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Ann Thorac Surg 2008;85:257-264. doi:10.1016/j.athoracsur.2007.06.066
© 2008 The Society of Thoracic Surgeons
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Paul H. Schipper
Francis C. Nichols
Claude Deschamps
Stephen D. Cassivi
Mark S. Allen
Peter C. Pairolero
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Original Articles: General Thoracic

Malignant Pleural Mesothelioma: Surgical Management in 285 Patients

Paul H. Schipper, MDa, Francis C. Nichols, MDa,*, Kristine M. Thomse, BAb, Claude Deschamps, MDa, Stephen D. Cassivi, MDa, Mark S. Allen, MDa, Peter C. Pairolero, MDa

a Division of General Thoracic Surgery, Mayo Clinic, Rochester, Minnesota
b Division of Biostatistics, Mayo Clinic, Rochester, Minnesota

Accepted for publication June 22, 2007.

* Address correspondence to Dr Nichols, Division of General Thoracic Surgery, Mayo Clinic, 200 First St, SW, Rochester, MN 55905 (Email: nichols.francis{at}mayo.edu).

Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 
Background: Malignant pleural mesothelioma is a rare, aggressive, and deadly malignancy. Despite increasing incidence, no treatment modality is accepted standard of care. This report analyzes our experience with surgical management of mesothelioma.

Methods: All patients with surgery for mesothelioma from January 1985 through December 2003 were retrospectively reviewed.

Results: There were 285 patients with a median age of 66 years (range, 26 to 91 years). One hundred forty-six patients (51%) had biopsy only, 73 (26%) had extrapleural pneumonectomy, 34 (12%) had subtotal parietal pleurectomy, 22 (8%) underwent exploration without resection, and 10 (3%) had total pleurectomy. Histopathology was epithelial, nonepithelial, and unclassified in 134, 108, and 43 patients, respectively. Twenty patients were stage IA, 82 patients were stage IB, 24 patients were stage II, 75 patients were stage III, 60 patients were stage IV, and 24 patients were of unknown stage. Fifty-three patients (19%) had chemotherapy alone, 16 (5.6%) had radiation alone, and 42 (14.7%) had both. Thirty-day operative mortality was 6.3% and was not significantly associated with the operative procedure (p = 0.79). Fifty-one percent of extrapleural pneumonectomy patients had major complications, significantly greater than patients having any other procedure (p < 0.001). Median follow-up was 11 months (range, 0 to 7 years). Overall median survival was 10.7 months; however, for patients having extrapleural pneumonectomy, median survival was 16 months. One-, 2-, and 3-year survival after extrapleural pneumonectomy was 61%, 25%, and 14%, respectively.

Conclusions: Extrapleural pneumonectomy can be performed with similar 30-day mortality as other procedures for malignant pleural mesothelioma with a median survival better than subtotal pleurectomy, exploration without resection, and biopsy alone. However, extrapleural pneumonectomy has significant morbidity and a 3-year survival of only 14%.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 References
 
Malignant pleural mesothelioma (MPM) is a rare, aggressive, and often deadly malignancy commonly associated with asbestos exposure. It affects approximately 3,000 people in the United States yearly, and its worldwide incidence continues to rise [1]. Malignant pleural mesothelioma rarely metastasizes until late in its course; however, it can relentlessly invade adjacent structures such as the chest wall, diaphragm, and mediastinum. Malignant pleural mesothelioma presents unique challenges with regard to diagnosis, staging, and treatment. Therapy for MPM has included chemotherapy, gene therapy, hyperthermia, immunotherapy, photodynamic therapy, radiation therapy, surgery, and supportive care. The effect of these various therapies for MPM on patient outcomes has been difficult to assess. To better understand our progress in the surgical treatment of MPM, we retrospectively reviewed all patients having surgery for MPM at our institution.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 References
 
From a prospectively maintained database, all patients who underwent surgery for MPM between January 1, 1985, and December 31, 2003, at the Mayo Clinic in Rochester, Minnesota, were identified and then retrospectively reviewed. Their medical records were reviewed for age, sex, symptoms, histopathology, operative procedure, neoadjuvant or adjuvant therapy, length of hospitalization, operative mortality and morbidity, and long-term survival. The Mayo Foundation Institutional Review Board granted approval for this study on September 16, 2003, with waiver of informed consent and waiver of the Health Insurance Portability and Accountability Act.

The operative procedures were grouped into one of five categories: extrapleural pneumonectomy, total pleurectomy, subtotal pleurectomy, exploration without resection, and biopsy alone. Extrapleural pneumonectomy consisted of en bloc resection of the involved ipsilateral parietal pleura, lung, pericardium, and diaphragm. The diaphragm and right pericardium were reconstructed with polytetrafluoroethylene soft-tissue patch. Total pleurectomy consisted of a complete extrapleural stripping of the parietal and mediastinal pleura and involved visceral pleura from the ipsilateral hemithorax without performing pulmonary resection. Total pleurectomy also included resection of the diaphragm and pericardium when necessary. Both subtotal pleurectomy and exploration without resection were undertaken in anticipation of performing either an extrapleural pneumonectomy or total pleurectomy; however, intraoperative findings prevented the completion of those procedures. In our series, subtotal pleurectomy was defined as removal of up to 70% of the parietal pleura with debulking of as much of the mesothelioma as possible. Subtotal pleurectomy was a less extensive resection than total pleurectomy. Exploration without resection consisted of posterolateral thoracotomy with an extensive dissection performed; however, resection of mesothelioma was not ultimately performed because of identification of unresectable disease. Biopsy alone was performed by means of video-assisted thoracic surgery or limited thoracotomy. Biopsy alone involved very limited dissection and resulted in only a pleural biopsy. Talc was insufflated during these procedures at the discretion of the surgeon. Malignant pleural mesothelioma staging was done according to the American Joint Committee on Cancer [2]. For patients having biopsy alone, lymph node staging was clinically obtained from chest computerized tomography and positron emission tomography.

Operative mortality included all deaths occurring within 30 days of the operative procedure and those who died later but during the same hospitalization. Survival data not available in the medical record were obtained from the Social Security Death Index. Late survival was estimated using the Kaplan–Meier survival method [3]. The starting time for follow-up began the later of postoperative day 31 or date of hospital discharge. One-, 2-, 3-, and 5-year survival estimates were reported with 95% confidence intervals (CI), as well as median survival. The association between risk factors and patient survival, adjusting for age and sex, were assessed using Cox proportional hazard regression, reporting the hazard ratio (HR) and 95% CI [4]. Risk factors assessed included the operative procedure performed with the reference procedure being extrapleural pneumonectomy, histopathology, and stage with the reference stage being stages IA and IB combined. The association between late morbidity and the operative procedure were evaluated in the same manner. Mortalities that occurred beyond the defined operative mortality timeframe were considered a late morbidity. A probability value less than 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 References
 
There were 285 patients (236 men, 49 women). Median age was 66 years (range, 26 to 91 years). Malignant pleural mesothelioma occurred on the right side in 176 patients (62%) and the left side in 106 patients (37%), and was bilateral in 3 patients (1%) The operative procedure was biopsy alone in 146 patients (51%), extrapleural pneumonectomy in 73 patients (26%), subtotal pleurectomy in 34 patients (12%), exploration without resection in 22 patients (8%), and total pleurectomy in 10 patients (3%). Forty-nine patients who had extrapleural pneumonectomy (17%), 3 patients who had exploration without resection (1%), 2 patients who had total pleurectomy (0.7%), and 1 patient who had subtotal pleurectomy (0.4%) had a prior operative biopsy. None of the 146 patients who had biopsy alone had any other thoracic surgical procedure performed. Overall, a talc chemical pleurodesis was performed in 134 patients (47%). Thirty-four of the patients (47%) undergoing extrapleural pneumonectomy had an antecedent talc pleurodesis. A right extrapleural pneumonectomy was performed in 47 patients (64%) and a left extrapleural pneumonectomy was performed in 26 patients (36%). For right extrapleural pneumonectomy, the pericardium was not resected in 3 patients (6.4%). In the remaining 44 patients, the resulting pericardial defect was reconstructed with bovine pericardium in 35 patients (80%), polytetrafluoroethylene soft-tissue patch in 8 patients (18%), and unknown in 1 patient. For left extrapleural pneumonectomy, the pericardium was resected in 24 patients (92%) and not resected in 2 patients. Only 2 (8.3%) of these patients had the pericardial defect reconstructed. Chemotherapy alone was administered in 53 patients (18.6%), radiotherapy in 16 patients (5.6%), and both in 42 patients (14.7%). The timing of chemotherapy or radiation therapy varied throughout the study with no consistent regimen being used (Table 1). Histopathologic diagnosis was epithelial MPM in 134 patients (47%), biphasic in 39 patients (14%), sarcomatous in 39 patients (14%), desmoplastic in 30 patients (10%), and unclassified in 43 patients (8%). The stage was IA in 20 patients (7%), IB in 82 patients (29%), II in 24 patients (8%), III in 75 patients (26%), IV in 60 patients (21%) and unknown in 24 patients (8%).


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  		Table 1 Chemotherapy and Radiation Therapy in 285 Patients Having Surgery for Malignant Pleural Mesothelioma
 
Eighteen patients died (operative mortality, 6.3%). Nine patients (6.2%) died after biopsy alone, 6 patients (8.2%) after extrapleural pneumonectomy, 2 patients (9.1%) after exploration without resection, and 1 patient (2.9%) after subtotal pleurectomy. Of note, 8 of the patients who had biopsy alone received only supportive care postoperatively, with death occurring within 30 days of surgery. The causes of death are outlined in Table 2.


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  		Table 2 Cause of Death After Surgery in 18 Patients With Malignant Pleural Mesothelioma a
 
Overall median hospitalization was 5 days (range, 1 to 112 days). Median hospitalization for biopsy alone was 3 days (range, 1 to 30 days), exploration without resection was 6 days (range, 1 to 11 days), subtotal and total pleurectomy was 6.5 days each (range, 2 to 18 days), and extrapleural pneumonectomy was 9 days (range, 5 to 112 days).

Major complications occurred in 56 patients (19.7%), 37 in patients who had extrapleural pneumonectomy (50.7%), 2 in patients who had total pleurectomy (20%), 2 in patients who had subtotal pleurectomy (5.9%), 2 in patients who had exploration without resection (9.1%) and 13 in patients who had biopsy alone (8.9%) (Table 3). There was a significant association between the type of operative procedure and major complications (p < 0.001). Patients who had extrapleural pneumonectomy experienced more complications.


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  		Table 3 Major Complications in 285 Patients Having Surgery for Malignant Pleural Mesothelioma a
 
Minor complications occurred in 25 patients who had extrapleural pneumonectomy (34.2%), 4 patients who had subtotal pleurectomy (11.8%), 3 patients who had exploration without resection (13.6%), 1 patient who had total pleurectomy (10%), and 11 patients who had biopsy alone (7.5%) (Table 4).


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  		Table 4 Minor Complications in 285 Patients Having Surgery for Malignant Pleural Mesothelioma a
 
Follow-up was complete in 278 patients (97%). Median follow-up was 11 months (range, 1 month to 7.1 years). Two hundred forty-seven patients (87%) have died. Thirty-eight patients (13%) are alive, and include 14 patients who had extrapleural pneumonectomy, 16 patients who had biopsy alone, 4 patients who had subtotal pleurectomy, and 4 patients who had total pleurectomy. Cause of death was related to MPM in all patients with subtotal pleurectomy, exploration without resection, and biopsy alone. Cause of death for patients with total pleurectomy was related to MPM in 5 patients (50%) and was unknown in 1 patient. Three patients with total pleurectomy are alive with recurrent MPM, and 1 patient has no evidence of mesothelioma. Excluding the operative deaths, the cause of death for extrapleural pneumonectomy patients was related to MPM in 39 patients (59%), unknown in 8 patients (12%), and unrelated to MPM in 6 patients (9%). Fourteen patients (19%) after extrapleural pneumonectomy are alive. Seven patients (11%) have recurrent disease, and 6 patients (9%) have no evidence of recurrence.

Overall median survival was 10.7 months (Fig 1). Median survivals for patients after extrapleural pneumonectomy, total pleurectomy, subtotal pleurectomy, exploration without resection, and biopsy alone were 16.0, 17.2, 8.1, 6.8, and 9.2 months, respectively (Fig 2). Median survival for patients after total pleurectomy was the greatest at 17.2 months; however, any meaningful comparison of this group to others is difficult because of the small total pleurectomy sample size. One-, 2-, 3-, and 5- year survivals for patients after extrapleural pneumonectomy were 61% (95% CI, 50% to 74%), 25% (95% CI, 16% to 40 %), 14% (95% CI, 7% to 28%), and 9% (95% CI, 3.5% to 23%), respectively. One- and 2-year survivals for patients after total pleurectomy were 80% (95% CI, 59% to 100%) and 35% (95% CI, 14% to 86%), respectively. One-, 2-, and 3-year survivals for patients after subtotal pleurectomy were 30% (95% CI, 17% to 52%), 15% (95% CI, 6% to 36%), and 3.7% (95% CI, 0% to 25%), respectively. One-, 2-, and 3-year survivals for patients after exploration without resection were 45% (95% CI, 27% to 73%), 10% (95% CI, 27% to 37%), and 0%, respectively. Finally, 1-, 2-, and 3-year survivals for patients after biopsy alone were 36% (95% CI, 28% to 45%), 13% (95% CI, 8% to 21%), and 6% (95% CI, 3% to 12%), respectively.


Figure 1
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  		Fig 1. Overall survival of 266 operative survivors who had surgery for malignant pleural mesothelioma. Zero point on the x axis represents 30 days after operation.

 

Figure 2
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  		Fig 2. Survival of the 266 operative survivors who had various operative procedures for malignant pleural mesothelioma. Zero point on the x axis represents 30 days after operation.

 
In the multivariable Cox model, including age, sex, and procedure type as predictors, both age (p = 0.007; HR = 1.10) and male sex (p = 0.003; HR = 1.74) were significantly associated with worse survival. The HR for total pleurectomy relative to extrapleural pneumonectomy was 0.74 (95% CI, 0.32 to 1.76) (Table 5). The HR for biopsy alone, exploration without resection, and subtotal pleurectomy relative to extrapleural pneumonectomy was 1.51, 1.97, and 1.62, respectively (Table 5).


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  		Table 5 Results of Multivariable Cox Model Assessing Association of Surgical Procedure and Long-Term Survival a
 
Twenty-nine patients (40%) who had extrapleural pneumonectomy required an additional 135 operative procedures (median 2; range, 1 to 28) to manage postoperative morbidity (Table 6).


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  		Table 6 Subsequent Operations in 29 Patients After Extrapleural Pneumonectomy
 
When operative mortality is excluded, histopathologic diagnosis was epithelial-type MPM in 128 patients, and nonepithelial type in 135 patients. The survival was significantly lower for patients with nonepithelial type histopathologic diagnosis (p = 0.001). Median survivals for epithelial-type and nonepithelial types were 465 days and 222 days, respectively. One-, 2-, and 3-year survivals for epithelial-type MPM were 59% (95% CI, 51% to 68%), 29% (95% CI, 22% to 39%), and 13% (95% CI, 8% to 22%), respectively. However, in a multivariable Cox proportional hazard model when adjusted for age and sex, the survivals after extrapleural pneumonectomy for epithelial-type and nonepithelial type MPM were not statistically different (p = 0.2) (Table 7).


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  		Table 7 Results of Multivariable Cox Model Assessing Association of Extrapleural Pneumonectomy Combined With Epithelial Versus Nonepithelial Type Histopathologic Diagnosis a b
 
Median survival for patients with stage IA and IB MPM was 344 days as compared with 161 days for patients with stage IV. In a model adjusting for age and sex, there was significantly decreased survival in patients with stage IV MPM relative to stages IA and IB combined (p < 0.001; HR = 2.6; 95% CI, 1.8 to 3.8). There was no significant worsening in survival for patients with stages II and III relative to IA and IB (p= 0.36; HR = 1.2; 95% CI, 0.8 to 1.6).


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 References
 
Malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm arising from mesothelial cells. Although MPM can occur in any body cavity, the pleura are the most common site [5]. The first case of MPM was reported in 1931, and its association with asbestos was later confirmed in a series of reports throughout the 1960s [6–8]. Approximately 3,000 new cases of MPM occur in the United States each year. The incidence is expected to continue rising until the year 2020 [9, 10] because of the long latency period between occupational exposure and the development of MPM. The latency period can range from 12 to 50 years [11, 12]. Peterson and associates [13], in a review of the literature, identified asbestos exposure in 13% to 100% of patients with MPM. Thus, asbestos exposure is not a universal finding in MPM. Other factors associated with MPM include exposures to certain organic chemicals, nonasbestos mineral fibers, chronic pleural inflammation and scarring, and simian virus 40 (SV40) infections [14–16]. Ionizing radiation also had been considered a risk factor for MPM; however, large cohort studies have failed to confirm this association [17].

The diagnosis of MPM can be challenging. Radiographic studies including chest roentgenogram, computerized tomography, and magnetic resonance imaging are all useful. Computerized tomography is helpful to assess the tumor burden, whereas magnetic resonance imaging is better at defining local tumor extension [18]. Both pleural fluid cytology and transthoracic fine-needle aspiration are unreliable in establishing a diagnosis. Bouton and Rey [19] recommend pleural biopsy by video-assisted thoracic surgery as the optimal diagnostic procedure. If extensive disease does not allow video-assisted thoracic surgery, then pleural biopsy through a small thoracotomy is reasonable. In our 285 patients having surgery for MPM, biopsy alone with or without talc insufflation was the most frequently performed procedure. Positron emission tomography may have a role in assessing for distant metastatic disease. During the timeframe of this study, positron emission tomography scanning was not in widespread use.

It is undeniable that the overall treatment results for MPM have been less than rewarding [20]. Optimal treatment for MPM remains clouded in controversy, perhaps because of the lack of any large prospective clinical trials. Traditional single-modality treatments for MPM have included chemotherapy, radiation therapy, and surgery. Used alone, these modalities have generally been disappointing. Surgical treatments have ranged from biopsy alone with or without palliative pleurodesis, to total pleurectomy and extrapleural pneumonectomy.

Biopsy alone is most commonly performed in patients whose extent of disease or performance status precludes a more aggressive resection. Median survival for our patients having biopsy alone was 9.2 months. This is considerably less than the median survival of 18 months reported on by Law and colleagues [21], but similar to the 30-week median survival reported by Hulks and associates [22]. In both of those studies, there were patients treated with supportive care alone after diagnosis. Hulks and coworkers [21] found that patients presenting with dyspnea lived significantly longer than patients presenting with pain (44 weeks versus 22 weeks). At tertiary referral centers, such as ours, it is not uncommon for considerable time to pass between when a patient first becomes symptomatic and their referral. This latter point may best explain the lower than expected median survival in our patients having biopsy alone.

Total pleurectomy is a debulking operation that spares pulmonary resection. Patients should be considered for this procedure when they have limited pulmonary function. Extrapleural pneumonectomy is a far more radical debulking operation that in addition to visceral pleurectomy routinely includes pneumonectomy and resection of the pericardium and diaphragm. Extrapleural pneumonectomy has the appeal of possibly removing more disease; however, even with extrapleural pneumonectomy, obtaining wider negative margins is not possible because of tumor proximity to vital structures such as the heart, aorta, vena cava, and esophagus. No randomized controlled studies comparing total pleurectomy with extrapleural pneumonectomy have been done, and the efficacy of extrapleural pneumonectomy relative to total pleurectomy remains undefined. Pass and colleagues [23] reviewed their experience in patients having these two procedures. In their nonrandomized series, the mesothelioma recurrence rates for extrapleural pneumonectomy and total pleurectomy were similar at 79% and 69%, respectively. Of importance in that series was the pattern of recurrence. Local recurrence was more common in patients having total pleurectomy compared with patients having extrapleural pneumonectomy (69% versus 38%, respectively), and distant recurrence was more common for patients having extrapleural pneumonectomy (10% versus 31%, respectively) [23]. Total pleurectomy is associated with an operative mortality of 1.5% to 5% [24, 25]; however, there were no operative deaths in our 10 patients having total pleurectomy. In our series, considerably fewer patients having total pleurectomy had major complications compared with those having extrapleural pneumonectomy (20% versus 50.7%, respectively); moreover, median survival for total pleurectomy exceeded extrapleural pneumonectomy (17.2 months versus 16 months). In addition to the nonrandomized nature of our data, meaningful comparisons of our total pleurectomy cohort are difficult because of its small sample size.

Most MPM cannot be surgically removed. Similar to the report from the MPM Lung Cancer Study Group trial [26], in which only 20 of 83 eligible patients (24%) underwent extrapleural pneumonectomy, only 73 of our 285 patients with MPM (26%) underwent this procedure. Historically, extrapleural pneumonectomy had an unacceptably high mortality, most likely because of the extent of resection. In an early report by Butchart and colleagues [27], operative mortality for extrapleural pneumonectomy was 31%, and in the MPM Lung Cancer Study Group trial, operative mortality was 15% [26]. With improvements in patient selection and improved perioperative care, the mortality for extrapleural pneumonectomy has decreased to 3.4% in one recent series [28]; however, major complications in this series occurred in 60% of patients and included atrial fibrillation (44.2%), prolonged intubation (7.9%), vocal cord paralysis (6.7%), deep venous thrombosis (6.4%), and technical complications (patch dehiscence or hemorrhage; 6.1%). Less common complications included cardiac tamponade (3.6%), acute respiratory distress syndrome (3.6%), cardiac arrest (3%), constrictive pericarditis (2.7%), aspiration (2.7%), pulmonary failure (1.8%), pulmonary embolus (1.5%), and bronchopleural fistula (1.5%) [28]. Our operative mortality of 8.2% for patients having extrapleural pneumonectomy is consistent with other reports [29]. Interestingly, the 8.2% extrapleural pneumonectomy operative mortality was not significantly different from the operative mortality for either biopsy alone (6.2%) or exploration without resection (9.1%), which likely reflects the extensive nature of the MPM in the latter patients. Our series morbidity of 50.7% in patients having extrapleural pneumonectomy is consistent with other series, including our 11% incidence of bronchopleural fistula, which according to Pass [30] can range from 3% to 20%.

The median survival of only 16.0 months for our patients having extrapleural pneumonectomy, and 1-, 2-, and 3-year survivals of 61%, 25%, and 14%, respectively, are disappointing, but consistent with others. Rusch and Venkatraman [31] reported a median survival of 10 months, and Pass and colleagues [23] reported a median survival of 9.4 months. Similar to others, epithelial-type MPM appeared to have an overall improved survival in our study. However, despite a 20% 1-year better survival for patients with epithelial-type MPM compared with nonepithelial type having extrapleural pneumonectomy, this was not significant. Similarly, although patients with stages IA and IB did better than patients with stage IV, meaningful stage comparisons were again limited by small numbers. With such dismal results, much remains to be learned about the optimal treatment for MPM. Novel therapies under investigation include intracavitary lavage of the pleural cavity with hyperthermic cisplatin [32]. Kaiser [33] has reported on suicide gene therapy, and Friedberg and colleagues [34] on photodynamic therapy

Although chemotherapy and radiation therapy were used in both neoadjuvant and adjuvant fashions throughout the 18-year period of this review, a consistent chemotherapy or radiation treatment protocol was difficult to establish. Currently at our institution, patients are considered for extrapleural pneumonectomy if MPM is confined to one hemithorax without invasion of vital structures, age is younger than 75 years, Karnofsky performance status is greater than 70, postoperative predicted forced expiratory volume in 1 second is greater than 0.8 L, there is no evidence of pulmonary artery hypertension on echocardiography, and the dobutamine stress echocardiogram is negative for myocardial ischemia. These selected patients then most commonly receive three cycles of systemic intravenous chemotherapy consisting of carboplatin and pemetrexed disodium heptahydrate (Alimta; Lilly France SAS, Fegersheim, France). Chemotherapy is followed by clinical restaging and, if appropriate, extrapleural pneumonectomy. Radiation therapy is begun between 4 and 6 weeks postoperatively with treatment of the entire pleural surface and mediastinal lymph nodes to 50 Gy. Areas of concern receive a boost to 60 Gy.

In conclusion, this nonrandomized retrospective review of our surgical experience with MPM demonstrates that overall survival is poor. Extrapleural pneumonectomy can be performed with acceptable mortality, and has a median survival significantly better than for subtotal pleurectomy, exploration without resection, or biopsy alone. However, this improved survival for extrapleural pneumonectomy comes at the expense of high morbidity, and a 3-year survival of only 14%. Indeed, the optimal treatment for MPM remains elusive.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
References
 
DR WILLIAM R. SMYTHE (Temple, TX): Thanks very much. I enjoyed your presentation. Doctor Schipper and colleagues at the Mayo Clinic should be congratulated for presenting one of the three largest retrospective group studies that have been brought to light at present, the other two being from Dana Farber and from Memorial Sloan-Kettering. I would like to start out by saying that I think that the only real benefit of this study is in proving two things. One, that treating mesothelioma patients in this particular time in a nontrial setting and treating them inconsistently with adjuvant or neoadjuvant therapies will lead to the findings that you mention, and that is, poor survival.

In your abstract you mention that 30-day mortality for extrapleural pneumonectomy was similar to other treatments, but actually 8.2% mortality is almost three times that of the subtotal pleurectomy group and about two times that of the two other large retrospective studies that have been published. I am wondering if this is related to the large number of patients in stages III and IV? If this is true, why did you operate on so many patients that were stage IV, and how did you stage these patients, because we know that patients in that category are unlikely to do well, and of course your overall numbers will look poor resultant to that?

he next question is what criteria did you use to perform each procedure? Again, in your abstract, although you didn’t make a strong statement, here you say that pleurectomy and extrapleural pneumonectomy have relatively similar survivals. The problem of course is selection bias. The group at Memorial Sloan-Kettering published a similar paper with similar conclusions comparing extrapleural pneumonectomy to pleurectomy; however, since it wasn’t a randomized study, the feeling was that many of the patients who received pleurectomy were likely to have been earlier staged patients and that it is difficult to make definitive statements about survival comparisons in those two groups.

Was there any effort at all to correlate other treatments with survival in your study? A large number of them got chemotherapy, but that being said, as you know, in the pre-Alimta era chemotherapy was relatively ineffective, less than 20% response rates and little impact on survival. Only 17 patients received radiation therapy, which was surprising, because I think now there are two good papers in the literature, one from Memorial and one from the group that I recently was associated with at M.D. Anderson, showing that adjuvant radiation therapy can improve local control and survival.

Lastly, did you make an effort to compare local and distant failure rates in your patients? I would assume that the local failure rates were quite high in this study because of the low number of patients that received adjuvant radiation therapy. And also, even though extrapleural pneumonectomy is a morbid procedure, your complication rate actually is relatively high, and your rate of empyema, at 19%, is the highest I have seen in the literature for this procedure. Do you have any comments or any ideas about why you might have had this problem? Thanks very much.

DR SCHIPPER: Thank you, Dr Smythe. I am going to make an attempt to answer your questions. Your first comment that this is a retrospective trial is a valid one, and the better trial would be the prospective randomized trial, and I would hope someday that can be done. Our mortality from extrapleural pneumonectomy is in fact similar to our mortality from pneumonectomy over the same time period, which was reported a few years ago, and was 7%. It is not the same mortality as reported in the literature by Dr Sugarbaker and others, in the 3.4% to 5% range, but it is consistent with the entire range in the literature, which is 3.4% up to 15%. Furthermore, it is better than the first report in the literature, which was a 31% operative mortality.

The staging of our patients was problematic, and the reason for that is the large number of our patients who had biopsy only performed. For these patients their staging is predominantly clinical. Although we do get some T staging during thoracoscopy and the biopsy, their nodal staging is based on CT (computerized tomographic) scans and, in the latter part of the study, on PET (positron emission tomographic) scans.

Our criteria for performing an extrapleural pneumonectomy, in this study, being retrospective, was primarily based on the Mayo Clinic surgeons who believed in this procedure. Patients for extrapleural pneumonectomy needed to have good functional status, generally a Karnofsky score greater than 70; good cardiac performance with a negative dobutamine stress echo; a predicted postoperative FEV1 (forced expiratory volume in 1 second) greater than 0.8 L, so that we knew we could do a pneumonectomy.

The subtotal pleurectomy patients and the dissection but ultimately no resection patients were patients who were brought to the operating room with the intent of doing a complete resection, but because of the extent of the disease found, it was felt that that would not be possible, and a palliative procedure was then performed. We would want to be able to resect all the disease before doing a total pleurectomy or an extrapleural pneumonectomy.

Our comparison of other treatments other than operative treatments is problematic because this is based on a prospectively acquired surgical database, and it would not include patients whose diagnosis of mesothelioma was made otherwise and received just chemotherapy or radiation therapy. Also because of the long time range, 18 years, the chemotherapy protocol that was used differed, and many of these patients would come from outside institutions having already received some chemotherapy.

We did not look at local compared to distant failure rates, and I cannot comment on that.

Our complication rate is high, and putting together this database, I tried to be as honest as possible about the complications. Minor complications included such things as atrial fibrillation, a requirement for postoperative blood transfusion because of bleeding, wound infection, postoperative pneumonia, and the major complications you saw listed. The complication rates in the literature ranged, as you said, from 19% up to a 50% complication rate in Dr Sugarbaker’s most recently published article with, I believe, approximately 300 patients.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 

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