Commentary (Flores/Rusch): Diffuse Malignant Mesothelioma of the Pleural Space and Its Management

Drs. Zellos and Sugarbaker nicely summarize the current treatment strategies for malignant pleural mesothelioma. The management of this disease remains controversial, and several aspects of the review merit discussion.

The risk factors associated with the development of malignant pleural mesothelioma-principally asbestos exposure-are well accepted. However, the natural history of this disease is not as well defined. The median survival of 4 to 12 months cited in this review does not reflect contemporary information about the survival of patients with early-stage disease. For example, Boutin reported that patients diagnosed with stage Ia malignant pleural mesothelioma treated with only thoracoscopic talc pleurodesis had a median survival of 22 months.[1,2]

Survival is also affected by tumor histology and by, as yet, poorly understood biological factors. It is important to consider these variations in clinical behavior and outcome when assessing the potential impact of new treatment regimens. The authors imply that metastases are uncommon. However, autopsy series show that distant disease is found in at least 50% of patients, whether or not surgical resection was performed. Thus, control of systemic disease poses a significant challenge in the treatment of this malignancy.[3]

Radiologic Controversies

The radiologic evaluation of malignant pleural mesothelioma also remains controversial. The use of magnetic resonance imaging (MRI) is not as well accepted as the authors suggest. Indeed, a prospective trial comparing computed tomography (CT) and MRI for the preoperative staging of malignant pleural mesothelioma showed that MRI was not significantly more accurate than CT.[4] The exploratory thoracotomy rate remains high (approximately 20%) at all institutions specializing in the surgical management of this disease.

The physical characteristics of this tumor make it difficult to determine resectability with current imaging modalities. The tumor is diffuse and abuts vital structures such as the aorta, subclavian artery, cavae, heart, diaphragm, and esophagus. However, direct invasion of these structures occurs infrequently. The most common reason for unresectability at thoracotomy is diffuse chest wall invasion, and both CT and MRI fail to image this area reliably.

The use of positron-emission tomography (PET) scanning remains an investigational approach in this setting. Although malignant pleural mesothelioma is virtually always fluorodeoxyglucose (FDG)-avid, the lack of spatial localization on PET has thus far failed to make it useful in imaging the chest wall and mediastinum. The use of echocardiography for preoperative staging is optional, and there are no data showing that this modality enhances the staging information provided by chest CT scan. However, radionuclide stress testing is useful prior to extrapleural pneumonectomy because most patients with malignant pleural mesothelioma are older and have underlying coronary artery disease.

Histopathologic Diagnosis

Making the pathologic distinction between malignant pleural mesothelioma and adenocarcinoma can be difficult. Immunohistochemistry, and occasionally electron microscopy, are required to support the histologic diagnosis. Table 1 in the article by Drs. Zellos and Sugarbaker presents a good summary of the distinguishing characteristics based on histology, immunohistochemistry, and electron microscopy. Recently, calretinin has been added to the standard battery of immunohistochemical stains because it is almost always positive in malignant pleural mesothelioma.

The Brigham group should be commended for determining resection margins on a consistent basis. Their method uses 10 to 15 sections through resection specimens and central pathology review. Although it is universally accepted that a true R0 resection in this disease is unlikely to be obtained, this method appears to be a good measure of cytoreduction, as demonstrated by a statistically significant difference in survival between specimens that have "negative" as opposed to "positive" margins.

Treatment Options

The need for multimodality therapy in malignant pleural mesothelioma is emphasized by the rapid recurrence of disease in patients who undergo resection with no additional treatment.[5] The authors correctly point out that adjuvant postoperative radiation can decrease the risk of local recurrence. In a recent prospective trial at our institution, we found that high-dose radiation (54 Gy) after extrapleural pneumonectomy is associated with a less than 10% rate of local recurrence.[6]

The use of adjuvant chemotherapy is less well established because most chemotherapeutic agents are ineffective in malignant pleural mesothelioma. In particular, paclitaxel has no significant activity in this disease. Recently, however, Byrne et al reported a 47% response rate for gemcitabine (Gemzar) and cisplatin in a phase II trial in patients with exclusive malignant pleural mesothelioma.[7] Further investigation of this apparently active regimen is warranted.

In addition, the lack of a universally accepted staging system for malignant pleural mesothelioma has been a significant problem in evaluating new treatment regimens. The International Mesothelioma Interest Group (IMIG) staging system mentioned by the authors has now been accepted by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) as the standard staging system.[8] However, the system requires further revision. Analysis of larger numbers of patients via multi-institutional efforts is necessary to improve the IMIG staging system.

Conclusions

Overall, this article is an excellent overview of the challenges associated with the management of malignant pleural mesothelioma. As outlined by Drs. Zellos and Sugarbaker, progress in this area will depend on continued investigation into the biology, staging, and novel approaches to treatment of this difficult disease.

References:

1. Boutin C, Rey F: Thoracoscopy in pleural malignant mesothelioma: Aprospective study of 188 consecutive patients. Part I: Diagnosis. Cancer72:389-393, 1993.

2. Boutin C, Rey F, Gouvernet J, et al: Thoracoscopy in pleural malignantmesothelioma: A prospective study of 188 consecutive patients. Part 2: Prognosisand staging. Cancer 72:394-404, 1993.

3. Ruffie P, Feld R, Minkin S, et al: Diffuse malignant mesothelioma of thepleura in Ontario and Quebec: A retrospective study of 332 patients. J ClinOncol 7:1157-1168, 1989.

4. Heelan R, Rusch V, Begg C, et al: Malignant pleural mesothelioma:Comparison of CT and MR imaging for staging. Am J Roentgenol 173:1039-1047,1999.

5. Rusch V, Piantadosi S, Holmes E: The role of extrapleural pneumonectomy inmalignant pleural mesothelioma. A Lung Cancer Study Group study. J ThoracCardiovasc Surg 102:1-9, 1991.

6. Rusch V, Rosenzweig K, Ennapadam V, et al: A phase II trial of surgicalresection and adjuvant high dose hemithoracic radiation for malignant pleuralmesothelioma. J Thorac Cardiovasc Surg 122(4):788-795, 2001.

7. Byrne M, Davidson J, Musk A, et al: Cisplatin and gemcitabine treatmentfor malignant mesothelioma: A phase II study. J Clin Oncol 17:25-30, 1999.

8. Rusch VW: A proposed new international TNM staging system for malignantpleural mesothelioma. From the International Mesothelioma Interest Group. Chest108:1122-1128, 1995.