SURGERY AND PLEUROPNEUMONECTOMY FOR MESOTHELIOMA

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keywords, Surgery and pleuropneumonectomy, mesothelioma, treatment, surgery, pleuropneumonectomy,  

26.0 TREATMENT OVERVIEW


26.01 Overview

In early stage non-small lung cancer patients, the tumor is removed leading in some cases to a complete cure. That type of surgery is rarely an option in mesothelioma. “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.

26.02 Surgery Combined with Chemotherapy and Radiation

Where surgery is recommended, it is generally combined with chemotherapy and radiation. This three-pronged 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, Butchert (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 investigate less intrusive gene therapies. Given the complexity of this surgery, it is generally recommended only for patients with a certain type of early disease though scientists have not precisely defined when it should be performed. The originator of this treatment plan explains, “Cytoreductive surgery (pleuropneumonectomy) followed by sequential chemotherapy and radiotherapy have demonstrated improved survival, especially for patients with epithelial histology, negative resection margins, and no metastases to extrapleural lymph nodes.” Jaklitsch (13).


26.1 PLEUROPNEUMONECTOMY 

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.”

26.11 Eligibility for Surgery

26.111 Performance Status

This is major and complicated surgery suitable for fit patients with normal cardiopulmonary function.” Butchart (1).

“Patients were considered surgical candidates if they had a
Karnofsky performance status of greater than 70%, a creatinine level within normal limits, liver function test results within the norm. (Exclusive criteria included lower readings on various pulmonary function tests.)” Sugarbaker (2).

26.12 Mortality Rates

Mortality levels from this surgery are not low, and one 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 surgery risk and complexity, choosing a hospital and physician with substantial experience in the procedure should be a prerequisite.

26.13 Type

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-epithelial cell type (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-epithelial 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 epithelial 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 epithelial type improved survival. Serisoli (7).

26.14 Stage

Not surprisingly, patients with limited disease received the most benefit from this surgery.

“Negative resection margins and lack of extrapleural 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 cell lung cancer and even small cell, with surgery recommended for those with early disease.

26.141 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 epithelial 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).

26.142 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 epithelial and non-epithelial mesothelioma; if we include only epithelial 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 will derive little benefit from the trimodality therapy according to the protocols used by Sugarbaker and collagues.” Butchart (1).

26.143 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 year 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).

26.15 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.

In the future, more sophisticated techniques 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.
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.

26.16 Specialized Facilities

Since mesothelioma is a relatively rare disease and pleuropneumo-nectomy is 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.

26.2 PLEURECTOMY

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.

ARTICLE ABSTRACTS

 J Cardiovasc Surg (Torino). 2006 Oct;47(5):595-601.
5-year prospective results of trimodality treatment for malignant pleural mesothelioma.
Pagan V, Division of Thoracic Surgery, Umberto I General Hospital, Venezia-Mestre, Italy. vittore.pagan@ulss12.ve.it

AIM: Even though followed by a prolonged survival in highly selected patients, the promising results of Sugarbaker's trimodality treatment for malignant pleural mesothelioma (MPM) are debated and not yet uniformly replicated.The purpose of this study is to evaluate prospectively the reproducibility of the trimodality treatment results in a patient population with mesothelioma staged by the IMIG classification. METHODS: Fifty-four patients with MPM have been judged candidable to extended pleuropneumonectomy (EPP), to be followed by chemotherapy (paclitaxel+carboplatin) and radiotherapy (50 Gy). RESULTS: At thoracotomy, 44 of the 54 surgical candidates (81%) underwent EPP; 73% of the operated patients completed the entire adjuvant chemo-radiotherapy with no major toxicity. The 30-day or in-hospital operative mortality rate was 4.5% (2 deaths), the major morbidity 36%, and the overall complication rate 50%. At 5 years the projected survival of the 42 surgical survivors submitted to EPP is 19%; median survival is 20 months. The restricted group of patients with epithelial, N0-1, completely resected MPM (microscopic negative margins) exhibits a projected 50% 5-year survival. Clinical understaging has shown up to be noticeable both at the thoracotomy exploration and pathology examination. Most of the disease recurrences are loco-regional and the current insufficiency of intraoperative or postsurgical radicality needs improvement, along with earlier diagnosis, more accurate staging, and preoperative induction for the multimodality treatment of pleural mesothelioma to become an established curative option. CONCLUSIONS: This series confirms the reproducibility of the trimodality treatment for MPM,which is associated with prolonged survival for early-stage tumors at the cost of a not prohibitive treatment-related mortality rate.

2: Chir Ital. 2003 Jan-Feb;55(1):13-20.
[Pleuro-pneumonectomy, RT and CT for pleural mesothelioma. Prospective study]
[Article in Italian] Pagan V, Cappelli R,

Though associated with substantially prolonged survival, the favourable results of Sugarbaker's trimodality treatment for malignant pleural mesothelioma are controversial and have yet to be extensively reproduced. The aim was to evaluate the prospective medium-term (3-year) reproducibility of the results of trimodality treatment in a significant group of patients staged using the international IMIG classification. Forty-three patients with malignant pleural mesothelioma were candidates for extended pleuropneumonectomy, followed by chemo- and radiotherapy. At thoracotomy, 33 of the 43 surgical candidates underwent extended pleuropneumonectomy and 71% of the 30 evaluable operated patients completed the scheduled course of adjuvant chemotherapy. The perioperative mortality rate was 6% and the major morbidity rate 36%. At 3 years the overall survival of the 30 evaluable patients was 30% and the disease-free survival rate was 25%, with a prevalence of epithelial pI and pII IMIG stages. Clinical understaging was appreciable. Survival was less favourable for stage pIII and for mixed tumours. Most of the disease recurrences were due to incomplete local postsurgical monitoring. This series confirms the reproducibility of trimodality treatment for malignant pleural mesothelioma. The treatment is associated with prolonged survival in the case of early-stage tumours and has an acceptable complication rate. Early diagnosis, accurate staging, preoperative induction and better local monitoring are avenues to be explored when seeking to achieve curability of malignant pleural mesothelioma.
Pneumonectomy and mesothelioma 
English Abstract

3.: Lung Cancer. 2001 Jan;31(1):57-65.
Surgical approach to pleural diffuse mesothelioma in Japan.
Takagi K, Department of Thoracic and Cardiovascular Surgery, Toho Unversity School of Medicine, Tokyo 143-8541, Japan. keigo@med.toho-u.ac.jp

The current status of the surgical treatment of patients with pleural diffuse mesothelioma in Japan was surveyed from the results of a questionnaire sent to members of The Japanese Association for Chest Surgery. Physicians at 57 institutions returned the questionnaire, and a total of 189 surgical cases of diffuse mesothelioma between 1987 and 1996 were analyzed. The age of the patients ranged between 18 and 80 years. They consisted of 154 males and 33 females (the gender of two patients was not indicated). By histological type, 104 cases had the epithelial type, 29 cases had the sarcomatous type, and 46 cases had the mixed type of diffuse mesothelioma (the histology of 10 patients was not indicated). As to the type of surgery, pleuropneumonectomy was performed in 116 cases (61%), and limited resection [including decortication (5 cases) and tumorectomy (68 cases)] was performed in 73 cases (39%). The goal of pleuropneumonectomy is radical resection of the tumor, which often requires combined resection of adjacent structures. The tumor was completely removed macroscopically in 84 (72%) of the 116 cases who underwent pleuropneumonectomy; however, among those with an epithelial-type tumor that was completely removed by pleuropneumonectomy, the tumor recurred postoperatively in 43% of these patients. Perioperative adjuvant therapy was performed in 83 of the 116 patients who underwent pleuropneumonectomy. The 2-year and 5-year survival rates of those who had undergone pleuropneumonectomy were 29.7 and 9.1%, respectively, and the perioperative mortality rate of this procedure was 6%. Limited resection, on the other hand, did not involve radical resection of the tumor. The 2-year and 5-year survival rates of the patients who had undergone limited resection were 26.1 and 9.5%, respectively, and the perioperative mortality rate was 6%. The survival rates and perioperative mortality rate of the patients who had undergone pleuropneumonectomy or limited resection did not significantly differ. The prognostic factors for survival included gender (P=0.0019) and adjuvant therapy (P=0.0034) by Cox's Regression Analysis. The goals of surgical treatment of pleural diffuse mesothelioma are relief of symptoms and prolongation of survival time. Selecting the appropriate surgical procedure and more effective adjuvant therapy for each particular case is necessary under a new, accurate staging system for diffuse mesothelioma.

4: Kyobu Geka. 2000 Dec;53(13):1101-4. Related Articles, Links
[Surgical treatment for malignant pleural mesothelioma in eight cases]
[Article in Japanese]
Watanabe S, Second Department of Surgery, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.

Between 1987 and March 2000, we have operated on eight patients for malignant mesothelioma which consisted of four of localized type and four of diffuse type. We have aggressively resected mesothelioma combined with chemotherapy whether the tumor was primary or recurrent, and concluded the following. 1) In localized malignant mesothelioma, en-bloc primary tumor resection was possible and additional resection for recurrence was effective and useful for long time survival. 2) In diffuse malignant mesothelioma, complete tumor resection was impossible to even perform pleuropneumonectomy accompanied with partial resection of pericardium and diaphragm and, therefore, the prognosis was poor in four patients and all died around one year. 3) Because recurrent pattern for localized type was diffuse type, diagnosis and surgical treatment in early stage was essential for long time survival.

Pneumonectomy and mesothelioma 

5: Oncologist. 1999;4(6):488-500.
Contemporary management of malignant pleural mesothelioma.
Butchart EG.University Hospital of Wales, Cardiff, United Kingdom. egbutchart@aol.com

The rapidly increasing incidence of malignant pleural mesothelioma underlines the urgency to achieve a consensus in the management of this tumor, which is biologically distinct from most other tumors. For patients with stage I tumors of epithelial type and good performance status, pleuropneumonectomy combined with chemotherapy and radiotherapy provides the best chance of prolonged survival, but further investigation is required to determine the optimum combination of adjuvant therapy. Debulking pleurectomy/decortication combined with adjuvant therapy is a worthwhile alternative for patients with more advanced disease, impaired performance status or tumors of less favorable histology (sarcomatous or biphasic). More clinical trials are urgently required to identify better adjuvant therapy for tumors containing sarcomatous elements. On currently available evidence, neither radiotherapy nor chemotherapy offer worthwhile prolonged disease control when used in isolation, although both have an important role as part of multimodality therapy. Hyperthermia may enhance the effect of both radiotherapy and chemotherapy, and newer radiosensitizing agents also need evaluating. Research into immunotherapy and gene therapy suggests that these newer approaches may have a place if tumor volume is small. In practice they will probably need to be combined with other therapeutic modalities, and further clinical trials are required. Consensus in mesothelioma management currently remains elusive but it seems clear that the way forward will involve striving for much earlier diagnosis, the use of multimodality therapy and collaboration between centers with special expertise in mesothelioma treatment to organize multicenter trials.

Pneumonectomy and mesothelioma 

6: Chest. 1999 Dec;116(6 Suppl):450S-454S.
Pleuropneumonectomy in the treatment of malignant pleural mesothelioma.
Grondin SC, Sugarbaker DJ. Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

STUDY OBJECTIVES: Malignant pleural mesothelioma (MPM) is predominantly a local/regional disease that results in a survival time that ranges from 4 to 12 months without treatment. Single-modality therapy using surgery, chemotherapy, or radiotherapy alone is largely ineffective. The objective of the study was presentation of the use of pleuropneumonectomy in a multimodality treatment setting and the results. DESIGN: Didactic presentation. SETTING: Academic tertiary-care hospital. PATIENTS: One hundred eighty-three patients who underwent multimodality therapy. INTERVENTIONS: Of all the single-modality treatment approaches, pleuropneumonectomy has been associated most consistently with long-term disease-free survival and has provided the greatest amount of tumor cytoreduction. The technique of pleuropneumonectomy traditionally has been linked with high perioperative mortality and morbidity when compared with that of other cytoreductive techniques such as pleurectomy/decortication. Recently, improvements in operative mortality (< 5%) have been reported, largely due to improvements in patient selection and perioperative management. Multimodality therapy, including chemotherapy, radiotherapy, and extrapleural pneumonectomy, was used to treat patients. RESULTS: Outcomes were presented for 183 patients with MPM who underwent multimodality therapy. CONCLUSIONS: With the development of multimodality therapy, pleuropneumonectomy followed by sequential chemotherapy and radiotherapy has demonstrated a significant survival benefit, especially for patients who have epithelial tumor histology, tumor-free resection margins, and tumor-free extrapleural node status.
 

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Howard Gutman is a New Jersey attorney based in Parsippany, New Jersey who has handled numerous legal claims involving pulmonary tumors.   A member of the board of directors of a leading cancer support group and a caregiver, he is the author of the new book Lung Cancer and Mesothelioma.   In his legal capacity, he has appeared on Good Day New York, spoken at the National Press Club  and been interviewed by NBC Nightly News.

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