Chest
Volume 126, Issue 4, October 2004, Pages 1318-1329
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Reviews
Malignant Pleural Mesothelioma: Update, Current Management, and Newer Therapeutic Strategies

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The diagnosis and management of malignant pleural mesothelioma are major challenges that often frustrate both patient and clinician alike. Occupational asbestos exposure to crocidolite or amosite forms of the fiber is the most important known risk factor in North America and Western Europe. Other mineral fibers such as erionite, a naturally occurring fibrous zeolite crystal, are associated with mesothelioma in volcanic tuffs of the Cappadocia region of central Anatolia in Turkey. In addition, other possible factors such as the presence of simian virus 40 and genetic susceptibility have been associated recently with the development of mesothelioma in animal models. These latter findings are increasing our understanding of this disease. In addition, the discovery of elevated levels of various markers such as folic acid receptor α, cyclooxygenase 2, and multidrug resistance proteins 1 and 2 in mesothelioma tissue have opened up new areas of potential diagnostic and therapeutic importance. However, traditional treatment modalities—surgery, radiotherapy, and chemotherapy—have evolved slowly, and few gains in therapeutic efficacy have occurred. Recently, however, continuing research efforts have led to novel treatment strategies that are changing the way clinicians view a disease that has traditionally been managed with almost universal therapeutic nihilism. This review explores our current knowledge of this disease and presents current and novel therapeutic strategies.

Section snippets

Epidemiology

Wagner et al4 initially reported 33 cases of mesothelioma in a South African asbestos mining community in 1960. Since then, data have been collected through various databases in the United States, Western Europe, some Eastern European countries, and the United Kingdom. Mesothelioma is usually diagnosed in the fifth to seventh decades of life, with a strong male predominance where occupational exposure to asbestos is involved.5 There are approximately 2,500 new cases of mesothelioma annually in

Pathogenesis and Biology

Exposure to asbestos, a family of naturally occurring silicate minerals, is the main risk factor for the development of MPM. The association between asbestos exposure and cancer was first established in a case-control study of lung cancer patients in 1955.8 Several varieties of asbestos fibers occur naturally; those that are narrow and needle-like (amphiboles such as crocidolite and amosite) appear to be more carcinogenic and mutagenic in animal models and tissue culture than those that are

Clinical Manifestations and Natural History

Dyspnea and nonpleuritic chest wall pains are the most common presenting complaints of patients with MPM.19 Examination may show signs of a unilateral pleural effusion with dullness to percussion and decreased air entry at one base, with a slight right-sided predominance. Patients may also be asymptomatic, with evidence of a pleural effusion noted only incidentally on physical examination or by chest radiography. A pleural mass is often present but may be obscured by pleural fluid on chest

Biopsy

Patients presenting with a clinical picture consistent with MPM require further investigation to establish a pathologic diagnosis and the stage of disease. Thoracentesis is often the initial diagnostic intervention. Cytologic diagnosis of MPM from pleural fluid is, however, unreliable since reactive mesothelial cells and cells from other malignant tumors such as sarcomas and adenocarcinomas are often very difficult to distinguish from malignant mesothelial cells.22 As a result, histologic

Palliative Care

Given that the prognosis for patients with mesothelioma has been historically poor regardless of the type of anticancer treatment, palliation of symptoms has been the primary goal of most therapy to date. Palliative therapy focuses on two major symptoms, dyspnea and chest wall pain. All previously described modalities may contribute to the palliation of patients with MPM. Radiation has shown palliative benefit in reducing pain and symptoms of dyspnea,40 surgical pleurodesis can reduce the

Novel Therapies

Several novel approaches to the treatment of MPM that incorporate new chemotherapeutic, biological, and targeted therapies are under development. Pemetrexed is a multitargeted antifolate that inhibits multiple enzymes important in folate metabolism, including thymidylate synthetase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase.8182 The key enzyme targets for pemetrexed are TS, DHFR, and

Conclusion

Despite a long history of therapeutic nihilism in the treatment of MPM, recent advances have renewed enthusiasm for aggressive management of the disease in all stages. The combination of pemetrexed with cisplatin, which demonstrated a positive benefit on multiple outcomes including survival, time-to-progressive disease, and quality of life, will likely become a major component of the standard of care for patients with advanced disease, and has provided renewed hope for the development of other

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  • Cited by (0)

    Dr. Pistolesi is a consultant of Eli Lilly and Company in the phase III study of pemetrexed in malignant pleural mesothelioma.

    Dr. Rusthoven is a consultant and former employee of Eli Lilly and Company.

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