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Eur J Cardiothorac Surg 2001;19:346-350
© 2001 Elsevier Science NL

Trimodality management of malignant pleural mesothelioma

Department of Thoracic Surgery, University of Torino, San Giovanni Battista Hospital, via Genova 3, 10126 Torino, Italy

Received 9 October 2000; received in revised form 10 January 2001; accepted 13 January 2001.

Corresponding author. Tel.: +39-11-633-6635/55; fax: +39-11-696-0170
e-mail: giuliano.maggi{at}unito.it

	Abstract

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Objective: We reviewed our experience with trimodality management of malignant pleural mesothelioma (MPM). Methods: From September 1998 to August 2000, 32 consecutive patients with histological diagnosis of MPM underwent trimodality therapy, including surgery followed by adjuvant chemotherapy and radiation therapy. Surgery consisted of pleurectomy/decortication (P/D) or pleural-pericardial-pneumonectomy and diaphragm (PPPD). Pre-operative staging according to the Brigham Staging System was accomplished using computed tomography (CT) and magnetic resonance imaging (MRI); patients with evident extrapleural spread were excluded. Results. Our series included 21 men and 11 women with a median age of 53.5 years (range 40–69). Histologically, there were 26 epithelial, four mixed and two sarcomatous MPM. Post-surgical staging was as follows: six patients were at Stage I; of these, two received a P/D and four a PPPD. Ten patients were at Stage II and all received a PPPD; 16 patients were at Stage III (under-staged pre-operatively): of these, nine patients presented extrapleural lymph node metastases (N2) and all received a PPPD, seven patients presented with chest wall or mediastinal invasion (T4) with macroscopic residual tumour, and all received a de-bulking P/D. We observed major complications in ten patients: six bleeding, two respiratory insufficiency and two nerve paralysis. There were two perioperative deaths (6.25% mortality). Twenty-seven patients out of 30 surviving surgery had a follow-up greater than 6 months; 21 patients out of 27 are alive with a median follow-up of 12.5 months. Conclusions: (1) Trimodality therapy is feasible in selected patients with MPM and has an acceptable operative mortality rate. (2) Our current pre-operative staging based on CT/MRI looks rather inaccurate and needs to be improved. (3) The high rate of post-surgical N2 patients or with diffusion to the inferior surface of the diaphragm may suggest the use of routine mediastinoscopy and laparoscopy for a more appropriate patient selection.

Key Words: Malignant pleural mesothelioma • Pleural disease • Extrapleural pneumonectomy • Pleurectomy/decortication

	1. Introduction

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Approximately 2200 new cases of malignant pleural mesothelioma (MPM) occur annually in the United States [1]. In Europe the incidence of MPM is increasing in most industrialized countries such as Great Britain, France, Sweden [2–4] and Italy [5].

In Italy, during the period 1969–1994, the mortality rate related to MPM increased by 15% every 5 years and mortality increased from 500 to 900 deaths every year [5]. MPM related mortality is higher in areas where shipyards or industries associated with asbestos exposure are present. Turin is the capital of Piedmont where a quarry of asbestos and some cement works are located: in Casale (a town with many cement factories) MPM is 11 times more frequent than in most other Italian towns [6].

The natural history of MPM includes a median survival of 4–12 months irrespective of therapy [7], and there is no accepted useful medical treatment.

Between 1992 and 1998 only three patients were submitted to surgical management with radical excision of MPM at our department and all these patients were operated on at their wish in spite of our doubt on the advantages. Since 1998 results referred by Sugarbaker et al. at the AATS Congress of Boston (5-year survival rate of 46% in the group with negative margins and negative lymph nodes) increased our interest and authorized us to consider the trimodality therapy as a therapeutic possibility in the treatment of MPM [8].

In September 1998 we decided to evaluate possibilities, risks and results of a multimodality therapy (surgery, chemotherapy and radiation therapy) as proposed by Sugarbaker et al. at the Brigham and Women's Hospital of Boston in 1991 [9].

	2. Material and methods

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion Appendix A. Conference... References

 
During the last two years, 45 patients with either suspected or certain diagnosis of MPM were referred to our department for confirmation of the diagnosis or evaluation for trimodality therapy.

Most patients present with dyspnoea (80%), cough (69%), chest pain and weight loss are also common symptoms (40%).

If patients had no definitive histological diagnosis, pleuroscopy and a biopsy under direct vision was performed. Patients with definitive histological diagnosis of sarcomatous type MPM were excluded and those with epithelial or mixed type MPM were submitted to pre-operative evaluation.

Patients who had performance status greater than 70%, creatinine level within normal limits and liver function test within the normal range were submitted to pre-operative staging according to the Brigham Staging System (BSS) modified in 1999 [10].

As noted by Sugarbaker and colleagues [10], the International TNM Staging System categorized by TNM the majority of surgical patients as Stage III, and it is difficult to separate patients with different tumour characteristics that are necessary to stratify survival in these patients. The T descriptor alone was not a statistically significant predictor of survival, reflecting the inability of IMIG-TNM system to describe the behaviour of this tumour.

All patients were submitted to lung functional tests, computed tomography (CT), magnetic resonance imaging (MRI) of the chest and echocardiography. In patients suspected of having extrapleural diffusion, evaluation was completed by submitting them to mediastinoscopy (two cases) or laparoscopy (two cases), thoracoscopy of the contralateral hemithorax (one case) or total body bone scintigraphy (three cases). If vertebral or chest wall direct invasion, spread of the tumour to the opposite hemithorax or to the peritoneum or bone metastases were detected, the patient was excluded from surgery.

Functional exclusion criteria included room air arterial PCO₂ greater than 45 mmHg, room air arterial PO₂ less than 65 mmHg, echocardiography demonstrating an ejection fraction of less than 45% and a predicted post-operative forced expiratory volume in 1 s (FEV₁) of less than 1 l. Patients with a pre-operative FEV₁ of less than 2 l underwent quantitative radionuclide perfusion scanning to predict post-operative pulmonary function more accurately in case of extended surgical procedures.

Approximately 20% of the observed patients with MPM were considered unsuitable for trimodality therapy. Trimodality therapy consisted of surgical resection of the tumour followed by intravenous post-operative chemotherapy and radiation therapy.

From September 1998 to August 2000, 32 patients with histological diagnosis of epithelial or mixed type of MPM underwent trimodality therapy. The series included 21 men and 11 women with median age of 53.5 (range 40–69) years. Ten patients were under 50 years old. The tumour was right-sided in 21 cases and left-sided in 11. Twenty-nine patients were symptomatic for dyspnoea and their radiographs evidenced pleural effusion, 18 patients referred chest wall pain and 15 cough.

Surgical management of the tumour required wide posterolateral thoracotomy. Intraoperative staging was as accurate as possible and inspection influenced the extension of the surgical resection; the tumour was excised by performing a pleurectomy/decortication (P/D) [11], in some cases associated with the resection of the pericardium (four cases) and diaphragm (one case). P/D was performed in two patients with a tumour limited to the parietal pleura, with absent or very few nodes on the lung surface, and in seven patients with a macroscopic extrapleural spread into the surrounding tissues (vertebral column, intercostal muscles, inferior surface of the diaphragm, aorta or conjunction foramina of the vertebral column): in these patients a complete macroscopic de-bulking was impossible and pneumonectomy was considered useless. In the majority of cases a presumable radical excision of the tumour is feasible with pleuro-pericardium-pneumonectomy with resection of the diaphragm (PPPD) because of the macroscopic evidence of direct lung invasion [12]: the procedure allowed an en-bloc resection with lung enclosed in the tumour cortex of the parietal pleura, the hemipericardium and the diaphragm.

The resection of the involved diaphragmatic pleura or diaphragm was allowed by performing a second thoracotomy (in the eighth intercostal space) in 14 cases and by the resection of the sixth rib in 18 cases.

Pericardial reconstruction after its removal by using Vicryl mesh was required in 15 patients (the tumour was right-sided in 11 cases and left-sided in four cases); diaphragmatic peritoneum was reinforced by Vicryl mesh in 12 patients.

Intrapleural and extrapleural lymph node sampling (mediastinum, intercostal spaces and mammary artery chain) was carried out and a biopsy of resection margins was performed in the more suspected sites.

Patients begun adjuvant chemotherapy 4–6 weeks after surgery and received paclitaxel (200 mg/m² by continuous intravenous 3-h infusion) and carboplatin (at an area under the curve of 6) for two cycles administered 3 weeks apart. Radiation therapy was then given with concurrent weekly paclitaxel 60 mg/m². Two cycles of paclitaxel and carboplatin were repeated following radiation therapy. Radiotherapy was administered after the chemotherapy. Utilizing linear accelerators (4–10 MV), a dose of approximately 30 Gy was delivered to the ipsilateral hemithorax and mediastinum with subsequent boosts given to positive margins and areas of previous bulky disease [10]. The total maximum dose was 55 Gy, as proposed by Sugarbaker's group. The seven patients with macroscopic residual tumour received an adjunctive 10-Gy dose on these areas.

	3. Results

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Histologically, 26 patients were affected by epithelial type MPM, four patients by mixed-cell type and two patients, considered mixed before the operation, by sarcomatous type MPM. Post-surgical staging was as follows: six patients (18.7%) were at Stage I of BSS [10]: two of them had no or few nodes on the visceral pleura and received a P/D, four patients had diffused lung invasion without lymph node involvement and were submitted to PPPD, all patients received an apparently complete resection with negative margins; ten patients (31%) were at Stage II of BSS: four patients revealed metastases to the intrapleural lymph nodes and six cases had microscopic invasion of the resection margins, all received PPPD; 16 patients (50%) were at Stage III of the BSS: seven patients had a deep extrapleural invasion of the surrounding tissues (detected at surgical time) and received a de-bulking P/D with macroscopic residual tumour; nine revealed extrapleural lymph nodes involvement, all were submitted to PPPD. The involved lymph nodes stations were: three subcarinal, two paraesophageal, two inferior pulmonary ligament, one aortopulmonary window and one paratracheal. Resuming the operation were: nine P/D (28%) (7 with gross residual disease) and 23 PPPD (72%) (six with microscopic positive margins and 20 apparently radical).

Median hospital stay was 11.5 (range 5–19) days. Pleural effusion, the main objective pre-operative sign encountered in this series, did not recur perioperatively in any patient. Perioperative complication and mortality rates are defined as occurring within 30 days of the operation. During the perioperative period we observed major morbidity in ten out of 32 patients (31.25%): six patients (18.75%) had perioperative bleeding (Hb range 7–9 g/100 ml) treated with repeated haemotransfusions; two patients out of them developed persistent anaemia requiring other transfusions for 3 weeks, one patient (3.1%) required a redo-thoracotomy on day 7 for bleeding and she had uneventful successive hospital stay; two patients (6.25%) had acute respiratory insufficiency (one for acute respiratory distress syndrome (ARDS) and one for pneumonia of the residual lung) requiring oro-tracheal intubation, one (3.1%) had a little bronchopleural fistula closed after endoscopical injection of glue, one patient (3.1%) had vocal cord paralysis. Minor morbidity occurred in four patients (12.8%): two patients (6.25%) developed atrial fibrillation (treated only with medical therapy), one patient (3.1%) had a transitory contralateral radial nerve paralysis which spontaneously receded on day 8, and one patient (3.1%) experienced subcutaneous seroma which resolved after drainage.

Perioperative mortality rate was 6.25% (two patients out of 32): one died of acute respiratory insufficiency with typical signs of ARDS on day 5, and the second died of pneumonia of the residual lung on day 14.

Among 30 patients surviving surgery, 27 have follow-up longer than 6 months (median 11.5, range 6–27 months). Eight patients out of 27 medium-term survivors died with a median survival of 9.5 months. Twenty-one patients are alive with median follow-up of 12.5 months. Causes of death of the eight patients who died after discharge were: five peritoneal spread of MPM with ascites, two distant metastases and one local recurrence of tumour.

Among the 27 patients who completed post-surgical chemotherapy and radiation therapy, 24 referred gastroenteric (nausea, vomiting and mucositis), 24 cutaneous (alopecia), 6 haematological (neutropenia) and 4 neurological (somnolence) toxicity. In all cases symptoms were reversible and patients restored completely.

	4. Discussion

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion Appendix A. Conference... References

 
MPM was considered a non-surgical disease for many years: the results were poor and the perioperative mortality rate was high (30% before 1980) [13]. Only three series from United States during the period between 1985 and 1995 [14–16] presented an acceptable perioperative mortality rate and recently only Sugarbaker's series presented a good 5-year survival rate in a selected group of patients (31 out of 183) who had negative margins after resection and absence of lymph nodes metastases [10].

Two years ago we decided to offer surgery to patients with MPM because no other therapy is available, and the trimodality therapy seems to offer advantages to some patients.

Over the last 10 years incidence of MPM increased in Europe and in Italy. During the same period the use of thoracoscopy became widespread in hospitals: diagnosis of MPM could be obtained in a shorter time and the disease could be recognized at an earlier stage. The technique of radical surgical excision was described in 1992 [12]; the resection of the hemidiaphragm and pericardium is well tolerated with adequate repair. We always repair pericardial large defects, both right- or left-sided, by suturing a Vicryl mesh to their margins. The diaphragmatic pleura must be removed; rarely peeling is possible, in most cases the muscle infiltrated by the tumour must be removed. The peritoneum is generally separated from the tumour, but in the central area the abdominal cavity is always opened. In all cases we were able to close the abdominal cavity by suturing the peritoneum with care and thus avoid filling of blood in it. The peritoneal dome was reinforced by suturing a Vicryl mesh over the peritoneum; we never used Gore-Tex or other non-absorbable sheets or meshes.

Diaphragmatic prosthetic repair resulted in a few days in a dense fibrous tissue as we noted during the redo-thoracotomy performed in one patient for bleeding on post-operative day 7. Five deaths out of eight patients surviving surgery occurred after peritoneal mesothelioma and no one received pre-operative laparoscopy: we think that it is more probable that the disease was already present before the operation than due to a diffusion during surgery or through the Vicryl mesh, always used to reinforce the sutured peritoneum.

Perioperative morbidity is represented by respiratory failure more serious than after pneumonectomy in patients with lung cancer: the patients affected by MPM often have a well-functioning lung and the pneumonectomy can be badly tolerated. After a simple pneumonectomy we usually remove the chest drain on the first or second peri-operative day, but after PPPD we observed that blood or exudates are evacuated even after 5 or 8 days: we delay the removal of the chest drain generally for a week. Acceptable peri-operative mortality rate (6.25% in our series) allows the thoracic surgeon to be more aggressive in trying to perform extended radical resections.

The intraoperative staging is essential in correctly evaluating the extent of the surgical removal; biopsy samples should be collected to allow correct microscopic evaluation of the resection margins in the suspected areas.

In two patients the tumour was limited to the parietal or diaphragmatic or mediastinal pleura, while the lung surface was disease-free in one case and with two little tumour nodes in the other: we avoided pneumonectomy. In seven cases, during the extrapleural dissection, the tumour was found deeply invading the neighbouring structures such as the chest wall, mediastinal organs, vertebral column or diaphragmatic crura (T4 of IMIG staging) [11]. In these seven patients the pleural space was free: we considered pneumonectomy to be of no use because gross disease had to be left behind and the resection was clearly not radical. The sites of residual tumour were marked with clips for subsequent radiation therapy. In all 23 remaining cases the resection was carried out by performing radical PPPD associated with intra- or extrapleural lymph node sampling.

All of our patients were referred to our department with computed tomography (CT) scan of the chest and upper abdomen. Pre-operative chest magnetic resonance imaging (MRI) was carried out because it is considered to be of substantial benefit in helping us to determine extent of disease, particularly the sagittal planes demonstrating evidence of disease in the paravertebral sulcus or disease extending through the diaphragm. In addition, sagittal views are of help in predicting mediastinal involvement of the vena cava, esophagus or trachea.

At the time of surgery, pre-operative staging seemed rather inaccurate and CT or MRI were found to be unable to reveal extrapleural lymph node involvement or extrapleural spread. The involved stations were subcarinal (three cases), paraesophageal (two cases), inferior pulmonary ligament (two cases), aortopulmonary window (one case) and paratracheal (one case). Mediastinoscopy was carried out only in two patients, but we think that in the majority of cases it could not resolve this problem because of the inaccessibility of the involved stations. Perhaps transcarinal needle biopsy would be more useful.

MRI was unable to confirm or reveal extrapleural direct invasion in seven patients with unremovable diffusion to the surrounding tissue, not clearly demonstrable.

Only two patients with suspected transdiaphragmatic invasion were submitted to laparoscopy, and the procedure demonstrated absence of abdominal invasion in one case and diffusion in the other (excluded from surgery).

Overall survival at 10 months median follow-up, despite the limited series, parallels that noted by Sugarbaker et al. [10]. Stage-related survival indicates a better prognosis for those patients at Stage I disease (100% 10-month survival) than for patients at Stage II or Stage III (80 and 75% 10-month survival, respectively). The differences of stage-related prognosis are not significant in our series (P=0.335), probably related to the limited series and follow-up. In our study the frequency of Stage III disease is higher than that referred by others [10] probably because of a lower accuracy of pre-operative staging. According to the results referred by Sugarbaker et al. the patient survival is related to the histological type, lymph node involvement and extrapleural spread of the disease.

We conclude that: (1) a more aggressive attitude of the thoracic surgeon is mandatory, because PPPD is no longer a life-threatening operation; (2) the operation must obtain the maximal radicality; (3) the resection of the ipsilateral pericardium and diaphragm can be routinely performed without complications; (4) plastic repair can easily be obtained with absorbable materials, and is well tolerated.

Pneumonectomy is certainly the most important life-threatening procedure of the operation but this important reduction of the respiratory function is almost always necessary to obtain a radical resection: we avoided pneumonectomy when a gross residual tumour was left behind. It is evident that when an adhesion of the two pleural surfaces is established, the only solution is a largely not radical PPPD but, when the pleural space is conserved and the lung is relatively free, we should try to avoid pneumonectomy in the presence of a deep unremovable parietal invasion. We think that a patient who received a non-radical operation will have a better quality of life with both lungs.

Many questions are still unresolved: is de-bulking (incomplete resection) with gross residual disease of MPM useful? What is the percentage of invaded mediastinal lymph nodes accessible with pre-operative mediastinoscopy? Will positron emission tomography scanning help to ascertain extrapleural diffusion of MPM?

In our series too many operated patients resulted as Stage III (50%). A better pre-operative evaluation and selection is mandatory: we currently decide to perform in our patients transbronchial biopsy to obtain sampling from subcarinal nodes when judged inaccessible by mediastinoscopy; laparoscopy will be carried out to exclude transdiaphragmatic spread of the tumour. The most difficult task is to establish how to confirm suspected deep vertebral body or foramina invasion in the absence of radiological signs of osteolysis.

	Footnotes

 
Presented at the 14th Annual Meeting of the European Association for Cardio-thoracic Surgery, Frankfurt, Germany, October 7–11, 2000.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Material and methods 3. Results 4. Discussion Appendix A. Conference... References

 
Dr V.V. Sokolov (Kiev, Ukraine): What is your personal opinion as a thoracic surgeon on surgical treatment of malignant mesothelioma, because this devastating operation probably substantially influences the quality of life of patients. That's the first question. The second question is, was rib resection needed in cases of malignant mesothelioma in your patients?

Dr Maggi: Resection of a mesothelioma is a big operation, more difficult and life-threatening than a simple pulmonectomy. But nowadays with the intensive care unit, I demonstrated that mortality is 6%, and that the quality of life, I think, is ameliorated. Many patients with mesothelioma have a severe pain, although I have a patient operated on in October who went skiing 2 months later. We have nothing else to use against this horrible disease, and I think we should try to do all we can for mesothelioma patients.

To enter the thorax, I remove the sixth rib, or I perform two thoracotomies, in the fifth and eighth intercostal space, but it's easier removing the sixth rib. Sugarbaker removes the sixth rib always. I tried both techniques.

Dr J. Thorpe (Leeds, UK): I congratulate you on doing this very difficult operation in this group of patients where there is very little hope without any other form of treatment. In Sugarbaker's series he does chemotherapy pre-operatively, operatively, and post-operatively. Was yours all post-operative chemotherapy and radiotherapy, or do you do pre-operative chemotherapy?

Dr Maggi: Sugarbaker says that he used pre-operative chemotherapy, but he will stop because the post-operative period is more complicated. Currently Sugarbaker makes use only of post-operative chemotherapy, and I do the same. I prefer to use only post-operative chemotherapy, because I think that after chemotherapy the post-operative period is too complicated.

Dr P. Baptista (Lisbon, Portugal): I have one technical question. When you resect the diaphragm, how do you repair that gap?

Dr Maggi: I repair the diaphragm with Vicryl mesh, never with Gore-Tex. I think that the Vicryl mesh is sufficient.

	References

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