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Pleural mesothelioma: is the surgeon still there?
Invited Review
Pleural mesothelioma: is the surgeon still there?
Running head: Surgery for mesothelioma
I. Opitz and W. Weder Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Address for Correspondence: Professor Isabelle Opitz, FEBTS Department of Thoracic Surgery University Hospital Zurich Raemistrasse 100 8091 Zurich Switzerland +41 44 255 88 02 [email protected]
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]. Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
Abstract MPM is a rare malignancy with some unique characteristics. Tumor biology is aggressive and prognosis is poor. Despite more knowledge on histology, tumor biology and staging, there is still a relevant discrepancy between clinical and pathologic staging resulting in difficult prediction of prognosis and treatment outcome, making treatment allocation more challenging than in most other malignancies. After years of nihilism in the late eighties, a period of activism started evaluating different treatment protocols combined with research driven mainly by academic centers; at the time, selection was based on histology and stage only. This period was important to gain knowledge about the disease. However, the interpretation of data was difficult since selection criteria and definitions varied substantially. Not surprisingly, until now there is no common agreement on best treatment even among specialists. Hence, a review of our current concepts is indicated and personalized treatment should become applicable in the future. Surgery was and still is an issue of debate. In principle, surgery is an effective approach as it allows macroscopic complete elimination of a tumor, which is relatively resistant to medical treatment. It helps to set the clock back and other therapies that have also just a limited effect can be applied sequentially before or after surgery. Furthermore, to date best longterm outcome is reported from surgical series in combination with other modalities. However, part of the community consider surgery associated with too high morbidity and mortality when balanced to the limited life expectancy. This criticism is understandable, since poor results after surgery are reported. The present article will review the indication for surgery and discuss the different procedures available for macroscopic complete resection– such as lung-preserving (extended) pleurectomy/decortication as well as extrapleural pneumonectomy to illustrate that “The surgeon is still there!”.
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Key Words Malignant pleural mesothelioma – macroscopic complete resection – extrapleural pneumonectomy – pleurectomy/decortication – multimodality treatment - surgery
Key Message Best long-term outcome is still reported from series including surgery. The surgical approach shifted from extrapleural pneumonectomy to lung-preserving pleurectomy/decortication, which became the first choice for most cases. Quality of surgery improved in specialized centers with relevant reduction of surgical morbidity and mortality and treatment allocation scores allow better patient selection.
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Introduction The treatment of malignant pleural mesothelioma (MPM) was and still is complex for all involved disciplines. Surgery for MPM is indicated at several stages of the disease starting from biopsies for diagnosis, over to macroscopic complete resection (MCR) to improve longterm outcome and surgical measures for palliation. The most critically discussed part is the role of surgery for cure of MPM in view of missing high level evidence on one hand and some reports of relevant surgical mortality and morbidity associated with long time recovery period for the benefit of only a few months gain of prolonged life on the other hand. This article aims to give a “tour d’horizon” about the different indications of surgery for diagnosis, for cure of MPM patients and lastly palliation discussing the most recent literature available. Surgical biopsies with or without talc pleurodesis The Guidelines of the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons [1] (ESTS) strongly recommend a pleural biopsy by video-assisted thoracoscopic surgery (VATS) in order to obtain multiple and deep tissue biopsies of pleural tissue for histopathological and tissue marker analysis. It is mandatory for final MPM diagnosis and not replaceable by cytological assessment, which is not sensitive and specific enough when compared to a biopsy [1]. VATS positive predictive value has been reported to be as high as 99.7% [2]. Furthermore, delivery of enough material for multiple analyses in the era of genomic medicine is only guaranteed by a surgical biopsy. Besides, MPM is a very heterogeneous cancer and the pleura is a common site for metastatic disease, which requires representative material for precise diagnosis as well. Therefore multiple biopsies need to be obtained from different locations including full thickness biopsies in order to prove fat and/or muscle invasion by the tumor [3]. Because of the known incidence of tumor tract invasion after diagnostic procedures, the incision for the biopsy should be located at the same intercostal space as the later approach for complete resection, which is unfortunately often disregarded by centers with little expertise. Uniportal VATS in the 6th intercostal space is an attractive approach to get a good view to the pleural space and allows excision of the port-site during subsequent MCR avoiding future local recurrences [4]. It can also be accomplished in sedation and local anesthesia [5]. Another critical topic is the application of talc for pleurodesis at the time of diagnostic biopsies. Some groups advocate to seal the pleural space at this time point, not only for prevention of pleural effusion but also for improved dissection during tumor resection at a later time point [6]. This concept is not supported by the whole surgical community and bears the risk of misinterpretation during restaging PET-CT imaging post induction treatment, where talc can give false positive results. Furthermore, the option of intracavitary therapy might be missed for those cases where resection is not feasible if the pleural space is sealed. Therefore, we do not perform talc pleurodesis when MCR is planned. Palliative surgery MPM is often diagnosed at an advanced stage of the disease and surgery might be indicated with palliative intent, aiming to evacuate pleural effusion to allow re-expansion for entrapped lungs and prevent effusion relapse. Palliative surgical procedures should be primarily minimally invasive, to reduce the potential harmful effects of a thoracotomy [7]. After demonstration of the feasibility of pleurectomy by VATS [8], there were reports of symptomatic improvement [9] and even possible survival benefit [7]. The particular 4 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
advantage of this procedure is the option to free entrapped lungs by peeling off the tumorthickened visceral pleura resulting in re-expansion of the lungs with a regained contact to the chest wall and hence successful pleurodesis. The question if this approach (partial pleurectomy by VATS – VAT-PP) has an advantage over standard talc pleurodesis was studied in a randomised controlled trial in 12 centres in the UK (MesoVATS trial ClinicalTrials.gov NCT00821860) [10]. The primary outcome was overall survival at 1 year. There were no differences in the overall survival (OS) neither at 1-year between groups (HR 1.04 (95% CI 0.76 to 1.42) nor at 6 months follow-up, so that the authors concluded that VAT-PP was not recommended to improve OS in patients with pleural effusion. However, resolution of pleural effusion was significantly higher in the VAT-PP group than in the talc pleurodesis group at 1 month (37% vs 59%) and 6 months (57% vs 77%). Quality of life (measured with EQ-5D) was significantly improved in the VAT-PP group at months 6 (MD 0.08 (95% CI 0.003 to 0.16)) and 12 (MD 0.19 (95% CI 0.05 to 0.32)). The authors concluded that talc pleurodesis remains the preferred treatment of choice, but this obviously holds true only for patients with expanded lungs. For patients with entrapped lungs, fit enough for surgery, partial pleurectomy is a valid therapy option for effusion control, if indwelling permanent catheters [11] are not an option. Indwelling pleural catheters (IPC) are a definitive alternative to pleurodesis for management of recurrent pleural effusions [12, 13]. These are soft, small-bore silicone catheters that can be tunneled under the skin to avoid risks of wound-site infections [14] and that can be connected to a pleural drainage system applicable for patients at home. Spontaneous pleurodesis may develop in up to 70% of patients without a trapped lung after an average of 52 days, and the catheter can then be safely removed [14]. Catheter-related complications include malfunction, blockage, and site-related pain [15]. The reported incidence of procedure-tract metastases ranges in available literature from <1% to 10% [16, 17]. Currently, comparative data are missing whether talc pleurodesis or IPC produces superior palliation, shorter hospital stay, and less morbidity. A study by Freeman et al. showed that IPC provided freedom from re-intervention equal to talc pleurodesis by thoracoscopy, but with shorter hospital stay, shorter interval to the initiation of systemic therapy, and lower rates of operative morbidity [18]. Several trials to clarify this question are underway, such as the TIME2 (unblinded randomized controlled trials (RCT) comparing IPC to talc as the second therapeutic intervention in malignant effusion), AMPLE (multicenter, randomized study comparing IPC versus talc pleurodesis for malignant pleural effusion) and TAPP trial (open-label controlled trial, designed to randomize 330 patients, with a confirmed malignant pleural effusion requiring intervention, to undergo either small bore (<14 Fr) Seldinger chest drain insertion followed by instillation of sterile talc (4 g), or to undergo medical thoracoscopy and simultaneous poudrage (4 g)) [19]. The question if VATpleurectomy/decortication (VAT-PD) is more effective than continuing drainage of the effusion with an IPC for patients with entrapped lungs in MPM is currently addressed in the multicenter, randomized feasibility MesoTRAP trial [20]. Macroscopic complete resection (MCR) for MPM Surgical removal of all cancerous tissue in order to obtain macroscopic clearance of tumor tissue is the basis and principle of surgical oncological therapy since the very beginning of cancer therapy. General oncological surgical principles such as microscopically free resection margins including a security distance cannot be achieved in MPM for given anatomical circumstances. Therefore, the principle of MCR was created as surgical treatment aim embedded into multimodality concepts. This has been discussed and supported by a group of specialists of surgeons, medical oncologists, radiation oncologists, 5 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
epidemiologists, and basic scientists during the 2012 IMIG conference [21]. The question is, if this statement is still supported by the medical community 5 years later. MCR for MPM is obtained by either extrapleural pneumonectomy (EPP) or (extended) pleurectomy/decortication (EPD / P/D). Whereas EPP is well defined with complete resection of parietal and visceral pleura including the underlying lung plus hemidiaphragm and pericardium, P/D can be performed as sole resection of parietal and visceral pleura (Figure 1) preserving the underlying lung, but hemidiaphragm and pericardium are often removed as well (EPD). In contrast to EPP, definition of P/D has not been uniformly used in the past [22]. Having a closer look at the literature and the existing evidence searching for RCTs comparing surgical to non-surgical therapeutic approaches in patients with malignant pleural mesothelioma gives limited result: one randomised controlled trial (MARS trial) [23] and two observational studies [24, 25]. Substantial controversy about the role of surgery for MPM treatment is related primarily to the results and interpretation of the MARS trial, which is the only surgical multicenter RCT assessing the feasibility to randomize patients to undergo EPP or not [23], performed in 12 UK hospitals. Out of 112 patients, 50 were randomized: 24 to EPP and 26 to non-EPP; 33 patients were excluded for disease progression, five patients were deemed inoperable and 19 patients refused surgery. Perioperative EPP-associated intend to treat mortality was 19% and also the actual mortality of 10.5% was high in comparison to most EPP series of the literature (30 day mortality up to 11.8%) [26]. In general, presentation as 90-day mortality data would be much more representative and looking closer to available data of-90 day mortality, the range goes up to 13.5% [27] (summarized in [28]). The hazard ratio (HR) for overall survival (OS) between the EPP and non-EPP groups was 1.9 (95% CI, 0.92–3.93; exact P=0.082), median survival was 14.4 months (range, 5.3–18.7 months) for the EPP group and 19.5 months (13.4 to time not yet reached) for the non-EPP group. [20]. It has been concluded by the authors that the data, although limited, suggested that radical surgery in the form of EPP within tri-modal therapy offered no benefit and possibly harmed patients [23]. This conclusion was not supported by the data because the required sample size for this question would have been much higher and the present cohort was underpowered for an adequate comparison [29]. Another weak point of the study was a poor protocol compliance as 6 out of 26 patients in the non-EPP group underwent off-protocol surgery and on the other hand only 16 out 24 randomly assigned EPP patients actually received EPP [20]. Results from retrospective cohort studies, differ from the MARS trial. The largest one of 1365 consecutive patients with MPM suggested that patients with good prognostic factors (i.e. age less than 70, epithelial histology) have statistically a similar survival whether they received medical therapy only (n=172), P/D (n=202), or EPP (n=301) [24]. However, patients receiving palliative treatment or chemotherapy alone had overall median survival of 11.7 months (95% CI 10.5–12.5 months) in comparison to patients who underwent P/D with a median survival of 20.5 months (95% CI, 18.2–23.1), which shows with 9-month survival benefit a clear trend in favor of surgery. Furthermore, median survival of patients undergoing surgical resection with adjuvant therapy was significantly longer than that of patients undergoing chemotherapy only (19.8 versus 11.7 months; χ2 2df = 74.541; p < 0.0001). Additionally, it has to be critically taken into account that these studies report on data, which go back almost thirty years in which progress in surgical treatment might have happened but not much in medical therapy during this period. 6 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
Another retrospective study in 150 patients showed a non-significant trend to better overall survival and disease-free survival in those patients undergoing surgical resection (P/D or EPP) with a median OS in those with surgical intervention of 18.4 months vs 10.7 months in those without (p=0.095); 21.6 months in P/D vs 18.4 months in EPP (p=0.652) [25]. Besides this, several studies over the last decades have demonstrated that patients with favorable disease characteristics may benefit from surgery with curative intent, in the context of multimodality therapy [30]. Looking at our own data from the past 2 decades, patients undergoing induction chemotherapy followed by MCR had a significantly longer OS in comparison to those patients undergoing chemotherapy alone. “Real-world evidence” and realistic scenario reflections about clinical practice and subsequent outcome arederived from huge population-based datasets, such as the Surveillance, Epidemiology, and End Results (SEER) database. The analysis of the so far biggest dataset (14.228 patients) demonstrated significantly better survival when comparing the first population-based dataset of surgery with other therapies (figure 2). Cancer-directed surgery has been independently associated with better survival [31], alongside with female gender, younger age, and earlier stage. In comparison to no treatment, surgery alone was associated with significant improvement in survival (adjusted hazard ratio 0.64 (0.61-0.67)) but not radiation (adj HR 1.15 (1.08-1.23). In the last decade a transition from EPP to P/D took place in most centers [32], because increasing evidence from several retrospective cohort studies showed similar OS [33] (figure 3). The main reasons were a much lower mortality (2 ½-fold), lower short-term mortality and morbidity, and better quality of life with P/D than after EPP [34]. Furthermore, the shift in demographics of mesothelioma patients with increasingly elder patients [27] was also supporting P/D. Due to the overall limited life expectancy of MPM patients, QoL for the remaining survival time is extremely important. A comprehensive review of quality of life (QoL) to assess differences between P/D and EPP showed that symptoms like lung function parameters, and physical and social functioning were still compromised 6 months following surgery, but P/D patients felt better than EPP patients across QoL measures [35]. One bias across all studies is that the outcomes of P/D or EPP depend largely on the institutions’ experience. There is a huge variability of outcome reporting, what concerns morbidity, mortality, quality of life, and overall and disease-free survival. The impact of the center’s experience, in particular for the morbidity after EPP has been demonstrated in a large STS database, where univariate analysis showed that the center volume influences significantly morbidity and mortality after MPM surgery. This becomes even clearer looking at specific complications such as the acute respiratory distress syndrome (ARDS). For those centers offering induction chemotherapy to their patients, the perioperative anesthesiological protocol is critical, as it has been well documented that high intraoperative FiO2 and/or barotrauma can trigger postoperative ARDS [36]. The management can be very challenging in patients following pneumonectomy and it has been demonstrated that the centers’ experience plays a crucial role here. Centers with less than 5 EPPs per year have a significant higher incidence of postoperative ARDS [37]. Eventually, centers offering ECLS (extracorporeal life support) programs provide to date more experience in handling these patients. 7 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
Looking over nearly 20 years’ experience of multimodality treatment including MCR at our own institution, we recently analyzed our data in a propensity score matched analysis [38] comparing our EPP to EPD cohort and observed similar morbidity rates (see table 1, updated from publication with unpublished data) although different complication patterns. In terms of long-term survival, overall survival is also comparable (figure 4, unpublished data), but 30day and 90-day mortality are clearly in favor of P/D. The argument that EPP only allows hemithoracic radiotherapy to prevent locoregional recurrences cannot hold true anymore because improvement and further development of complex intensity modulated radiotherapy techniques have shown that it can be performed with acceptable safety in appropriately selected patients after P/D as well [39]. However, the use of hemithoracic radiotherapy did not show significant survival benefit according to the results of a recent randomized, international, multicenter phase 2 trial [40], although the protocol of this trial has been criticized by the radio oncology community EPP may still play a role in MPM surgery for particular situations when tumor invasion precludes sparing of the lung, and only pneumonectomy guarantees macroscopic tumor clearance [28]. Furthermore, the functional aspect may justify EPP, meaning that some patients are already functionally “pneumonectomized” before the operation with a V/Q scan showing significantly reduced perfusion of the underlying lung. Additionally, the SMART protocol with induction radiotherapy followed by EPP with very promising cumulative overall survival of 58% at 3 years is another argument pro EPP, as it is so far performed only in the setting of subsequent EPP [41]. Furthermore, extensive decortication may lead to sponge-like “too small” remaining lungs with substantial pleural-space problems with remaining sero-pneumothorax prone for later infection. These situations should be avoided and in these cases, EPP could be an option especially on the left side. Unfortunately, these complications after P/D are widely underreported in the literature, because the cited morbidity rates (27.9% P/D vs 62.0%; EPP RR, 0.44; 95% CI, 0.30–0.63; p < 0.0001; I2 = 44%) [33] certainly not reflect the prolonged air leak rate which is close to 100%. Selection of candidates with potential benefit from surgery is crucial and one of the most important decision makings in the whole treatment algorithm, as already stated by Butchart in 1976, when he first described EPP for MPM and highlighted the importance of an accurate patient selection [42]. Selection criteria for surgery The unpredictable biological behavior of mesothelioma, the lack of correlation between clinical and pathological staging in addition to patients’ individual risk factors make best treatment allocation for an individual patient difficult. In general, single factors such as histology, involvement of mediastinal nodes, tumor resectability assessed by CT scan, and patient characteristics such as age and cardiovascular and pulmonary risk factors were the most common individual parameters used for treatment allocation in the past. Regardless of the type of operation, the estimated postoperative lung capacity needs to be evaluated preoperatively using known algorithms (43). Preoperative selection parameters were unsatisfactory and even in experienced centers early recurrences and rapid tumor progression were observed, also in ” early” or good prognostic cases. Traditionally, TNM stage is the classical prognosticator for cancer 8 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
treatment. Both parameters – T and N-stage - are difficult to assess clinically and in particular the discrimination between T2 and T3 (infiltration of chest wall) is almost impossible. In general, the clinical staging based on CT-scan, PET/CT scan, or MRI has a poor correlation with pathological staging [43]. Analyses of large data sets identified single poor prognostic factors such as non-epithelioid histology, poor performance status (PS), low hemoglobin, male gender, high platelet count, high lactate dehydrogenase, and high white blood cell count [44]. It turned out that measurement of tumor volume assessed preoperatively on CT scan can predict outcome as described first in the late 90ies by Pass and colleagues [45], and later confirmed by other groups [46-48]. Poorer overall survival in presence of tumor volume over 500 cm3 was confirmed by Gill et al. [48]. This theory was further evaluated in a multicenter study by Rusch and colleagues and the correlation between tumor volume and pT/pN stages and overall survival could be confirmed. They defined three groups with tumor volumes of 91.2, 245.3, and 511.3 cm3 and showed that this tumor volume was associated with a median overall survival of 37, 18, and 8 months, respectively [47]. As a consequence of these studies, tumor volume might be included in upcoming IASLC TNM staging classifications. However, one single factor alone cannot be distinctive for such a complicated and heterogeneous disease; therefore, several groups were summarizing multiple variables in one score in order to take into account this more complex situation. The most widely used scores are the EORTC score and CALGB scores, which have been assessed mostly for risk stratification for low- and high risk groups in patients treated with chemotherapy alone [49]. More recently, the scores have been validated in surgical patients, but for palliative and curative surgery, and the EORTC score turned out to be an independent prognosticator for this cohort [50]. The problem with most of the scores so far is the lack of validation in independent cohorts and the inclusion of clinical variables being available before surgery (and not thereafter, such as pTNM staging), to help decision-making for or against surgical resection. For this purpose we established a multimodality prognostic score (MMPS) to screen patients and defining subgroups, eligible or especially not eligible for surgery. All variables included in the score (tumor volume before chemotherapy greater than 500 ml, non-epithelioid histological subtype, C-reactive protein (CRP) value greater than 30 mg/liter before chemotherapy, and progressive disease (PD) after chemotherapy assessed by modified RECIST criteria) are available BEFORE the operation. The analyses showed that patients with a score of zero had the longest overall survival, whereas patients with a score of three or higher had an overall survival comparable to untreated MPM patients. The specificity of score three and four was 100%. The knowledge we gained from the MMPS is important for counselling patients because it allows to reliably identify patients which may have a good chance to benefit from multimodality therapy including surgery and rule out those where aggressive treatment may even cause harm. With a score of three or higher, patients are not considered to profit from a macroscopic complete resection in a multimodality therapy approach [51] (Figure 5, updated unpublished data). The score was further validated in an independent cohort from Vienna treated with the identical multimodality concept [51], so that currently we are prospectively evaluating the score as inclusion criterion for clinical trials.
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Conclusion The role of the surgeon for diagnosis and palliation of mesothelioma is unquestioned. In appropriately selected patients with acceptable risk profile, surgical resection (P/D or EPP) as part of a multimodality concept, should still be offered if performed in high volume and low-mortality centers. If macroscopic complete resection is technically feasible, P/D should be the treatment of first choice, if not, EPP should be considered. Currently, the MARS 2 trial is accruing patients, comparing EPD versus no P/D [52]. Furthermore, the results of ongoing trials assessing further modalities such as immunotherapy (ClinicalTrials.gov Identifier: NCT02707666) or targeted therapy might be a promising extension in the multimodality treatment panel for MPM, in adjunct to surgery.
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Acknowledgments We thank our pathology colleague Dr. B. Vrugt for pictures of post-resectional EPP specimens and Dr. C. Spichiger and Dr Friess for support in the formatting and editing process of the article.
Funding This work and cited studies from Zurich were supported by Swiss National Science Foundation (SNSF) Professorship (Nr. PP00P3_133657, Nr. PP00P3_159269) to Isabelle Opitz.
Disclosure The authors have declared no conflicts of interest.
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Mesothelioma Interest Group Congress, September 11-14, 2012, Boston, Mass. J Thorac Cardiovasc Surg 2013; 145: 909-910. 22. 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: 1304-1312. 23. Treasure T, Lang-Lazdunski L, Waller D et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. The Lancet Oncology 2011; 12: 763-772. 24. Bovolato P, Casadio C, Bille A et al. Does surgery improve survival of patients with malignant pleural mesothelioma?: a multicenter retrospective analysis of 1365 consecutive patients. J Thorac Oncol 2014; 9: 390-396. 25. Kucukoner M, Ali Kaplan M, Inal A et al. Clinical characteristics, treatment and survival outcomes in malignant pleural mesothelioma: an institutional experience in Turkey. J BUON 2014; 19: 164-170. 26. Cao CQ, Yan TD, Bannon PG, McCaughan BC. A systematic review of extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Oncol 2010; 5: 1692-1703. 27. Sharkey AJ, Tenconi S, Nakas A, Waller DA. The effects of an intentional transition from extrapleural pneumonectomy to extended pleurectomy/decortication. Eur J Cardiothorac Surg 2016; 49: 1632-1641. 28. Opitz I, Weder W. A nuanced view of extrapleural pneumonectomy for malignant pleural mesothelioma. Ann Transl Med 2017; 5: 237. 29. Weder W, Stahel RA, Baas P et al. The MARS feasibility trial: conclusions not supported by data. Lancet Oncol 2011; 12: 1093-1094; author reply 1094-1095. 30. Mineo TC. Malignant Pleural Mesothelioma: Present Status and Future Directions. In. Bentham Science Publishers 2016. 31. Taioli E, Wolf AS, Camacho-Rivera M et al. Determinants of Survival in Malignant Pleural Mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) Study of 14,228 Patients. PLoS One 2015; 10: e0145039. 32. Batirel HF. Extrapleural pneumonectomy (EPP) vs. pleurectomy decortication (P/D). Ann Transl Med 2017; 5: 232. 33. Cao C, Tian D, Park J et al. A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma. Lung Cancer 2014; 83: 240-245. 34. Taioli E, Wolf AS, Flores RM. Meta-analysis of survival after pleurectomy decortication versus extrapleural pneumonectomy in mesothelioma. Ann Thorac Surg 2015; 99: 472-480. 35. Schwartz RM, Watson A, Wolf A et al. The impact of surgical approach on quality of life for pleural malignant mesothelioma. Ann Transl Med 2017; 5: 230. 36. Muraoka M, Oka T, Akamine S et al. Postoperative complications of pulmonary resection after platinum-based induction chemotherapy for primary lung cancer. Surg Today 2003; 33: 1-6. 37. Burt BM, Cameron RB, Mollberg NM et al. Malignant pleural mesothelioma and the Society of Thoracic Surgeons Database: an analysis of surgical morbidity and mortality. J Thorac Cardiovasc Surg 2014; 148: 30-35. 38. Kostron A, Friess M, Inci I et al. Propensity matched comparison of extrapleural pneumonectomy and pleurectomy/decortication for mesothelioma patients. Interactive CardioVascular and Thoracic Surgery 2017; accepted for publication. 39. Rimner A, Rosenzweig KE. Novel radiation therapy approaches in malignant pleural mesothelioma. Ann Cardiothorac Surg 2012; 1: 457-461. 40. Stahel RA, Riesterer O, Xyrafas A et al. Neoadjuvant chemotherapy and extrapleural pneumonectomy of malignant pleural mesothelioma with or without hemithoracic radiotherapy (SAKK 17/04): a randomised, international, multicentre phase 2 trial. Lancet Oncol 2015; 16: 1651-1658.
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41. Cho BC, Feld R, Leighl N et al. A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" approach for resectable malignant pleural mesothelioma. J Thorac Oncol 2014; 9: 397-402. 42. Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax 1976; 31: 15-24. 43. Frauenfelder T, Kestenholz P, Hunziker R et al. Use of computed tomography and positron emission tomography/computed tomography for staging of local extent in patients with malignant pleural mesothelioma. J Comput Assist Tomogr 2015; 39: 160-165. 44. Edwards JG, Abrams KR, Leverment JN et al. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax 2000; 55: 731-735. 45. Pass HI, Kranda K, Temeck BK et al. Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997; 4: 215-222. 46. Frauenfelder T, Tutic M, Weder W et al. Volumetry: an alternative to assess therapy response for malignant pleural mesothelioma? Eur Respir J 2011; 38: 162-168. 47. Rusch VW, Gill R, Mitchell A et al. A Multicenter Study of Volumetric Computed Tomography for Staging Malignant Pleural Mesothelioma. Ann Thorac Surg 2016; 102: 10591066. 48. Gill RR, Richards WG, Yeap BY et al. Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume. AJR Am J Roentgenol 2012; 198: 359-363. 49. Fennell DA, Parmar A, Shamash J et al. Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials. J Clin Oncol 2005; 23: 184-189. 50. Sandri A, Guerrera F, Roffinella M et al. Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma. J Thorac Dis 2016; 8: 2121-2127. 51. Opitz I, Friess M, Kestenholz P et al. A New Prognostic Score Supporting Treatment Allocation for Multimodality Therapy for Malignant Pleural Mesothelioma: A Review of 12 Years' Experience. J Thorac Oncol 2015; 10: 1634-1641. 52. Lim E. Surgery for Mesothelioma - MARS 2 update 2017. In. Available online: https://www.drericlim.com/news/2017/1/1/surgery-for-mesothelioma-mars-2-update-2017: 2017. Figure legends
Figure 1: Decortication step during EPD – peeling off the visceral pleura leaving behind unprotected lung tissue full of air leaks.
Figure 2: Survival according to type of treatment (SEER database). From Taioli et al 2015 [31].
Figure 3: Summary of median overall survival outcomes for patients with malignant pleural mesothelioma who underwent extended pleurectomy/decortication (EPD) or extrapleural pneumonectomy (EPP). Circle radius is logistically proportional to the size of individual studies. Solid lines indicate survival measured from the date of diagnosis, and dotted lines indicate survival measured from the date of surgery. From Cao et al 2014 [33].
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Figure 4: Induction chemotherapy followed by extrapleural pneumonectomy (EPP) versus induction chemotherapy followed by (extended) pleurectomy/decortication (P/D). KaplanMeier curve comparing (not propensity score matched) overall survival (OS) in patients treated with induction chemotherapy followed by EPP (n=150) (median OS 22 months; 95% confidence interval (CI): 20-24 months) versus patients treated with induction chemotherapy followed by P/D (n=73) (median OS 30 months; 95% CI: 26-34 months), log rank test p=0.005. Pathological IMIG stage and histological subtype at the time point of surgery was not significantly different between the two groups. Zurich unpublished data (1999-2017).
Figure 5: MMP Score. Kaplan-Meier curve comparing overall survival (OS) according to the multimodality prognostic score (MMP score) in patients treated with induction chemotherapy followed by macroscopic complete resection (MCR) (n=223): score 0 (n=28): median OS 46 months (95% confidence interval (CI): 0-97 months); score 1 (n=57): median OS 23 months (95% CI: 13-33 months); score 2 (n=28): median OS 15 months (95% CI: 11-18 months); score 3 (n=4): median OS 6 months (95% CI: 0-12 months); score 4 (n=1): median OS 4 months (95% CI: not available); p<0.001.
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Decortication step during EPD – peeling off the visceral pleura leaving behind unprotected lung tissue full of air leaks. 110x86mm (150 x 150 DPI)
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Survival according to type of treatment (SEER database). From Taioli et al 2015 [31]. 93x66mm (300 x 300 DPI)
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Summary of median overall survival outcomes for patients with malignant pleural mesothelioma who underwent extended pleurectomy/decortication (EPD) or extrapleural pneumonectomy (EPP). Circle radius is logistically proportional to the size of individual studies. Solid lines indicate survival measured from the date of diagnosis, and dotted lines indicate survival measured from the date of surgery. From Cao et al 2014 [33]. 118x81mm (113 x 113 DPI)
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Induction chemotherapy followed by extrapleural pneumonectomy (EPP) versus induction chemotherapy followed by (extended) pleurectomy/decortication (P/D). Kaplan-Meier curve comparing (not propensity score matched) overall survival (OS) in patients treated with induction chemotherapy followed by EPP (n=150) (median OS 22 months; 95% confidence interval (CI): 20-24 months) versus patients treated with induction chemotherapy followed by P/D (n=73) (median OS 30 months; 95% CI: 26-34 months), log rank test p=0.005. Pathological IMIG stage and histological subtype at the time point of surgery was not significantly different between the two groups. Zurich unpublished data (1999-2017). 116x89mm (600 x 600 DPI)
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: MMP Score. Kaplan-Meier curve comparing overall survival (OS) according to the multimodality prognostic score (MMP score) in patients treated with induction chemotherapy followed by macroscopic complete resection (MCR) (n=223): score 0 (n=28): median OS 46 months (95% confidence interval (CI): 0-97 months); score 1 (n=57): median OS 23 months (95% CI: 13-33 months); score 2 (n=28): median OS 15 months (95% CI: 11-18 months); score 3 (n=4): median OS 6 months (95% CI: 0-12 months); score 4 (n=1): median OS 4 months (95% CI: not available); p<0.001. 134x106mm (600 x 600 DPI)
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Table 1: Comparison of induction chemotherapy plus EPP versus induction chemotherapy plus EPDs performed at University Hospital Zurich. Ind. CTX induction chemotherapy; EPP extrapleural pneumonectomy; EPD / P/D (extended) pleurectomy/decortication; OS overall survival; PFS progression free survival. Zurich unpublished data.
Ind. CTX & EPP
Ind. CTX & EPD / P/D
Time frame
1999 – December 2017
July 2008 – December 2017
Number of patients
151
73
Median age at surgery
61 years (range 36 – 77)
65 years (range 33 – 77)
47 (31%) 104 (69%) 0
1 (1%) 72 (98%) 1 (1%)
Major morbidity
38% (58/151)
27% (20/73) Prolonged air leak: 77% (56/73)
Re-operation
35% (53/151)
26% (19/73)
Median hospitalization time
14 days (range 4 – 131)
19 days (range 7-106)
30-day mortality
5% (7/148)
0% (0/72)
90-day mortality
11% (16/148)
0% (0/69)
Median OS
18 months (95% CI: 16-21) (9% censored)
25 months (95% CI: 21-29) (59% censored)
Median PFS
10 months (95% CI: 8-13) (21% censored)
8 months (95% CI: 7-9) (27% censored)
Induction Chemotherapy − − −
platinum/gem platinum/pem Other
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Pleural mesothelioma: is the surgeon still there?
Running head: Surgery for mesothelioma
I. Opitz and W. Weder Department of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland
Address for Correspondence: Professor Isabelle Opitz, FEBTS Department of Thoracic Surgery University Hospital Zurich Raemistrasse 100 8091 Zurich Switzerland +41 44 255 88 02 [email protected]
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]. Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
Abstract MPM is a rare malignancy with some unique characteristics. Tumor biology is aggressive and prognosis is poor. Despite more knowledge on histology, tumor biology and staging, there is still a relevant discrepancy between clinical and pathologic staging resulting in difficult prediction of prognosis and treatment outcome, making treatment allocation more challenging than in most other malignancies. After years of nihilism in the late eighties, a period of activism started evaluating different treatment protocols combined with research driven mainly by academic centers; at the time, selection was based on histology and stage only. This period was important to gain knowledge about the disease. However, the interpretation of data was difficult since selection criteria and definitions varied substantially. Not surprisingly, until now there is no common agreement on best treatment even among specialists. Hence, a review of our current concepts is indicated and personalized treatment should become applicable in the future. Surgery was and still is an issue of debate. In principle, surgery is an effective approach as it allows macroscopic complete elimination of a tumor, which is relatively resistant to medical treatment. It helps to set the clock back and other therapies that have also just a limited effect can be applied sequentially before or after surgery. Furthermore, to date best longterm outcome is reported from surgical series in combination with other modalities. However, part of the community consider surgery associated with too high morbidity and mortality when balanced to the limited life expectancy. This criticism is understandable, since poor results after surgery are reported. The present article will review the indication for surgery and discuss the different procedures available for macroscopic complete resection– such as lung-preserving (extended) pleurectomy/decortication as well as extrapleural pneumonectomy to illustrate that “The surgeon is still there!”.
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Key Words Malignant pleural mesothelioma – macroscopic complete resection – extrapleural pneumonectomy – pleurectomy/decortication – multimodality treatment - surgery
Key Message Best long-term outcome is still reported from series including surgery. The surgical approach shifted from extrapleural pneumonectomy to lung-preserving pleurectomy/decortication, which became the first choice for most cases. Quality of surgery improved in specialized centers with relevant reduction of surgical morbidity and mortality and treatment allocation scores allow better patient selection.
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Introduction The treatment of malignant pleural mesothelioma (MPM) was and still is complex for all involved disciplines. Surgery for MPM is indicated at several stages of the disease starting from biopsies for diagnosis, over to macroscopic complete resection (MCR) to improve longterm outcome and surgical measures for palliation. The most critically discussed part is the role of surgery for cure of MPM in view of missing high level evidence on one hand and some reports of relevant surgical mortality and morbidity associated with long time recovery period for the benefit of only a few months gain of prolonged life on the other hand. This article aims to give a “tour d’horizon” about the different indications of surgery for diagnosis, for cure of MPM patients and lastly palliation discussing the most recent literature available. Surgical biopsies with or without talc pleurodesis The Guidelines of the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons [1] (ESTS) strongly recommend a pleural biopsy by video-assisted thoracoscopic surgery (VATS) in order to obtain multiple and deep tissue biopsies of pleural tissue for histopathological and tissue marker analysis. It is mandatory for final MPM diagnosis and not replaceable by cytological assessment, which is not sensitive and specific enough when compared to a biopsy [1]. VATS positive predictive value has been reported to be as high as 99.7% [2]. Furthermore, delivery of enough material for multiple analyses in the era of genomic medicine is only guaranteed by a surgical biopsy. Besides, MPM is a very heterogeneous cancer and the pleura is a common site for metastatic disease, which requires representative material for precise diagnosis as well. Therefore multiple biopsies need to be obtained from different locations including full thickness biopsies in order to prove fat and/or muscle invasion by the tumor [3]. Because of the known incidence of tumor tract invasion after diagnostic procedures, the incision for the biopsy should be located at the same intercostal space as the later approach for complete resection, which is unfortunately often disregarded by centers with little expertise. Uniportal VATS in the 6th intercostal space is an attractive approach to get a good view to the pleural space and allows excision of the port-site during subsequent MCR avoiding future local recurrences [4]. It can also be accomplished in sedation and local anesthesia [5]. Another critical topic is the application of talc for pleurodesis at the time of diagnostic biopsies. Some groups advocate to seal the pleural space at this time point, not only for prevention of pleural effusion but also for improved dissection during tumor resection at a later time point [6]. This concept is not supported by the whole surgical community and bears the risk of misinterpretation during restaging PET-CT imaging post induction treatment, where talc can give false positive results. Furthermore, the option of intracavitary therapy might be missed for those cases where resection is not feasible if the pleural space is sealed. Therefore, we do not perform talc pleurodesis when MCR is planned. Palliative surgery MPM is often diagnosed at an advanced stage of the disease and surgery might be indicated with palliative intent, aiming to evacuate pleural effusion to allow re-expansion for entrapped lungs and prevent effusion relapse. Palliative surgical procedures should be primarily minimally invasive, to reduce the potential harmful effects of a thoracotomy [7]. After demonstration of the feasibility of pleurectomy by VATS [8], there were reports of symptomatic improvement [9] and even possible survival benefit [7]. The particular 4 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
advantage of this procedure is the option to free entrapped lungs by peeling off the tumorthickened visceral pleura resulting in re-expansion of the lungs with a regained contact to the chest wall and hence successful pleurodesis. The question if this approach (partial pleurectomy by VATS – VAT-PP) has an advantage over standard talc pleurodesis was studied in a randomised controlled trial in 12 centres in the UK (MesoVATS trial ClinicalTrials.gov NCT00821860) [10]. The primary outcome was overall survival at 1 year. There were no differences in the overall survival (OS) neither at 1-year between groups (HR 1.04 (95% CI 0.76 to 1.42) nor at 6 months follow-up, so that the authors concluded that VAT-PP was not recommended to improve OS in patients with pleural effusion. However, resolution of pleural effusion was significantly higher in the VAT-PP group than in the talc pleurodesis group at 1 month (37% vs 59%) and 6 months (57% vs 77%). Quality of life (measured with EQ-5D) was significantly improved in the VAT-PP group at months 6 (MD 0.08 (95% CI 0.003 to 0.16)) and 12 (MD 0.19 (95% CI 0.05 to 0.32)). The authors concluded that talc pleurodesis remains the preferred treatment of choice, but this obviously holds true only for patients with expanded lungs. For patients with entrapped lungs, fit enough for surgery, partial pleurectomy is a valid therapy option for effusion control, if indwelling permanent catheters [11] are not an option. Indwelling pleural catheters (IPC) are a definitive alternative to pleurodesis for management of recurrent pleural effusions [12, 13]. These are soft, small-bore silicone catheters that can be tunneled under the skin to avoid risks of wound-site infections [14] and that can be connected to a pleural drainage system applicable for patients at home. Spontaneous pleurodesis may develop in up to 70% of patients without a trapped lung after an average of 52 days, and the catheter can then be safely removed [14]. Catheter-related complications include malfunction, blockage, and site-related pain [15]. The reported incidence of procedure-tract metastases ranges in available literature from <1% to 10% [16, 17]. Currently, comparative data are missing whether talc pleurodesis or IPC produces superior palliation, shorter hospital stay, and less morbidity. A study by Freeman et al. showed that IPC provided freedom from re-intervention equal to talc pleurodesis by thoracoscopy, but with shorter hospital stay, shorter interval to the initiation of systemic therapy, and lower rates of operative morbidity [18]. Several trials to clarify this question are underway, such as the TIME2 (unblinded randomized controlled trials (RCT) comparing IPC to talc as the second therapeutic intervention in malignant effusion), AMPLE (multicenter, randomized study comparing IPC versus talc pleurodesis for malignant pleural effusion) and TAPP trial (open-label controlled trial, designed to randomize 330 patients, with a confirmed malignant pleural effusion requiring intervention, to undergo either small bore (<14 Fr) Seldinger chest drain insertion followed by instillation of sterile talc (4 g), or to undergo medical thoracoscopy and simultaneous poudrage (4 g)) [19]. The question if VATpleurectomy/decortication (VAT-PD) is more effective than continuing drainage of the effusion with an IPC for patients with entrapped lungs in MPM is currently addressed in the multicenter, randomized feasibility MesoTRAP trial [20]. Macroscopic complete resection (MCR) for MPM Surgical removal of all cancerous tissue in order to obtain macroscopic clearance of tumor tissue is the basis and principle of surgical oncological therapy since the very beginning of cancer therapy. General oncological surgical principles such as microscopically free resection margins including a security distance cannot be achieved in MPM for given anatomical circumstances. Therefore, the principle of MCR was created as surgical treatment aim embedded into multimodality concepts. This has been discussed and supported by a group of specialists of surgeons, medical oncologists, radiation oncologists, 5 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
epidemiologists, and basic scientists during the 2012 IMIG conference [21]. The question is, if this statement is still supported by the medical community 5 years later. MCR for MPM is obtained by either extrapleural pneumonectomy (EPP) or (extended) pleurectomy/decortication (EPD / P/D). Whereas EPP is well defined with complete resection of parietal and visceral pleura including the underlying lung plus hemidiaphragm and pericardium, P/D can be performed as sole resection of parietal and visceral pleura (Figure 1) preserving the underlying lung, but hemidiaphragm and pericardium are often removed as well (EPD). In contrast to EPP, definition of P/D has not been uniformly used in the past [22]. Having a closer look at the literature and the existing evidence searching for RCTs comparing surgical to non-surgical therapeutic approaches in patients with malignant pleural mesothelioma gives limited result: one randomised controlled trial (MARS trial) [23] and two observational studies [24, 25]. Substantial controversy about the role of surgery for MPM treatment is related primarily to the results and interpretation of the MARS trial, which is the only surgical multicenter RCT assessing the feasibility to randomize patients to undergo EPP or not [23], performed in 12 UK hospitals. Out of 112 patients, 50 were randomized: 24 to EPP and 26 to non-EPP; 33 patients were excluded for disease progression, five patients were deemed inoperable and 19 patients refused surgery. Perioperative EPP-associated intend to treat mortality was 19% and also the actual mortality of 10.5% was high in comparison to most EPP series of the literature (30 day mortality up to 11.8%) [26]. In general, presentation as 90-day mortality data would be much more representative and looking closer to available data of-90 day mortality, the range goes up to 13.5% [27] (summarized in [28]). The hazard ratio (HR) for overall survival (OS) between the EPP and non-EPP groups was 1.9 (95% CI, 0.92–3.93; exact P=0.082), median survival was 14.4 months (range, 5.3–18.7 months) for the EPP group and 19.5 months (13.4 to time not yet reached) for the non-EPP group. [20]. It has been concluded by the authors that the data, although limited, suggested that radical surgery in the form of EPP within tri-modal therapy offered no benefit and possibly harmed patients [23]. This conclusion was not supported by the data because the required sample size for this question would have been much higher and the present cohort was underpowered for an adequate comparison [29]. Another weak point of the study was a poor protocol compliance as 6 out of 26 patients in the non-EPP group underwent off-protocol surgery and on the other hand only 16 out 24 randomly assigned EPP patients actually received EPP [20]. Results from retrospective cohort studies, differ from the MARS trial. The largest one of 1365 consecutive patients with MPM suggested that patients with good prognostic factors (i.e. age less than 70, epithelial histology) have statistically a similar survival whether they received medical therapy only (n=172), P/D (n=202), or EPP (n=301) [24]. However, patients receiving palliative treatment or chemotherapy alone had overall median survival of 11.7 months (95% CI 10.5–12.5 months) in comparison to patients who underwent P/D with a median survival of 20.5 months (95% CI, 18.2–23.1), which shows with 9-month survival benefit a clear trend in favor of surgery. Furthermore, median survival of patients undergoing surgical resection with adjuvant therapy was significantly longer than that of patients undergoing chemotherapy only (19.8 versus 11.7 months; χ2 2df = 74.541; p < 0.0001). Additionally, it has to be critically taken into account that these studies report on data, which go back almost thirty years in which progress in surgical treatment might have happened but not much in medical therapy during this period. 6 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
Another retrospective study in 150 patients showed a non-significant trend to better overall survival and disease-free survival in those patients undergoing surgical resection (P/D or EPP) with a median OS in those with surgical intervention of 18.4 months vs 10.7 months in those without (p=0.095); 21.6 months in P/D vs 18.4 months in EPP (p=0.652) [25]. Besides this, several studies over the last decades have demonstrated that patients with favorable disease characteristics may benefit from surgery with curative intent, in the context of multimodality therapy [30]. Looking at our own data from the past 2 decades, patients undergoing induction chemotherapy followed by MCR had a significantly longer OS in comparison to those patients undergoing chemotherapy alone. “Real-world evidence” and realistic scenario reflections about clinical practice and subsequent outcome arederived from huge population-based datasets, such as the Surveillance, Epidemiology, and End Results (SEER) database. The analysis of the so far biggest dataset (14.228 patients) demonstrated significantly better survival when comparing the first population-based dataset of surgery with other therapies (figure 2). Cancer-directed surgery has been independently associated with better survival [31], alongside with female gender, younger age, and earlier stage. In comparison to no treatment, surgery alone was associated with significant improvement in survival (adjusted hazard ratio 0.64 (0.61-0.67)) but not radiation (adj HR 1.15 (1.08-1.23). In the last decade a transition from EPP to P/D took place in most centers [32], because increasing evidence from several retrospective cohort studies showed similar OS [33] (figure 3). The main reasons were a much lower mortality (2 ½-fold), lower short-term mortality and morbidity, and better quality of life with P/D than after EPP [34]. Furthermore, the shift in demographics of mesothelioma patients with increasingly elder patients [27] was also supporting P/D. Due to the overall limited life expectancy of MPM patients, QoL for the remaining survival time is extremely important. A comprehensive review of quality of life (QoL) to assess differences between P/D and EPP showed that symptoms like lung function parameters, and physical and social functioning were still compromised 6 months following surgery, but P/D patients felt better than EPP patients across QoL measures [35]. One bias across all studies is that the outcomes of P/D or EPP depend largely on the institutions’ experience. There is a huge variability of outcome reporting, what concerns morbidity, mortality, quality of life, and overall and disease-free survival. The impact of the center’s experience, in particular for the morbidity after EPP has been demonstrated in a large STS database, where univariate analysis showed that the center volume influences significantly morbidity and mortality after MPM surgery. This becomes even clearer looking at specific complications such as the acute respiratory distress syndrome (ARDS). For those centers offering induction chemotherapy to their patients, the perioperative anesthesiological protocol is critical, as it has been well documented that high intraoperative FiO2 and/or barotrauma can trigger postoperative ARDS [36]. The management can be very challenging in patients following pneumonectomy and it has been demonstrated that the centers’ experience plays a crucial role here. Centers with less than 5 EPPs per year have a significant higher incidence of postoperative ARDS [37]. Eventually, centers offering ECLS (extracorporeal life support) programs provide to date more experience in handling these patients. 7 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
Looking over nearly 20 years’ experience of multimodality treatment including MCR at our own institution, we recently analyzed our data in a propensity score matched analysis [38] comparing our EPP to EPD cohort and observed similar morbidity rates (see table 1, updated from publication with unpublished data) although different complication patterns. In terms of long-term survival, overall survival is also comparable (figure 4, unpublished data), but 30day and 90-day mortality are clearly in favor of P/D. The argument that EPP only allows hemithoracic radiotherapy to prevent locoregional recurrences cannot hold true anymore because improvement and further development of complex intensity modulated radiotherapy techniques have shown that it can be performed with acceptable safety in appropriately selected patients after P/D as well [39]. However, the use of hemithoracic radiotherapy did not show significant survival benefit according to the results of a recent randomized, international, multicenter phase 2 trial [40], although the protocol of this trial has been criticized by the radio oncology community EPP may still play a role in MPM surgery for particular situations when tumor invasion precludes sparing of the lung, and only pneumonectomy guarantees macroscopic tumor clearance [28]. Furthermore, the functional aspect may justify EPP, meaning that some patients are already functionally “pneumonectomized” before the operation with a V/Q scan showing significantly reduced perfusion of the underlying lung. Additionally, the SMART protocol with induction radiotherapy followed by EPP with very promising cumulative overall survival of 58% at 3 years is another argument pro EPP, as it is so far performed only in the setting of subsequent EPP [41]. Furthermore, extensive decortication may lead to sponge-like “too small” remaining lungs with substantial pleural-space problems with remaining sero-pneumothorax prone for later infection. These situations should be avoided and in these cases, EPP could be an option especially on the left side. Unfortunately, these complications after P/D are widely underreported in the literature, because the cited morbidity rates (27.9% P/D vs 62.0%; EPP RR, 0.44; 95% CI, 0.30–0.63; p < 0.0001; I2 = 44%) [33] certainly not reflect the prolonged air leak rate which is close to 100%. Selection of candidates with potential benefit from surgery is crucial and one of the most important decision makings in the whole treatment algorithm, as already stated by Butchart in 1976, when he first described EPP for MPM and highlighted the importance of an accurate patient selection [42]. Selection criteria for surgery The unpredictable biological behavior of mesothelioma, the lack of correlation between clinical and pathological staging in addition to patients’ individual risk factors make best treatment allocation for an individual patient difficult. In general, single factors such as histology, involvement of mediastinal nodes, tumor resectability assessed by CT scan, and patient characteristics such as age and cardiovascular and pulmonary risk factors were the most common individual parameters used for treatment allocation in the past. Regardless of the type of operation, the estimated postoperative lung capacity needs to be evaluated preoperatively using known algorithms (43). Preoperative selection parameters were unsatisfactory and even in experienced centers early recurrences and rapid tumor progression were observed, also in ” early” or good prognostic cases. Traditionally, TNM stage is the classical prognosticator for cancer 8 Downloaded from https://academic.oup.com/annonc/advance-article-abstract/doi/10.1093/annonc/mdy195/5037888 by MIT Libraries user on 14 June 2018
treatment. Both parameters – T and N-stage - are difficult to assess clinically and in particular the discrimination between T2 and T3 (infiltration of chest wall) is almost impossible. In general, the clinical staging based on CT-scan, PET/CT scan, or MRI has a poor correlation with pathological staging [43]. Analyses of large data sets identified single poor prognostic factors such as non-epithelioid histology, poor performance status (PS), low hemoglobin, male gender, high platelet count, high lactate dehydrogenase, and high white blood cell count [44]. It turned out that measurement of tumor volume assessed preoperatively on CT scan can predict outcome as described first in the late 90ies by Pass and colleagues [45], and later confirmed by other groups [46-48]. Poorer overall survival in presence of tumor volume over 500 cm3 was confirmed by Gill et al. [48]. This theory was further evaluated in a multicenter study by Rusch and colleagues and the correlation between tumor volume and pT/pN stages and overall survival could be confirmed. They defined three groups with tumor volumes of 91.2, 245.3, and 511.3 cm3 and showed that this tumor volume was associated with a median overall survival of 37, 18, and 8 months, respectively [47]. As a consequence of these studies, tumor volume might be included in upcoming IASLC TNM staging classifications. However, one single factor alone cannot be distinctive for such a complicated and heterogeneous disease; therefore, several groups were summarizing multiple variables in one score in order to take into account this more complex situation. The most widely used scores are the EORTC score and CALGB scores, which have been assessed mostly for risk stratification for low- and high risk groups in patients treated with chemotherapy alone [49]. More recently, the scores have been validated in surgical patients, but for palliative and curative surgery, and the EORTC score turned out to be an independent prognosticator for this cohort [50]. The problem with most of the scores so far is the lack of validation in independent cohorts and the inclusion of clinical variables being available before surgery (and not thereafter, such as pTNM staging), to help decision-making for or against surgical resection. For this purpose we established a multimodality prognostic score (MMPS) to screen patients and defining subgroups, eligible or especially not eligible for surgery. All variables included in the score (tumor volume before chemotherapy greater than 500 ml, non-epithelioid histological subtype, C-reactive protein (CRP) value greater than 30 mg/liter before chemotherapy, and progressive disease (PD) after chemotherapy assessed by modified RECIST criteria) are available BEFORE the operation. The analyses showed that patients with a score of zero had the longest overall survival, whereas patients with a score of three or higher had an overall survival comparable to untreated MPM patients. The specificity of score three and four was 100%. The knowledge we gained from the MMPS is important for counselling patients because it allows to reliably identify patients which may have a good chance to benefit from multimodality therapy including surgery and rule out those where aggressive treatment may even cause harm. With a score of three or higher, patients are not considered to profit from a macroscopic complete resection in a multimodality therapy approach [51] (Figure 5, updated unpublished data). The score was further validated in an independent cohort from Vienna treated with the identical multimodality concept [51], so that currently we are prospectively evaluating the score as inclusion criterion for clinical trials.
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Conclusion The role of the surgeon for diagnosis and palliation of mesothelioma is unquestioned. In appropriately selected patients with acceptable risk profile, surgical resection (P/D or EPP) as part of a multimodality concept, should still be offered if performed in high volume and low-mortality centers. If macroscopic complete resection is technically feasible, P/D should be the treatment of first choice, if not, EPP should be considered. Currently, the MARS 2 trial is accruing patients, comparing EPD versus no P/D [52]. Furthermore, the results of ongoing trials assessing further modalities such as immunotherapy (ClinicalTrials.gov Identifier: NCT02707666) or targeted therapy might be a promising extension in the multimodality treatment panel for MPM, in adjunct to surgery.
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Acknowledgments We thank our pathology colleague Dr. B. Vrugt for pictures of post-resectional EPP specimens and Dr. C. Spichiger and Dr Friess for support in the formatting and editing process of the article.
Funding This work and cited studies from Zurich were supported by Swiss National Science Foundation (SNSF) Professorship (Nr. PP00P3_133657, Nr. PP00P3_159269) to Isabelle Opitz.
Disclosure The authors have declared no conflicts of interest.
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41. Cho BC, Feld R, Leighl N et al. A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the "SMART" approach for resectable malignant pleural mesothelioma. J Thorac Oncol 2014; 9: 397-402. 42. Butchart EG, Ashcroft T, Barnsley WC, Holden MP. Pleuropneumonectomy in the management of diffuse malignant mesothelioma of the pleura. Experience with 29 patients. Thorax 1976; 31: 15-24. 43. Frauenfelder T, Kestenholz P, Hunziker R et al. Use of computed tomography and positron emission tomography/computed tomography for staging of local extent in patients with malignant pleural mesothelioma. J Comput Assist Tomogr 2015; 39: 160-165. 44. Edwards JG, Abrams KR, Leverment JN et al. Prognostic factors for malignant mesothelioma in 142 patients: validation of CALGB and EORTC prognostic scoring systems. Thorax 2000; 55: 731-735. 45. Pass HI, Kranda K, Temeck BK et al. Surgically debulked malignant pleural mesothelioma: results and prognostic factors. Ann Surg Oncol 1997; 4: 215-222. 46. Frauenfelder T, Tutic M, Weder W et al. Volumetry: an alternative to assess therapy response for malignant pleural mesothelioma? Eur Respir J 2011; 38: 162-168. 47. Rusch VW, Gill R, Mitchell A et al. A Multicenter Study of Volumetric Computed Tomography for Staging Malignant Pleural Mesothelioma. Ann Thorac Surg 2016; 102: 10591066. 48. Gill RR, Richards WG, Yeap BY et al. Epithelial malignant pleural mesothelioma after extrapleural pneumonectomy: stratification of survival with CT-derived tumor volume. AJR Am J Roentgenol 2012; 198: 359-363. 49. Fennell DA, Parmar A, Shamash J et al. Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials. J Clin Oncol 2005; 23: 184-189. 50. Sandri A, Guerrera F, Roffinella M et al. Validation of EORTC and CALGB prognostic models in surgical patients submitted to diagnostic, palliative or curative surgery for malignant pleural mesothelioma. J Thorac Dis 2016; 8: 2121-2127. 51. Opitz I, Friess M, Kestenholz P et al. A New Prognostic Score Supporting Treatment Allocation for Multimodality Therapy for Malignant Pleural Mesothelioma: A Review of 12 Years' Experience. J Thorac Oncol 2015; 10: 1634-1641. 52. Lim E. Surgery for Mesothelioma - MARS 2 update 2017. In. Available online: https://www.drericlim.com/news/2017/1/1/surgery-for-mesothelioma-mars-2-update-2017: 2017. Figure legends
Figure 1: Decortication step during EPD – peeling off the visceral pleura leaving behind unprotected lung tissue full of air leaks.
Figure 2: Survival according to type of treatment (SEER database). From Taioli et al 2015 [31].
Figure 3: Summary of median overall survival outcomes for patients with malignant pleural mesothelioma who underwent extended pleurectomy/decortication (EPD) or extrapleural pneumonectomy (EPP). Circle radius is logistically proportional to the size of individual studies. Solid lines indicate survival measured from the date of diagnosis, and dotted lines indicate survival measured from the date of surgery. From Cao et al 2014 [33].
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Figure 4: Induction chemotherapy followed by extrapleural pneumonectomy (EPP) versus induction chemotherapy followed by (extended) pleurectomy/decortication (P/D). KaplanMeier curve comparing (not propensity score matched) overall survival (OS) in patients treated with induction chemotherapy followed by EPP (n=150) (median OS 22 months; 95% confidence interval (CI): 20-24 months) versus patients treated with induction chemotherapy followed by P/D (n=73) (median OS 30 months; 95% CI: 26-34 months), log rank test p=0.005. Pathological IMIG stage and histological subtype at the time point of surgery was not significantly different between the two groups. Zurich unpublished data (1999-2017).
Figure 5: MMP Score. Kaplan-Meier curve comparing overall survival (OS) according to the multimodality prognostic score (MMP score) in patients treated with induction chemotherapy followed by macroscopic complete resection (MCR) (n=223): score 0 (n=28): median OS 46 months (95% confidence interval (CI): 0-97 months); score 1 (n=57): median OS 23 months (95% CI: 13-33 months); score 2 (n=28): median OS 15 months (95% CI: 11-18 months); score 3 (n=4): median OS 6 months (95% CI: 0-12 months); score 4 (n=1): median OS 4 months (95% CI: not available); p<0.001.
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Decortication step during EPD – peeling off the visceral pleura leaving behind unprotected lung tissue full of air leaks. 110x86mm (150 x 150 DPI)
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Survival according to type of treatment (SEER database). From Taioli et al 2015 [31]. 93x66mm (300 x 300 DPI)
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Summary of median overall survival outcomes for patients with malignant pleural mesothelioma who underwent extended pleurectomy/decortication (EPD) or extrapleural pneumonectomy (EPP). Circle radius is logistically proportional to the size of individual studies. Solid lines indicate survival measured from the date of diagnosis, and dotted lines indicate survival measured from the date of surgery. From Cao et al 2014 [33]. 118x81mm (113 x 113 DPI)
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Induction chemotherapy followed by extrapleural pneumonectomy (EPP) versus induction chemotherapy followed by (extended) pleurectomy/decortication (P/D). Kaplan-Meier curve comparing (not propensity score matched) overall survival (OS) in patients treated with induction chemotherapy followed by EPP (n=150) (median OS 22 months; 95% confidence interval (CI): 20-24 months) versus patients treated with induction chemotherapy followed by P/D (n=73) (median OS 30 months; 95% CI: 26-34 months), log rank test p=0.005. Pathological IMIG stage and histological subtype at the time point of surgery was not significantly different between the two groups. Zurich unpublished data (1999-2017). 116x89mm (600 x 600 DPI)
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: MMP Score. Kaplan-Meier curve comparing overall survival (OS) according to the multimodality prognostic score (MMP score) in patients treated with induction chemotherapy followed by macroscopic complete resection (MCR) (n=223): score 0 (n=28): median OS 46 months (95% confidence interval (CI): 0-97 months); score 1 (n=57): median OS 23 months (95% CI: 13-33 months); score 2 (n=28): median OS 15 months (95% CI: 11-18 months); score 3 (n=4): median OS 6 months (95% CI: 0-12 months); score 4 (n=1): median OS 4 months (95% CI: not available); p<0.001. 134x106mm (600 x 600 DPI)
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Table 1: Comparison of induction chemotherapy plus EPP versus induction chemotherapy plus EPDs performed at University Hospital Zurich. Ind. CTX induction chemotherapy; EPP extrapleural pneumonectomy; EPD / P/D (extended) pleurectomy/decortication; OS overall survival; PFS progression free survival. Zurich unpublished data.
Ind. CTX & EPP
Ind. CTX & EPD / P/D
Time frame
1999 – December 2017
July 2008 – December 2017
Number of patients
151
73
Median age at surgery
61 years (range 36 – 77)
65 years (range 33 – 77)
47 (31%) 104 (69%) 0
1 (1%) 72 (98%) 1 (1%)
Major morbidity
38% (58/151)
27% (20/73) Prolonged air leak: 77% (56/73)
Re-operation
35% (53/151)
26% (19/73)
Median hospitalization time
14 days (range 4 – 131)
19 days (range 7-106)
30-day mortality
5% (7/148)
0% (0/72)
90-day mortality
11% (16/148)
0% (0/69)
Median OS
18 months (95% CI: 16-21) (9% censored)
25 months (95% CI: 21-29) (59% censored)
Median PFS
10 months (95% CI: 8-13) (21% censored)
8 months (95% CI: 7-9) (27% censored)
Induction Chemotherapy − − −
platinum/gem platinum/pem Other
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