Estimating the attributable fraction

Management and prognosis

Median survival of patients with MM treated with supportive care alone is approximately 7 months.

Surgery
The role of surgery is debated. The presence of different staging systems have so far not provided very accurate estimates of prognosis. However, in general, patients with stage I according to Butchart’s classification should be considered candidates for radical surgery; these patients have a tumor confined within the capsule of the parietal pleura, involving only the ipsilateral lung, pericardium and diaphragm. The preoperative staging procedures are, unfortunately, rather imprecise.
There are two main types of operation which have been employed in patients with malignant pleural mesothelioma: pleurectomy and extrapleural pneumonectomy. Pleurectomy consists of stripping the pleura from the apex of the lung to the diaphragm, along with the pericardium (if necessary). This operation generally requires a thoracotomy.

Operative mortality is only 1–2%, and complications include bronchopleural fistulas, hemorrhage and subcutaneous emphysema. The value of pleural decortication as a palliative measure in case of recurrent effusion has not been well established and might be taken into consideration if pleurodesis fails repeatedly.

Extrapleural pneumonectomy is en bloc removal of the parietal pleura, lung, pericardium and hemidiaphragm. Diaphragmatic resection is followed by reconstruction to prevent herniation. In the hands of experienced thoracic surgeons this complex procedure currently has an operative mortality of 5–9%, but serious complications are seen in 25% of patients, which include bronchopleural fistulas and empyema, vocal cord paralysis, chylothorax, arrhythmia and respiratory insufficiency. Extrapleural pneumonectomy is a complex operation, which should be performed by skilled surgeons and in select centers only.

Radiotherapy
The role of radiotherapy in the management of malignant pleural mesothelioma is unsettled, although radiotherapy alone probably has no major role to play in this disease. The most recent series do not indicate that irradiation improves survival when compared to best supportive care. The treatment volume is a crucial aspect of radiation of malignant pleural mesothelioma, and treatment of the entire pleura is indicated. 

This is extremely difficult to achieve without causing serious side effects in normal surrounding tissues, such as
the lung, heart and liver. Radical irradiation has delivered 40–50 Gy to the entire pleural space and the mediastinum, followed by boost irradiation up to 55–71 Gy to areas of gross disease; until now, however, no satisfactory technique has been developed which allows high-dose radiation without major risks for the adjacent normal tissues.

Radiotherapy is more often used for palliation of pain, or added to surgery in an attempt to improve local control. The results of the published literature are rather difficult to interpret, because radiotherapy was used as part of a multimodality treatment in locally advanced cases of pleural mesothelioma, the small number of patients reported in single studies and because of a lack of randomized trials. In a recent study 47 patients were given 40 Gy followed in some cases by doxorubicin/cyclophosphamide: there were only three responses, and median survival was only 7 months, with a high frequency of pneumonitis.

The only available randomized trial of radiotherapy has proven that radiotherapy to the thoracoscopy entry tract significantly reduces the incidence of local relapse: in this study 0/20 patients who received 21 Gy delivered in three fractions 10–15 days after thoracoscopy had local recurrence, whereas local recurrence developed in 8/20 (40%) patients who did not receive radiation.

Chemotherapy
A large number of chemotherapeutic agents have been investigated in MM. The level of activity of most agents is poor, and may vary greatly from study to study. Due to the rarity of the disease, phase II studies were usually performed in small numbers of patients especially in the past. Several patients with mesothelioma and sarcomatous histology have in the past been included in soft tissue sarcoma studies and these results are difficult to assess. Extensive reviews of chemotherapy in malignant mesothelioma have recently been published.

Combination chemotherapy does not, so far, appear to yield substantially higher response rates than single agents. The most common combinations contain doxorubicin and cisplatin. Although some of these combinations appear to give higher response rates than singe agents, responses are of short duration and complete responses are very rarely observed. In general, none of the published agents or com- binations appears to provide any advantage in survival compared with historical controls, although randomized trials against best supportive care have not been conducted.

At the 2002 American Society of Clinical Oncology meeting in Orlando an important randomized study was presented. This study is the largest study ever performed on this malignancy and included a total of 448 patients randomized between cisplatin alone and cisplatin plus pemetrexed (ALIMTA). This study confirmed modest activity of cisplatin alone and demonstrated superiority of the combination in terms of response rate, time to progression and overall survival. Pemetrexed alone has also been tested as a single agent and reported to have a response rate of 16%. Pemetrexed is a novel antimetabolite with multiple mechanisms of action.