© 2008 American Thoracic Society doi: 10.1164/rccm.200806-955ED
Screening for MesotheliomaMore Harm than Good?
University Hospital Malignant pleural mesothelioma (MPM) is a rare tumor with a generally poor prognosis, mainly associated with earlier occupational exposure to asbestos. In Western industrialized countries, approximately 85% of all cases have this causal link with a latency time from first exposure to a presentation of usually 3 to 5 decades. The epidemic of new cases of MPM is therefore still ongoing despite prohibitions against asbestos use in the 1980s and 1990s (1). The median age at diagnosis for MPM is in the sixth decade of life and overall survival after diagnosis averages less than 1 year. In recent years, an effect from chemotherapy has been repeatedly proven (2–4), and although, in many cases, an improvement of survival and quality of life has been observed, there is no cure. Radiotherapy has limited use; surgery has been used in early cases but not in any randomized study, and, in the vast majority of cases, recurrence is the rule. Hence, there is a high level of interest in early detection to improve outcome and reduce mortality. Parallel to the development of low-dose spiral computed tomography (CT) scan in the screening of lung cancer, investigators have looked at its role in the early detection of mesothelioma (5, 6). These efforts have been hindered by the low prevalence of the disease even in high-risk cohorts and the much higher prevalence of nonmalignant nodules detected by this sensitive, but not overly specific, technique. Soluble mesothelin–related protein (SMRP) is a split product of the cell membrane–bound antigen mesothelin, involved in intercellular contact, and abundant on serosal cells of the pleura and peritoneum. An ELISA using monoclonal antibodies against SMRP epitopes has been developed, validated, and registered with the Food and Drug Administration for the measurement of circulating levels of SMRP. Robinson and colleagues published a retrospective series on the use of this ELISA among patients exposed to crocidolite asbestos from the Wittenoom mine in West Australia (7). They found a specificity of 100% and a sensitivity of 84% for SMRP in diagnosing mesothelioma. Several other retrospective series have since confirmed this diagnostic accuracy and suggested a possible role in monitoring disease response and relapse (8–10). The still-controversial use of prostate-specific antigen for the screening of prostate cancer has spurred the interest of this and other blood-derived biomarkers for the early diagnosis of cancer in various populations at risk. In the present issue of the Journal (pp. 832–837) Park and colleagues report the results of the value of the SMRP-ELISA in a prospective cohort of individuals occupationally exposed to asbestos (11). Their investigation included 538 asbestos-exposed persons. A mesothelioma was not observed in any of these subjects, although 15 (almost 3%) had elevated SMRP levels. These patients were investigated with positron emission tomography (PET)–CT, resulting in the detection of one lung cancer and one suspected cardiac tumor. The specificity of the test is thus low, with a large number of false positives. The results of this study basically confirm earlier impressions, namely, that screening for mesothelioma is not a worthwhile effort. This article raises the important issue of screening for cancer in asbestos-exposed individuals. For screening to be meaningful, it should discover a disease with a high enough prevalence while still curable. Furthermore, the method should have high specificity and sensitivity and should be easy to perform while not being too expensive. Although the SMRP-ELISA fulfills the last two criteria, its high false-positive rate will necessitate further investigations. According to Robinson's early data, SMRP could be elevated a number of years before a mesothelioma is clinically diagnosed (7). The problem with PET is that a tumor must reach a certain size before it can be visible; the problem with CT is similar, with the very early changes being both difficult to see and nonspecific amid other asbestos-related pleural lesions. The consequence of a high SMRP level could therefore be that a large number of patients would need to be followed, with expensive and possibly harmful investigations for many years. Finally, there is no proof that early discovery of a MPM will cure the patient or even improve his or her survival. Combination treatment with chemotherapy, followed by "radical surgery" (pleuropneumonectomy) and high-dose radiation therapy, is being investigated in many centers, and long-term survival has been reported for a subset of selected patients. However, only patients with good performance status, with early-stage disease, and with the best prognostic epithelial subtype are likely to benefit from this procedure. The same patients have a more favorable outcome with chemotherapy alone and up to 5% of these patients will be alive 5 years after diagnosis without any cancer-directed treatment. In addition, a combination treatment of chemotherapy, surgery, and radiation therapy considerably lowers the quality of life for many months. We need randomized studies examining the treatment effects of surgery and/or radiotherapy in addition to chemotherapy compared with chemotherapy alone. Such a study is currently ongoing in the United Kingdom (12). The measurement of SMRP levels probably has a role in monitoring patients with MPM, with an increase heralding recurrence, although more data are necessary before such a conclusion can be drawn. For screening, the SMRP-ELISA should be avoided pending the results of ongoing large prospective studies that not only examine its diagnostic accuracy but also the relationship between SMRP levels and survival-specific and disease-specific mortality. FOOTNOTES Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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