Medical Malignant Pleural Mesothelioma - A Review

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1 Lung Cancer (2005) 48, Surgical management of malignant pleural mesothelioma: a systematic review and evidence summary Donna E. Maziak a,, Anna Gagliardi b, Adam E. Haynes c, Jean A. Mackay c, William K. Evans d The Cancer Care Ontario Program in Evidence-based Care Lung Cancer Disease Site Group 1 a University of Ottawa, Ottawa Hospital, General Campus, 501 Smyth Road, Ottawa, Ont., Canada K1H 8L6 b Surgical Oncology Network, Cancer Care Ontario, 620 University Avenue, Toronto, Ont., Canada M5G 2L7 c Practice Guidelines Initiative, Cancer Care Ontario Program in Evidence-based Care, McMaster University, DTC 3rd Floor, 1280 Main St W, Hamilton, Ont., Canada L8S 4L8 d Juravinski Cancer Centre at Hamilton Health Sciences;Cancer Care Ontario, 699 Concession St., Hamilton, Ont., Canada L8V 5C2 Received 5 July 2004; received in revised form 10 November 2004; accepted 11 November 2004 KEYWORDS Pleural mesothelioma; Pleurectomy; Extrapleural pneumonectomy; Systematic review Summary An evidence summary was developed for the surgical management of adult patients with diffuse or localized malignant pleural mesothelioma. This evidence summary is based on a systematic search and review ofthe literature published between 1985 and February Relevant studies were identified, according to pre-determined criteria by the authors and methodologists. No randomized controlled trials comparing pleurectomy (PL) with extrapleural pneumonectomy (EPP) or comparing surgery with an alternative treatment were identified. Four comparative studies, seven non-comparative prospective studies, and 16 retrospective case series were identified that looked at PL, or EPP, or PL and EPP. Trial results were not pooled due to the heterogeneity ofthe treatments in the trials and the fact that no trials were randomized and none were designed to directly compare different treatments. External feedback was obtained from Ontario clinicians, and the provincial Lung Cancer Disease Site Group approved the review. * Corresponding author. Tel.: x22530; fax: address: haynesa@mcmaster.ca (D.E. Maziak). 1 List ofcollaborators is included in Appendix A /$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved. doi: /j.lungcan

2 158 D.E. Maziak et al. Conclusions: The role ofsurgery in the management ofmalignant pleural mesothelioma cannot be precisely defined as the lack ofrandomized controlled clinical trials makes it impossible to determine whether the use ofepp or PL improves survival or effectively palliates the symptoms ofthe disease. Future studies ofthe role ofsurgery in the treatment ofmesothelioma should include evaluations ofquality oflife Elsevier Ireland Ltd. All rights reserved. 1. Introduction Mesotheliomas are neoplasms ofthe serosal membranes, with 80% originating in the pleural space. In fact, pleural mesothelioma is the most common primary tumour ofthe pleural cavity [1]. The Surveillance, Epidemiology, and End Results Registry ofthe National Cancer Institute ofthe United States reported an age-adjusted incidence rate of (95% confidence interval [CI]: ) cases per 100,000 people [2]. Each year, approximately 100 Canadians will be diagnosed with malignant mesothelioma [3], with an estimated median survival of4 12 months for untreated disease [4]. Mesotheliomas were, in the past, classified into three general categories (diffuse malignant, localized benign, and localized malignant), although most clinical studies do not specifically report these disease categories. Since diffuse malignant pleural mesothelioma was first described as a distinct disease, its treatment has been associated with controversy. Treatment of this disease has included various combinations of surgery, radiation, and chemotherapy. The two main surgical treatment approaches are pleurectomy (PL) and extrapleural pneumonectomy (EPP). The former procedure generally involves excision ofsections ofthe pleura. The latter procedure is a more aggressive approach, which involves the removal ofall or part ofa lung, as well as the parietal pleura, ipsilateral pericardium, and diaphragm. This evidence summary focuses on the role of surgery, specifically PL and EPP, in the treatment of diffuse and localized malignant mesothelioma, for which, no widely accepted standard ofcare currently exists. Outcomes ofinterest include clinical or sub-clinical adverse effects, survival, recurrence rates, prognostic factors, and quality of life. 2. Methods 2.1. Evidence summary development This evidence summary report was developed by the Practice Guidelines Initiative (PGI) ofcancer Care Ontario s Program in Evidence-based Care, using the methods ofthe Practice Guidelines Development Cycle [5]. The PGI is sponsored by, but is editorially independent of, Cancer Care Ontario and the Ontario Ministry ofhealth and Long-term Care. An evidence summary report contains the best evidence available on a specific clinical question when there is insufficient high-quality evidence on which to base a clinical practice guideline. Evidence for this report was selected and reviewed by two members ofthe PGI s Lung Disease Site Group (DSG) and methodologists from Cancer Care Ontario s Surgical Oncology Program and the PGI. Selection ofrelevant articles was determined according to predefined inclusion and exclusion criteria, and disagreements were resolved through discussion. The Lung DSG reviewed, provided feedback on, and approved the final report. External review ofthe report was obtained through a mail survey ofontario practitioners, and final approval was obtained from the Practice Guidelines Coordinating Committee. The report provides information for individuals and groups to use in making decisions and policies where the evidence is uncertain. Members ofthe Lung DSG disclosed potential conflict ofinterest information Literature search strategy MEDLINE, EMBASE (both databases 1985 through February, 2004), CANCERLIT (1985 through October 2002), and the Cochrane Library (2004, Issue 1) databases were searched using the Medical Subject Headings (MeSH) or Excerpta Medica Tree (EMTREE) terms for mesothelioma/surgery and lung neoplasms/surgery and the keyword or text word mesothelioma in combination with surgery, pleurectomy, decortication, pneumonectomy, and resection. These terms were then combined with the search terms for the following publication types and study designs: practice guidelines, meta-analyses, systematic reviews, randomized controlled trials, and controlled clinical trials. The search was limited to 1985 onwards, because the classification and staging ofpleural mesothelioma have varied tremendously over time, making the comparison ofdata from early trials with that ofmore recent trials difficult. Relevant articles were selected and reviewed by two reviewers, and the reference lists from these articles were

3 Surgical management ofmalignant pleural mesothelioma 159 searched for additional trials, as were the reference lists from relevant review articles. Ongoing clinical trials were identified using the Physician Data Query database at cancer.gov/search/clinical trials/. The Canadian Medical Association Infobase ( cpgsnew/cpgs/index.asp), and the National Guidelines Clearinghouse ( index.asp) were searched for existing evidencebased practice guidelines related to the surgical management ofmesothelioma Eligibility criteria Articles were selected for inclusion in this systematic review ofthe evidence ifthey were randomized controlled trials, systematic reviews (including meta-analyses or practice guidelines), phase II trials, or prospective or retrospective cohort studies, examining the role ofsurgical resection for malignant pleural mesothelioma. Studies must have reported on any of the following outcomes for the aforementioned topics: clinical or sub-clinical adverse effects, survival, recurrence rates, prognostic factors, and quality of life. Trials were excluded for the following reasons: the majority of patients had other malignant conditions; papers were published before 1985; studies were published as abstracts only, and letters and editorials describing trial results. Papers published in a language other than English were also excluded due to funding restrictions Evidence synthesis A statistical synthesis ofthe evidence was not conducted because no randomized trials involving surgical treatment for mesothelioma were identified and the prospective and retrospective studies included a variety ofadjuvant treatments. 3. Results 3.1. Literature search results No randomized controlled trials comparing PL with EPP or comparing surgery with an alternative treatment in patients with malignant pleural mesothelioma were identified. A total of32 studies met the inclusion criteria (Tables 1 3) and included the following: non-controlled prospective studies with case-series designs or comparative designs not containing similar, concurrent comparison groups, retrospective case-series, or summaries ofregistry data. Only 12 ofthe 32 studies [6 39] reported the type ofmesothelioma examined: 11 involved diffuse mesothelioma [16,17,19 21,26,27,30,33,34,38] and one involved localized disease [11]. No evidence-based clinical practice guidelines were identified, although the British Thoracic Society published a statement in 2001 intended to guide the management ofmalignant mesothelioma [40]. The statement was developed through a literature review and expert consensus; however, a comprehensive literature review was not attempted. The British Thoracic Society indicated that limitations to the quality ofevidence precluded the development ofrecommendations. The literature search identified one systematic review, published in 2003, on the surgical management ofmesothelioma [41]. While the conclusions ofthis review are not dissimilar to those ofthis evidence summary report, the authors did not report their search strategy and had only searched MEDLINE Outcomes Studies involving both extrapleural pneumonectomy and pleurectomy Prospective, non-controlled studies Eight prospective studies (Table 1) included both EPP and PL as treatment options [6 15]. None of the studies were randomized or provided similar, concurrent comparison groups, resulting in a relatively low level ofavailable evidence from which to draw conclusions for or against surgical intervention. One study, by Calavrezos et al. [6], did prospectively assign eligible patients to one oftwo treatments, supportive care, or combined modality therapy including surgery. However, assignment to best supportive care or surgery was according to patient preference, leading to an imbalance in the resulting treatment groups, by age, performance status, tumour histology, and tumour operability, which favoured the combined modality treatment group. All ofthe prospective studies analyzed a variety oftreatments in addition to surgery, including photodynamic therapy and/or immunotherapy [8 11], and chemotherapy or radiotherapy following surgery [6,7,12 15]. In the Rusch et al. phase II trial [15], the original protocol prescribed intraoperative radiotherapy for all patients undergoing EPP or PL. However, due to an unacceptable increase in operative time, the study protocol was changed to exclude intraoperative radiotherapy for patients receiving EPP. Table 1 includes only the 88 patients treated under the revised protocol.

4 160 D.E. Maziak et al. Table 1 Prospective studies involving both extrapleural pneumonectomy and pleurectomy Study (references) Patients Operative Survival Median followup Morbidity Mortality Median (months) 2-/3-/5-year a (months) Calavrezos [6] 57 CM NR NR 13 11/NR/NR 22 b 75 SC (39 NE 36 PC) NA NA NE: 5 NE: 7/NR/NR PC: 7 PC: 3/NR/NR 132 total NA NA NR NR Rice [7] 9PL NR NR NR NR NR 10 EPP NR NR NR NR 19 total NR/17/NR DF: 11 DF: NR/22/NR Pass [8] 39 PL NR NR 14.5 * NR EPP NR NR 9.4 * NR 17 UR NR NR 5.0 NR 95 total 36 2 NR NR Moskal [9] 28 PL 39 0 NR NR NR 7 EPP NR NR 5 PL + Lbctmy 40 NR NR NR 3UR NR NR NR NR 43 total c 23/NR/NR c Pass [10,11] 23 PL NR 0 22 ** NR EPP NR 4 11 ** NR 48 total d 21 NR 14.4 NR Rusch [12,13] 59 PL NR ** 40/NR/ EPP NR e ** 30/NR/6 57 palliative NR NR 8.7 NR PL/exploration 231 total NR 3.5 NR NR Maggi [14] 9 PL NR NR NR NR EPP NR NR NR NR 32 total Major NR 66/NR/NR f Minor-12.8 Rusch [15] 5 PL NR 0 NR NR NR 62 EPP NR NR/27/NR 21 exploration NR NR NR NR 88 total 38 NR NR NR Notes: CM, combined modality; DF, disease-free; EPP, extrapleural pneumonectomy; Lbctmy, lobectomy; NAL, not applicable; NE, not eligible for surgery; NR, not reported; PC, patient s choice; PL, pleurectomy; SC, supportive care; UR, unresectable disease (determined at beginning ofepp or PL); * p = 0.012; ** p = not significant. a Not all articles used the same time frame to determine survival rates. b Only minimum follow-up time reported. c Survival rates calculated for 37 patients who survived post-operatively. d Fifteen EPP or PL patients had unresectable disease. e Rusch et al. (1991) of20 EPP patients, 40% had arrhythmia, 20% had bronchial stump leak and empyema. f Twenty-one patients alive with median follow-up = 12.5 months. Only three ofthe eight studies reported survival data for both the PL and EPP treatment arms [8,10,12,13] (Table 1). Only Pass et al. [8] reported a significant difference in survival between the EPP (9.4 months) and PL (14.5 months) treatment arms (p = 0.012). However, conclusions cannot be made about preferred surgery because patients were generally selected for a specific surgical treatment. In addition, both studies by Pass et al. reported that preoperative tumour volume was significantly greater for patients having EPP compared with PL [p < [8] and p < [10], respectively]. In the study by Rusch and co-workers [12,13], EPP was performed for locally advanced

5 Surgical management ofmalignant pleural mesothelioma 161 disease and PL for minimal visceral pleural tumour. Calavrezos et al. [6] conducted a multivariate analysis ofprognostic factors (Cox model) in all 132 mesothelioma patients in his study. The following factors were associated with longer survival: age 50 years (p = 0.01), early stage disease (I/II) (p = 0.02), epithelial tumour histology (p = 0.01), absence ofpain (p = 0.01), good performance status (Karnofsky, ) (p = 0.005), and multimodality therapy (p = 0.03) [6]. For the 231 patients in the Rusch et al. study [12,13], a multivariate analysis (proportional hazards regression model) detected a significant positive association between survival and the following factors: earlier stage of disease, epithelial versus non-epithelial histology, female sex, and use ofadjuvant therapy (statistical significance not reported). However, the influence of adjuvant therapy on survival was difficult to determine because most patients received adjuvant therapy (142 of166 patients with available data received adjuvant therapy). In a later study reported by Rusch et al. [15], earlier stage ofdisease (p = 0.02) and lower T-node status (p < 0.01) were associated with improved survival in univariate analyses, but no associations were detected between individual prognostic factors and survival in a multivariate analysis. The authors emphasized that the analysis ofprognostic factors was not an intention of the study. In the studies involving intraoperative photodynamic therapy, multivariate analyses (Cox model) identified the following factors as associated with decreased survival: male sex [8,10], preoperative tumour volume >100 cm 3 [8,10], a high platelet count [8,10], biphasic versus epithelial or sarcomatoid histology [8], and post-operative tumour volume >9 cm 3 [10] (all p < 0.05). Early disease stage (p = ) and negative nodal status (p = 0.004) were associated with longer survival [9]. In a univariate analysis, Rice et al. [7] found tumour histology (epithelial versus sarcomatous or biphasic histology) to be the only significant factor associated with survival. Three studies [7,8,12] reported recurrence rates. Pass et al. [8] reported recurrence rates after a median follow-up time of 33.7 months to be 79% for PL and 69% for EPP (39 patients in each group), with locoregional recurrences accounting for 90 and 63% of events for EPP and PL, respectively. Rusch et al. [12] reported local recurrence rates at last follow-up of 35 and 0%, respectively, among 26 patients receiving PL and 20 patients receiving EPP, with higher rates ofdistant recurrence following EPP (25% versus 4%). Rice et al. [7], reported similar recurrence rates following PL (67%) or EPP (60%) as part ofa combined modality treatment approach. Operative mortality was reported separately for PL and EPP in four studies [9,11 13,15] as shown in Table 1. In one ofthe Rusch et al. reports [15], all deaths were related to pulmonary complications, although the period for operative mortality was not defined. In the other Rusch et al. study [12,13], post-operative mortality was defined as death within 30 days ofsurgery, but cause of death was not reported. Moskal et al. [9] reported a post-operative death due to bronchopleural fistula and two additional treatment-related deaths, at 39 days (empyema complicating a PL) and 93 days (bronchopleural fistula following EPP). Pass et al. [11] reported a post-operative death in a photodynamic therapy patient whose inferior vena cava avulsed after a right-sided EPP at the conclusion of anesthesia. Six studies reported post-operative complications [7 9,11 14]. Arrhythmias occurred in 36 40% ofpatients undergoing EPP [8,12,13], 5% undergoing PL [8], and % undergoing either EPP or PL [7,9,11,14]. Bronchopleural fistulas occurred following EPP in two studies (18 and 43%) [8,9] and EPP or PL in two studies (3 8% ofpatients) [11,14]. In the study by Pass et al. [8], only one patient experienced a bronchopleural fistula during the immediate post-operative period, however, an additional six patients were diagnosed between 40 and 420 days post-operatively. Other reported surgical complications included respiratory insufficiency [9,14], vocal cord paralysis [7,14], sepsis [9], bleeding [11,14], cardiac herniation [11], and pancreatitis [11], following either EPP or PL. Only one study reported the palliative effects of treatment, although the method and time frame of symptom assessment were not provided [7]. Rice et al. reported good to excellent palliation ofinitial symptoms in 84% of19 patients undergoing surgery (EPP or PL) with intrapleural chemotherapy and post-operative adjuvant chemotherapy. Preoperative symptoms included chest pain (68% ofpatients), cough (63%), and dyspnea (63%) [7] Retrospective studies The data from nine retrospective studies involving both EPP and PL as treatment options for malignant pleural mesothelioma are summarized in Table 2 [16 24]. The level ofevidence provided by these studies was relatively low; most were case series reports, and one study reported registry data [18]. The retrospective data were collected over extended periods oftime ranging from 9 years [23] to 36 years [20], and only two ofthe studies [20,24] focused

6 162 D.E. Maziak et al. exclusively on surgical patients. Given the variation in the classification and treatment ofmesothelioma over time, the utility ofthe retrospective data is limited and is only briefly summarized below. Most studies included some form of adjuvant treatment, although the treatment likely varied across time as well as across studies. Lampl and Jakob [22] reported that PL was performed only on patients with early disease (T1a and b), while EPP was performed on patients with more advanced disease (T2 or T3). In the Branscheid et al. study [19], EPP was performed with curative intent, and PL was considered palliative. In the study by Aziz et al. [23], patients with extensive disease including chest wall invasion and metastases were offered supportive care as were patients who were not fit for surgery. Patients with locally extensive disease were offered PL, but only to palliate symptoms of chest pain and shortness ofbreath. Patients who were offered EPP had to have disease confined to Table 2 Retrospective studies involving both extrapleural pneumonectomy and pleurectomy Study (references) Patients Operative Survival Morbidity Mortality Median (months) 1-/2-/5-year a Chailleux [16] 29 PL or EPP NR NR NR 54/25/NR 14 CT + PL or EPP NR NR NR 64/29/NR 41 no Sx NA NA NR 31 42/9 21/NR 79 SC NA NA NR 28/2/NR Ruffie [17] 63 PL NR NR 9.8 * NR 23 EPP * NR/17/NR 246 CT, RT, or SC NA NA 8 * NR Harvey [18] 9 PL NR 0 12 NR 7 EPP NR NR <6 NR 76 SC NA NA 7.6 NR Branscheid [19] 82 PL NR ** NR 76 EPP NR ** NR 143 CT, Sx b,orsc NA NA 7.8 ** NR Allen [20] 56 PL * 30.4/8.9/ EPP * 52.5/22.5/10.0 Huncharek [21] 17 PL or EPP NR NR 5.0 NR 21 CT + PL or EPP NR NR 23.9 *** NR 11CT NA NA 6.0 NR 4 RT NA NA 11.5 NR 26 SC NA NA 4.5 *** NR Lampl [22] 19 PL NR 0 14 NR 23 EPP NR NR 11 exploratory Sx NR NR 6 NR Aziz [23] 47 PL /0/0 d 13 EPP 21 c 9.1 c 13 25/0/0 d 51 EPP + CT 21 c 9.1 c 35 84/66/21 d 191 SC NA NA 7 NR de Vries [24] 29 PL NR 3.4 NR 22/13/7 *d 17 EPP e NR 42/27/16 *d Notes: CT, chemotherapy; EPP, extrapleural pneumonectomy; NR, not reported; PL, pleurectomy; RT, radiotherapy; SC, supportive care; Sx, surgery; * p, not significant; ** p, reported significant survival advantage; p = NR (EPP or PL compared to CT, SC, or other Sx); *** p < 0.01 (Wilcoxon); p < for 1-year survival. a Not all articles used the same time frame to determine survival rates. b Surgery was either exploratory or a thoracotomy. c Operative mortality reported for all EPP patients overall. d Survival rate determined from published survival curve. e Two patients were diagnosed post-operatively with adenocarcinoma.

7 Surgical management ofmalignant pleural mesothelioma 163 one hemithorax without invasion ofthe chest wall or mediastinum or any evidence ofabdominal or distant metastases, and the patient had to be less than 60 years ofage and ofsufficient health for a major surgery. None ofthe retrospective studies reported a significant difference in median survival for EPP compared to PL. However, Huncharek et al. [21] reported a significant difference in median survival for 26 patients (4.5 months) undergoing supportive care compared with 21 patients (23.9 months) undergoing EPP or PL combined with chemotherapy with or without radiotherapy (p < 0.01 Wilcoxon) [21]. Aziz et al. [23] reported a significant difference in 1- and 3-year survival for 13 EPP patients (49 and 0%) compared to 51 EPP/intrapleural chemotherapy/systemic chemotherapy patients (84 and 48%) (p = and , respectively). Ruffie et al. [17], in a multicentre retrospective chart review, included 118 of332 patients in a multivariate analysis and found that later disease stage (p < 0.001), a high platelet count (p = 0.001), and asbestos exposure (p = 0.02) were negatively associated with survival. The results ofa multivariate analysis (Cox model) reported by Allen et al. [20] suggested that lack ofpost-operative adjunctive therapy (p = ) and sarcomatous tumours (p = ) were adversely associated with survival. In the same study, surgical procedure, age, sex, mediastinal nodal metastases, and pain as the presenting symptom were not associated with any differences in survival. Branscheid et al. [19] conducted univariate analyses in a study of301 patients with pleural mesothelioma, ofwhom, 158 were treated surgically. They reported a longer median survival for patients with epithelial tumours compared with sarcomatous or biphasic tumours (9.8 months versus 3.0 months versus 5.8 months, respectively, p < 0.001), although whether survival was affected by other confounding factors was unclear. Other prognostic variables adversely affecting survival included age >40 years (p < 0.05), weight loss (p < 0.05), and the presence ofchest wall pain (p < 0.01); the latter was also associated with sarcomatous histology [19]. Aziz et al. [23] also conducted univariate analyses of51 patients treated with EPP and intrapleural and systemic chemotherapy. They reported a higher 3-year survival for patients with epithelial versus sarcomatous tumours (p = 0.07). Patients with T1 tumours had significantly higher 1- and 3-year survival compared to patients with T2 or T3 tumours (p = and 0.002, respectively). Operative mortality was similar for PL and EPP in four [20,22 24] ofthe five studies [19,20,22 24] reporting outcomes for both treatments (0 9.1%), and cause ofdeath included pulmonary embolism, myocardial infarction, organ failure, intraoperative bleeding, respiratory distress syndrome, and pneumonia [20,22,23]. In the fourth study [19], 30-day mortality was 11.8% following EPP and 2.4% following PL, although cause ofdeath was not reported. Morbidity for both PL and EPP was reported in one study [20], to have similar overall rates, 26.8 and 30%, respectively. Arrhythmia, tracheostomy, and pneumonia occurred following both surgeries; air leak and renal failure occurred following PL and bronchopleural fistula, vocal cord paralysis, chylothorax, myocardial infarction, effusion, and splenectomy occurred following EPP [20]. Ruffie et al. [17] and Aziz et al. [23] reported similar complications following EPP, with an overall morbidity rate of26 and 21%, respectively. None ofthe retrospective studies reported on symptom palliation; however, results reported by Ruffie et al. [17] suggested that PL prevented the recurrence ofpleural effusions in 86% of 63 patients Studies involving extrapleural pneumonectomy Three studies [25 27] reported outcomes following EPP for malignant pleural mesothelioma. One small, retrospective case-series study offive patients [27] provided limited outcome data and is not discussed further. The other two studies [25,26] examined survival in patients undergoing EPP, with or without adjuvant therapy. One ofthose studies [26] was an updated case series report of183 patients undergoing surgery as part ofa trimodality therapy program. Data were collected retrospectively from 1980 to 1997, although the authors indicated that all surviving patients were contacted at the time of the last update. The study did not include a comparison group, but given the relative currency ofthe data and the large sample size, the analysis ofpossible prognostic factors provides useful information. The other study [25] included both retrospective data collected between 1965 and 1978 and prospective registry data collected from 1978 to Patients in the early period ofthis study underwent PL, whereas patients treated more recently, more commonly underwent EPP; however, the number ofpatients undergoing each procedure was not reported separately. Although survival rates were reported by treatment group in this study [25], allocation ofpatients to a specific treatment appeared to be dependent on patient and disease characteristics, which would likely differentially impact outcomes. Median survival for patients undergoing EPP, with or without adjuvant chemotherapy, was similar

8 164 D.E. Maziak et al. in both studies at 18 months [25] to 19 months [26]. Sugarbaker et al. [26] reported a 2-year survival rate of38% and a 5-year survival rate of 15%. Antman et al. [25] did not report survival rates. The results ofa multivariate analysis (Cox model) reported by Antman et al. suggested that good performance status (0 1, p < 0.001), epithelial tumour histology (p < 0.001), and EPP with adjuvant chemotherapy (p = 0.018) were associated with longer survival, but chest pain at diagnosis (p < 0.001) and less than 6 months between the appearance ofsymptoms and diagnosis (p = 0.010) were associated with shorter survival [25]. Sugarbaker et al. [26] also conducted a multivariate analysis (proportional hazards regression model) and found that survival was adversely affected by the presence ofpositive resection margins (odds ratio, 1.7; 95% CI, ; p = ), sarcomatous or mixed tumour histology (odds ratio, 3.0; 95% CI, ; p < ), and metastatic extrapleural nodes (odds ratio, 2.0; 95% CI, ; p = ). Antman et al. [25] did not report operative morbidity or mortality. For 183 patients, Sugarbaker et al. [26] reported 3.8% 30-day operative mortality, 50% overall morbidity, and 24.5% major morbidity. Morbidity was defined as untoward events that prolonged hospitalization. Adverse events that occurred in at least five patients post-operatively included: cardiac arrest, aspiration, pulmonary failure or pulmonary embolism, bleeding or suspected cardiac tamponade, and vocal cord paralysis, with fatalities due to pulmonary embolism, myocardial infarction, cardiac herniation, and respiratory failure [26] Studies involving pleurectomy Four prospective studies and eight retrospective studies examined survival, morbidity, and mortality in patients undergoing PL for malignant mesothelioma [28 39]. Data from these studies are summarized in Table Prospective, non-controlled studies The four prospective studies [28 31] provided the study inclusion criteria, and two indicated that consecutive patients meeting the inclusion criteria were enrolled in the study [29,30], but the studies contained only limited evidence. All four studies [28 31] administered intrapleural chemotherapy during either a total or a subtotal PL, and most patients also received systemic chemotherapy post-operatively. All ofthe studies [28 31] were small (20 27 patients), and three did not include a concurrent comparison group [28,29,31]. Of these latter studies, one [28] excluded nine of 36 enrolled patients from the analysis because they were subsequently found to be unresectable (eight patients) or misdiagnosed (one patient), and another [31] reported data for 20 evaluable patients with the aim ofassessing the feasibility ofa multimodality treatment approach. The third study [29] enrolled 17 patients; however, two patients were re-diagnosed with metastatic pleural adenocarcinoma after the final pathologic examination and were excluded from the study. In the only comparative trial [30], 13 of20 patients were diagnosed preoperatively, while the seven remaining patients were diagnosed post-thoracotomy and underwent surgery without chemotherapy. However, the small number ofpatients in the two groups limits any comparison, and as noted by the study authors, fundamental differences may exist between patients who are or are not diagnosed preoperatively. Survival duration was assessed from the date of the thoracotomy in two studies [28,29], from the date ofstudy entry in one [31], and from an undefined time in a fourth [30]. Median survival was 18.3 months [28], 11.5 months (two studies) [29,31], and 9 months [30]. Two-year survival was also reported in three studies at 40% [28], 15% [30], and 12% [29]. In one study, tumours were considered completely resected in 20 of27 patients [28]. Two studies reported that gross residual disease remained in many cases post-operatively [30,31]; one study did not report on post-operative residual disease [29]. Three studies reported local recurrence, with rates of100% [29], 80% [28], and 75% [30] of patients. One patient died in the post-operative period in each oftwo studies [28,30], although post-operative morbidity was reported more frequently in the study by Rusch et al. [28], and included the following major morbidities: intrathoracic hemorrhage (one patient) and renal failure (two patients). Colleoni et al. [31] reported the following grades 1 4 side effects associated with surgery and intrapleural chemotherapy: fever (30%), pain (15%), infection (10%), and renal (50%), hematological (35%), cardiac (10%), and hepatic (10%) toxicities. Lee et al. [29] also reported the following grades 1 4 side effects: pain (100%), bleeding (73%), hyponatremia (73%), hypocalcemia (60%), hypokalemia (27%), hypomagnesemia (27%), infection (13%), and cardiopulmonary (67%), gastrointestinal (47%), and renal (27%) toxicities. None ofthe studies defined the post-operative time interval. Sauter et al. [30] assessed the palliative effects of PL combined with intrapleural and adjuvant chemotherapy in 20 patients. They reported improvements in dyspnea (47%) and pain (21%) and no

9 Surgical management ofmalignant pleural mesothelioma 165 Table 3 Studies examining pleurectomy Study (references) Patients Operative Survival Median Follow-up (months) Mortality Morbidity Median (months) 1-/2-/5-year Prospective studies Rusch [28] 27 PL + CT a /40/NR NR 8 UR NR NR NR NR NR Lee (29) 15 PL + CT a 13 b /12/0 c Sauter [30] 13 PL + CT 8 NR 9 NR/15 * /NR 53 7 PL (4 + RT) NR NR 21 NR/43 * /NR 20 total NR 5 NR NR Colleoni [31] 20 PL + CT 15 NR 11.5 NR 11 Retrospective studies Alberts [32] 26 PL NR NR NR 262 total d NA NR 9.6 NR Achatzy [33] 46 PL NR NR/NR/2.2 f NR 72 subtotal PL NR other Sx e NR NR/NR/ no Sx NA NA 6.0 NR/NR/2.2 f Ball [34] 13 PL NR NR 17 NR NR 22 RT+/ CT NA NA 9 NR Brancatisano [35] 45 subtotal PL 16 g 2 g 16 h NR/21/NR h NR Soysal [36] 100 PL/subtotal PL NR NR Ceresoli, 2001 [37] 38 PL NR NR /NR/NR NR 16 PL + CT NR NR /NR/NR 37 CT NA NA /NR/NR 30 SC NA NA 4 20/NR/NR Lee [38] 32 PL NR j 64/32/NR j 9.7 j Phillips [39] 15 PL ** 53.5/40/27 NR 40 palliative Sx k ** 17.5/10/0 15 pleural biopsy ** 20/6.7/0 Notes: CT, chemotherapy; NA, not applicable; NR, not reported; PL, pleurectomy; RT, radiotherapy; SC, supportive care; Sx, surgery; UR, unresectable disease (by pleurectomy); * p = 0.04; ** p = 0.03 (15 Pl pts compared to 55 other Sx and pleural biopsy pts). a Seventeen patients enrolled, two misdiagnosed. b Overall operative morbidity only reported for grade 3 or 4 hemorrhage, infection, or cardiopulmonary or renal toxicity. c From published survival curve. d Patients received CT and/or RT and/or Sx. e Among 82 patients undergoing other Sx, 78 were diagnostic thoracotomies, 2 EPPs, 1 partial removal ofthe diaphragm, and 1 total PL with upper lobectomy. f Five-year survival for 178 surgical patients. g Calculated from total of 50 patients. h Survival calculated for 49 patients who survived post-operatively. j Overall survival and follow-up based on 26 patients (three patients were unresectable, 1 was excluded because of recurrent disease, and there were two post-operative deaths). k Video-assisted thoracoscopic pleural biopsy and talc pleurodesis. recurrence of pleural effusions in 80% of patients. The five-grade National Cancer Institute Common Toxicity Criteria was used to assess dyspnea, with a reduction of 1 grade considered an improvement. Pain was assessed on an undefined patient-report measure Retrospective studies The eight retrospective studies, all case series reports, collected data over periods varying from 5 years [34,35] to 21 years [32], with a median ofbetween 32 and 38 patients undergoing PL [range 13 patients [34] to 118 patients [33]]. These studies are subject

10 166 D.E. Maziak et al. to the same limitations as the retrospective studies mentioned elsewhere in this report. Six ofthe eight retrospective studies reported the use ofadjuvant treatment involving chemotherapy and/or radiotherapy [32 34,36,37,39]. Seven ofthe eight retrospective studies reported median survival for patients undergoing PL, which varied between 10.9 months among 26 patients [32] and 18.1 months among 32 patients [38] (Table 3). Achatzy et al. reported a median survival of10.1 months for 178 patients undergoing some form of surgery, including 118 patients who underwent a total or subtotal PL [33]. Three studies assessed survival from the date of diagnosis [32,34,37], and three did not define the period ofassessment [33,35,36]. Three retrospective studies reported 2- year survival for surgical patients, ranging from 21% for 45 patients undergoing a subtotal PL and four patients undergoing thoracotomy [35] to 40% for 15 patients undergoing PL alone [39]. In a multivariate analysis (Cox model), Alberts et al. found that longer survival was associated with good performance status (p < ), duration ofsymptoms >6 months (p = ), and earlier disease stage (p = ) [32]. Ceresoli et al. [37] reported Cox multivariate analysis results showing good performance status (p = 0.001) and combined modality treatment with palliative PL, and chemotherapy (p = 0.003) were also associated with improved survival. In a univariate analysis, Phillips et al. [39] found that longer survival was associated with epithelial tumour histology compared to biphasic or sarcomatous tumour histology. Five studies reported post-operative mortality, with the range being from 1% of 100 patients undergoing either a total or a subtotal PL [36] to 11% of72 patients undergoing a subtotal PL [33]. The latter study [33] defined the post-operative period as 30 days. Three studies reported post-operative morbidity, ranging from 16% among 50 patients [35] to 22% among 100 patients [36]. Patients in all three studies [35,36,39] experienced empyema and air leak; other complications included respiratory failure, pleural effusion, hemorrhage, wound infection, and acute renal failure. Two retrospective studies reported that PL offered good palliation [35,36]. In one study, lifelong control ofpleural fluid was achieved in 49 of50 patients who had presented with unilateral pleural effusion unsuccessfully treated with thoracocentesis [35]. In the second study, which did not report the method ofsymptom assessment, symptom palliation was achieved for up to 6 months for cough (100% of 40 patients), dyspnea (100% of 37 patients), pleural fluid control (96% of54 patients), chest pain (85% of71 patients), pleural mass/thickening (55% of70 patients), and constriction ofthe hemithorax (40% of30 patients) [35] External review Feedback on a draft version of this report was obtained through a mail survey ofontario practitioners. The sample included surgeons, medical and radiation oncologists, respirologists, and a hematologist. Responses were received from 61 ofthe 111 surveys sent. Forty-three of61 practitioners responded that the report was relevant to their clinical practice and completed the survey. Ofthe 45 respondents who completed the survey, 82% agreed that there was a need for an evidence summary on this topic, and that the literature search was relevant and complete, 91% agreed with the overall interpretation ofthe evidence, and 69% felt that this type of evidence summary would be useful for clinical decision-making. The Practice Guidelines Coordinating Committee also reviewed and approved the report. 4. Discussion Diffuse malignant mesothelioma is a relatively rare but very insidious neoplasm associated with exposure to asbestos, typically diagnosed many years after exposure, and aggressive in its spread to local intrathoracic structures [4]. Ideally, the impact ofsurgery on this disease would be assessed through randomized controlled trials that compare different types of surgery or compare surgery with other treatment modalities. However, given the rarity ofthe disease, no controlled trials have been conducted to date. Our review identified only case series and non-comparative phase II studies, which constitute a relatively low level ofevidence. In addition, the classification, staging, and treatment ofthis disease have varied substantially throughout the years, making the comparison ofdata between studies and the results oftreatment very difficult. By focusing the search on the role of surgery in mesothelioma from 1985, we hoped to eliminate some ofthe confusion, but the quality ofevidence was still limited. Many studies incorporated data from earlier years, particularly retrospective case series reports that often included data from the 1960s and 1970s. Some authors republished old data or extracted data from other studies, further complicating the interpretation ofthe results. This evidence summary has, therefore, focused mainly on the results ofprospective studies and included

11 Surgical management ofmalignant pleural mesothelioma 167 only the latest publications ofongoing case series reports. Very limited evidence exists for the role of surgery in treating this rare disease. Even ifsurgery is very aggressive, patients usually succumb to their disease within 2 years. The role ofaggressive surgery alone, compared to other treatments including best supportive care, has not been directly assessed. Therefore, no conclusions can be made regarding the role ofsurgery alone for the treatment ofmalignant pleural mesothelioma. Multi-variate analyses from several noncomparative studies indicate that longer survival is associated with small, epithelial-type, nodenegative pleural mesotheliomas in patients who undergo aggressive surgery combined with adjuvant chemotherapy and/or radiotherapy. However, no conclusions can be made regarding the role ofaggressive surgery combined with adjuvant chemotherapy and/or radiotherapy as none of those studies were randomized. There are few data concerning symptom control and palliation, which may be particularly important outcomes for a disease where survival prospects are limited. While this evidence summary report has focused on the role ofsurgery in the treatment of mesothelioma, we did not find quality oflife data on patients receiving surgical treatment in the studies. There is a lack ofuniformity in reporting ofdata among the studies identified in this evidence summary. Study selection criteria and operative morbidity and mortality data were not reported in many ofthe studies included in this evidence summary. In addition, many studies reported survival data on only one ofseveral groups ofpatients or reported overall survival data on all patients as one group. Future studies should report data on selection criteria and operative morbidity and mortality for each treatment group as well as the entire patient group. There are many staging systems in use for malignant pleural mesothelioma, and many of the studies included in this evidence summary vary as to which staging system was used. All centres should begin using one staging system in order to make patient selection uniform between centres and consequently, future studies of pleural mesothelioma. However, it is outside the scope ofthis evidence summary report to compare malignant pleural mesothelioma staging systems, therefore, no conclusions can be made regarding which staging system should be used. Future trials in malignant pleural mesothelioma should examine the role ofepp in patients with good prognosis using a randomized controlled study design. For patients with a poorer prognosis randomized trials are needed to examine the role ofpl, pleurodesis for patients with pleural effusions, and PL versus pleurodesis for the palliation of symptoms ofmalignant pleural mesothelioma. Quality oflife as an outcome measure should be included in these future surgical trials. 5. Conclusions This evidence summary report applies to adult patients with diffuse or localized malignant pleural mesothelioma. Because ofthe lack ofsufficient high-quality evidence on the surgical management ofmesothelioma, the Lung DSG opinion is that: The role ofsurgery in the management ofmalignant pleural mesothelioma cannot be precisely defined. Specifically, the lack ofrandomized controlled clinical trials makes it impossible to determine whether the use ofepp or PL improves the survival ofpatients with malignant pleural mesothelioma or effectively palliates the symptoms ofthe disease. In the management ofmalignant pleural mesothelioma, limited data exist to support the use ofchemotherapy and/or radiotherapy for palliation in some patients. The role of these modalities will be explored further by the Lung DSG in two subsequent evidence summary reports. All future studies ofthe role ofsurgery in the treatment ofmalignant pleural mesothelioma should report study selection criteria and operative morbidity and mortality data. Future studies ofthe role ofsurgery in the treatment ofmalignant pleural mesothelioma need to include evaluations ofquality oflife. Practice guidelines developed by the PGI are reviewed and updated regularly. For updates to this guideline, please visit the PGI Web site at PEBC.htm. Acknowledgements Sponsored by Cancer Care Ontario and the Ontario Ministry ofhealth and Long-term Care. Appendix A. List of collaborators Yasmin Alam MD, Michael Brundage MD, A. Rashid Dar MD, Gail Darling MD, Peter Dixon MD, Peter Ellis MD, Conrad Falkson MD, Ronald Feld MD,

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