Malignant Mesothelioma of the Pleural Space

The article by Drs. Grondin and  Sugarbaker discussing the clinical management of malignant pleural mesothelioma provides an excellent overview but also highlights many of the controversies surrounding the diagnosis and treatment of this difficult disease. The natural history of mesothelioma, role of surgery and of multimodality therapy, best algorithm for preoperative staging, and, indeed, the system used for staging are all still subject to debate. Several points in this article warrant discussion.

The natural history of malignant mesothelioma is important because it provides insights into the development of treatment strategies for this disease. Grondin and Sugarbaker correctly describe the initial clinical presentation as variable in symptoms and duration, and disease progression as initially being local. However, the importance of systemic disease has been underemphasized. At least half of all patients have distant metastatic disease at autopsy, and systemic disease is the most common form of relapse in patients who have achieved local control of their disease via extrapleural pneumonectomy.

It is not clear whether aggressive local therapy promotes the development of systemic metastases through some undefined mechanism, or whether good local control merely highlights the problem of systemic disease. Nonetheless, distant metastases are a major problem in the treatment of mesothelioma and must be considered in the development of future therapies.

Optimal Preoperative Staging Algorithm

The optimal algorithm for preoperative staging is also debated. Grondin and Sugarbaker suggest that magnetic resonance imaging (MRI) should be a standard part of the staging evaluation. However, at least one prospective trial has failed to confirm the benefit of doing MRI routinely in addition to computed tomography (CT).

On the other hand, laparoscopy is probably the best way to determine whether or not disease extends through the diaphragm in cases in which CT is equivocal. Although mesotheliomas show increased uptake on positron emission tomography (PET), the role of PET scanning in staging this disease remains undefined.

As the authors point out, the decreasing mortality associated with extrapleural pneumonectomy is related to surgical expertise and to careful preoperative assessment of the patient. Patients with mesothelioma tend to be older (median age of 55 years in most series) and often have underlying pulmonary and cardiovascular disease. The hemodynamic stress and risk of supraventricular arrhythmias after extrapleural pneumonectomy are greater than after any other type of pulmonary resection.

In addition to the evaluation described by Grondin and Sugarbaker, routine measurement of the diffusion capacity is mandatory when pulmonary function tests are performed because mesothelioma patients often have significant underlying interstitial lung disease in the face of relatively well-preserved lung volumes or spirometry. A quantitative ventilation perfusion scan is also mandatory for determining whether the patient has adequate pulmonary reserve. It is usually wise to subject the patient to a pharmacologic stress test to make certain that there is no evidence of clinically silent myocardial ischemia before performing an extrapleural pneumonectomy.

Staging System

The staging system for malignant pleural mesothelioma remains controversial. The system proposed by the Brigham group differs somewhat from that developed by the International Mesothelioma Interest Group (IMIG). However, the latter system supercedes all previously proposed staging systems (of which there were at least six) because it was developed as a result of an international consensus conference on the staging of this disease.

Without doubt, both the IMIG and Brigham staging systems will need to be reexamined as further data on the natural history of this disease accumulate. Such data usually derive from meticulous staging and follow-up in surgical series, not from prospective, multicenter, randomized trials, as Grondin and Sugarbaker suggest.

Role of Chemotherapy

Chemotherapy has thus far had disappointing results in the treatment of malignant pleural mesothelioma. Grondin and Sugarbaker discuss the use of adjuvant paclitaxel (Taxol) and carboplatin (Paraplatin), and the Brigham group has previously used CAP (cyclophosphamide, Adriamycin, and Platinol) chemotherapy. However, multiple phase II trials suggest that all currently available chemotherapeutic agents, whether given alone or in combination, produce only a 20% to 25% response rate in patients with locally advanced disease.

Paclitaxel, in particular, has not been considered to be an active drug. However, this does not mean that chemotherapy does not deserve further investigation.

Because of the importance of systemic disease, particularly in patients who have achieved local control after extrapleural pneumonectomy and radiation, there is clearly a need for effective chemotherapy. In the United States, most patients present to surgeons when they have stage III disease. The use of surgical resection and radiation probably is of limited benefit in such patients.

Chemotherapy, given either preoperatively or adjuvantly, does need to be tested further but must still be considered investigational. Its benefit cannot be assumed at present.

Gene Therapy

Finally, Grondin and Sugarbaker describe some of the preliminary efforts in gene therapy for malignant mesothelioma. The association between SV-40 virus and malignant mesothelioma is now well documented, but the precise etiologic mechanism has not been elucidated. Whether the link to SV-40 could ever be the basis of vaccine therapy is entirely speculative.

Grondin and Sugarbaker are to be congratulated for their efforts in treating this disease, which is often viewed with complete nihilism by the thoracic oncology community at large. The differences in opinion and experience discussed above emphasize the importance of centers with expertise in this disease continuing to conduct careful prospective trials to evaluate the staging and treatment of malignant pleural mesothelioma.

References:

 Heelan RT, Rusch VW, Begg CB, et al: Malignant pleural mesothelioma: Comparison of CT and MR imaging for staging. Am J Radiol, 1999 (in press).

Rusch VW, The International Mesothelioma Interest Group: A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 108:1122-1128, 1995.

Rusch VW, Venkatraman E: The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 111:815-826, 1996.

Rusch VW, Venkatraman E: Important prognostic factors in patients with malignant pleural mesothelioma. Ann Thorac Surg, 1999 (in press).

  Testa JR, Carbone M, Hirvonen A, et al: A multi-institutional study confirms the presence and expression of simian virus 40 in human malignant mesotheliomas. Cancer Res 58:4505-4509, 1998.