1.0 THE ROLE OF SURGERY IN TREATING MESOTHELIOMA
1.01 Surgery Overview
Mesothelioma surgery differs from other forms of lung cancer. Non-small cell lung cancer presents as a single nodule which will enlarge and spread to lymph nodes and other organs in later stages. The typical presentation of mesothelioma is several nodules in the pleura, even at the initial stage, hence the term, diffuse malignant mesothelioma.
The alternative in non-small cell cancer of simply surgically removing a small tumor is not present. “Because the tumor is either broadly extensive on the pleural surface or multi-focal at the time of detection, it does not lend itself to localized surgical excision.“ Butchart (1) Instead, a more complicated procedure called pleuropneumonectomy is used.
1.02 Surgery in not Curative Alone
1.021 Contrast with Surgery for Stage 1 Non-Small Patients
In early non-small lung cancer cases, surgery is designed to be curative, with post or pre-operative chemotherapy experimental. In contrast, post-operative chemotherapy for mesothelioma is standard.
1.022 Surgery Combined with Chemotherapy and Radiation
Where surgery is advocated for mesothelioma, many believe it should be combined with chemotherapy and radiation. This approach was pioneered by Dr. David Sugarbaker at Boston‘s Langham and Woman‘s Hospital where they operated on a number of mesothelioma patients and generated at least four medical articles assessing longevity patterns. See, for example Butchart (1). Their conclusions as to when surgery is recommended have been adopted by many throughout the world, with the combination of surgery, radiation, and chemotherapy the starting point, though scientists continue to try to define the optimal mix, and inestigate less intrusive gene therapies. As we review below, given the complexity of this surgery, it is generally recommended only for patients with early disease and a certain type of disease, though here too, scientists have not precisely defined when it should be performed.
The primary surgery for mesothelioma is a pleuropneuemonectomy. “All of the ipsilateral pleura, lung and pericardium are removed, and because diaphragmatic pleura cannot be separated from the diaphramatic muscle... it is necessary to remove (that also). Butchart (1). “The goal of pleuropneumonectomy is radical resection of the tumor, which often requires combined resection of adjacent structures.”
1.11 Eligibility for Surgery
1.11 Performance Status
This is major and complicated surgery. “Radical surgery is a major operation, suitable only for fit patients with normal cardiopulmonary function.” Butchart (1). Sugarbaker writes:
Patients were considered surgical candidates if they had a
a Karnofsky performance status of greater than 70%, a creatinine level within normal limite, liver function test results within the norm. (Exclusive criterial included lower readings on various pulmonary function tests.) Sugarbaker (2)
1.12 Mortality Rates
Mortality levels from this surgery are not low. A Japanese study estimated 6% mortality rate from the surgery Takagi (6). A Scottish hospital reported 9% mortality during the course of its study, Aziz (3),
while another English hospital reported 30 day mortality of 7.8% Martin (8). Sugarbaker’s post-operative mortality of 4% is one of the lowest but is still substantial. Sugarbaker (3). Given the surgeryy risk and complexity, choosing a hospital and physician with substantial experience in the procedure should be a prerequisite.
Studies have study found that patients with the epithelial type benefited most from the surgery. Sugarbaker states, univariate analysis found epithelial cell type associated with improved survival in the study, (52% 2 year survival, 21% 5 year survival, 26 month median survival). Sugarbaker (2). In comparison,
“The patients with non-epethelial cell ctype (sarcomatoid and mixed cell type) have a significantly worse survival, with only 16% living for 2 years after the operation. This suggests that our current trimodality treatment plan is having a small impact within this group with unfavorable histologic features, and new strategies for local control are needed
Based on Sugarbaker’s data, those within the non-epethilial group should consider alternatives such as chemotherapy and gene therapy. While his results are persuasive, Sugarbaker is less successful in explaining why cell type should be so important and what it is about epethelial type that improves prognosis or conversely, what do the other types do that diminishes one’s chances for recovery. Another study found that cell type did not impact survival. Aziz (3). “Survival was surprisingly, not affected by lymph node involvement (P=0.08) or pathological type of MPM.” Aziz (3). However, an Italian study also found that epethelial type improved survival. Serisoli (7)
Not surprisingly, patients with limited disease received the most benefit from this surgery,
“Negative resection margins and lack of exprapleural lymph nodal involvement were significant prognostic factors associated with prolonged survival... The 66 patients with negative resection margins had a 2 year survival of 44% and a 5 year survival of 25% compared with the 110 patients with positive resection margins, who had a 2 year survival of 33% and a five year survival of 9%. the 136 patients with negative extrapleural nodal status had a 2 year survival of 42% and a 5 year survival of 17%; the 40 patients with extrapleural nodal status had a 2 year survival of 23% and none survived 4 years. Sugarbaker (2)
Similar findings were reported in an Italian study. Serisoli (7). This is consistent with results with non-small lung cancer and even small cell, with surgery recommended for those with early disease.
1.141 Stage 1 Patients
The impressive results of the tri-modal surgery make it a promising alternative for stage 1 patients. A later study reported “survival has improved to a mean of 35 months for patients treated by radical surgery followed by systemic post-operative chemotherapy.... In selected patients with MPM, complete surgical resection by EPP represents an important initial step in their management. Systemic chemotherapy improves survival in surgically treated patients.” Aziz (3). Again, patients would have to be in otherwise good medical condition. As to stage 1 with epethial type, Sugarbaker explains that. “thirty one patients with 3 positive variables had the best survival “68% 2 year survival, 46% 5 year survival, median 51 months. Sugarbaker (2).
1.142 Stage 2 Patients
Perhaps the most difficult determinations are to be made in this group. For patients with early disease, the combined regimen makes sense, for those with advanced disease, the risks are clearly too great and the benefits too limited. Where there is or may be limited spread, intelligent minds can disagree. Even with positive resection margins, the 2 year survival of 33% and 5 year of 9% reported by Sugarbaker still exceeds most other treatments. If the results in this group exceed other treatments, it may make sense. Indeed, these results include epethilial and non-epethelial mesothelioma; if we include only epethelial type, the two and five year survival figures would be higher in Sugarbaker’s study. But see, Butchart, (“it would appear that patients with sarcomatous histology or involved intrathoracic nodes with derive little benefit from the trimodality therapy according to the protocols used by Sugarbaker and collagues.” Butchart (1).
1.143 Quality of Life Issues
Difficult judgments must be made. Assessing quality of life in a demanding tri-modal regimen is difficult. Is 12 months of easier treatment better than 20 months enduring complex surgery, chemotherapy, and radiation? How does one evaluate the increased possibility of five long term survival when it is still only in the area of 10%.
Sloan Kettering reported median survival of 33.8 months for stage 1 and II grouped together. This study used surgery and radiation without chemotherapy. Rusch (9).
1.15 Nodal Status
Sugarbaker did not report his results based on stage, but on nodes and other factors. Sugarbaker writes, “the 136 patients with negative extrapleural nodal status had a 2 year survival of 42% and a 5 year survival of 17%; the 40 patients with positive extrapleural nodal status had a 2 year survival of 23%, and none survived 5 years. “Sugarbaker (2). Thus, the existence of positive nodes essentially precluded long-term survival in this tri-modal regimen. Positive nodes may not always be identified pre-operatively, indeed, it may be those with identifiable cancerous nodes would not have been eligible for the Sugarbaker trial. surgery. However, one can conclude that positive nodal status would preclude this regimen.
1.151 Tests to Ascertain Nodal Status
In the future, more sophisticated technigues may identify positive nodes. Pet Scans were not extensively used in the mid-90’s when the surgeries in the Sugarbaker study were conducted. Today, Pet-Scans, and other diagnostic tests may reveal positive nodal status.
1.152 Stage 3 and 4 Patients
Given the impact of positive nodes and positive resection margins, most physicians would not recommend the arduous tri-modal plan for patients with advanced mesothelioma. Sugarbaker found that positive lymph nodes essentially precluded long-term survival. Instead, less demanding chemotherapy and gene therapy regimens would be recommended because of the risks of surgery and to improve quality of life.
1.16 Specialized Facilities
Since mesothelioma is a relatively rare disease and pleuropneumonectomy, a difficult and unusual surgery, it should probably be done at a facility specializing in mesothelioma by a physician experienced in this surgery. “The attendant morbidity and potential mortality from extrapleural pneumonectomy stresses the importance of performing the procedure at specialized institutions.“ Sugarbaker (2). Indeed, with various types of surgery, experience not unexpectedly tends to reduce mortality rates.
A more modest surgery is called pleurectomy. Butchart distinguishes a pleurectomy as living diaphragmatic pleura in place which he suggest will usually result in some amount of tumor remaining. While pleurectomy is lesser surgery, its benefits are not clear.
1. Butchart, Contemporary Management of Malignant Pleural Mesothelioma, Oncologist, Vol 4, No 6, 488-500, December 1999.
2. Sugarbaker, Resection Margins, extra pleural nodal status, and cell type determine postoperative long term survival in trimodality therapy of Malignant Pleural Mesothelioma: results in 183 cases. J. Thoracic Cardiovascular Surgery 1999, Jan, 117:1, 54,65.
3. Aziz, The management of malignant pleural mesothelioma; single centre experience in 10 years, Eur. J. Cardiothorac Surg 2002 Aug;22(2):298-305
3. Melluni, Treatment of malignant pleural mesothelioma, Minerva Chir 2001 Jun;56(3):243-50
4. Jaklitchs, Treatment of Malignant Mesothelioma, World J Surg 25:210-217 (2001)
5. Takahashi, Extrapleural pneumonectomy for diffuse malignant pleural mesothelioma. A treatment option in selected cases? Jpn J Thorac Cardiovasc Surg 2001 Feb;49(2):89-93
6. Takagi, Surgical approach to pleural diffuse mesothelioma in Japan, Lung Cancer 2001 Jan;31(1):57-65
7. Serrisoli, Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma, Lung Cancer 2001 Nov;34(2):279-87
8. Martin, Palliative surgical debulking in malignant mesothelioma. Predictors of survival and symptom control, Eur J Cardiothorac Surg 2001 Dec;20(6):1117-21
8. Rusch, A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma, J Thorac Cardiovasc Surg 2001Oct;122(4):788-95
Leading Hospitals and Surgeons for Mesothelioma
Given that mesothelioma is a rare disease and the surgery is complicated, one would want to select a physician and hospital with considerable experience. I have listed some of the physicians and institutions which have done work specifically with mesothelioma and in some cases, journal articles where the institutution is cited. .
United States Hospitals
Brigham is probably the leading hospital for mesothelioma, with an extensive surgical clinical trial occuring there.
Dr. David Sugarbaker Department of Surgery, Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
Other U.S. Hospitals with specialized experience are:
M.D. Anderson Cancer Center, Houston, Texas
Sloan Kettering Cancer Center, New York, Rusch, A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001 Oct;122(4):788-95
University of New South Wales Department of Surgery, St George Hospital, Kogarah, New South Wales, Australia.
Institut Gustave-Roussy, Departement de Medecine, 39, rue Camille Desmoulins, F94805 Villejuif.
Department of Radiochemotherapy, San Raffaele H Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. firstname.lastname@example.org
Japan Division of Thoracic Surgery, National Cancer Center Hospital East,
Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Dr. Eric Butchart, University Hospital, Cardiff, CF 4, 4XW, Wales UK.
Department of Thoracic Surgery, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.
The foregoing is intended only to provide general information and the author of this page is not a physician. s For specific information regarding your medical condition, please see a qualified physician.