Cancer lung mesothelioma cure

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 [alpha], 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.

Key words: chemotherapy; epidemiology; gemcitabine; mesothelioma; pathogenesis; pemetrexed; treatment

Abbreviations: CALGB = Cancer and Leukemia Group B; COX-2 = cyclooxygenase-2; DHFR = dihydrofolate reductase; EORTC = European Organization for Research and Treatment of Cancer; EPP = extrapleural pneumonectomy; GARFT = glycinamide ribonucleotide formyltransferase; IMIG = International Mesothelioma Interest Group; MPM = malignant pleural mesothelioma; P/D = pleurectomy/decortication; SV = simian virus; TS = thymidylate Synthetase; VEGF = vascular endothelial growth factor.

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There has been no consensus in the literature guiding the appropriate management of patients with malignant pleural mesothelioma (MPM). This has been due primarily to a lack of convincing data identifying any single treatment modality or combination that might offer a clinically meaningful and significant improvement in survival or quality of life over best supportive care. (1,2) While many believe that radical surgical resection may offer the only chance of cure or meaningful improvement in survival, the majority of patients presenting with MPM are not candidates for radical surgical resection due to unresectable, locally advanced disease or comorbid medical illness. This intervention, even when applied to highly selected patient populations, is associated with a relatively high risk of severe morbidity and mortality and has not yet been clearly proven to have a significant beneficial impact on survival. (3) Many chemotherapeutic agents have been studied in patients with MPM, either as single agents or as part of a combination chemotherapy regimen. Response rates have ranged from 0 to 48%, with the highest response rates generally achieved using multiagent regimens. However, no dear standard of care using available agents has emerged due to a lack of clearly demonstrated survival or palliative benefit in the setting of well-designed, randomized, and controlled clinical trials. This article will review the epidemiology and biology of this disease as well as the evidence for benefit of various current and investigational treatments for MPM.

EPIDEMIOLOGY

Wagner et al (4) 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 eases of mesothelioma annually in the United States, of which 2,000 are in men and 500 are in women. (5,6) The incidence in the United States appears to be rising, mainly in men aged [greater than or equal to] 75 years, with the maximum lifetime risk in the from 1925 to 1929 birth cohort of men. (5) The incidence in women and in men < 75 years of age appears to have been stable since 1983. (5) This coincides with restrictions and regulations of the US Occupational Safety and Health Administration and the Environmental Protection Agency, enacted in the 1970s, regarding uses and permissible exposure limits for asbestos in the workplace. (5) The incidence of mesothelioma is also rising in Europe, from 5,000 men dying in 1998 to a projected 9,000 men dying by 2018, with the highest incidence in the from i945 to 1950 birth cohort of men. (7)

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 curled and more pliable (chrysotile). In addition, asbestos fibers are commonly seen in excised surgical specimens from patients with MPM. Similar to coal dust in coal miners, asbestos fibers are trapped in distal parts of the lung and concentrate to form black spots in the parietal pleura, the main anatomic site of mesothelioma in the chest. (9) The latency period between initial exposure and death has been reported up to 72 years (mean, 48.7 years; range, 14 to 72 years), with wide variability linked to the type of fibers and intensity of exposure. (10)

Although approximately 80% of patients with MPM have a history of asbestos exposure, only approximately 10% of those with asbestos exposure acquire mesothelioma, (11,12) suggesting that other factors may be important either independently or as cofactors in the development of this malignancy. Human mesothelioma cells are highly susceptible to infection by simian virus (SV)-40 in vitro and in animal models and often express virus sequences. (13-14) Furthermore, studies have demonstrated that SV-40 is a poor prognostic factor in MPM. (15) Some research has shown that asbestos and SV-40 can function as co-carcinogens, since the presence of asbestos fibers leads to an increase in the number of transformation loci that develop with SV-40 in tissue culture.

Chromosomal abnormalities such as deletions of chromosome regions 1p, 3p, 9p, and 6q, as well as loss of chromosome 22, are commonly found in MPM. These recurrent genomic losses are consistent with the loss of both defined and putative tumor suppressor genes important in the development of MPM, including the CDKN2A locus in chromosomal location 9p21 containing p16 and [p14.sup.ARF], and neurofibromatosis 2 in chromosome 22. (16,17)

Genetic susceptibility may also contribute to the etiology of malignant mesothelioma. Two small villages in file central Anatolia region of Turkey share a rare environmental pathogen for malignant mesothelioma (erionite exposure). While 50% of the men in one village died of malignant mesothelioma, only one case of malignant mesothelioma was reported in the other village, and that ease occurred in a woman who was originally from the former village.)s Six families have been identified with an obvious familial clustering of malignant mesothelioma, and these could be linked to one large six-generation pedigree, suggesting a founder effect and an autosomal dominant pattern of inheritance with incomplete penetrance.

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 radiography. Metastatic disease is uncommon at presentation, and contralateral pleural abnormalities are often due to asbestos-related pleural disease rather than metastatic disease.