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Original Articles: General Thoracic

Prognostic Features of Long-term Survivors After Surgical Management of Malignant Pleural Mesothelioma

^a Department of Cardiothoracic Surgery, The University of Sydney, Royal Prince Alfred Hospital, Sydney, Australia
^b The Baird Institute for Applied Heart and Lung Surgical Research, Sydney, Australia
^c Department of Medical Oncology, Royal Prince Alfred Hospital, Sydney, Australia
^e Department of Radiation Oncology, Royal Prince Alfred Hospital, Sydney, Australia
^d Sydney Cancer Center, Sydney, Australia

Accepted for publication January 13, 2009.

^_* Address correspondence to *Prof McCaughan, Royal Prince Alfred Hospital, Department of Cardiothoracic Surgery, Newton, Sydney, 2000, Australia (Email: bmccaughan{at}scts.com.au).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background: The primary aim of this study was to evaluate prognostic features of long-term survivors with pleural mesothelioma.

Methods: Overall survival outcome was analyzed in 456 patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy (EPP), pleurectomy/decortications, or pleurodesis/biopsy with at least 18 months of follow-up. Prospectively collected clinicopathologic and treatment data were assessed for their correlations with actual 18-month survivors in both univariate and multivariate analyses.

Results: The actual 18-month survival was 28%. Epithelial subtype was present in 185 patients (41%) and nonepithelial subtype in 183 (40%). Procedures were EPP in 59 patients (13%), pleurectomy/decortication in 250 (55%), and pleurodesis/biopsy in 147 (32%). Forty-two patients (9%) underwent positron emission tomography (PET) scanning. Forty patients (9%) received adjuvant radiotherapy and 45 (10%) received postoperative pemetrexed combination chemotherapy. In univariate analysis, age 65 years or younger (p < 0.001), malignant pleural effusion (p = 0.041), epithelial subtype (p < 0.001), EPP (p < 0.001), PET scan (p = 0.012), adjuvant radiotherapy (p = 0.042), and postoperative pemetrexed combination chemotherapy (p = 0.035) were strongly associated with 18-month survivors. In multivariate analysis, epithelial histopathologic subtype (p < 0.001) and EPP (p < 0.001) were independently associated with 18-month survivors.

Conclusions: The actual 18-month survival was 28% in 456 pleural mesothelioma patients who underwent operation. Epithelial histologic subtype and EPP were identified as independent predictors for 18-month survivors.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
In the United States, data from Surveillance, Epidemiology and End Results (SEER) showed a steep rise in the malignant pleural mesothelioma (MPM) incidence through the 1990s and no evidence that the peak incidence has been passed in this country [1]. Much higher incidence rates are seen in the United Kingdom and Australia due to the widespread use in the past of asbestos, a potent inducer of mesothelioma. The peak incidence for these two countries is projected to occur in 2015 [2]. The incidence is expected to continue to increase in areas of the world where asbestos use has not been curtailed. MPM is a rapidly fatal disease, without aggressive surgical treatments, the median survival has been quoted to be less than a year [3].

Some evidence during the past decade has suggested that the combined treatment approach using extrapleural pneumonectomy (EPP) or pleurectomy/decortication and adjuvant radiotherapy or chemotherapy, or both, is associated with an improved prognosis compared with historical controls [4, 5]. Several recent studies have used actuarial analysis to assess the survival results and prognostic factors. However, more precise long-term survival results and prognostic variables can only be obtained by assessment of actual long-term survivors, and the elucidation of this issue is very important in the future treatment and care of these patients. A cohort of patients with adequate length of follow-up and sufficient number of long-term survivors is prerequisite for such a study. The primary aim of this study was to evaluate prognostic features of long-term survivors in a prospective cohort of 456 patients who have been observed for at least 18 months after their initial operation at a high-volume tertiary referral center.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Patients
Between March 1984 and December 2007, 540 patients with MPM were surgically managed at the Royal Prince Alfred Hospital in Sydney, Australia. Informed consent was obtained from all patients before operation. Patient characteristics and clinical data were recorded in a prospective electronic database. Eligible patients were those with a tissue diagnosis of MPM confirmed by immunohistochemistry. These patients underwent extensive preoperative investigations, which included a review of all prior clinical information, physical examination, serum chemistry and hematology, chest roentgenogram, computed tomography (CT) of the chest and upper abdomen, and pulmonary function testing. Since 2000, positron emission tomography (PET) became available at our institution.

The present analysis excluded 19 patients (3.5%) who were lost to follow-up. The basis of this report is 456 patients who have been observed for more than 18 months from the time of operation.

Treatment
EPP was used more frequently as the en bloc resection of the disease involving the pleura, the lung, the ipsilateral hemidiaphragm, and the pericardium. Patients were considered for EEP if they had good performance status (World Health Organization performance status 2), normal results on renal and liver function tests, adequate cardiac (ejection fraction > 0.50 based on echocardiogram) and pulmonary function assessment (forced expiratory volume in 1 second > 70% and vital capacity > 3 L), and the extent of disease limited to the ipsilateral hemithorax with no radiologic evidence of transdiaphragmatic, transpericardial, or extensive chest wall involvement.

Formal mediastinal lymph node dissection was performed, and all tissues were sent for histologic examination. The pericardial and diaphragmatic defects were repaired with 2-mm GoreTex dual mesh (W. L. Gore and Assoc, Flagstaff, AZ).

During this time, 59 patients (13%) underwent EPP. Pleurectomy/decortication was reserved for patients with insufficient cardiopulmonary reserve, advanced age, anatomic constraints, or only limited disease. Patients who were not candidates for EPP or pleurectomy/decortication underwent palliative pleurodesis by thoracotomy or thoracoscopic technique, and talc was instilled to cause sterile pleural inflammation and subsequent obliteration of the pleural space. A total of 250 patients (55%) underwent pleurectomy/decortications, and 147 (32%) had palliative pleurodesis and biopsy.

Adjuvant radiotherapy was introduced in 2002 in an attempt to improve local and regional disease control [6]. Patients were typically referred to a radiation oncologist for assessment within 6 weeks of the operation. Selection criteria for radiotherapy include good performance status, adequate residual cardiopulmonary function, and satisfactory recovery from the operation. Radiotherapy commenced within 12 weeks of the operation. In most patients, a mixed photon and electron technique was used, delivering a total dose of 45 Gy in 25 daily fractions to the entire hemithorax, ipsilateral mediastinum bed, and ipsilateral chest wall. Postoperatively, 40 patients (9%) received radiotherapy, including 20 patients who underwent EPP. Chemotherapy had not routinely been used as an adjuvant therapy in the past; however, in recent years some evidence suggested that pemetrexed plus cisplatin or carboplatin resulted in superior survival time [7–9]. In the present study cohort, 3 patients (1%) received preoperative pemetrexed combined with cisplatin or carboplatin, and 45 patients (10%) received postoperative pemetrexed combined with cisplatin or carboplatin.

Study Methods
The chairperson of the ethics committee approved the current study and waived the need for patient consent for the study because individual patients were not identified. After hospital discharge, all patients had scheduled follow-up at 3-month intervals for the first year and every 6 months thereafter until the last time of contact or death. The follow-up review included clinical examination and assessment of chest CT scans. With an aim of constantly monitoring the postoperative and survival results in these patients, all the clinicopathologic, operative, perioperative, and follow-up data were prospectively collected and entered into a computerized database by a research assistant during this study period.

The overall survival was determined from the time of the operation. Perioperative deaths were included in survival analysis. Because the current series spanned a 24-year period during which an evolution occurred in surgical treatment strategies, logistic regression statistics using 18-month survival as dependent variable were used. MPM is a highly malignant disease, with current reports indicated a median survival of 12 months after nonaggressive treatments. Patients who lived for more than 18 months after their operation were considered to be long-term survivors in the present series.

Statistical Analysis
Actual 18-month survivors were analyzed for their association with all prospectively collected clinical variables. For univariate analysis, ² test, or Fisher exact test where appropriate, were used for categoric factors. Binary logistic regression was used for the multivariate analysis to identify the independent factors predictive of 18-month survivors. These statistical analyses were performed using SPSS 16.5 software (SPSS GmbH, Munich, Germany). A significant difference was assumed for values of p < 0.05.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
A total of 456 consecutive patients who underwent surgical management of MPM were prospectively observed for at least 18 months. All patients were monitored until December 2007 or until death, and the median follow-up period was 32 months (range, 18 to 115 months). At the time of the last follow-up, 20 patients (4.4%) remained alive. The actual 18-month survival was 28%, with an estimated 3-year survival of 10%. Perioperatively, 18 patients (4%) died, including 4 who underwent EPP.

Clinicopathologic Data
There were 390 men (86%). The mean age at the time of operation was 66 (SD, 10) years. The mean interval between the time of diagnosis and the time of surgery was 5 (SD, 24) days. Left-sided disease was present in 197 patients (43%) and right-sided disease in 259 (57%), and 318 (70%) had malignant pleural effusion. Epithelial subtype was present in 185 patients (41%), sarcomatoid/biphasic subtypes in 183 (40%), and the histologic subtype of the remaining 88 patients (19%) was not determined.

Treatment-related Data
Six surgeons were involved doing the procedures. One surgeon (B.C.M.) did 344 cases (75%), and the remaining 5 surgeons together did 112 cases (25%). Procedures comprised EEP in 59 patients (13%), pleurectomy/decortication in 250 (55%), and pleurodesis and biopsy in the remaining 147 (32%). A preoperative PET scan was done in 42 (9%). Postoperatively, 40 patients (9%) received adjuvant radiotherapy to the ipsilateral lung field, and 55 (12%) had chemotherapy, including 45 patients (10%) who received pemetrexed combination chemotherapy (pemetrexed combined with either cisplatin or carboplatin). Among the 59 patients who underwent EPP, 3 received preoperative pemetrexed combination chemotherapy, 14 received postoperative pemetrexed combination chemotherapy, and 20 patients received adjuvant radiotherapy.

Univariate Analysis of Prognostic Variables
Table 1 summarizes the correlation of clinicopathologic and treatment-related parameters with actual 18-month survivors after operation for MPM. Age 65 years or younger (p < 0.001), absence of malignant pleural effusion (p = 0.041), epithelial subtype (p < 0.001), EPP (p < 0.001), PET scan (p = 0.012), adjuvant radiotherapy (p = 0.042), and pemetrexed combination chemotherapy (p = 0.035) were strongly associated with 18-month survivors.

The discrepancies in actual survival results stratified by histologic subtype and treatment modalities are illustrated in Figures 1 and 2, respectively. The actual 18-month survival rates in epithelial subtype and nonepithelial subtype were 40% and 17%, respectively (Fig 1). The actual 18-month survival rates in patients who underwent EPP, pleurectomy/decortication, and pleurodesis/biopsy were 51%, 25%, and 24%, respectively (Fig 2).

View larger version (18K): [in this window] [in a new window]   Fig 1. Overall survival after surgical management of malignant pleural mesothelioma is shown stratified by histopathologic subtype. Survival outcome of epithelial subtype was significantly better than nonepithelial subtypes (p < 0.001).

View larger version (21K): [in this window] [in a new window]   Fig 2. Overall survival after surgical management of malignant pleural mesothelioma is shown stratified by operation type. Survival outcome of the patients who underwent extrapleural pneumonectomy was significantly better than those who underwent pleurectomy/decortication or pleurodesis/biopsy (p < 0.001).

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

Several studies have consistently demonstrated the significance of epithelial histology in the outcomes of mesothelioma patients. Sugarbaker and colleagues [4] reported 103 of 173 patients (59%) with epithelial histology were associated with a prolonged survival of 52% at 2 years compared with a 16% in nonepithelial tumors after EPP. Flores and colleagues [5] reported their results on 663 surgically treated patients and demonstrated epithelial histology was an independent prognostic variable for survival (35% vs 25% at 20 months). Ceresoli and coworkers [10] studied the therapeutic outcomes according to histologic subtype in 121 patients with MPM and showed 1-year survival of patients with epithelial subtype was 46% vs 19% in patients with sarcomatoid histology. These data strongly suggest that MPM is a disease largely governed by its biologic aggressiveness, and perhaps more caution should be taken when considering patients with nonepithelial histology for aggressive surgical approach.

The role of surgical intervention in the past was mainly to provide palliation by using pleurodesis and pleurectomy/decortication [11]. Without a curative intent, the survival outcomes associated with these procedures might be little different from the natural course of the disease. Whether EPP or pleurectomy/decortication should be used as the cytoreductive approach is a subject of ongoing debate; however, it seems certain that the goal of curative surgical intent is to obtain complete macroscopic cytoreduction [12]. Our experience showed that complete macroscopic cytoreduction can only be achieved by using EPP.

Patients at our center who underwent EPP were assessed preoperatively as having a good performance status, and pleural disease limited to the ipsilateral hemithorax. Because the present study is nonrandomized, it cannot be used to prove EPP is superior to pleurectomy/decortication. The study possessed inherent selection bias, in that it is likely the superior survival outcomes in EPP patients were partly due to favorable prognostic features associated with these patients. Nevertheless, the results of this selected group of patients were encouraging: more than 50% of the EPP patients survived more than 18 months compared with less than 25% for patients who had pleurectomy/decortication or pleurodesis.

The present study also demonstrated that preoperative PET, adjuvant radiotherapy, and pemetrexed combination chemotherapy were significant variables in univariate analysis. Flores and colleagues [13] studied 137 patients with MPM who underwent PET scan. Multivariate analysis showed tumors with a high standard uptake value were associated with a 1.9 times greater risk of death than those with a low standard uptake value, and the authors suggested PET can be used to stratify patients for treatment and clinical trials. PET only became available in recent years at our center, and it has been used to exclude extrathoracic spread of disease. Unfortunately, we have not prospectively collected the data on how many patients were excluded from EPP based on preoperative PET scan. This should be a subject of study in our future research.

Although the data were nonrandomized, it is encouraging that adjuvant radiotherapy and pemetrexed combined with cisplatin or carboplatin were also associated with an improved survival in univariate analysis. The main value of these significant prognostic factors is to provide a reference point for future prospective trials.

One surprising negative finding is that the outcomes of patients who underwent pleurectomy/decortication were little different from those who just had pleurodesis and pleural biopsy. In patients who were not the candidates for aggressive therapy, the main aim of the operation was to control pleural fluid, usually by using pleurodesis. During the study period, pleurectomy/decortication was reserved for patients with recurrent pleural effusion or those whose lung failed to expand. This mixture of surgical indications and patient selection may partly explain the similar survival outcomes between patients who underwent pleurodesis and pleurectomy/decortication. Another plausible explanation is that the outcomes of these patients could have been influenced by underlying confounding factors that have not been determined. In other words, our current patient selection criteria, using preoperative blood tests, pulmonary function tests, echocardiogram, and radiologic assessment for the extent of disease, are inadequate to stratify patients for pleurectomy/decortication or pleurodesis/biopsy.

This has prompted us to establish a tissue bank for MPM at our institution and to define different subtypes of prognosis and response to therapy based on their molecular markers (biomarkers). A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic, pathologic process or response to a therapeutic intervention. The ability to forecast prognosis and predict response to therapy could help the surgeons to better stratify patients to the most appropriate treatments that they will respond to without delay. We hope that in the future this approach would lead to an improvement of the overall outcomes and at the same time improve the quality of life by minimizing all unnecessary side effects and complications associated with the treatments that the patients would otherwise not respond to.

This approach is best illustrated in the advancement of breast cancer management. The clinical and experimental observation of the sensitivity of some breast cancers to estrogen led to the hypothesis and ultimately the discovery and application of effective endocrine therapy (eg, tamoxifen) targeting the estrogen receptor. Subsequently, the identification of Her2/neu amplification as a marker of poor prognosis led to the development of the anti-erbB2 monoclonal antibody trastuzumab (Herceptin, Genentech, South San Francisco, CA) as a targeted therapy. Stratification or "personalization" of therapy is a key area of research in clinical oncology because current cancer therapeutic modalities or agents only benefit a subset of MPM patients.

The limitations of the present study include that the data were nonrandomized, and the outcome may have been influenced by the presence of unknown confounders. The inherent presence of selection bias and the temporal factor may account for the apparent improved survival in patients who received adjuvant radiotherapy and pemetrexed combination chemotherapy. In addition, the selection of patients to undergo adjuvant therapy was biased because it was based on their postoperative functional status, which may partly explain the discrepancies between patients receiving adjuvant therapy and those only undergoing operations. To prove the relevance of adjuvant radiotherapy and pemetrexed combination chemotherapy, it must be further evaluated in a prospective manner.

Several tumor-staging systems have been proposed, and none are perfect to reliably predict prognosis and response to therapy. Tumor staging has not been routinely used in our patients; therefore, stratification according to TNM is not possible at this point. Verification of the current staging systems and identification of potential biomarkers are important objectives for our future research.

In conclusion, this study of a cohort of 456 patients with extended follow-up period helps elucidate the long-term prognosis after operation for MPM patients by demonstrating valuable clinical data on 18-month survivors. The clinicopathologic and treatment-related data of long-term survivors have been clarified in detail, and epithelial histologic subtype and EPP were identified as independent predictors for 18-month survivors.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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