By Lee M. Krug, MD
Malignant pleural mesothelioma (MPM) is a rare disease, with an incidence 100-fold less common than lung cancer. As such, the optimal treatment for a patient with MPM is not always clear-cut, and management can vary greatly from one institution to another. Large prospective studies do not exist to guide even our most basic treatment decisions, such as when to perform surgery. If possible, patients should seek care from a specialized center where the treating physicians can rely on their experience as well as the available literature to personalize an appropriate course of therapy.
How do I work up a patient with suspected mesothelioma?
Most patients will present with a pleural effusion, but cytology from a thoracentesis is almost always non-diagnostic. Thus, a more invasive procedure such as video thoracoscopy is generally required to provide adequate tissue for analysis.
Epithelioid mesothelioma can be difficult to distinguish histologically from adenocarcinoma, but immunohistochemical stains can be quite helpful. MPM generally has positive staining for calretinin and WT1, and negative staining for TTF1 and CEA. The opposite is true for adenocarcinoma. Sarcomatoid mesothelioma is challenging to differentiate from other entities such as metastatic sarcoma or sarcomatoid carcinoma. Since this tumor is often poorly differentiated, immunohistochemical stains may not be as helpful in this regard.
Is surgery beneficial in this disease?
The controversy regarding the role of surgery in this disease rages on. With that debate, the view towards the choice of surgical procedure has also evolved, particularly over the last few years. Historically, an extrapleural pneumectomy (EPP) was thought to be the only procedure approaching a complete resection. The benefit of EPP was largely called into question with a retrospective analysis that showed that, stage for stage, patients who underwent a less aggressive pleurectomy/decortication (P/D) had better survival than those who had an EPP.
Multiple centers are now more inclined to perform a lung-sparing surgery, and in many cases, a carefully performed radical P/D can successfully debulk a patient’s disease. The question of whether any surgery improves survival has not been answered (though a study in the UK is trying). But in my opinion, it may serve the patient well to have the disease “optimally debulked” by P/D in the same context as ovarian cancer, even though local relapse after that procedure is inevitable.
Who should be considered for surgery?
Fit patients with early stage disease may be considered for a combined modality approach which includes surgery. Chest wall invasion, which is classified as T4 and also stage 4 in the currently employed IMIG staging system, is the most common exclusion for resectability.
The histology also plays an important role; patients with sarcomatoid, or even biphasic histology, generally fare poorly and are unlikely to benefit from surgery. Response to chemotherapy also portends a more favorable natural history for the disease.
As such, I prefer to give patients preoperative chemotherapy. In my view, patients who rapidly progress on up-front chemotherapy have aggressive disease and are far more likely to relapse briskly after surgery.
If a patient is considered appropriate for surgery, what other therapies do you administer?
It has long been understood that surgery alone is inadequate for control of this disease. In order to decrease the risk of relapse, other modalities of therapy have been added over the years, including hemithoracic radiation after EPP to improve local control, and chemotherapy to reduce the risk of metastatic disease. Even after treatment with chemotherapy, EPP, and hemithoracic radiation, survival rates remain poor with a median survival of 17 months. This dampens the enthusiasm further for such an aggressive surgery, and also supports the use of P/D instead.
In patients with an intact lung, hemithoracic radiation is not feasible due to the risk of pneumonitis. At our center, we are exploring the use intensity modulated radiation therapy (IMRT) to the pleura, which presents significant treatment-planning challenges, but can be administered safely. In our retrospective cohort, patients treated with chemotherapy, P/D, and pleural IMRT had a median survival of 26 months. We are now testing this approach in a prospective trial.
What is the best treatment for patients with advanced disease?
This is one area where phase III data inform our treatment decision -- pemetrexed/cisplatin was demonstrated to improve survival over cisplatin alone, and has thus become the standard first-line regimen.
Pemetrexed/carboplatin is a reasonable alternative based on comparable outcomes in large phase II trials. Although the efficacy of maintenance pemetrexed has not been tested in MPM, I have used it in select patients who are tolerating it well based on the NSCLC paradigm (the CALGB is conducting a trial addressing this issue).
What is an appropriate second-line regimen?
Extremely limited data exist to answer this question. Some patients benefit from being rechallenged with a pemetrexed-based regimen, particularly if the disease previously responded and it has been several months since that treatment was administered. Vinorelbine is my usual second-line choice (outside of a clinical trial) based on one small phase II trial that reported a 16% response rate, as well as the MRC phase III trial in which first-line vinorelbine showed a trend toward improved survival over best supportive care.
Should patients with MPM be started on chemotherapy immediately?
There are MPM cases in which patients have an indolent disease course, and so asymptomatic patients with a low disease burden can often times be closely observed off treatment.
Lee M. Krug, MD, is Associate Attending Physician in the Division of Thoracic Oncology, Department of Medicine, and Director of the Mesothelioma Program at Memorial Sloan-Kettering Cancer Center.