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Ann Thorac Surg 2010;89:207-210. doi:10.1016/j.athoracsur.2009.09.028
© 2010 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Second Surgery for Recurrence of Malignant Pleural Mesothelioma After Extrapleural Pneumonectomy

Leonardo Politi, MDa,*, Giuseppe Borzellino, MDb

a Department of Medical and Surgical Critical Care, University of Florence, Florence
b Department of Surgery, University of Verona, Verona, Italy

Accepted for publication September 14, 2009.

* Address correspondence to Dr Politi, Department of Medical and Surgical Critical Care, Azienda Ospedaliero Universitaria Careggi, Viale Morgagni 85, Firenze, I-50134, Italy (Email: leonardo.politi{at}unifi.it).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Extrapleural pneumonectomy is a treatment option for malignant pleural mesothelioma (MPM), but disease recurrence is common. Among different therapeutic options for recurrence, we have found no reports for second surgical procedures.

Methods: We retrospectively evaluated the types and outcomes of surgical management of solid recurrences of MPM, in a series of 74 patients treated with extrapleural pneumonectomy over a 20-year period.

Results: Of 57 patients for whom follow-up data were available, 11 patients experienced recurrent disease in the form of a solid mass, 1.5 to 12 years after the initial treatment; 8 of these patients had sufficiently good clinical conditions to undergo a second surgery with curative intent. Chest wall resection was performed in 4 cases of parietal recurrence, radical retroperitoneal resection was done in 3 cases of retroperitoneal relapse, and segmental resection of the remaining lung was done in one case of pulmonary metastasis. In this latter case, although computed tomographic images showed a solid mass, at surgery the disease was found to have a serosal nature, precluding the possibility of a curative surgery. Median survival after the second surgery was 14.5 months (range, 6 to 29); no association between survival and site of recurrence, age or disease-free interval was found.

Conclusions: In this series, the second surgery did not offer the expected survival benefit of curative treatment strategies and should therefore be considered palliative. Second surgery may be a treatment option in a subset of patients who experience a solid recurrence of MPM that is symptomatic or near vital organs and who cannot undergo additional radiotherapy.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Curative treatment of malignant pleural mesothelioma (MPM) has been challenging [1]. Although clinical trials have recently shown improved survival with combination chemotherapy (eg, Vogelzang and colleagues [2]), radical surgery has been the preferred treatment for patients with resectable cancer. One commonly used surgical procedure is extrapleural pneumonectomy, which involves the en bloc resection of the diseased lung, pleura, pericardium, and hemidiaphragm, followed by reconstruction of the pericardium and diaphragm [3, 4]. Extrapleural pneumonectomy is an aggressive surgery that results in substantial mortality and morbidity; in one large series, 3.4% of patients died postoperatively and 60% had complications [5]. Numerous papers in the past 10 years have described clinical experiences with extrapleural pneumonectomy in a multimodal regimen (reviewed by Rice [4]); in these studies, median survival time ranged from 11 to 23 months and rates of local and distant recurrence were 13% to 62% and 29% to 56%, respectively.

The patterns of disease recurrence after surgery and the factors associated with recurrence have been reported [6, 7] but no published report has described, to our knowledge, the therapeutic management of recurrent disease in patients already subjected to multimodal therapy for MPM. Therefore, in the present study we report our experience with surgical treatment of recurrent disease in a series of patients initially submitted to bimodal therapy.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
We retrospectively reviewed medical records at the Department of Medical and Surgical Critical Care, Careggi Hospital of Florence and at the Department of Thoracic Surgery at the University Hospital of Verona, to identify patients who underwent extrapleural pneumonectomy for Butchart's stage I or II MPM since 1988. We received approval to retrospectively analyze the data in clinical records from the Department of Medical and Surgical Critical Care, Careggi Hospital, University of Florence and from the Department of Surgery, University of Verona, which both waived the need to obtain patients' informed consent for inclusion in the study. All patients had given informed consent to the surgical procedures and were treated according to the ethical and clinical standards of the same universities and their hospitals.

Patient Selection
Over the 20-year period, 74 patients with stage I and II MPM were treated with extrapleural pneumonectomy and, when possible, adjuvant chemotherapy or radiotherapy. The surgical procedures used in these patients and the clinical outcomes up to 12 years have been recently reported [8]. Three patients died in the postoperative period and 14 were lost to follow-up. Of the remaining 57 patients, four are alive without disease. In 42 patients, a serosal recurrence was diagnosed in the peritoneal or pericardiac cavities or in the contralateral pleura within 18 months of the initial operation; no further surgical treatment was possible for these patients. Finally, a solid recurrence was observed in 11 patients, but surgery was contraindicated in the 3 oldest patients (72 to 75 years of age): one patient with respiratory failure was given chemotherapy, but died in 3 months; one patient with a retroperitoneal relapse 26 months after the initial treatment died of heart failure in 2 months; finally, one patient with pulmonary recurrence and respiratory failure underwent radiosurgery and is alive at 8 months. A surgical treatment for the solid recurrence was considered a feasible option in the remaining eight patients, who are the subject of the present study.

Statistical Analysis
Statistical analyses were performed using Medcalc version 9.5.2.0 (Medcalc Software; Mariakerke, Belgium). One-way analysis of variance (ANOVA) was used to test associations between survival time and both recurrence site and gender. Kendall {tau} was used to assess correlations between survival and both age at recurrence and age at disease-free interval.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Surgical retreatment for a solid recurrence of MPM was done in eight patients initially treated with extrapleural pneumonectomy. There were 6 men and 2 women with a mean age of 53.6 years (Table 1). All had been followed clinically and with computed tomography (CT) in 6 cases and CT-positron emission tomography (CT-PET) in 2 cases. The disease-free interval ranged from 18 months to 12 years. The recurrent cancer was parietal and ipsilateral (but outside of the drain sites) and caused chest pain in 4 patients; the remaining 4 patients were asymptomatic but the recurrent tumor was seen with diagnostic imaging, retroperitoneally in 3 patients, and in the contralateral lung in 1 patient. Considering the evolution of our surgical technique over the 20-year period, 5 patients had received diaphragmatic or pericardial prostheses in PTFE and 2 patients had also undergone a second minithoracotomy. None of the 3 patients with retroperitoneal recurrence had had the second minithoracotomy.


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  		Table 1 Characteristics of Eight Patients who Experienced a Solid Recurrence After Extrapleural Pneumonectomy (EPP) and Who Were Eligible for a Second Surgical Treatment
 
All patients were reoperated with curative intent. In the 4 patients with parietal recurrence, we performed chest wall resection, placed a suction drain, and applied a 2 mm PTFE prosthesis that was anchored with interrupted sutures to the ribs immediately above and below the resected area and then covered externally with a parietal muscle flap. In the 3 patients of retroperitoneal relapse, we performed radical retroperitoneal resection. Because these 3 relapses were all on the left side, we used a left subcostal access; this showed that the relapses originated at the internal arch of the eleventh and twelfth ribs and developed suprarenally and laterally to the splenic flexure of the colon. In the single retreated case with metastasis to the contralateral lung, we performed segmental (wedge) resection of the upper lobe of the remaining lung. In 5 patients the recurrence was located at the site of the previous radiotherapy so only chemotherapy could be administered as adjuvant treatment; the other patients received radiotherapy or radiotherapy and chemotherapy.

All 8 patients tolerated the second surgery well: there was no mortality nor were there major complications; mean postoperative stay was 10 days (range, 8 to 16 days). Surgery relieved the chest pain in the 4 patients with parietal recurrence. Although all surgical procedures had curative intent, in 1 patient it became apparent that cure was impossible: in the patient with contralateral lung metastasis, the recurrence appeared to be a solid mass on CT images but at surgery the disease was found to have progressed in the contralateral visceral pleura and to have invaded the outer parenchymal layer, simulating a mass. The wedge resection, even with chemotherapy, could therefore not be curative and the disease continued to invade the parietal pleura and diaphragm. Had this patient undergone surveillance with PET, the serosal nature of the recurrence might have been revealed, leading to a more appropriate treatment such as stereotactic radiosurgery.

Histologic examination of the resected tissues after the second surgery revealed, in a patient who had retroperitoneal recurrence 5 years after the primary surgery, a change in cell type from epithelial to sarcomatoid. This patient had been monitored after the initial treatment with both abdominothoracic CT and PET, which also revealed a metastasis in the ipsilateral greater pectoral muscle (Fig 1). Despite accurate resection and chemotherapy, the patient died from local dissemination, proctorrhagia, and distant metastases to the liver and contralateral lung.


Figure 1
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  		Fig 1. The flourodeoxyglucose (FDG)-PET image of the thorax and abdomen of a patient with retroperitoneal relapse of MPM (patient 6) shows a smaller left hemithorax due to the primary surgery, the recurrent tumor at the level of the eleventh and twelfth left ribs, and a distant metastasis in the left greater pectoral muscle near the axilla.

 
After the second surgery, the patients survived a median period of 14.5 months (range, 6 to 29 months). No trend emerged between survival time and site of recurrence (one-way ANOVA, p = 0.473) nor between survival time and gender (one-way ANOVA, p = 0.3). There also was no correlation between survival time and age at relapse (Kendall {tau} = –0.182; 95% confidence interval [CI], –0.923 to 0.565), nor between survival time and disease-free interval (Kendall {tau} = 0.148; 95% CI, –0.662 to 0.826).


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
This retrospective study on the use of extrapleural pneumonectomy in the treatment of MPM analyzes the possibility of offering a second, presumably curative treatment to patients who experience locoregional recurrence. Of 11 patients with MPM who experienced a solid recurrence, surgery with curative intent was considered feasible in 8 patients with generally good cardiac and respiratory status. The surgery was well-tolerated by these patients and relieved symptoms in the four patients with parietal recurrence. However, survival after the second surgical intervention, with adjuvant chemotherapy or radiotherapy, ranged from 6 to 29 months.

Although the second surgical treatment did not offer the expected survival benefit of curative treatment strategies, it was the only treatment option able to palliate symptoms. Radiotherapy was not possible in these patients because they had already received 50 Gy for the primary tumor. Furthermore, chemotherapy alone could not be considered efficacious because the recurrent tumor in many cases was located in areas of radiation-induced fibrosis. Moreover, in asymptomatic recurrences, second surgery may be considered as a treatment option when radiotherapy is not feasible. In the present series, especially in the patients with retroperitoneal recurrence, second surgery may have protected against local dissemination to contiguous organs such as kidney, spleen, and colon.

As our surgical technique has evolved over time since 1988, patients treated more recently underwent a second minithoracotomy that facilitated resection of the diaphragm and placement of the prosthesis, which otherwise was done through the fifth intercostal space of a posterolateral thoracotomy [8, 9]. This procedure may have had a beneficial effect on the clinical outcomes in that no case of retroperitoneal recurrence was observed among the 24 patients who underwent the second minithoracotomy, which allowed a more radical surgery. Retroperitoneal diffusion was observed altogether in 4 patients (3 retreated surgically and one patient ineligible for surgery) and manifested after a long disease-free interval (up to 12 years). This type of recurrence, if diagnosed early, should be easier to treat with conventional or stereotactic radiotherapy, at the level of the psoas muscle if not involved during the first treatment.

The unusual finding of recurrent MPM after 5 years, with a change in histology from epithelial to sarcomatoid, might be attributed to the initial radiotherapy. In fact, there is mounting evidence that therapeutic irradiation to treat cancers may cause mesothelioma [10]. In our case, it is unknown if the original tumor was mutated during irradiation or if the radiotherapy induced a new primary cancer.

This study is limited by its retrospective nature over a long period of time in which diagnostic and therapeutic strategies evolved and improved. Moreover, the study is purely observational and no comparisons have been made with other treatment strategies. The small number of cases may have precluded the possibility of identifying factors significantly associated with survival.

On the basis of our 20-year experience with extrapleural pneumonectomy, we have observed that the majority of recurrent disease occurs within 18 months and is due to locoregional serous diffusion not surgically treatable. In a subset of patients (11 cases in a follow-up group of 57 patients), recurrent cancer may manifest later (between 18 months and 12 years). A second surgery, if possible, may be the only treatment option to palliate symptoms and prevent local dissemination.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
Valerie Matarese provided editorial advice and scientific editing.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Ismail-Khan R, Robinson LA, Williams Jr CC, Garrett CR, Bepler G, Simon GR. Malignant pleural mesothelioma: a comprehensive review Cancer Control 2006;13:255-263.[Medline]
  2. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma J Clin Oncol 2003;21:2636-2644.[Abstract/Free Full Text]
  3. van Ruth S, Baas P, Zoetmulder FA. Surgical treatment of malignant pleural mesothelioma: a review Chest 2003;123:551-561.[Medline]
  4. Rice D. Surgery for malignant pleural mesothelioma Ann Diagn Pathol 2009;13:65-72.[Medline]
  5. Sugarbaker DJ, Jaklitsch MT, Bueno R, et al. Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies J Thorac Cardiovasc Surg 2004;128:138-146.[Abstract/Free Full Text]
  6. Stewart DJ, Martin-Ucar A, Pilling JE, Edwards JG, O'Byrne KJ, Waller DA. The effect of extent of local resection on patterns of disease progression in malignant pleural mesothelioma Ann Thorac Surg 2004;78:245-252.[Abstract/Free Full Text]
  7. Baldini EH, Recht A, Strauss GM, et al. Patterns of failure after trimodality therapy for malignant pleural mesothelioma Ann Thorac Surg 1997;63:334-338.[Abstract/Free Full Text]
  8. Politi L, Girbino G, De Anna D, et al. Progress in radical surgery for malignant pleural mesothelioma Eur J Cardiovasc Surg 2009(in press).
  9. Politi L, Scanagatta P, Salani A, Montinaro F, Andreani M, Crisci C. Double unilateral thoracotomy for malignant pleural mesothelioma J Cardiovasc Surg (Torino) 2004;45:591-592.[Medline]
  10. Teta MJ, Lau E, Sceurman BK, Wagner ME. Therapeutic radiation for lymphoma: risk of malignant mesothelioma Cancer 2007;109:1432-1438.[Medline]

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