Lambros S. Zellos [MEDLINE LOOKUP]
David J. Sugarbaker [MEDLINE LOOKUP]

• Abstract
• Clinical Presentation, Diagnostic Workup, and Staging
• Single Modality Treatment
• Multimodality Treatment
• Conclusions
• References
• Publishing and Reprint Information

Diffuse malignant pleural mesothelioma (DMPM) is a challenging disease in all of its aspects, from presentation and diagnosis to staging and treatment. Single-modality therapy was the initial approach to this disease. It generally has not been effective in changing the natural history of DMPM. As a result, multimodality regimens involving surgery with radiation, chemotherapy, or immunotherapy delivered regionally or systemically have been evaluated. Randomized controlled studies comparing various strategies are lacking and, thus, the debate continues regarding the effectiveness of different treatment approaches.
Semin Oncol 29:41-50. Copyright © 2002 by W.B. Saunders Company.

Clinical presentation

The typical DMPM patient who presents for surgical evaluation is a male over the age of 55 (3:1 male-to-female ratio) with unilateral disease (95%). DMPM tends to be right-sided (60%).³ Patients usually report symptoms related to the presence of a pleural effusion, such as dyspnea, cough, chest pain that may be nonpleuritic in nature, and occasionally fever, night sweats, fatigue, and weight loss.³ Unrelenting local spread with invasion into the chest wall, the lung and its fissures, the mediastinal structures, and diaphragm are characteristic. The time from presentation to diagnosis can be as long as 2 to 3 months.

Diagnosis

A high index of suspicion is needed, especially in patients with exposure to asbestos. Options include thoracentesis, closed pleural biopsy, and video-assisted thoracic surgery (VATS). Cytologic examination has a low diagnostic yield (35% to 50%), and, similarly, closed pleural biopsy has a high false-negative rate.^4>6 While repeated procedures and computed tomography (CT) guidance can increase the diagnostic yield of closed pleural biopsies, seeding of the needle tracts can occur, resulting in the eventual development of chest wall masses. When DMPM is suspected, it is appropriate to proceed directly to VATS. VATS can effectively drain a loculated effusion, and by providing adequate tissue samples for histology, immunohistochemistry, and electron microscopy⁷ (Table 1), a 90% or better diagnostic yield can be achieved.⁸

Staging

Staging is crucial in deciding the appropriate regimen for patients with DMPM. Because those with positive resection margins, N2 nodal disease, or advanced stage do not enjoy prolonged survival (especially with sarcomatous or mixed pathology), staging procedures should attempt to identify these patients.⁹ While all patients should undergo CT scans of the chest and abdomen, debate continues regarding the utility of magnetic resonance imaging (MRI). MRI can provide a better assessment than CT scan of apical and diaphragmatic regions, as well as chest wall involvement.¹⁰ Unnecessary thoracotomies can be avoided by better defining resectability. We currently require both CT and MRI scans of the chest and abdomen.

The role of positron emission tomography (PET) scan in staging DMPM was evaluated in 18 patients by Schneider et al.¹¹ PET scan detected distant disease in two patients who had negative CT scans. PET scan was also more accurate in the assessment of mediastinal nodes. Benard et al assessed the standard uptake value (SUV) of lesions on PET scans as a predictor of survival. High SUV values (mean SUV, 6.6 v 3.2) were found to have a negative impact on survival, suggesting that tumor burden could be quantified.¹²

While PET scan can have quite low false-negative rates, its increased sensitivity does result in false-positive scans. The standard of staging remains cervical mediastinoscopy, which can accurately assess tumor involvement of N2 nodes with minimal discomfort to the patient. When CT scan is the principal staging method, a high number of patients undergoing exploratory surgery will be found to be technically unresectable or have advanced disease. Rusch and Venkatraman reported that of 131 patients staged with CT scan, 32 (24%) had technically unresectable disease and 46 (35%) had mediastinal nodal involvement.¹³

Echocardiogram is another useful test in the preoperative workup of patients. It can assess pericardial invasion by the tumor, determine cardiac function, and hence assist in determining the appropriate management.

Several mesothelioma staging systems have been proposed, but none are universally accepted. While a staging system should stratify survival and hence direct therapy, most staging systems have failed to so. Butchart et al introduced the first mesothelioma staging system in 1976 (Table 2).¹⁴

Surgery

The three surgical procedures that have been used for the treatment or palliation of DMPM are pleurodesis, pleurectomy/decortication (P/D), and EPP. There have been no randomized studies comparing these three procedures. The retrospective studies use different staging systems and do not always group patients by stage.

VATS with pleurodesis is performed to palliate without cytoreduction. The effusion is effectively drained, and any loculations present can be disrupted. Four agents have been used to sclerose: tetracycline, doxycycline, bleomycin, and talc. Randomized trials of talc versus bleomycin, tetracycline versus bleomycin, and doxycycline versus bleomycin found the resulting inflammatory reaction and palliation to be equivalent with each agent.^22>24 While pleurodesis increases the difficulty of future cytoreductive procedures, P/D or EPP can still be performed by experienced surgeons without prohibitive complication rates.

Proponents of this procedure suggest it should be the definitive treatment for mesothelioma because cytoreductive surgery (EPP or P/D) as a single modality has not resulted in significant prolongation of median survival and subject the patient to added morbidity and mortality. Additionally, they point to in vitro studies that have shown a 39% tumoricidal effect of talc on cell lines to propose that talc could be used as the sole treatment.²⁵ However, large studies that have used talc pleurodesis as the sole surgical treatment have reported median survival similar to that of the natural history of the disease.²⁶ This procedure may be appropriate for patients with multiple comorbidities that preclude aggressive surgery, however.

The cytoreductive procedures include P/D and EPP. While both are performed with curative intent, there is debate regarding which technique is most appropriate.

The visceral and parietal pleura, the pericardium, and the diaphragm can be removed during P/D. This procedure is not as technically demanding as EPP and because it does not remove the entire lung, it poses less physiologic strain on patients. It can be tolerated by patients whose functional status precludes EPP, and it can be performed by most centers without prohibitive mortality rates. Most series have reported mortality rates in the range of 1.5% to 5%.²⁷ Proponents of P/D point to these benefits and also to the high mortality rates reported after EPP in older studies (30% mortality) and the failure of EPP to prolong survival as a single modality (10% 5-year survival).¹⁴

There are several disadvantages to P/D: mesothelioma can invade the lung fissures making complete resection difficult; postoperative radiation is limited due to the presence of the lung; and local recurrence occurs in the vast majority of the patients (80% in some studies).²⁸ Additionally, large, modern studies have markedly reduced the operative mortality of EPP to less than 4%, making it a more attractive procedure for some patients with good functional status and an appropriate disease setting.⁹

EPP is a more aggressive procedure that involves en bloc resection of the parietal and visceral pleura with the enclosed lung, pericardium, ipsilateral diaphragm, and mediastinal nodes. It is a more effective cytoreductive procedure than P/D. In addition, with the lung removed, a higher amount of radiation can be delivered. EPP has a more pronounced physiologic impact on the patient. The obvious disadvantage of EPP is the greater physiologic reserve required of the patient and the higher incidence of postoperative morbidity and mortality than seen with P/D. Postoperative complication rates can vary widely between centers. The Butchart series of 29 patients¹⁴ reported a mortality rate of 30% after EPP. As experience with this procedure has grown, numerous series have reported lower mortality rates, but there are still modern series that report significant mortality rates. The largest series of EPP reported a mortality rate of 3.8%.⁹

Selection of the appropriate patient subset for EPP is crucial. This procedure should be done by a surgeon who has experience in the postoperative management of complications and in an institution with the support to manage these complicated patients. Potential complications of EPP include bronchial leaks, empyema, vocal cord paralysis, chylothorax, patch failure, and post-EPP constrictive physiology.

There has not been a randomized study that compares P/D to EPP as a single-modality treatment for DMPM. However, neither procedure as a single modality has resulted in significant prolongation of the median survival. It is within the setting of multimodality therapy that EPP has resulted in improved survival of patients with early-stage disease.

Chemotherapy

Chemotherapy regimens for mesothelioma are extensively reviewed in the articles by Drs Baas, Fizazi, and Kindler in this issue. It suffices to state that chemotherapy is not curative, and while there may be new regimens with promising activity, there are currently no data to indicate that chemotherapy as a single modality affects survival in this disease.^29>31

EPP and adjuvant chemoradiation

Brigham and Women's Hospital has the largest series evaluating multimodality treatment of DMPM.^32,33 This protocol includes EPP followed by sequential chemotherapy and radiation. EPP was chosen for the protocol because it provides the maximum local cytoreduction. A standardized preoperative assessment protocol helps select only those patients who can tolerate EPP. Eligibility criteria include presence of potentially resectable disease, absence of significant systemic comorbidities (cardiac, renal, hepatic), and adequate functional status. Resectability is determined with CT scans, MRI, and echocardiograms. All three tests are obtained for each patient. These studies should demonstrate no chest wall invasion, no contralateral disease, no transdiaphragmatic involvement, and no mediastinal invasion.

Preoperative functional status is assessed with the Karnofsky performance score, pulmonary function tests, arterial blood gases (ABG), and echocardiograms. The Karnofsky performance score should be greater than 70. The ABGs should show PCO₂ less than 45 mm Hg and PO₂ greater than 65 mm Hg. The echocardiogram should demonstrate an ejection fraction greater than 45%. Adequate postoperative functional status is mainly determined with predicted postoperative FEV₁ and quantitative ventilation-perfusion scans (V/Q). The predicted postoperative FEV₁ should be greater than 1 L. For patients with borderline pulmonary function (preoperative FEV₁ of 2 L), V/Q scans can predict postoperative FEV₁ more accurately.^9,34

EPP requires en-bloc resection of the parietal pleura, lung, pericardium, and diaphragm. The pericardial and diaphragmatic defects are reconstructed with patches (Gore-Tex, W.L. Gore, Flagstaff, AZ) to prevent cardiac or abdominal organ herniation. The postoperative care of EPP patients is similar to that of standard pneumonectomy. Pain control with epidural catheter placement is essential in order to reduce atelectasis and pulmonary dysfunction. Arterial lines, central venous lines, pulse oximeters, and monitoring in the intensive care unit are crucial to avoid significant intravascular volume changes. A high index of suspicion for deep vein thrombosis (DVT) is important because pulmonary embolus cannot be tolerated by these patients. DVT prophylaxis is done with subcutaneous heparin and pneumatic boots. Avoiding episodes of fluid overload and pulmonary edema is crucial. Fluid restriction (1 L/d) should be instituted during the first 3 to 5 days and a diuretic should be administered if indicated as early as postoperative day 0. Mediastinal shift can occur after pneumonectomy and results in tamponade or venous flow obstruction. Occasionally, fluid from the ipsilateral chest may need to be drained to decrease the mediastinal shift. Vocal cord paralysis can occur and a high index of suspicion and low threshold for endoscopy are essential to prevent aspiration. After a recovery period of 4 to 6 weeks, the patient is referred to a multidisciplinary program for adjuvant chemoradiation.

One hundred eighty-three patients underwent EPP between 1980 and 1997 at Brigham and Women's/DFCI. There were seven perioperative deaths, for a mortality rate of 3.8%. The 176 surviving patients underwent adjuvant treatment. Adjuvant chemoradiation is initiated after a recovery period of 4 to 6 weeks. Several adjuvant chemotherapy regimens have been evaluated at the DFCI over time. Patients treated prior to 1985 received doxorubicin and cyclophosphamide. Cisplatin was included in the regimen in 1985. In 1994, the regimen was revised to two cycles of carboplatin and paclitaxel, followed by radiation with concomitant weekly paclitaxel. The regimen concludes with two additional cycles of carboplatin and paclitaxel. More recently, chemotherapy has included gemcitabine with either cisplatin or carboplatin.

Radiation is delivered to the hemithorax at a dose of 30 Gy, while the mediastinum receives 40 Gy. If gross residual disease, positive microscopic margins or positive nodes are present, then a boost dose of 14 Gy is given. The total dose that can potentially be delivered is 54 Gy.⁹

The 176 patients achieved 2- and 5-year survival rates of 38% and 15%, respectively⁹ (Fig 1).

A survival analysis determined the following to be significant prognostic variables: histologic subtype, lymph node involvement, resection margins, and invasion beyond the pleural envelope. These variables form the basis of the revised Brigham/DFCI staging system⁹

The subset of patients with epithelial histology and stage I disease (revised Brigham/DFCI staging system, ie, negative lymph nodes and negative margins) had a median survival of 51 months and 2- and 5-year survival rates of 68% and 46%, respectively. None of the patients with sarcomatous histology and positive N2 nodes or positive margins survived 5 years.⁹

The 176 patients were also staged according to the IMIG and Butchart staging systems. While the revised Brigham/DFCI system stratified patient survival by stage (P= .0011), the other two staging systems failed to do so (Butchart system. P= .09; IMIG system, P= .31). This aggressive trimodality approach and the revised Brigham/DFCI staging system identified the most appropriate subset of patients who should undergo such therapy: patients with epithelial histology, negative nodes, and completely resectable disease.⁹

The importance of accurate clinical staging cannot be overstated. Accurate determination of resectability with MRI is crucial. While PET scan has shown promise in staging mediastinal disease, mediastinoscopy remains the standard. Biopsy of mediastinal nodes can accurately stage patients and prevent operations in patients with nonepithelial histology when resectability is questionable.

A subset of these 183 patients (n = 49) who underwent trimodality therapy were reviewed to assess patterns of failure. Between 1987 and 1993, 49 patients with DMPM were evaluated. There were three perioperative deaths; therefore, 46 of 49 patients were eligible for analysis. The median follow-up was 18 months. Twenty-five (54%) patients had disease recurrence.³⁵ Ipsilateral chest recurrence was seen in 35% of patients, abdominal recurrence in 26%, and contralateral chest recurrence in 17%.³⁵ Despite this aggressive protocol, locoregional recurrence was still the predominant mode of failure. However, systemic failure was seen more frequently, suggesting that the multimodality therapy may have an impact in the natural history of this disease.

For patients who do not meet the inclusion criteria for EPP, cytoreduction is achieved with P/D. Patients receive similar adjuvant therapy except that the radiotherapy is focused on the wound to prevent chest wall metastasis due to seeding rather than on the entire hemithorax because the lung is still present.

P/D with brachytherapy and external-beam radiation

The Memorial Sloan-Kettering Cancer Center has evaluated a multimodality approach that incorporates intraoperative brachytherapy after P/D, followed by external-beam radiation.²⁷ Between 1976 and 1988, 105 patients had ¹²⁵I seeds or ¹⁹²Ir implants placed in the ipsilateral hemithorax after P/D in areas with gross residual disease. A total external-beam radiation dose of 4,500 cGy was given to the ipsilateral hemithorax. Median survival was 12.5 months. One- and 2-year overall survival rates were 52% and 23%, respectively. Patients with early disease and epithelial tumors had a better survival. In the 27 patients with epithelial histology and minimal residual disease, median survival was 15 months, and 1- and 2-year survival rates were 68% and 35%, respectively. Despite cytoreduction and brachytherapy, 61% of patients had local recurrence.²⁷

P/D or EPP with intrapleural and systemic chemotherapy

Intrapleural drug delivery can achieve increased local drug concentrations and prolonged drug exposure with less systemic toxicity; cytotoxicty is limited by tissue penetration of drug. The Memorial Sloan-Kettering Cancer Institute and the Cleveland Clinic have evaluated intrapleural chemotherapy immediately after cytoreduction followed by systemic chemotherapy.^28,36 The Memorial Sloan-Kettering group used P/D with immediate intrapleural cisplatin and mitomycin C (100 mg/m² and 8 mg/m², respectively). Systemic chemotherapy with the same agents was initiated 3 to 5 weeks postoperatively. Thirty-six patients were enrolled, and 28 underwent P/D and intrapleural chemotherapy.²⁸

There was one perioperative death (3.6%) and two episodes of grade 4 renal failure. Twenty-three of the 27 surviving patients received systemic chemotherapy. The 1- and 2-year survival rates for the 27 patients were 68% and 40%, respectively; the median survival was 17 months. Sixteen of 20 patients (80%) had locoregional recurrence.²⁸

The Cleveland Clinic used a similar regimen in 19 patients with clinical stage I disease. Nine patients underwent P/D and 10 had EPP. The P/D patients received intrapleural cisplatin and mitomycin C immediately postprocedure, while the patients who underwent EPP received intrapleural cisplatin 1 to 2 weeks after the procedure. There was one perioperative death for a mortality rate of 5%. Fifteen patients received systemic, cisplatin-based chemotherapy, which was poorly tolerated and resulted in one death. Median survival was 13 months and the median disease-free survival was 11 months.³⁶

A recently reported series by Juturi et al from the Cleveland Clinic investigated the role of intracavitary paclitaxel as a component of multimodality therapy.³⁷ Twenty-two patients accrued since 1995 underwent EPP or P/D, intracavitary paclitaxel, then chemoradiation with intravenous paclitaxel. The toxicity of this regimen was considerable, including empyema, wound dehiscence, mucositis, neutropenia, neutropenic sepsis, and one toxic death. Median survival was 9 months. Locoregional metastases developed in 64% despite the aggressive multimodality regimen.

While median survival appears to have been prolonged in the Memorial Sloan-Kettering series of intrapleural and systemic chemotherapy following P/D, this was not replicated in the Cleveland Clinic series. Additionally, locoregional recurrence was not affected despite intracavitary chemotherapy.

P/D or EPP with hyperthermic, intrapleural, chemotherapeutic infusion

Hyperthermia has been shown to induce cell death. It also appears to improve the efficacy of chemotherapeutic agents. Stehlin pioneered its use for the treatment of melanoma, where the addition of hyperthermia markedly improved the efficacy of the chemotherapeutic agents.³⁸ In theory, hyperthermia with intracavitary chemotherapy could improve the tumoricidal effects against DMPM. Few studies of intracavitary hyperthermic perfusion of cisplatin have been conducted. Matsuzaki and colleagues used hyperthermic cisplatin at 43°C to treat pleural implants or effusions in lung cancer patients.³⁹ They observed high concentrations of cisplatin in the pleural cavity during perfusion. Ratto et al studied hyperthermic intrapleural perfusion in DMPM. Three patients underwent P/D and normothermic cisplatin, three patients underwent P/D and hyperthermic cisplatin, and four patients underwent EPP and hyperthermic perfusion. The cisplatin dose used was 100 mg/m². There was higher systemic absorption of the cisplatin with P/D than EPP. Hyperthermic perfusion achieved higher local tissue concentrations of cisplatin than normothermic perfusion.⁴⁰

The Brigham and Women's Hospital has completed a phase I, dose-escalating study to determine the maximum tolerated dose of cisplatin after EPP; the results have not yet been published. A similar phase I study for P/D is ongoing. Phase II trials are in development.

Photodynamic therapy after EPP or P/D

Photodynamic therapy (PDT) combines light with a photosensitizer that has selective uptake in malignant cells. A phase III study performed by Pass et al compared cytoreduction, postoperative cisplatin, interferon-2b, and tamoxifen with and without intraoperative PDT using photofrin.⁴¹ From 1993 to 1996, 63 patients were entered into this study; 15 patients could not achieve cytoreduction to less than 5 mm. Twenty-five patients received PDT and 23 patients did not. A total of 23 P/Ds and 25 EPPs were performed. The two groups of patients were comparable in terms of type of resection and stage. Although patients were selected based on localized disease preoperatively, 79% of patients were found to have stage III disease at surgery. There was no difference in median survival (14.4 v 14.1 months), major morbidity, nor sites of first recurrence between the two groups.⁴¹

Moskal et al reported the Roswell Park Cancer Institute experience of 40 patients with DMPM who underwent cytoreduction and intracavitary PDT. Twenty-four of 40 patients had advanced disease (stage III or IV). While median survival was 15 months for the 37 patients who survived postoperatively, patients with early disease (stage I and II, n = 13) had a median survival of 36 months; those with advanced disease had a median survival of 10 months.⁴²

Second-generation photosensitizers are now under investigation.

Novel therapies

Newer therapies, such as chemoimmunotherapy, angiogenesis inhibitors, and vaccines, have not been evaluated in multimodality regimens to date. If these or other approaches begin to show promise in advanced disease, they may be incorporated into adjuvant multimodality regimens. The review by Nowak et al in this issue discusses these agents in detail.

Acknowledgment

The authors thank Mary S. Visciano for editorial assistance

  Connelly RR, Spirtas R, Myers MH, et al: Demographic patterns for mesothelioma in the United States. J Natl Cancer Inst 78:1053-1060, 1987