumonectomy (EPP)-based multimodality therapy for MPM in surgical candidates with resectable tumors has been associated with median survival in the range of 18 months [4 6], with a significant number of patients experiencing long-term survival [7]. Although pathologic features predictive of poor prognosis have been incorporated in published MPM staging systems, /$ see front matter # 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. doi: /j.ejcts

2 D.J. Sugarbaker et al. / European Journal of Cardio-thoracic Surgery 40 (2011) Table 1. Histology and staging of 3-year survivors. Survival range (months) Stage I Stage II Stage III Stage IV Epithelial (n = 107, 91%) AJCC/UICC stage [13] 7 (7%) 20 (19%) 72 (68%) 7 (7%) BWH stage [4] 13 (12%) 51 (48%) 43 (40%) 0 Proposed epithelial TNM stage [8] 20 (19%) 55 (52%) 25 (24%) 6 (6%) Biphasic (n = 8, 7%) AJCC/UICC stage 1 (13%) 2 (25%) 4 (50%) 1 (13%) BWH stage 0 5 (63%) 3 (38%) 0 Papillary (n = 2, 2%) AJCC/UICC stage (100%) 0 BWH stage 0 2 (100%) 0 0 the currently accepted staging systems have not consistently stratified the survival of surgical patients [8,9]. It has become clear that additional factors play a role in determining outcome. In an effort to further refine selection criteria for surgerybased multimodality treatment of MPM, we sought to identify factors associated with good prognosis among patients, who experienced extended survival after surgery for mesothelioma. In a cohort of patients who survived at least 3 years following surgery, we evaluated established demographic, clinical, and pathologic predictors of overall survival (age, gender, histology, white blood cell count, hemoglobin, and platelet count) [10 12], in addition to stage, neo-adjuvant and adjuvant therapy, perioperative morbidity, and length of hospital stay. The analysis was restricted to patients who had undergone EPP and thus had complete pathologic assessment and staging of their tumors. 2. Materials and methods With Institutional Review Board approval (protocol number 2005-p ), we retrospectively reviewed records in the International Mesothelioma Program Patient Data Registry of all patients with MPM, who underwent EPP at our institution between 1 January 1988 and 31 May Vital status was confirmed as of 31 May For all patients, demographics (gender and age), preoperative laboratory factors related to prognosis (white blood cell count, hemoglobin, and platelet count) that had been identified in several large meta-analyses of non-surgical treatment trials [11,12], and histologic subtype were retrieved. All patients had a minimum Karnofsky performance status of 80%, as this was a criterion for selection for surgery [4]. Tumor pathology was subjected to a comprehensive consensus review and resolution of any ambiguities by pulmonary pathologists, as previously reported [8]. Epithelial cases were specifically audited to distinguish cases of welldifferentiated papillary mesothelioma, as the clinical behavior of the latter differs markedly from that of other MPM cell types. For patients surviving at least 3 years from date of surgery, length of postoperative hospitalization, perioperative morbidity, and pathologic staging data were also obtained. The administration of additional neo-adjuvant, intra-operative, and/or adjuvant therapy was documented to the degree possible. Descriptive statistics were performed to delineate the patterns of perioperative morbidity, length of hospitalization, and pathologic stage distribution of 3-year survivors for the purpose of comparison to historical reports. Fisher s exact test was used to compare the proportions of patients with and without factors known to be associated with good prognosis between 3-year survivors and those who had died less than 3 years following surgery. These factors were epithelial histology, female gender, younger patient age at the time of surgery (defined as less than or equal to the overall median value), and preoperative laboratory values dichotomized based on institutionally defined normal limits: white blood cell count ml 1, hemoglobin 11.5 g dl 1 for women or 13.5 g dl 1 for men, and platelet count ml 1. Table 2. Morbidity of 3-year survivors: the complications in the current series are compared to those reported for all patients in our prior series. Current series (n = 112) a Sugarbaker et al. [18] (n = 328) Median age (range) 56 years (27 77) 58 years (28 77) Median length of stay (range) 10 days (5 55) 10 days (4 101) Atrial fibrillation 38.4% (43/112) b 44.2% (145/328) Myocardial infarction 2.7% (3/112) 1.5% (5/328) Reoperation for 0.9% (1/112) 2.4% (8/328) constrictive physiology Prolonged intubation 0.9% (1/112) 7.9% (26/328) Aspiration 3.6% (4/112) 2.7% (9/328) Tracheostomy 1.8% (2/112) 1.8% (6/328) Vocal cord paresis 10.7% (12/112) 6.7% (22/328) Renal failure 5.4% (6/112) c 2.7% (9/328) Deep vein thrombosis 7.1% (8/112) 6.4% (21/328) Pulmonary embolus 2.7% (3/112) 1.5% (5/328) Stroke 0.9% (1/112) 0.3% (1/328) Empyema 3.6% (4/112) 2.4% (8/328) Bronchopleural fistula 1.8% (2/112) 0.6% (2/328) Bleeding requiring reoperation 3.6% (4/112) Not reported (NR) Right heart failure 0.9% (1/112) NR Chylous effusion 0.9% (1/112) NR Wound infection/cellulites 6.3% (7/112) NR Clostridium difficile colitis 2.7% (3/112) NR Feeding tube 1.8% (2/112) NR Horner s syndrome 1.8% (2/112) NR Gastric herniation 1.8% (2/112) NR Other: perforated duodenal ulcer, acalculous cholecystitis, fungal UTI requiring suprapubic tube 2.7% (3/112) NR a Five patients from the earliest years in the series did not have records available for thorough review of morbidity. b Includes one case of atrial flutter and one case of uncharacterized supraventricular tachycardia. c No patient required dialysis.

3 300 D.J. Sugarbaker et al. / European Journal of Cardio-thoracic Surgery 40 (2011) Table 3. Multimodality therapy for 3-year survivors. Neo-adjuvant radiation Neo-adjuvant chemotherapy Heated intra-operative chemotherapy Adjuvant radiation a Adjuvant chemotherapy a Both adjuvant chemotherapy and radiation a Yes (%) 1 (1%) 8 (7%) 43 (37%) 70 (60%) 66 (56%) 57 (49%) No (%) 116 (99%) 109 (93%) 74 (63%) 16 (13%) 20 (17%) 28 (24%) a For 31 patients (27%), the status of adjuvant therapy is not available as these data were retrieved retrospectively for this cohort of US and international patients treated on and off a variety of protocols, with adjuvant therapy in the form of chemotherapy and/or radiation completed with variable consistency, frequently at outside institutions. Table 4. Univariate analysis. [()TD$FIG] Survival years n = Survival <3 years n = 519 Fisher s exact p-value n % N % Age median 78 67% % Female 39 33% 96 18% Epithelial % % < Normal white blood % % cell count Normal hemoglobin 89 76% % < Normal platelet count % % < Kaplan Meier analysis was used to estimate the cumulative survival probability as a function of months since surgery for all 3-year survivors. Given prior evidence of a differential effect of age on survival for men and women [10], we explored this interaction with the Kaplan Meier analysis of survival in the 3-year survivor cohort grouped by age and stratified by gender. 3. Results A total of 636 patients, who had undergone EPP between 1 January 1988 and 31 May 2007, were identified. Of these, the median age at the time of surgery was 59 years (17 78), 135 (21%) were female, 295 (46%) had left-sided MPM, and 117 (18%) had survived for at least 3 years following surgery. Among the 3-year survivors, 39 (33%) were female, 61 (52%) had left-sided disease, and the median age was 56 years (range 27 77). At the time of analysis, 87 of the 3-year surviving patients were deceased, 26 patients remained alive and continued to be followed, and four were lost to followup. Of the 26 patients who remained alive and in follow-up, 13 (50%) have experienced recurrent mesothelioma. Treatment for recurrence has included resection in seven cases and chemotherapy in six cases. Two patients with recent diagnoses of recurrence have not yet initiated treatment. Tumor histology, staging distributions, and survival durations of the 3-year survivors are presented in Table 1. The majority had epithelial tumor histology, but 7% had biphasic histology and only 2% had well-differentiated papillary tumors. The ranges of survival duration associated with these two less common histologic subtypes were similar and not extreme within the 3-year survivor cohort. Three-year survivors did not represent primarily early stage tumors, with 67% of patients classified as Stage III and another 7% classified as Stage IV by American Joint Committee on Cancer/ International Union Against Cancer (AJCC/UICC) criteria [13]. Similarly, by Brigham Stage criteria [4], 39% were Fig. 1. Cumulative survival for 3-year survivors. classified as Stage III, with intrapleural and extrapleural lymph nodes positive in 36 (31%) and 17 (15%) patients, respectively, and at least one surgical margin positive in 75 (64%) cases. However, based on proposed modifications to the tumor, node, metastasis (TNM) criteria for epithelial tumors [8], 24% of epithelial tumors were classified as Stage III, and another 6% as Stage IV. The subgroup of 3-year survivors was found to be similar in terms of perioperative hospitalization and morbidity to all MPM patients undergoing EPP (Table 2). While 43 patients (37%) received intra-operative heated chemotherapy, very few had received neo-adjuvant therapy of any type. Adjuvant therapy, including radiation and/or chemotherapy, was variably used to treat these patients (Table 3). When compared with MPM patients who underwent EPP but survived less than 3 years (n = 519), significantly higher proportions of 3-year survivors exhibited favorable prognostic factors (Table 4). Relatively more 3-year survivors were younger than, or at the median age ( p = ), or female ( p = ); had epithelial tumor histology ( p < ); and/or had normal white blood cell count ( p = ), hemoglobin ( p < ), or platelet count ( p < ) preoperatively. The median survival of the 117 patients who survived for 3 years was 59 months, with 5-year and 10-year survival rates of 43.8% and 13.6%, respectively (Fig. 1). Among these patients, a significant association between age and survival was found only for women (Fig. 2). 4. Discussion Of 636 patients who underwent EPP for MPM over 19 years, we found a 3-year survival rate of 18%, comparable to that reported for other surgically treated thoracic malignancies,

4 [()TD$FIG] D.J. Sugarbaker et al. / European Journal of Cardio-thoracic Surgery 40 (2011) Fig. 2. Kaplan Meier survival curves depicting cumulative survival probability for (a) men and (b) women grouped by age (dichotomized about the overall median of 56 years). such as superior sulcus tumors [14], Stage IIIa and IIIb nonsmall-cell lung cancer [15], Stage III esophageal cancer [16], as well as other recalcitrant non-thoracic malignancies treated surgically, such as Stage II pancreatic cancer [17]. This study evaluated the clinicopathologic features of MPM patients, who survived 3 or more years following EPP. These patients were found to be younger and more commonly women, had fewer cases of non-epithelial tumors, and had higher prevalence of laboratory values (white blood cell, hemoglobin, and platelet count) within normal limits, compared with patients who died within 3 years of surgery. Although favorable prognostic features were more common, the cohort of 3-year survivors did include a substantial number of patients with late-stage disease diagnosed using any of the current staging systems. Papillary histology was associated with 3-year survival (40 50 months in this series), but these cases were too rare to account for the extended survival experienced by the cohort. Among the 3-year survivors, the types and rates of perioperative morbidity were similar to those previously reported for all patients undergoing this type of resection [18]. Finally, many, but not all, of these patients received non-surgical therapy in addition to EPP, and no pattern was discernable in the type or timing of such treatment to account for extended survival. There are two ways to improve the efficacy of surgical resection: (1) improve patient selection and (2) develop more effective strategies to eradicate or prevent the spread of micrometastatic disease. The process of improving patient selection for surgery in MPM continues to evolve. Initial clinicopathologic features identified as indicative of unfavorable prognosis, such as non-epithelial cell type and extrapleural nodal disease [4], are now being applied to select appropriate treatment strategies for individual patients. Patients with non-epithelial histology are generally offered surgery less often and, at our institution, all patients undergo staging mediastinoscopy, and those found to have N2 involvement with tumor are referred for primary chemotherapy. Recently proposed modifications to the AJCC/UICC staging system [8], which improve survival stratification of patients with epithelial MPM, and molecular staging with a four-gene expression ratio test [19], represent further efforts to refine patient selection for surgery. Importantly, the results of the current study emphasize the impact of tumor biology on survival. A substantial number of patients (30 75% depending on staging system used) among the 3-year survivors had pathologic Stage III or IV disease (Table 1). Moreover, the operative morbidity experienced by 3-year survivors in this series was similar to that reported for all patients undergoing EPP (Table 2), implying that perioperative complications do not substantially prohibit extended survival. Rather, tumor biology appears to be a major determinant of extended survival. Continued investigation of genetic and molecular prognostic factors [20,21] will likely enable further refinement of patient selection criteria for surgery and other therapeutic modalities. The merging of biologic data with clinicopathologic data will thereby allow the more precise application of surgery to those patients most likely to benefit from radical resection. The observed 59-month median survival among the 3-year survivor cohort (Fig. 1) indicates that patients, who survive at least 3 years, have a 50% chance of surviving beyond 5 years. The goal of cytoreductive surgery in mesothelioma is to accomplish macroscopic complete resection, or resection of all gross disease (equivalent to R1, in contrast to R0, resection) [22,23], with remaining microscopic disease the target of adjuvant therapy and the host s immune system. It is reasonable to speculate that a homeostasis is reached between the patient s immune response and residual microscopic MPM that leads to a period of stability. Efforts should be encouraged to develop treatment strategies to tip the balance in favor of the patient, allowing MPM to be managed as a chronic disease. The longest survival (median greater than 7 years) was experienced by women under the median age of 56 years (Fig. 2(b)). This supports our hypothesis that young women are disproportionately represented among long-term survivors of MPM, a phenomenon that has been described in the literature [10]. Although data regarding the hormonal status of the women in this study are not available, it is likely that many of the younger women were pre-menopausal. We

5 302 D.J. Sugarbaker et al. / European Journal of Cardio-thoracic Surgery 40 (2011) speculate that hormone stimulation in MPM may regulate tumor growth, similar to hormone modulation in other epithelial solid tumors, such as ovarian carcinoma. The role of estrogen receptor-b observed in tumor suppression [24] supports this hypothesis and merits further investigation. The chief limitation of this study is its retrospective nature, and thus it represents analysis of a heterogeneous group of patients, who underwent surgery over 19 years at a referral center for national and international patients. Surgery-based therapy was part of a variety of regimens on and off protocols, and patients received intracavitary chemotherapy and/or adjuvant treatment with variable consistency, the latter frequently at outside institutions. A randomized prospective study would enable more stringent evaluation, but the relatively small number of patients undergoing EPP for mesothelioma each year, compared with the number of patients undergoing resection for other thoracic malignancies, limits the ability to conduct and power a large randomized trial. Moreover, we acknowledge that the 3-year survivor cohort in this study represents a group of patients selected for their favorable prognosis. The goal of this selection was to focus on factors associated with extended survival to identify criteria for improved patient selection for surgery and potential targets for systemic therapy. The current study was limited to patients undergoing EPP in an effort to select a relatively homogeneous cohort with complete pathologic staging available for evaluation. If macroscopic complete resection can be achieved with pleurectomy/decortication, as observed with early stage less bulky tumors, extended survival may be observed with radical pleurectomy-based therapy as well [25]. Using the treatment paradigm of macroscopic complete resection followed by eradication/prevention of micrometastatic spread, we have reached a transition point in the management of mesothelioma in which survival has paralleled (and in some cases, surpassed) that of other recalcitrant solid tumors. The technique of removing all macroscopic disease through EPP has evolved over the past three decades, and this procedure can reliably reduce disease to a microscopic level, with morbidity and mortality rates comparable to those reported for other major oncologic resections, such as esophagectomy, pancreaticoduodenectomy, and hepatectomy [23]. Now, our center and others [4 6] are reporting acceptable mortality rates with cumulative survival approaching 15% at 5 years. While it is difficult not to focus on the overall poor prognosis of this aggressive disease, those who have been engaged in mesothelioma research over the past several decades will recognize this 15% 5-year survival rate as a major milestone in MPM. The treatment of MPM is positioned for a major advance, based not only on improved patient selection, but also on the development of systemic, immunologic, biologic, hormonal, and/or locoregional therapies that would eradicate or chronically control microscopic disease. References [1] Tsao AS, Wistuba I, Roth JA, Kindler HL. Malignant pleural mesothelioma. J Clin Oncol 2009;27: [2] Merritt N, Blewett CJ, Miller JD, Bennett WF, Young JE, Urschel JD. Survival after conservative (palliative) management of pleural malignant mesothelioma. J Surg Oncol 2001;78: [3] Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21: [4] Sugarbaker DJ, Flores RM, Jaklitsch MT, Richards WG, Strauss GM, Corson JM, DeCamp Jr MM, Swanson SJ, Bueno R, Lukanich JM, Baldini EH, Mentzer SJ. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999;117:54 63 [discussion 63 55]. [5] Weder W, Stahel RA, Bernhard J, Bodis S, Vogt P, Ballabeni P, Lardinois D, Betticher D, Schmid R, Stupp R, Ris HB, Jermann M, Mingrone W, Roth AD, Spiliopoulos A. Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. Ann Oncol 2007;18: [6] de Perrot M, Feld R, Cho BC, Bezjak A, Anraku M, Burkes R, Roberts H, Tsao MS, Leighl N, Keshavjee S, Johnston MR. Trimodality therapy with induction chemotherapy followed by extrapleural pneumonectomy and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27: [7] Aziz T, Jilaihawi A, Prakash D. The management of malignant pleural mesothelioma; single centre experience in 10 years. Eur J Cardiothorac Surg 2002;22: [8] Richards WG, Godleski JJ, Yeap BY, Corson JM, Chirieac LR, Zellos L, Mujoomdar A, Jaklitsch MT, Bueno R, Sugarbaker DJ. Proposed adjustments to pathologic staging of epithelial malignant pleural mesothelioma based on analysis of 354 cases. Cancer 2010;116: [9] Richards WG. Recent advances in mesothelioma staging. Semin Thorac Cardiovasc Surg 2009;21: [10] Wolf AS, Richards WG, Tilleman TR, L.R. C, Hurwitz L, Bueno R, Sugarbaker DJ. Characteristics of malignant pleural mesothelioma in women. Ann Thorac Surg 2010;90(3): [11] Curran D, Sahmoud T, Therasse P, van Meerbeeck J, Postmus PE, Giaccone G. Prognostic factors in patients with pleural mesothelioma: the European Organization for Research and Treatment of Cancer experience. J Clin Oncol 1998;16: [12] Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the cancer and leukemia group B. Chest 1998;113: [13] International Union Against Cancer (UICC): TNM classification of tumors. 7th edition. Sobin LH, Gaspodarowicz MK, Wittekind Ch (eds.), Wiley- Blackwell, a John Wiley & Sons Ltd. Publication, West Sussex, UK, [14] Komaki R, Roth JA, Walsh GL, Putnam JB, Vaporciyan A, Lee JS, Fossella FV, Chasen M, Delclos ME, Cox JD. Outcome predictors for 143 patients with superior sulcus tumors treated by multidisciplinary approach at the University of Texas M.D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys 2000;48: [15] Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi 3rd AT, Weick JK, Lonchyna VA, Presant CA, McKenna RJ, Gandara DR. Concurrent cisplatin/ etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study J Clin Oncol 1995;13: [16] Malaisrie SC, Untch B, Aranha GV, Mohideen N, Hantel A, Pickleman J. Neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: experience at a single institution. Arch Surg 2004;139:532 8 [discussion 538 9]. [17] Bilimoria KY, Bentrem DJ, Ko CY, Ritchey J, Stewart AK, Winchester DP, Talamonti MS. Validation of the 6th edition AJCC pancreatic cancer staging system: report from the National Cancer Database. Cancer 2007;110: [18] Sugarbaker DJ, Jaklitsch MT, Bueno R, Richards W, Lukanich J, Mentzer SJ, Colson Y, Linden P, Chang M, Capalbo L, Oldread E, Neragi-Miandoab S, Swanson SJ, Zellos LS. Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 2004;128: [19] Gordon GJ, Dong L, Yeap BY, Richards WG, Glickman JN, Edenfield H, Mani M, Colquitt R, Maulik G, Van Oss B, Sugarbaker DJ, Bueno R. Four-gene expression ratio test for survival in patients undergoing surgery for mesothelioma. J Natl Cancer Inst 2009;101:

6 D.J. Sugarbaker et al. / European Journal of Cardio-thoracic Surgery 40 (2011) [20] Sugarbaker DJ, Richards WG, Gordon GJ, Dong L, De Rienzo A, Maulik G, Glickman JN, Chirieac LR, Hartman ML, Taillon BE, Du L, Bouffard P, Kingsmore SF, Miller NA, Farmer AD, Jensen RV, Gullans SR, Bueno R. Transcriptome sequencing of malignant pleural mesothelioma tumors. Proc Natl Acad Sci U S A 2008;105: [21] Bueno R, De Rienzo A, Dong L, Gordon GJ, Hercus CF, Richards WG, Jensen RV, Anwar A, Maulik G, Chirieac LR, Ho KF, Taillon BE, Turcotte CL, Hercus RG, Gullans SR, Sugarbaker DJ. Second generation sequencing of the mesothelioma tumor genome. PLoS One 2010;5:e [22] Sugarbaker DJ. Macroscopic complete resection: the goal of primary surgery in multimodality therapy for pleural mesothelioma. J Thorac Oncol 2006;1: [23] Sugarbaker DJ, Wolf AS. Surgery for malignant pleural mesothelioma. Expert Rev Respir Med 2010;4: [24] Pinton G, Brunelli E, Murer B, Puntoni R, Puntoni M, Fennell DA, Gaudino G, Mutti L, Moro L. Estrogen receptor-beta affects the prognosis of human malignant mesothelioma. Cancer Res 2009;69: [25] Flores RM. Surgical options in malignant pleural mesothelioma: extrapleural pneumonectomy or pleurectomy/decortication. Semin Thorac Cardiovasc Surg 2009;21(2): Appendix A. Conference discussion Dr I. Opitz (Zürich, Switzerland): Dr Sugarbaker, These impressive numbers truly represent the highest number of multimodality treated patients for malignant pleural mesothelioma. Are there questions from the audience? Dr T. D Amico (Durham, NC): Dr Sugarbaker, could you just clarify one point: did the surgery-based trials include any trials using preoperative chemotherapy followed by surgery, or are all of the trials using surgery first followed by adjuvant therapy? Dr Sugarbaker: Tom, you are right. I included all trials with either induction chemotherapy followed by surgery, or surgery followed by adjunctive chemoradiation. There was a blend of data. And if you review the data, there really isn t a survival advantage if you look at all the data with one approach versus another, although I would say that the neo-adjuvant approach is a very promising one. Dr D Amico: The other tumors that you compared mesothelioma to Stage III lung cancer, pancreatic adenocarcinoma, and esophageal cancer those are all tumors that we treat with induction therapy followed by surgery. Even though there is difference between all of the tumors, do you think we should try to push in the direction of using induction therapy as opposed to adjuvant therapy, or do you think it really is not going to matter? Dr Sugarbaker: A number of investigators are looking at that. Certainly, Walter Weder s group has done a lot in that area; we had a multicenter trial in the United States that looked at induction therapy and I think we should continue to do so. I have been reticent with neo-adjuvant chemotherapy because I think the resectability rate is a little bit lower, and so our approach has been intra-operative chemotherapy. But I think all approaches based around a surgical resection with no residual macroscopic disease will have a real chance at improving survival. Dr A. Turna (Istanbul, Turkey): My question is about mediastinoscopy. Five years ago you advocated mediastinoscopy in almost every patient, and I think you shifted your strategy to selected patients. I would like to learn what your strategy is right now. Do you recommend it for all patients and what is the role of mediastinoscopy in long-term survival? Dr Sugarbaker: Our approach based on our data is to perform mediastinoscopy in all cases where we are considering surgical resection. The presence of positive extrapleural nodes on mediastinoscopy would preclude an operative approach and the patient would then go for chemotherapy. Dr W. Klepetko (Vienna, Austria): David, you have shown us the complication rates that are quite usual in these kinds of operations. Given your long experience with these operations, did you see a tendency to reduce the complications? Could you speak about that, particularly on the problem of postoperative empyema in the presence of foreign material in the chest? Dr Sugarbaker: There is no question that as the technique and our experience have evolved, the morbidity and mortality rates have come down, equal I think to published studies of pneumonectomy for non-small cell lung cancer. So there is no question that experience reduces morbidity and mortality, which has been our experience. This is why surgeons who perform extrapleural pneumonectomy, like other complex procedures, should do a relatively high volume of cases if they expect to get low complication and mortality rates from this procedure. In terms of the empyema, we have a two-fold strategy. If the patient suffers chest infection within three weeks of the date of surgery, we perform a thoracoscopic washout with five days of irrigation of antibiotic solution in the chest followed by intravenous antibiotics for six weeks. There is no hard and fast rule, but the later empyemas, which usually occur after the first or second cycle of chemotherapy, are treated with a two-stage approach: first, drainage followed about three weeks later by removal of the patch material and flap closure with a muscle flap. The strategy for empyema management depends upon how soon after the initial procedure the complication has occurred. Dr S. Bölükbas (Wiesbaden, Germany): Dr Flores published a paper showing that pleurectomy decortication was at least equal to EPP in all stages but Stage II. Do you suggest a stage-based surgical approach? What is your experience now? Dr Sugarbaker: That is a good question. I think that the publication by Flores, if it is not read carefully, can lead to false conclusions about the application of extrapleural pneumonectomy in this disease. The number one driver of prognosis, or survival, in this disease is tumor volume. Harvey Pass showed it first, others have shown it as well, and our data in pre-publication is going to show the same thing. You cannot resect advanced volume with a pleurectomy. Therefore, pleurectomy for macroscopic complete resection, which is the goal of treatment (I am not talking about palliation where you leave disease behind, but pleurectomy for macroscopic complete resection) will be reserved for earlier stages of disease when the extent of disease in the lung fissures and the distribution of the disease throughout the chest will allow that to occur. You are really comparing apples to oranges. You are talking about patients with advanced volume getting pleural pneumonectomy and those with more minimal volume getting pleurectomy, both of which will lead to macroscopic complete resection and both of which in his (Flores ) publication had approximate survival, suggesting that if the tumor volume is greater in the EPP group, the therapeutic efficacy of that treatment strategy or that procedure is greater. But we would in some patients perform pleurectomy, of course, if there is minimal disease. Dr Bölükbas: I do not agree with you, Dr Sugarbaker, because those patients who underwent EPP had a higher incidence of multimodality treatment in this study compared to a very low incidence of multimodality treatment in pleurectomy decortication, and survival, even in Stage III, was equal to EPP. What is your comment on that? Dr Sugarbaker: Well, there are some confounding issues with stage, which I just showed you. That is why I referenced tumor volume. The biology of mesothelioma is different from most solid tumors, and currently the staging systems are not predictive of survival. So when you compare Stage III EPP patients with Stage III pleurectomy patients, it really doesn t mean much. It is all going to come down to tumor volume. Tumor volume is what drives survival.