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.
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.