• Pasi A Jänne and Elizabeth H Baldini.
• Harvard Medical School, Boston, MA 02115, USA. pjanne@partners.org
• Thorac Surg Clin. 2004 Nov 1; 14 (4): 567-73.

AbstractThe optimum therapeutic strategy for patients with localized malignant mesothelioma continues to evolve. For patients who are eligible candidates, surgical resection plays an important role. An encouraging 45% 5-year survival rate has been reported for patients with early-stage disease who undergo EPP and have the favorable features of epithelial histology and the absence of mediastinal lymph node involvement. Most patients present with more advanced disease, however, and the optimum local and systemic treatment for these patients has not been defined. No randomized trials evaluating the various surgical or adjuvant therapeutic approaches have been performed. Evaluation of treatment efficacy based on observed patterns of failure may suffer from treatment selection biases. Most studies also do not separate out the failure patterns based on the initial stage (clinical or pathologic) of the disease. Consequently, it is difficult to discern the potential impact of a given adjuvant therapy. Given these limitations, however, some consistent observations from the available data can be made. For patients who undergo P/D, local recurrence (within the surgically operated hemithorax) is the most common form of recurrence. Efforts to decrease the chance of local recurrence after P/D have included the use of intrapleural and intravenous chemotherapy, brachytherapy, and external beam radiation therapy. None of these adjuvant treatment trials was randomized, and when compared with historical controls, none of the treatments used suggested a consistent outcome benefit. After P/D, the use of radiation is limited by the potential toxicity of the underlying organs, most importantly, the intact lung. Doses required to treat mesothelioma effectively are above the doses that would lead to damage to the lung parenchyma. Cisplatin and mitomycin have been used as agents have modest activity against mesothelioma. The doses of cisplatin used may not have been optimal, although they were based on prior pharmacokinetic studies. Alternative approaches for patients who undergo P/D, such as the use of escalating doses of heated intrapleural cisplatin (given with a renal protecting agent, sodium thiosulfate, which provides the opportunity to deliver higher doses of chemotherapy), are being pursued by Sugarbaker et al. The availability of more active systemic chemotherapy agents or other intrapleural agents also may offer better therapeutic options for patients who undergo P/D. Recently, Vogelzang et al presented the findings of a large randomized study that compared cisplatin/premetrexed to cisplatin and demonstrated an improvement in response rate (41% for cisplatin/pemetrexed versus 19% for cisplatin) and median survival (12.1 versus 9.3 months, respectively; P = 0.020). Other chemotherapy regimens with encouraging activity in mesothelioma include the combination of cisplatin and gemcitabine, with response rates ranging from 16% to 48%. From a review of available data, patients with mesothelioma who have undergone P/D (with or without intrapleural chemotherapy) who are evaluated at the Dana Farber Cancer Institute and Brigham and Women's Hospital are offered therapy with systemic chemotherapy alone. After P/D, radiation is used only for palliative treatment. Patients who have undergone P/D are also appropriate candidates to receive chemotherapy or other novel therapeutic strategies being evaluated in clinical trials. For patients who have undergone EPP, the pattern of recurrence is predominantly a combination of local and distant failure (Table 1). The local recurrence rates, however, seem to be lower than rates seen after P/D. This observation may represent a shift of the natural history of the disease. Metastatic mesothelioma is often seen late in the course of the disease, but it may become the dominant source of disease after aggressive local surgical management. Many studies define abdominal recurrence as a site of distant recurrence, although this may represent transdiaphragmatic extension of the pleural mesothelioma. Advances in local therapy also may decrease the rate of abdominal recurrences. True distant recurrences (bone, central nervous system, contralateral hemithorax) remain less common. The lowest rate of local recurrence (13%), with a 4% local-only recurrence rate, was seen in the study by Rusch et al, who used 54 Gy hemithorax radiation as adjuvant therapy. This is the lowest rate of local recurrence after an EPP that has been reported. Baldini et al reported a 50% local recurrence rate, with a 13% local-only rate, after trimodality therapy. One possibility for the differences between these two reports is the lower dose of radiation (30.6 Gy) used in the latter study. In the study by Rusch et al, distant failures predominate, and the patients are appropriate candidates for systemic chemotherapy, which could be administered either as neoadjuvant or adjuvant therapy. Kestenholz et al currently are performing a phase II clinical trial of neoadjuvant cisplatin and gemcitabine administered for three cycles followed by EPP and adjuvant radiation therapy. A similar approach also is being pursued in an ongoing clinical trial using neoadjuvant cisplatin/pemetrexed for four cycles before EPP followed by 54 Gy of adjuvant hemithorax radiation. Alternatively, patients who have undergone EPP could be treated with adjuvant chemotherapy in addition to adjuvant radiation therapy. Currently, patients evaluated at the Dana Farber Cancer Institute and Brigham and Women's Hospital who have undergone EPP are offered adjuvant chemotherapy followed by hemithorax radiation to 54 Gy in an effort to maximize local and distant control rates. Further clinical studies are needed for all patients with mesothelioma to define the optimum surgery and duration and types of adjuvant therapy. The appropriate multimodality approaches most likely will differ based on disease stage, histology, and patient performance status. intrapleural chemotheraphy treatments. These two For Patients who have undergone EPP, the pattern

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