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Treatment of MPM remains controversial. There is much conflicting information in the medical literature regarding the effect of various treatments with respect to survival and disease-free interval. Factors that complicate the establishment of standardized treatment protocols include a lack of randomized prospective trials, the relative rarity of the disease (which makes it difficult to accumulate large series), and the lack of a uniform TNM staging system that correlates well with prognosis.
Surgery
There is active controversy in the surgery literature about the role of surgical resection in the treatment of MPM. In patients with disease confined to the pleural space, two surgical procedures may be of therapeutic value: pleurectomy (decortication) and extrapleural pneumonectomy (33).
Pleurectomy entails the stripping of the pleura and pericardium from the lung apex to the diaphragm. It is generally a palliative procedure performed in patients with stage II, III, or IV disease in an attempt to prevent recurrent effusions and to relieve chest wall pain. Complications of this procedure include bronchopleural fistulas, hemorrhage, subcutaneous emphysema, cardiac volvulus, and incomplete tumor removal (33). These patients tend to have local tumor recurrence before distant metastatic spread.
In patients with stage I disease, an attempt is made to remove all tumor by performing an extrapleural pneumonectomy (pleuropneumonectomy). This procedure is an en bloc resection of the parietal and mediastinal pleura, lung, hemidiaphragm, and ipsilateral pericardium (21,66). Serious complications, including bronchial leaks, empyema, vocal cord paralysis, chylothorax, and respiratory insufficiency, occur in 25% of patients who undergo this procedure (Figure 38, Figure 39) (33). Epithelioid subtype and preoperative pulmonary function are the best predictors of outcome, but no study has demonstrated a significantly improved survival with extrapleural pneumonectomy. Although disease-free survival is improved, no difference in overall survival is seen (20). For this reason, adjuvant chemotherapy and radiation therapy may be instituted to control micrometastatic disease and residual local tumor (67). Patients who undergo extrapleural pneumonectomy tend to have distant metastases rather than local tumor recurrence as the first evidence of recurrent disease.
Radiation Therapy
MPM is relatively radioresistant, and large radiation therapy fields covering an entire hemithorax are required, which leads to considerable toxicity. High-dose external-beam radiation (more than 4,000 cGy) may prolong survival (4), and it helps alleviate chest wall pain, reduce pleural effusions, and sterilize needle biopsy tracks (21). Brachytherapy, the local implantation of radioactive isotopes, has been used in an attempt to increase the radiation dose to the tumor and decrease systemic toxicity and damage to normal tissue (21).
Chemotherapy
Chemotherapy can be administered systemically or directly into the pleural space and may consist of a single agent or multiple agents. Doxorubicin, an anthracycline, is considered the most active single agent; its response rates in various trials have ranged from 0% to 16%. Some alkylating agents have shown promise in relatively small trials: cyclophosphamide (0%- 13% response), mitomycin (21% response), cisplatin (13% response), and carboplatin (11% response) (33). Testing of antifolate compounds is in progress, and methotrexate has been shown to have a response rate of 37%; trimetrexate, a rate of 12%; and edatrexate, a rate of 25% (33).
Combination chemotherapy has been tested in small and often inadequate trials that included MPM with other types of tumors. New studies are now based on the existing data for single agents, and most combination regimens contain doxorubicin, cyclophosphamide, or cisplatin (33). Multiple small trials have been performed with regimens based on one of these three agents, but the results have been disappointing, with response rates ranging from 9% to 22% (33).
Intrapleural chemotherapy with radionuclides or biologic agents may be of use in early, superficial disease. This method is limited by the ever-decreasing pleural surface as the tumor spreads over the pleura and by the inability of the chemotherapeutic agents to penetrate more than a few millimeters into the tumor (33). Although intraperitoneal cisplatin administration has evoked some responses in the treatment of peritoneal mesothelioma, the intrapleural administration of cisplatin alone for the treatment of MPM has been less successful (33).
Immunotherapy
Response rates to systemic administration of a-interferon and b-interferon or to systemic therapy with interleukin-2 and lymphokine-activated killer cells are currently being evaluated in clinical trials (68). Astoul et al (69) have studied the intrapleural administration of interleukin-2. Of 15 patients with MPM, seven (47%) responded and had a median survival of 21.2 months; the nonresponders' median survival was 4.4 months. The same researchers studied the intrapleural administration of g-interferon in 99 patients with MPM. Response to this therapy varied with the stage of the disease; 44% of patients with stage I disease responded, but only 6% of patients with stage II disease showed a response. When response rate was correlated with disease stage according to Boutin and Rey's modification of Butchart's classification, the researchers found complete responses in 38.4% of patients with stage IA disease (tumor confined to parietal and diaphragmatic pleura), 12% of patients with stage IB disease (involvement of parietal, diaphragmatic, and visceral pleura), and 2% of patients with stage II disease (70).
Photodynamic Therapy
A new adjuvant approach to the treatment of MPM is intrapleural photodynamic therapy after surgery. This technique involves the instillation of a light-activated, photosensitizing drug into the pleural space in combination with surface illumination of the pleura to achieve tumor necrosis. The normally stable photosensitizing molecule is boosted to an excited state by absorbing light of the appropriate wavelength, and the molecule produces oxygen-free radicals through a series of chemical reactions. Tumor necrosis is caused by direct cytotoxicity and by destruction of the blood supply of the tumor. Complications of phototherapy encountered so far include bronchopleural fistulas and esophageal perforations. The sensitizer Photofrin II is currently being evaluated in phase III trials (71).
Gene Therapy
In the future, knowledge of specific genes whose mutations have been linked to the carcinogenesis of mesothelioma (chromosome 17p, an apparent "tumor-suppressor" gene producing the protein p53) may allow introduction of foreign DNA, either by retroviral or adenoviral vectors. These DNA molecules may supply lost tumor-suppressor genes and allow dedifferentiation of the tumor to a normal phenotype (68).
Multimodality Therapy
Several multimodality regimens are being investigated in clinical trials throughout the country. These combination therapies include (a) pleurectomy, intraoperative brachytherapy, and postoperative irradiation; (b) pleurectomy and intrapleural chemotherapy, with or without postoperative chemotherapy; and (c) extrapleural pneumonectomy, intravenous chemotherapy, and postoperative irradiation (55,67,68). So far, none of these regimens has significantly increased median survival time or affected overall survival (68).
Treatment