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A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma
Accepted Manuscript Title: A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma Author: Christopher Cao David Tian John Park James Allan Kristopher A. Pataky Tristan D. Yan PII: DOI: Reference:
S0169-5002(13)00540-0 http://dx.doi.org/doi:10.1016/j.lungcan.2013.11.026 LUNG 4497
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
10-9-2013 25-11-2013 28-11-2013
Please cite this article as: Cao C, Tian D, Park J, Allan J, Pataky KA, Yan TD, A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma, Lung Cancer (2013), http://dx.doi.org/10.1016/j.lungcan.2013.11.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Article type: Original article Title: A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma
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Authors: Christopher Cao1,2,3, David Tian1, John Park1, James Allan1, Kristopher A.
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Pataky1, Tristan D. Yan1,4
Affiliations: The Systematic Review Unit, Collaborative Research (CORE) Group,
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Sydney, Australia1; Department of Cardiothoracic Surgery, St George Hospital,
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Sydney, Australia2; The Baird Institute for Applied Heart and Lung Surgical Research, Sydney, Australia;3 Department of Cardiothoracic Surgery, Royal Prince
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Alfred Hospital, University of Sydney, Sydney, Australia4
Keywords: mesothelioma, meta-analysis, pneumonectomy, pleurectomy, systematic
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review Abstract word count: 250
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Main text word count: 2274
Corresponding Author: Christopher Cao, Collaborative Research (CORE) Group, Sydney, Australia; e-mail: [email protected]; Phone: +61291131111 Fax: +61291133393
Disclaimers: No potential conflicts of interest. Funding: None Acknowledgements: Sunil Gupta, Thomas Nienaber, David Chandrakumar for data editing; Nil funding sources decalred.
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ABSTRACT Background
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Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis. Surgical treatments of MPM with a curative intent include
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extrapleural pneumonectomy and extended pleurectomy/decortication (P/D). This
and extended P/D for selected surgical candidates.
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Methods
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meta-analysis aimed to compare the perioperative and long-term outcomes of EPP
A systematic review of the literature was performed on five electronic databases to
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identify all relevant data on comparative outcomes of extended P/D and EPP in a multimodality setting. Endpoints included perioperative mortality and morbidity, as
Results
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well as long-term overall survival.
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Seven relevant studies with comparative data on EPP (n= 632) versus extended P/D (n=513) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (2.9% vs 6.8%, p=0.02) and morbidity (27.9% vs 62.0%, p<0.0001) for patients who underwent extended P/D compared to EPP. Median overall survival ranged between 13 – 29 months for extended P/D and 12 – 22 months for EPP, with a trend favouring extended P/D. Conclusions Although it must be emphasized that patient selection and treatment strategies differ between EPP and extended P/D, a number of comparative studies have recently
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been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that selected patients who underwent extended P/D had lower perioperative morbidity and mortality with similar, if not
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superior, long-term survival compared to EPP, in the context of multi-modality therapy. This may represent an important paradigm shift in the surgical management
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of MPM.
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INTRODUCTION Malignant pleural mesothelioma (MPM) is an aggressive form of malignancy with a dismal prognosis of less than 12 months from the time of diagnosis. The incidence of
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MPM is expected to peak in most industrial nations within the coming decade.[1] Currently, selected patients with resectable disease can be treated with a curative
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intent through macroscopic complete resection. This can be achieved by either
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extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D), both of which can be combined with a wide range of adjuvant therapies, such as intrapleural
chemotherapy
and
photodynamic
therapy.[2-4]
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chemoradiation,
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Technical aspects of these procedures have been described previously.[5]
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Despite encouraging results from large institutional reports and prospective registries
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involving multi-modality therapy, outcomes of EPP and extended P/D have been highly variable and the selection of the ‘preferred’ surgical procedure remains highly
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controversial within the thoracic community.[6, 7] Indeed, authors of a feasibilitytesting randomized controlled trial have questioned the role of any form of radical surgery for patients with MPM.[8-10]
The purpose of the present study was to
review the current literature on perioperative and long-term outcomes of EPP and extended P/D, and to compare these two surgical procedures using the available evidence.
Extended P/D
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Historically, the definition of P/D has been inconsistent, varying from minimallyinvasive partial pleural excisions with a palliative intent to radical resections involving the pericardium and hemidiaphragm with a curative goal. To clarify and unify the
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definition of P/D, the International Mesothelioma Interest Group (IMIG), in collaboration with the International Association for the Study of Lung Cancer
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(IASLC), recently published a Consensus Report that classified pleurectomy-related
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procedures into three well-defined categories according to surgical technique[11]: 1. Extended P/D: parietal and visceral pleurectomy to remove all gross tumour
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with resection of the diaphragm and/or pericardium as required. 2. P/D: parietal and visceral pleurectomy to remove all gross tumour without
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resection of the diaphragm or pericardium.
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3. Partial pleurectomy: partial removal of parietal and/or visceral pleura for
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diagnostic or palliative purposes but leaving gross tumour behind.
A systematic review of studies on extended P/D reported a perioperative mortality rate of 0 – 11% (inter-quartile 0 – 3.4%) and a morbidity rate of 20 – 43%.[6] Patients who underwent extended P/D were found to have a trend towards longer overall survival at the cost of higher perioperative morbidity and mortality when compared to patients who underwent P/D or partial P/D. This was likely a reflection of the more aggressive surgical approach by removing the diaphragm and/or pericardium to achieve macroscopic complete resection.
Extrapleural pneumonectomy 5 Page 5 of 25
EPP involves en bloc resection of the parietal pleurae, lung, ipsilateral hemidiaphragm, and pericardium. As a result of removing the ipsilateral lung, local control of disease progression may be enhanced postoperatively by adjuvant high-
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dose radiotherapy, without the risk of radiation pneumonitis. A cross-sectional survey of thoracic surgeons with a special interest in MPM recently reported that 90% of
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resection, as compared to 68% for extended P/D.[11]
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respondents believed EPP to be capable of achieving macroscopic complete
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A systematic review of all studies on EPP reported an inter-quartile mortality rate of 3.7 – 7.6% and an inter-quartile median overall survival of 12 – 20 months.[7] A
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focused systematic review on trimodality therapy involving neoadjuvant or adjuvant chemotherapy, EPP and adjuvant radiotherapy reported a perioperative mortality
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rate of 0 – 12.5%, a morbidity rate of 50 – 83% and a median overall survival of 12.8
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– 46.9 months.[12] Specifically, four prospective studies involving a standardized treatment regimen with neoadjuvant chemotherapy reported favourable survival
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outcomes of 16.8 – 25.5 months on intention-to-treat analysis.[13-16] More recently, EPP has been described to be performed through the minimally invasive videoassisted thoracoscopic approach.[17]
PATIENTS AND METHODS Literature search strategy
To compare the outcomes of patients who underwent EPP versus extended P/D, electronic searches were performed using Ovid Medline, Embase, Cochrane Central Register of Controlled Trials (CCTR), Cochrane Database of Systematic Reviews
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(CDSR), ACP Journal Club, and Database of Abstracts of Review of Effectiveness (DARE) from their dates of inception to September 2013. To achieve the maximum sensitivity of the search strategy and identify all studies, we combined the terms
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“mesothelioma” with “pleurectomy” and “pneumonectomy” as either key words or MeSH terms. All identified articles were systematically assessed using the inclusion
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and exclusion criteria.
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Selection Criteria
Eligible comparative studies for the present meta-analysis included those in which
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patients with histologically proven MPM were treated by EPP or extended P/D. All types of MPM were included, as were patients who underwent various forms of
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adjuvant therapies. For studies that included patients with MPM who underwent
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radical surgery as a subset of patients who had other types of treatment, results for patients who underwent EPP or extended P/D were extracted when possible. When
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centres have published duplicate trials with accumulating numbers of patients or increased lengths of follow-up, only the most complete reports were included for qualitative appraisal at each time interval. It is acknowledged that patient selection for surgery varied amongst institutions and sometimes within an institution at different time periods. All publications were limited to human subjects and in English language. Abstracts, case reports, conference presentations, editorials and expert opinions were excluded. Review articles were omitted due to potential publication bias and possible duplication of results. Studies that included fewer than twenty patients in either treatment arm were also excluded.
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All data were extracted from article texts, tables and figures. Two investigators (D.T. and K.A.P.) independently reviewed each retrieved article. Discrepancies between the two reviewers were resolved by discussion and consensus. The final results
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were reviewed by the senior investigators (C.C. and T.D.Y.).
Statistical analysis
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Meta-analysis was performed by combining the results of reported incidences of perioperative mortality and morbidity. The relative risk (RR) was used as a summary
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statistic. X2 tests were used to study heterogeneity between trials. I2 statistic was used to estimate the percentage of total variation across studies, due to
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heterogeneity rather than chance. I2 can be calculated as: I2 = 100% x (Q - df)/Q, with Q defined as Cochrane’s heterogeneity statistics and df defined as degree of
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freedom.[18] An I2 value of greater than 50% was considered substantial
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heterogeneity. If there was substantial heterogeneity, the possible clinical and
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methodological reasons for this were explored qualitatively. In the present metaanalysis, the results using the random-effects model were presented to take into account the possible clinical diversity and methodological variation amongst studies. Specific analyses considering confounding factors were not possible because raw data were not available. All P values were 2-sided. A significant difference was defined as p < 0.05. Statistical analysis was conducted with Review Manager Version 5.1.2 (Cochrane Collaboration, Software Update, Oxford, United Kingdom).
RESULTS Quantity and Quality of Trials
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A total of 155 references were identified through the five electronic database searches and additional sources. After exclusion of duplicate or irrelevant references, 37 potentially relevant articles were retrieved for more detailed
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evaluation. After applying the selection criteria, seven comparative studies remained for assessment. [19-25] Manual search of the reference lists did not identify any
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additional relevant studies. Of the seven studies included in the present meta-
analysis, all were from observational studies, as summarized in Table 1. In these
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studies, 1145 patients with MPM were compared, including 632 patients who
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underwent EPP and 513 patients who underwent extended P/D. Baseline patient characteristics and adjuvant therapy regimens varied between studies, as
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summarized in Tables 2.
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Assessment of Perioperative Mortality and Morbidity
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All-cause perioperative mortality was found to be significantly lower after extended P/D compared to EPP (2.9% vs 6.8%; RR, 0.53; 95% confidence interval [CI], 0.31 –
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0.91; P = 0.02; I2 = 0%). These results are summarized in Figure 1. Perioperative morbidity was also found to be significantly lower after extended P/D compared to EPP (27.9% vs 62.0%; RR, 0.44; 95% CI, 0.30 – 0.63; P < 0.0001; I2 = 44%). These results are summarized in Figure 2. One study reported only major complications, but a sensitivity analysis excluding this study did not affect the statistical outcome.[24] Another study only reported the number of adverse events rather than the number of patients who had complications, and was thus excluded from statistical analysis, as one patient could have had multiple complications.[23]
Assessment of Overall Survival
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Survival was calculated from the date of surgery in 4 studies [19, 22-24] and the date of diagnosis in 3 studies [20, 21, 25]. There was insufficient data for meta-analysis to compare the overall survival outcomes between the two treatment arms. A bubble
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graph is presented in Figure 3 to summarize median survival outcomes in relation to
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study size.
DISCUSSION
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The present meta-analysis compared EPP with extended P/D using all the available
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evidence in the current literature. Prior to the reclassification of P/D by IMIG and IASLC, pleurectomy procedures varied significantly in surgical technique and
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therapeutic intent. Minimally invasive procedures consisting of little more than pleural biopsies were sometimes categorized with radical procedures that required
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extensive resection and reconstruction of the pericardium and diaphragm. By only
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including studies that reported on extended P/D, the present meta-analysis aimed to compare two surgical techniques with the same therapeutic intent, which was to
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achieve macroscopic complete resection to provide long-term oncologic efficacy in patients with resectable disease.
Results of the present study suggested that EPP was associated with significantly higher perioperative morbidity and mortality rates compared to extended P/D. These findings were consistent with recent institutional reports that claimed P/D to be a ‘superior’ technique to the ‘harmful’ EPP.[20, 22] However, extreme caution must be exercised in interpreting these results, as emphasized by Flores et al., who reported on a series of 663 consecutive patients that also demonstrated superior mortality and morbidity outcomes for patients who underwent extended P/D compared to 10 Page 10 of 25
EPP.[23] As the authors correctly highlighted, a number of reasons may have accounted for the differences in the outcomes of these two procedures, and patients were subject to selection bias. Furthermore, it should be pointed out that many
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surgeons do not consider these two procedures to be interchangeable, and that for selected patients, particularly those with bulky parenchymal disease or disease
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involving the fissure, EPP may be the only option to offer complete macroscopic
resection.[23] Nonetheless, direct comparisons between the two procedures are
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increasingly reported in the recent literature.[21, 22, 25]
A number of limitations to the present study need to be acknowledged. Firstly, the
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primary endpoints were reported according to different definitions from individual institutions. The classification of perioperative morbidity varied significantly and
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grading systems were not uniformly reported. Similarly, overall survival was
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calculated from the date of surgery in some reports but the date of diagnosis was
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reported in others, which can significantly prolong survival as a result of lead time bias. Due to significant heterogeneity in the clinical and radiographic follow-up protocols between institutions, disease-free survival outcomes were not assessed in the present study. Secondly, all comparative studies were retrospective observational studies, and potential differences in baseline clinicpathological characteristics that are known to have a significant impact on prognosis may exist between treatment arms.[26] The lack of any completed randomized controlled trials comparing extended P/D and EPP or conservative management highlights the relative rarity of MPM and the logistical difficulties in conducting such a study. Thirdly, the retrospective categorization of P/D-related procedures may not have been precise for all patients reported in individual studies. Studies that described 11 Page 11 of 25
resection of diaphragm and/or pericardium were classified as ‘extended P/D’ even if not every patient required such extensive resections, because the IASLC definition stated resection of these structures only when required. Finally, we should
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acknowledge the variations in the extent of decortication performed in different institutions, and future studies should describe the extent of visceral pleurectomy in
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more detail.
In an attempt to provide more robust evidence on the radical surgical treatment of
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MPM, the Mesothelioma and Radial Surgery (MARS) pilot trial was conducted in 12 institutions from the United Kingdom between 2005 – 2008.[27] The primary aim of
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this study was to assess the feasibility of obtaining sufficient patient acceptance and recruitment rate to conduct a larger trial with longer follow-up. Unfortunately, the
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study was concluded at three years, after accruing only 50 patients who were
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randomized to either EPP or no EPP. Retrospectively analysing the limited data, authors of the MARS trial concluded that radical surgery in the form of EPP within
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trimodality therapy offers no benefit, and possibly harm patients. The study design, analysis and interpretation of the MARS trial have since drawn criticism related to the small number of patients accrued, inconsistent adjuvant therapy regimen and significant cross-over rates between the treatment arms.[28] Although the safety and efficacy of EPP versus conservative management has not been adequately addressed, the MARS 2 trial will shift its focus to extended P/D.[29]
In conclusion, systematic reviews of EPP and extended P/D have demonstrated that these procedures can be performed relatively safely with long-term oncological efficacy for selected patients at specialized centres within a multi-disciplinary 12 Page 12 of 25
framework. Whilst acknowledging a number of important limitations to the existing evidence in the current literature, results of the present meta-analysis suggested that extended P/D can be performed with lower morbidity and mortality outcomes, as well
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as comparable long-term survival outcomes to EPP. However, it is important to emphasize that EPP and extended P/D are not interchangeable procedures for all
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disease, patient comorbidities and surgeon’s experience.
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patients, and that individualised treatment plans should be based on the extent of
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Conflict of Interest Statement
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None to declare
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Cao CT, D.; Manganas, C.; Matthews, P.; Yan TD. Systematic review of trimodality therapy for patients with malignant pleural mesothelioma. Ann Cardiothorac Surg 2012; 1: 428 - 437.
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Van Schil PE, Baas P, Gaafar R, Maat AP, Van de Pol M, Hasan B, Klomp HM, Abdelrahman AM, Welch J, van Meerbeeck JP. Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial. Eur Respir J 2010; 36: 1362-1369.
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FIGURE LEGENDS
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International Association for the Study of Lung Cancer 2009; 4: 1189-1191.
Figure 1. Search strategy of meta-analysis on extended pleurectomy/decortication
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versus extrapleural pneumonectomy for patients with malignant pleural mesothelioma
Figure 2. Forest plot of the relative risk (RR) of all-cause mortality after extended pleurectomy/decortication (E P/D) versus extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma. The estimate of the RR of each study corresponds to the middle of the squares, and the horizontal line shows the 95% confidence interval (CI). On each line, the numbers of events as a fraction of the total number treated are shown for both treatment groups. For each subgroup, the sum of the statistics, along with the summary RR, is represented by the middle of the solid
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diamonds. A test of heterogeneity between the trials within a subgroup is given below the summary statistics. Figure 3. Forest plot of the relative risk (RR) of perioperative morbidity after
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extended pleurectomy/decortication (E P/D) versus extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma. The estimate of the RR of
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each study corresponds to the middle of the squares, and the horizontal line shows
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the 95% confidence interval (CI). On each line, the numbers of events as a fraction of the total number treated are shown for both treatment groups. For each subgroup,
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the sum of the statistics, along with the summary RR, is represented by the middle of the solid diamonds. A test of heterogeneity between the trials within a subgroup is
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given below the summary statistics.
Figure 4. Summary of median overall survival outcomes for patients with malignant
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pleural mesothelioma who underwent extended pleurectomy/decortication (E P/D) or
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extrapleural pneumonectomy (EPP). Circle radius is logistically proportional to the
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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.
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Study period
Institution
2001 - 2013 2004 - 2011 1999 - 2010
Yedikule Hospital, Turkey Guy’s Hospital, UK Glenfield Hospital, UK Maggiore of Charity University Hospital, Italy Memorial Sloan-Kettering Cancer Center, USA Hyogo Cancer Center, Japan Freiburg University Medical Center, Germany
1998 - 2009 2008
Okada (24)
2008
1990 - 2006 1986 - 2006
Ploenes (25)
2013
NR
37 278 34
Follow-up (months) E P/D EPP 25.0 23.7 15.7 12.9 16.2 20.5
40
NR 17
385 31
9
23
25
NR
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Flores (23)
Study size E P/D EPP 20 31 54 22 67 98
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Bedirhan (19) Lang-Lazdunski (20) Nakas (21) Rena (22)
Year of publication 2013 2012 2012 2012
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Author (ref no.)
Lang-Lazdunski (20)
67
Flores (23) Okada (24) Ploenes (25)
64
78
I
II
III
NS IMIG
IMIG
EPP – Stage (%)
IV
I
II
III
Adjuvant therapy regimen
IV
NS
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26
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Nakas (21) Rena (22)
84
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75
E P/D – Stage (%)
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Bedirhan (19)
Staging system
50
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Epitheloid Histology (%) E P/D EPP
Author (ref no.)
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Table 1. Summary of study characteristics comparing extended pleurectomy/decortication (E P/D) to extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma; NR, not reported
13
9
5
Adj Chemo (n=20) 55
32
Adj Chemo (n=54) Adj Radio (n=54) Hyperthermic pleural lavage (n=54)
EPP Adj Chemo (n=31) Adj Radio (n=31) Neoadj Chemo (n=22) Adj Radio (n=17)
Neoadj Chemo (n=25) Adj Chemo (n=26) Adj Radio (n=33) Neoadj Chemo (n=31) Neoadj Chemo (n=33) Adj Chemo (n=6) Adj Chemo (n=7) Adj radio (n = 37) Adj radio (n=40) Chemo (n=186), Adj Radio (n=152) Combined Chemo-Radio (n=89) Neoadj Chemo (n=5) NS Adj Radio (n=9) Intra-op hyperthermic NS chemo (n=6) Neoadj Chemo (n=8) Adj Chemo (n=32)
NS
84
87
Butchart
24
76
0
0
18
83
0
0
64
70
AJCC
15
21
49
16
3
22
71
4
85
61
IMIG
24
24
47
6
0
16
77
6
87
80
UICC
NS
E P/D
Table 2. Summary of baseline patient- and treatment-related characteristics in studies comparing extended pleurectomy/decortication (E P/D) with extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma. IMIG, International Mesothelioma Interest Group; AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; Adj, adjuvant; Neoadj, neoadjuvant ; NS, not specified.
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Additional records identified through other sources (n = 1)
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Records identified through database searching (n = 154)
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Screening
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Records after duplicates removed (n = 155)
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Identification
Figure
Records excluded (n = 118)
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Full-text articles assessed for eligibility (n = 37)
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Included
Eligibility
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Records screened (n = 155)
Full-text articles excluded (n = 30) Not extended P/D (17) Duplicate dataset (6) N<20 (3) No primary outcome (2) Review (2)
Studies included in quantitative analysis (n = 7)
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Figure
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S0169-5002(13)00540-0 http://dx.doi.org/doi:10.1016/j.lungcan.2013.11.026 LUNG 4497
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
10-9-2013 25-11-2013 28-11-2013
Please cite this article as: Cao C, Tian D, Park J, Allan J, Pataky KA, Yan TD, A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma, Lung Cancer (2013), http://dx.doi.org/10.1016/j.lungcan.2013.11.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Article type: Original article Title: A systematic review and meta-analysis of surgical treatments for malignant pleural mesothelioma
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Authors: Christopher Cao1,2,3, David Tian1, John Park1, James Allan1, Kristopher A.
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Pataky1, Tristan D. Yan1,4
Affiliations: The Systematic Review Unit, Collaborative Research (CORE) Group,
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Sydney, Australia1; Department of Cardiothoracic Surgery, St George Hospital,
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Sydney, Australia2; The Baird Institute for Applied Heart and Lung Surgical Research, Sydney, Australia;3 Department of Cardiothoracic Surgery, Royal Prince
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Alfred Hospital, University of Sydney, Sydney, Australia4
Keywords: mesothelioma, meta-analysis, pneumonectomy, pleurectomy, systematic
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review Abstract word count: 250
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Main text word count: 2274
Corresponding Author: Christopher Cao, Collaborative Research (CORE) Group, Sydney, Australia; e-mail: [email protected]; Phone: +61291131111 Fax: +61291133393
Disclaimers: No potential conflicts of interest. Funding: None Acknowledgements: Sunil Gupta, Thomas Nienaber, David Chandrakumar for data editing; Nil funding sources decalred.
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ABSTRACT Background
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Malignant pleural mesothelioma (MPM) is an aggressive disease of the pleural lining with a dismal prognosis. Surgical treatments of MPM with a curative intent include
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extrapleural pneumonectomy and extended pleurectomy/decortication (P/D). This
and extended P/D for selected surgical candidates.
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Methods
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meta-analysis aimed to compare the perioperative and long-term outcomes of EPP
A systematic review of the literature was performed on five electronic databases to
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identify all relevant data on comparative outcomes of extended P/D and EPP in a multimodality setting. Endpoints included perioperative mortality and morbidity, as
Results
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well as long-term overall survival.
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Seven relevant studies with comparative data on EPP (n= 632) versus extended P/D (n=513) were identified from the current literature. Comparison of these two groups demonstrated significantly lower perioperative mortality (2.9% vs 6.8%, p=0.02) and morbidity (27.9% vs 62.0%, p<0.0001) for patients who underwent extended P/D compared to EPP. Median overall survival ranged between 13 – 29 months for extended P/D and 12 – 22 months for EPP, with a trend favouring extended P/D. Conclusions Although it must be emphasized that patient selection and treatment strategies differ between EPP and extended P/D, a number of comparative studies have recently
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been conducted to compare these two surgical techniques for patients with resectable MPM. The present study indicated that selected patients who underwent extended P/D had lower perioperative morbidity and mortality with similar, if not
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superior, long-term survival compared to EPP, in the context of multi-modality therapy. This may represent an important paradigm shift in the surgical management
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of MPM.
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INTRODUCTION Malignant pleural mesothelioma (MPM) is an aggressive form of malignancy with a dismal prognosis of less than 12 months from the time of diagnosis. The incidence of
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MPM is expected to peak in most industrial nations within the coming decade.[1] Currently, selected patients with resectable disease can be treated with a curative
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intent through macroscopic complete resection. This can be achieved by either
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extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D), both of which can be combined with a wide range of adjuvant therapies, such as intrapleural
chemotherapy
and
photodynamic
therapy.[2-4]
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chemoradiation,
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Technical aspects of these procedures have been described previously.[5]
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Despite encouraging results from large institutional reports and prospective registries
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involving multi-modality therapy, outcomes of EPP and extended P/D have been highly variable and the selection of the ‘preferred’ surgical procedure remains highly
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controversial within the thoracic community.[6, 7] Indeed, authors of a feasibilitytesting randomized controlled trial have questioned the role of any form of radical surgery for patients with MPM.[8-10]
The purpose of the present study was to
review the current literature on perioperative and long-term outcomes of EPP and extended P/D, and to compare these two surgical procedures using the available evidence.
Extended P/D
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Historically, the definition of P/D has been inconsistent, varying from minimallyinvasive partial pleural excisions with a palliative intent to radical resections involving the pericardium and hemidiaphragm with a curative goal. To clarify and unify the
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definition of P/D, the International Mesothelioma Interest Group (IMIG), in collaboration with the International Association for the Study of Lung Cancer
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(IASLC), recently published a Consensus Report that classified pleurectomy-related
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procedures into three well-defined categories according to surgical technique[11]: 1. Extended P/D: parietal and visceral pleurectomy to remove all gross tumour
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with resection of the diaphragm and/or pericardium as required. 2. P/D: parietal and visceral pleurectomy to remove all gross tumour without
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resection of the diaphragm or pericardium.
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3. Partial pleurectomy: partial removal of parietal and/or visceral pleura for
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diagnostic or palliative purposes but leaving gross tumour behind.
A systematic review of studies on extended P/D reported a perioperative mortality rate of 0 – 11% (inter-quartile 0 – 3.4%) and a morbidity rate of 20 – 43%.[6] Patients who underwent extended P/D were found to have a trend towards longer overall survival at the cost of higher perioperative morbidity and mortality when compared to patients who underwent P/D or partial P/D. This was likely a reflection of the more aggressive surgical approach by removing the diaphragm and/or pericardium to achieve macroscopic complete resection.
Extrapleural pneumonectomy 5 Page 5 of 25
EPP involves en bloc resection of the parietal pleurae, lung, ipsilateral hemidiaphragm, and pericardium. As a result of removing the ipsilateral lung, local control of disease progression may be enhanced postoperatively by adjuvant high-
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dose radiotherapy, without the risk of radiation pneumonitis. A cross-sectional survey of thoracic surgeons with a special interest in MPM recently reported that 90% of
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resection, as compared to 68% for extended P/D.[11]
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respondents believed EPP to be capable of achieving macroscopic complete
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A systematic review of all studies on EPP reported an inter-quartile mortality rate of 3.7 – 7.6% and an inter-quartile median overall survival of 12 – 20 months.[7] A
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focused systematic review on trimodality therapy involving neoadjuvant or adjuvant chemotherapy, EPP and adjuvant radiotherapy reported a perioperative mortality
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rate of 0 – 12.5%, a morbidity rate of 50 – 83% and a median overall survival of 12.8
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– 46.9 months.[12] Specifically, four prospective studies involving a standardized treatment regimen with neoadjuvant chemotherapy reported favourable survival
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outcomes of 16.8 – 25.5 months on intention-to-treat analysis.[13-16] More recently, EPP has been described to be performed through the minimally invasive videoassisted thoracoscopic approach.[17]
PATIENTS AND METHODS Literature search strategy
To compare the outcomes of patients who underwent EPP versus extended P/D, electronic searches were performed using Ovid Medline, Embase, Cochrane Central Register of Controlled Trials (CCTR), Cochrane Database of Systematic Reviews
6 Page 6 of 25
(CDSR), ACP Journal Club, and Database of Abstracts of Review of Effectiveness (DARE) from their dates of inception to September 2013. To achieve the maximum sensitivity of the search strategy and identify all studies, we combined the terms
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“mesothelioma” with “pleurectomy” and “pneumonectomy” as either key words or MeSH terms. All identified articles were systematically assessed using the inclusion
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and exclusion criteria.
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Selection Criteria
Eligible comparative studies for the present meta-analysis included those in which
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patients with histologically proven MPM were treated by EPP or extended P/D. All types of MPM were included, as were patients who underwent various forms of
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adjuvant therapies. For studies that included patients with MPM who underwent
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radical surgery as a subset of patients who had other types of treatment, results for patients who underwent EPP or extended P/D were extracted when possible. When
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centres have published duplicate trials with accumulating numbers of patients or increased lengths of follow-up, only the most complete reports were included for qualitative appraisal at each time interval. It is acknowledged that patient selection for surgery varied amongst institutions and sometimes within an institution at different time periods. All publications were limited to human subjects and in English language. Abstracts, case reports, conference presentations, editorials and expert opinions were excluded. Review articles were omitted due to potential publication bias and possible duplication of results. Studies that included fewer than twenty patients in either treatment arm were also excluded.
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All data were extracted from article texts, tables and figures. Two investigators (D.T. and K.A.P.) independently reviewed each retrieved article. Discrepancies between the two reviewers were resolved by discussion and consensus. The final results
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were reviewed by the senior investigators (C.C. and T.D.Y.).
Statistical analysis
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Meta-analysis was performed by combining the results of reported incidences of perioperative mortality and morbidity. The relative risk (RR) was used as a summary
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statistic. X2 tests were used to study heterogeneity between trials. I2 statistic was used to estimate the percentage of total variation across studies, due to
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heterogeneity rather than chance. I2 can be calculated as: I2 = 100% x (Q - df)/Q, with Q defined as Cochrane’s heterogeneity statistics and df defined as degree of
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freedom.[18] An I2 value of greater than 50% was considered substantial
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heterogeneity. If there was substantial heterogeneity, the possible clinical and
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methodological reasons for this were explored qualitatively. In the present metaanalysis, the results using the random-effects model were presented to take into account the possible clinical diversity and methodological variation amongst studies. Specific analyses considering confounding factors were not possible because raw data were not available. All P values were 2-sided. A significant difference was defined as p < 0.05. Statistical analysis was conducted with Review Manager Version 5.1.2 (Cochrane Collaboration, Software Update, Oxford, United Kingdom).
RESULTS Quantity and Quality of Trials
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A total of 155 references were identified through the five electronic database searches and additional sources. After exclusion of duplicate or irrelevant references, 37 potentially relevant articles were retrieved for more detailed
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evaluation. After applying the selection criteria, seven comparative studies remained for assessment. [19-25] Manual search of the reference lists did not identify any
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additional relevant studies. Of the seven studies included in the present meta-
analysis, all were from observational studies, as summarized in Table 1. In these
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studies, 1145 patients with MPM were compared, including 632 patients who
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underwent EPP and 513 patients who underwent extended P/D. Baseline patient characteristics and adjuvant therapy regimens varied between studies, as
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summarized in Tables 2.
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Assessment of Perioperative Mortality and Morbidity
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All-cause perioperative mortality was found to be significantly lower after extended P/D compared to EPP (2.9% vs 6.8%; RR, 0.53; 95% confidence interval [CI], 0.31 –
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0.91; P = 0.02; I2 = 0%). These results are summarized in Figure 1. Perioperative morbidity was also found to be significantly lower after extended P/D compared to EPP (27.9% vs 62.0%; RR, 0.44; 95% CI, 0.30 – 0.63; P < 0.0001; I2 = 44%). These results are summarized in Figure 2. One study reported only major complications, but a sensitivity analysis excluding this study did not affect the statistical outcome.[24] Another study only reported the number of adverse events rather than the number of patients who had complications, and was thus excluded from statistical analysis, as one patient could have had multiple complications.[23]
Assessment of Overall Survival
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Survival was calculated from the date of surgery in 4 studies [19, 22-24] and the date of diagnosis in 3 studies [20, 21, 25]. There was insufficient data for meta-analysis to compare the overall survival outcomes between the two treatment arms. A bubble
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graph is presented in Figure 3 to summarize median survival outcomes in relation to
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study size.
DISCUSSION
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The present meta-analysis compared EPP with extended P/D using all the available
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evidence in the current literature. Prior to the reclassification of P/D by IMIG and IASLC, pleurectomy procedures varied significantly in surgical technique and
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therapeutic intent. Minimally invasive procedures consisting of little more than pleural biopsies were sometimes categorized with radical procedures that required
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extensive resection and reconstruction of the pericardium and diaphragm. By only
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including studies that reported on extended P/D, the present meta-analysis aimed to compare two surgical techniques with the same therapeutic intent, which was to
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achieve macroscopic complete resection to provide long-term oncologic efficacy in patients with resectable disease.
Results of the present study suggested that EPP was associated with significantly higher perioperative morbidity and mortality rates compared to extended P/D. These findings were consistent with recent institutional reports that claimed P/D to be a ‘superior’ technique to the ‘harmful’ EPP.[20, 22] However, extreme caution must be exercised in interpreting these results, as emphasized by Flores et al., who reported on a series of 663 consecutive patients that also demonstrated superior mortality and morbidity outcomes for patients who underwent extended P/D compared to 10 Page 10 of 25
EPP.[23] As the authors correctly highlighted, a number of reasons may have accounted for the differences in the outcomes of these two procedures, and patients were subject to selection bias. Furthermore, it should be pointed out that many
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surgeons do not consider these two procedures to be interchangeable, and that for selected patients, particularly those with bulky parenchymal disease or disease
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involving the fissure, EPP may be the only option to offer complete macroscopic
resection.[23] Nonetheless, direct comparisons between the two procedures are
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increasingly reported in the recent literature.[21, 22, 25]
A number of limitations to the present study need to be acknowledged. Firstly, the
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primary endpoints were reported according to different definitions from individual institutions. The classification of perioperative morbidity varied significantly and
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grading systems were not uniformly reported. Similarly, overall survival was
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calculated from the date of surgery in some reports but the date of diagnosis was
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reported in others, which can significantly prolong survival as a result of lead time bias. Due to significant heterogeneity in the clinical and radiographic follow-up protocols between institutions, disease-free survival outcomes were not assessed in the present study. Secondly, all comparative studies were retrospective observational studies, and potential differences in baseline clinicpathological characteristics that are known to have a significant impact on prognosis may exist between treatment arms.[26] The lack of any completed randomized controlled trials comparing extended P/D and EPP or conservative management highlights the relative rarity of MPM and the logistical difficulties in conducting such a study. Thirdly, the retrospective categorization of P/D-related procedures may not have been precise for all patients reported in individual studies. Studies that described 11 Page 11 of 25
resection of diaphragm and/or pericardium were classified as ‘extended P/D’ even if not every patient required such extensive resections, because the IASLC definition stated resection of these structures only when required. Finally, we should
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acknowledge the variations in the extent of decortication performed in different institutions, and future studies should describe the extent of visceral pleurectomy in
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more detail.
In an attempt to provide more robust evidence on the radical surgical treatment of
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MPM, the Mesothelioma and Radial Surgery (MARS) pilot trial was conducted in 12 institutions from the United Kingdom between 2005 – 2008.[27] The primary aim of
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this study was to assess the feasibility of obtaining sufficient patient acceptance and recruitment rate to conduct a larger trial with longer follow-up. Unfortunately, the
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study was concluded at three years, after accruing only 50 patients who were
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randomized to either EPP or no EPP. Retrospectively analysing the limited data, authors of the MARS trial concluded that radical surgery in the form of EPP within
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trimodality therapy offers no benefit, and possibly harm patients. The study design, analysis and interpretation of the MARS trial have since drawn criticism related to the small number of patients accrued, inconsistent adjuvant therapy regimen and significant cross-over rates between the treatment arms.[28] Although the safety and efficacy of EPP versus conservative management has not been adequately addressed, the MARS 2 trial will shift its focus to extended P/D.[29]
In conclusion, systematic reviews of EPP and extended P/D have demonstrated that these procedures can be performed relatively safely with long-term oncological efficacy for selected patients at specialized centres within a multi-disciplinary 12 Page 12 of 25
framework. Whilst acknowledging a number of important limitations to the existing evidence in the current literature, results of the present meta-analysis suggested that extended P/D can be performed with lower morbidity and mortality outcomes, as well
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as comparable long-term survival outcomes to EPP. However, it is important to emphasize that EPP and extended P/D are not interchangeable procedures for all
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disease, patient comorbidities and surgeon’s experience.
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patients, and that individualised treatment plans should be based on the extent of
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Conflict of Interest Statement
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None to declare
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FIGURE LEGENDS
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International Association for the Study of Lung Cancer 2009; 4: 1189-1191.
Figure 1. Search strategy of meta-analysis on extended pleurectomy/decortication
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versus extrapleural pneumonectomy for patients with malignant pleural mesothelioma
Figure 2. Forest plot of the relative risk (RR) of all-cause mortality after extended pleurectomy/decortication (E P/D) versus extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma. The estimate of the RR of each study corresponds to the middle of the squares, and the horizontal line shows the 95% confidence interval (CI). On each line, the numbers of events as a fraction of the total number treated are shown for both treatment groups. For each subgroup, the sum of the statistics, along with the summary RR, is represented by the middle of the solid
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diamonds. A test of heterogeneity between the trials within a subgroup is given below the summary statistics. Figure 3. Forest plot of the relative risk (RR) of perioperative morbidity after
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extended pleurectomy/decortication (E P/D) versus extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma. The estimate of the RR of
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each study corresponds to the middle of the squares, and the horizontal line shows
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the 95% confidence interval (CI). On each line, the numbers of events as a fraction of the total number treated are shown for both treatment groups. For each subgroup,
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the sum of the statistics, along with the summary RR, is represented by the middle of the solid diamonds. A test of heterogeneity between the trials within a subgroup is
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given below the summary statistics.
Figure 4. Summary of median overall survival outcomes for patients with malignant
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pleural mesothelioma who underwent extended pleurectomy/decortication (E P/D) or
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extrapleural pneumonectomy (EPP). Circle radius is logistically proportional to the
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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.
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Study period
Institution
2001 - 2013 2004 - 2011 1999 - 2010
Yedikule Hospital, Turkey Guy’s Hospital, UK Glenfield Hospital, UK Maggiore of Charity University Hospital, Italy Memorial Sloan-Kettering Cancer Center, USA Hyogo Cancer Center, Japan Freiburg University Medical Center, Germany
1998 - 2009 2008
Okada (24)
2008
1990 - 2006 1986 - 2006
Ploenes (25)
2013
NR
37 278 34
Follow-up (months) E P/D EPP 25.0 23.7 15.7 12.9 16.2 20.5
40
NR 17
385 31
9
23
25
NR
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Flores (23)
Study size E P/D EPP 20 31 54 22 67 98
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Bedirhan (19) Lang-Lazdunski (20) Nakas (21) Rena (22)
Year of publication 2013 2012 2012 2012
cr
Author (ref no.)
Lang-Lazdunski (20)
67
Flores (23) Okada (24) Ploenes (25)
64
78
I
II
III
NS IMIG
IMIG
EPP – Stage (%)
IV
I
II
III
Adjuvant therapy regimen
IV
NS
11
26
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Nakas (21) Rena (22)
84
M
75
E P/D – Stage (%)
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Bedirhan (19)
Staging system
50
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Epitheloid Histology (%) E P/D EPP
Author (ref no.)
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Table 1. Summary of study characteristics comparing extended pleurectomy/decortication (E P/D) to extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma; NR, not reported
13
9
5
Adj Chemo (n=20) 55
32
Adj Chemo (n=54) Adj Radio (n=54) Hyperthermic pleural lavage (n=54)
EPP Adj Chemo (n=31) Adj Radio (n=31) Neoadj Chemo (n=22) Adj Radio (n=17)
Neoadj Chemo (n=25) Adj Chemo (n=26) Adj Radio (n=33) Neoadj Chemo (n=31) Neoadj Chemo (n=33) Adj Chemo (n=6) Adj Chemo (n=7) Adj radio (n = 37) Adj radio (n=40) Chemo (n=186), Adj Radio (n=152) Combined Chemo-Radio (n=89) Neoadj Chemo (n=5) NS Adj Radio (n=9) Intra-op hyperthermic NS chemo (n=6) Neoadj Chemo (n=8) Adj Chemo (n=32)
NS
84
87
Butchart
24
76
0
0
18
83
0
0
64
70
AJCC
15
21
49
16
3
22
71
4
85
61
IMIG
24
24
47
6
0
16
77
6
87
80
UICC
NS
E P/D
Table 2. Summary of baseline patient- and treatment-related characteristics in studies comparing extended pleurectomy/decortication (E P/D) with extrapleural pneumonectomy (EPP) in the treatment of malignant pleural mesothelioma. IMIG, International Mesothelioma Interest Group; AJCC, American Joint Committee on Cancer; UICC, Union for International Cancer Control; Adj, adjuvant; Neoadj, neoadjuvant ; NS, not specified.
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Additional records identified through other sources (n = 1)
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Records identified through database searching (n = 154)
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Screening
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Records after duplicates removed (n = 155)
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Identification
Figure
Records excluded (n = 118)
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Full-text articles assessed for eligibility (n = 37)
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Included
Eligibility
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Records screened (n = 155)
Full-text articles excluded (n = 30) Not extended P/D (17) Duplicate dataset (6) N<20 (3) No primary outcome (2) Review (2)
Studies included in quantitative analysis (n = 7)
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Figure
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Figure
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Figure
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