Journal of Thoracic Oncology:
State of the Art: Concise Review
A Systematic Review of Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma
Cao, Christopher Q. BSc (Med), MBBS*†; Yan, Tristan D. BSc (Med), MBBS, PhD*†; Bannon, Paul G. MBBS, PhD, FRACS*†; McCaughan, Brian C. MBBS, FRACS*†
*Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, the University of Sydney; and †the Baird Institute for Applied Heart and Lung Surgical Research, Sydney, Australia.
Disclosure: The authors declare no conflicts of interest.
Address for correspondence: Tristan D. Yan, BSc (Med), MBBS, PhD, Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. E-mail: Tristan.firstname.lastname@example.org
Introduction: The primary objective of the present systematic review was to evaluate the safety and efficacy of extrapleural pneumonectomy (EPP) for patients with malignant pleural mesothelioma.
Methods: A systematic review of relevant studies identified through five online search databases was performed. Two reviewers independently appraised each study.
Results: Thirty-four of 58 relevant studies from 26 institutions containing the most updated data were evaluated for survival and perioperative outcomes after EPP. The median overall survival varied from 9.4 to 27.5 months, and 1-, 2-, and 5-year survival rates ranged from 36 to 83%, 5 to 59%, and 0 to 24%, respectively. Overall perioperative mortality rates ranged from 0 to 11.8%, and the perioperative morbidity rates ranged from 22 to 82%. Quality of life assessments from three studies reported improvements in nearly all domains at 3 months postoperatively. Patients who underwent trimodality therapy involving EPP and adjuvant chemoradiotherapy had a median overall survival of 13 to 23.9 months.
Discussions: The current evidence suggests that selected patients with malignant pleural mesothelioma may benefit from EPP, especially when combined with neoadjuvant or adjuvant chemotherapy and adjuvant radiotherapy.
Malignant pleural mesothelioma (MPM) is a rare and aggressive disease arising from the pleural mesothelium, with a reported survival of less than 12 months.1 Despite advances in modern systemic chemotherapy, long-term survival in patients with MPM remains limited.2 Because of the lag time between asbestos exposure and disease manifestation, the peak incidence of MPM in the United States is projected to be between 2010 and 2020. Other developed countries show similar epidemiological trends, and the health, medicolegal, and industrial implications of this disease will continue to intensify in the years to come.3–5
The standard of care for patients with MPM has not been established. Extrapleural pneumonectomy (EPP) has been performed as a treatment option.6–63 This procedure involves en bloc resection of the parietal pleurae, lung, ipsilateral hemidiaphragm, and ipsilateral pericardium. A number of studies have demonstrated encouraging results for selected patients with MPM who underwent EPP. However, because of the relentless nature of the disease, treatment failure after EPP alone remains high.48 Since then, a number of institutions have combined EPP with adjuvant chemotherapy and/or radiotherapy. In comparison with procedures such as pleurectomy and decortication, EPP aims to achieve radical cytoreduction and facilitate maximal delivery of postoperative radiotherapy.
Despite a heightened interest in EPP over the past decade, concerns about the morbidity and mortality of this surgical procedure, and its efficacy, have delayed a consensus in its practice. In addition, there is a lack of robust clinical data on prognostic factors for overall survival and quality of life evaluation. To date, no randomized controlled trials (RCTs) have been conducted to examine the potential benefits of EPP. The most recent systematic review conducted by Maziak et al.64 provided an informative summary of existing literature up to February 2004. However, significant changes have taken place since that time. More recently, innovative multimodalities such as neoadjuvant chemotherapy and hyperthermic intraoperative chemotherapy (HIOC) have been evaluated.6–8 The current systematic review aims to determine the efficacy of EPP either alone or as part of a multimodality therapy in the current medical setting, with a primary focus on survival and perioperative outcomes. In addition, quality of life assessments were also systematically examined.
Literature Search Strategy
Electronic searches were performed using Ovid Medline, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Review of Effectiveness from January 1985 to January 2010. To achieve the maximum sensitivity of the search strategy and identify all studies, we combined “mesothelioma” as a Medical Subject Headings (MeSH) term or a keyword and “pneumonectomy” as a MeSH term or keyword. The reference lists of all retrieved articles were reviewed for further identification of potentially relevant studies. All relevant articles identified were assessed with application of inclusion and exclusion criteria.
Eligible studies for the present systematic review included those in which patients with histologically proven MPM were treated by EPP. Adjuvant therapy included chemotherapy, radiotherapy, photodynamic therapy, and hyperthermic or normothermic intrapleural chemotherapy. Neoadjuvant therapy included systemic chemotherapy. For studies that included patients who underwent EPP as a subset of patients who had other treatments, results for patients who underwent EPP were extracted when possible. When centers 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. It is acknowledged that criteria for patient selection for EPP varied among institutions and sometimes within an institution in 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 are omitted due to potential publication bias and possible duplication of results. Studies published before 1990 and those that included 10 or fewer patients who underwent EPP were also excluded.
Data Extraction and Critical Appraisal
Findings from initial scoping searches were used to decide outcomes for the present review. The primary outcomes included overall survival, 30-day mortality and morbidity, and quality of life assessments. The secondary outcomes included disease-free survival, recurrence rates, prognostic factors on overall survival, intraoperative blood loss, length of hospitalization, and operation time. All data were extracted from article texts, tables, and figures. Two investigators (C.Q.C. and T.D.Y.) independently reviewed each retrieved article. Discrepancies between the two reviewers were resolved by discussion and consensus. The final results were reviewed by the senior investigators (P.G.B. and B.C.M.).
Quantity of Trials
A total of 428 references were identified through the five electronic database searches. After exclusion of duplicate or irrelevant references, 121 potentially relevant articles were retrieved for more detailed evaluation. After applying the selection criteria, 58 remained for assessment (Table 1). A number of centers published studies with duplicating patients at different follow-up periods or different primary objectives. Thirty-four of 58 studies from 26 institutions containing the most complete or updated data were included in the final analysis on survival and perioperative outcomes (Table 2). Overall, a total of 3749 patients who underwent EPP for MPM were identified from the 58 selected studies, with 2462 patients included in the final evaluation.
Assessment of Survival
A summary of survival outcomes for patients undergoing EPP for MPM is presented in Table 2. The median overall survival ranged from 9.4 to 27.5 months.6–63 However, it should be noted that a number of studies calculated survival from the date of diagnosis or commencement of chemotherapy rather than the date of surgery.17,35,43,48–50,56 The 1-, 2-, 3-, and 5-year survival rates varied from 36 to 83%, 5 to 59%, 0 to 41%, and 0 to 24%, respectively. Median disease-free survival ranged from 7 to 19 months, and an additional study reported 20 months for distant recurrence and 26 months for local recurrence.6–63 When the middle two quartiles of the included studies are analyzed, median overall survival ranged from 12 to 20 months, and the 1-, 2-, 3-, and 5-year survival rates varied from 50 to 68%, 26.5 to 40.5%, 19 to 30%, and 10 to 19%, respectively.6–63
Assessment of Perioperative Outcomes
The perioperative outcomes are presented in Table 2. The overall perioperative mortality rates ranged from 0 to 11.8%, with the middle two quartiles falling between 3.7% and 7.6%. Overall perioperative morbidity rates ranged from 22 to 82%, and major morbidity rates ranged from 12.5 to 48%.6–63 A number of studies reported the number of events rather than the number of patients with postoperative complications and were excluded from the analysis as it was not possible to determine how many patients had multiple complications.14,15,19,49,52 Intraoperative blood loss ranged from 500 to 2314 ml. Operative time ranged from 3.25 to 6.5 hours. Hospitalization duration ranged from 8 to 43 days.6–63
Assessment of Quality of Life
Three studies reported quality of life assessments using a variety of questionnaires. Ribi et al.53 and Weder et al.35 assessed 45 patients who underwent EPP and evaluated their quality of life using the Rotterdam Symptom Checklist (RSCL) and Schedule for the Evaluation of Quality of Life-Direct Weighting (SEIQoL-DW) before surgery, on day 1 of cycle 3, and at 1 month, 3 months, and 6 months postoperatively. Results indicated that both RSCL and SEIQoL-DW scores remained stable during chemotherapy, followed by a significant deterioration 1 month postoperatively. RSCL overall scores improved at 3 months but remained beneath baseline levels until 6 months after surgery. SEIQoL scores improved to baseline levels at 3 months but deteriorated at 6 months. Ambrogi et al.39 used the Short-Form-36 (SF-36) item and St. George's Respiratory Questionnaire to assess 16 patients who underwent EPP preoperatively and at 3, 6, 12, and 24 months postoperatively. Comparable with the Swiss reports, this study found improvements in nearly all the SF-36 domains at 3 months. After 12 months, only physical domains remained significantly above the baseline levels, followed by deterioration in all domains at 24 months. Similarly, the St. George's Respiratory Questionnaire results found improvements in all domains at 3 months, remaining stable at 12 months, followed by deterioration at 24 months. Interestingly, SF-36 physical-component-summary at 3 months postoperatively was found to be correlated significantly with overall survival.
EPP With Adjuvant Chemo/Radiotherapy
A large number of studies on EPP in recent years have included subsets of patients who received adjuvant or neoadjuvant chemotherapy with radiotherapy. However, only 14 studies focused on trimodality therapy (TMT) and provided detailed treatment protocols. A summary of chemotherapy regimens, perioperative outcomes, and survival data of these studies are presented in Table 3. One of the earlier studies involving the largest number of patients to date reported a retrospective series of 183 patients who completed EPP, adjuvant chemotherapy, and adjuvant radiotherapy.18 The chemotherapy regimen changed during the study period, with earlier patients receiving doxorubicin and cyclophosphamide with or without cisplatin, followed by later patients who received carboplatin and paclitaxel. A number of other studies that included adjuvant chemotherapy also varied in their regimens (Table 3). Generally, agents such as carboplatin, cyclophosphamide, and gemcitabine have largely been replaced by pemetrexed and cisplatin. Perioperative mortality for TMT involving adjuvant chemoradiotherapy ranged from 0 to 11%, and the median overall survival ranged from 13 to 23.9 months.18,19,39,43,55,57,60
Neoadjuvant Chemotherapy, EPP, and Adjuvant Radiotherapy
More recently, TMT involving neoadjuvant therapy has been reported in several centers. The rationale for this regimen originated from encouraging results for patients with stage IIIA non-small cell lung cancer and aiming to increase the proportion of patients who are able to complete TMT after EPP.6 Common neoadjuvant regimens included gemcitabine and cisplatin, with more recent studies using pemetrexed and cisplatin.6,32,50 The proportion of intention-to-treat (ITT) patients who completed the planned TMT regimens ranged from 50 to 71% and the proportion of ITT patients who completed neoadjuvant chemotherapy and EPP ranged from 74 to 84%. Perioperative mortality rates ranged from 0 to 6.7%.6,32,35–37,50,56 Median overall survival for the ITT population ranged from 14 to 25.5 months, although some survival data were calculated from the date of diagnosis or chemotherapy rather than the date of surgery.32,35,36,50
A number of novel therapeutic approaches have been described in several studies. To achieve maximum tumor cytoreduction after EPP, HIOC was reported by Sugarbaker and coworkers14,15 in two studies. The goal of HIOC was to reduce local recurrence by achieving enhanced local drug delivery at the site of resection in the thorax. A phase I study involving 29 patients who underwent EPP and HIOC with an escalating dose of cisplatin reported a 30-day mortality rate of 3.4% and a median overall survival of 20 months.14 The following phase II study analyzed 92 patients who completed EPP and HIOC at a higher dosage and reported a 30-day mortality rate of 1% and an overall median survival of 13.1 months.15 Morbidity had been relatively high in both studies, with 61 and 84 major adverse events, respectively. van Sandick et al.45 conducted a comparative study involving 20 patients who either underwent EPP (n = 8) or P/D (n = 12) followed by HIOC and compared their outcome with 15 patients who underwent EPP and adjuvant radiotherapy. The median overall survival was 11 months and 29 months, respectively. The authors also found that patients in the HIOC group had a longer operative time, a longer intensive care unit stay, and a shorter time to local tumor recurrence than patients who underwent EPP and adjuvant radiotherapy.
Normothermic intrapleural chemotherapy was reported in one study by Aziz et al.,59 who compared 51 patients who completed EPP, adjuvant intrapleural carboplatin, and systemic chemotherapy with 13 patients who underwent EPP alone. This study found the median overall survival to be significantly improved in the group that received adjuvant intrapleural and systemic chemotherapy (35 versus 13 months), but it was unclear which form of adjuvant chemotherapy was responsible for the improvement.
One study reported the use of intraoperative photodynamic therapy. Schouwink et al.46 prescribed 0.075 to 0.15 mg/kg of meta-tetrahydroxyphenylchlorin to 28 patients, with 26 patients undergoing illumination 4 to 6 days later. Although local disease control was achieved in 50% of the patients, the authors reported a 30-day mortality of 10.7% and a median survival of 10 months. Overall postoperative morbidity was reported as 82%.
MPM is most commonly caused by exposure to asbestos, which provokes carcinogenesis through its physical composition.65 Traditionally, MPM has been regarded by the medical community as a preterminal condition with an expected life expectancy of less than 12 months. This nihilistic view is due to the aggressive nature of the disease and its resistance to any single-modality treatment.1,65 Early chemotherapy regimens included anthracyclines such as doxorubicin and platinum compounds such as cisplatin, with response rates of usually less than 20% and a median survival of less than 12 months.66–68 More recently, the combination of pemetrexed and cisplatin has emerged as the first-line chemotherapy regimen, with a multicenter, randomized, single-blinded study assigning 226 patients to this treatment, resulting in a significantly longer median survival than cisplatin alone (12.1 versus 9.3 months, p = 0.020).2 EPP was first described by Sarot69 for the treatment of tuberculous empyema in 1949. Butchart et al.70 were one of the first to perform EPP for patients with MPM, with a study in 1976 reporting a prohibitive perioperative mortality rate of 31% and a median survival of only 10 months. In a personal communication reported by Treasure et al.71 Butchart was quoted as saying “We have recently analyzed our experience with both pleuropneumonectomy and pleurectomy/decortication for mesothelioma. The very strong message from this analysis is that adjuvant therapy is essential to achieve any degree of long term survival with either surgical procedure.”
Since those early reports, advances in patient selection, surgical technique, and perioperative care have enabled improvements in the surgical outcomes of patients with MPM who undergo EPP. In addition, studies involving adjuvant and neoadjuvant therapies such as systemic chemotherapy, intrapleural chemotherapy, radiotherapy, and photodynamic therapy have reported varying degrees of success. Overall, the current systematic review on EPP for patients with MPM found a perioperative mortality rate of 0 to 11.8% and a median overall survival of 9.4 to 27.5 months. The majority of patients were within the middle two quartiles of these ranges, and the perioperative mortality rate in these studies ranged from 3.7 to 7.6%, with an overall median survival of 12 to 20 months. The reporting of postoperative complications varied between institutions, and the reported overall morbidity rate was between 22% and 82%, with major morbidities between 12.5% and 48%. According to the largest series to date involving 385 patients who underwent EPP, the most common morbidities include atrial arrhythmia, respiratory failure, respiratory infections, pulmonary embolus, and myocardial infarction.7 Quality of life assessments were found in three studies, two of which reported on the same set of patients who underwent TMT. All three studies found improvements in nearly all domains at 3 months postoperatively, either close to or better than at baseline levels preoperatively.35,39,53
An important subset of patients identified in the current systematic review includes those who received TMT, which is becoming the preferred treatment in a number of institutions. One of the earlier studies on TMT consisted of 183 patients who completed EPP, adjuvant chemotherapy, and adjuvant radiotherapy.18 Selection criteria in this large series included good performance status, adequate organ function, and resectable tumor without evidence of metastatic disease on imaging. The results of this retrospective study was encouraging, with a perioperative mortality rate of 3.8%, and a median overall survival of 19 months for patients who survived the first 30 days. The authors also found that patients with epithelial cell type, negative extrapleural nodes, and complete resection margins had a significantly improved survival outcome on multivariate analysis. Following this study, two prospective series have shown similar outcomes, with perioperative mortality of 5% and median overall survival of more than 20 months for patients who completed TMT.55,57
More recently, the use of neoadjuvant chemotherapy has been reported in seven studies, with the aim of maximizing cytoreduction and increasing the proportion of patients who are able to complete the TMT regimen after EPP. The largest prospective study to date by Krug et al.6 incorporated three cycles of neoadjuvant cisplatin and pemetrexed followed by EPP and adjuvant radiotherapy in the form of 54 Gy to the hemithorax in 1.8 Gy fractions. Inclusion criteria were T1-3 N0-2 disease, no prior surgical resection, adequate organ function, and performance status 0 to 1. Of the 77 patients included in the ITT population, 52% completed the planned TMT regimen. Perioperative mortality was 3.7%, and the median overall survival rates for the ITT population and patients who completed TMT were 16.8 months and 29.1 months, respectively. Other trials on TMT involving neoadjuvant chemotherapy included in the current systematic review have also shown encouraging results, with the perioperative mortality rate of 0 to 6.7% and median overall survival of 14 to 25.5 months for the ITT population.6,32,35–37,50,56 Disease-free survival for patients who had completed neoadjuvant chemotherapy and EPP ranged from 13.5 to 18.3 months.6,32,35–37,50,56 Despite these findings, it should be noted that patients who received neoadjuvant chemotherapy and had evidence of disease progression were often excluded from undergoing EPP. From a sceptical perspective, the improvement in overall survival could reflect a selection of patients with less aggressive disease rather than treatment efficacy. A method to assess the proportion of patients who complete TMT is to calculate the completion rate from the ITT population. For studies on TMT involving neoadjuvant chemotherapy, this ranged from 50 to 71%.6,32,35–37,50,56
It has to be acknowledged that there was a distinct heterogeneity among the assessed studies, including patient selection, treatment regimens, follow-up methods, and even survival calculation. Patient selection using performance status and staging of disease at the time of operation differed between institutions and at times between different study periods within one institution. Rusch and Venkatraman11 highlighted the importance of staging in the treatment of MPM and advocated for the systematic use of a unified staging system. However, individual institutions still vary in the staging system they use. Generally, patients eligible for EPP included those who have tumors which appeared resectable on preoperative investigations, good performance status, and adequate cardiorespiratory, hepatic, and renal function. Presence of N2 lymph node involvement was found to be a significant prognostic factor on multivariate analysis when grouped with internal thoracic lymph nodes and compared with N1 and N0 disease (hazard ratio: 1.7, p < 0.0001).8 However, the practice of routine mediastinoscopy and exclusion of patients with mediastinoscopy-positive N2 disease from undergoing EPP remains controversial.25 Median follow-up of all the studies in the current systematic review ranged from 8.8 to 31.2 months but varied greatly in the form and frequency of radiologic follow-up.6–63 Partly because of this, recurrence rates and disease-free survival should be interpreted with caution. Finally, overall survival was reported from the date of chemotherapy or diagnosis from a number of studies, and this will inevitably present a longer survival compared with studies that calculate survival from the date of surgery.17,35,43,48–50,56 Future studies should aim to be conducted in a prospective manner with careful patient selection and regular radiographic follow-up, with clear and uniform reporting of perioperative and long-term survival outcomes.
Because of the relative rarity of MPM and its aggressive nature, as well as a multitude of challenges in the randomization process, there has been no completed RCT to date. Authors of the upcoming Mesothelioma and Radical Surgery trial pointedly highlighted numerous potential flaws in the evidence from the current literature based primarily on case series studies.71–73 At the time of writing, this group reported that 50 of 112 potentially eligible patients have been randomized in their planned trial, with 24 assigned to undergo EPP and 26 to have continued best care.74 If this trial is successfully completed, the results may provide additional insight on any potential benefit of EPP as part of a multimodality treatment. However, it remains to be seen if data from one RCT will be able to establish a firm consensus within the surgical community, especially considering the differences in patient selection, surgical experience, and treatment protocols between centers. Alternatively, a multiinstitutional registry based on an ITT principle may provide valuable information on prognostically similar patients who undergo different management pathways.
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