Serum Osteopontin Levels — Is It Time to Screen Asbestos-Exposed Workers for Pleural Mesothelioma?
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《新英格兰医药杂志》
In this issue of the Journal, Pass et al.1 remind us yet again that the fallout from the once uncontrolled use of asbestos will remain with us for years to come. Thankfully, primary prevention of mesothelioma and the far more prevalent consequence of exposure to asbestos — carcinoma of the lung — has been aggressively pursued to varying degrees in all developed countries: most potential sources of human exposure have now been removed or encapsulated, and the introduction of additional asbestos severely curtailed or banned outright. Unfortunately, among the millions exposed occupationally in the past who remain at high risk and the millions of those with less exposure who remain at finite but smaller risk, mesothelioma — with its decades-long latency — still looms as a dread possibility. Between 2500 and 3000 cases occur annually in the United States, most associated with exposure to asbestos, although the epidemic appears to have crested,2 probably as the result of regulation and responses to rampant litigation.
Success in the primary prevention of pleural mesothelioma has sadly not been paralleled by success in identifying even a single viable strategy for secondary prevention or any substantial progress in treatment; the mean survival after diagnosis remains 6 to 10 months.3,4 Even differential diagnosis remains problematic: for at-risk patients who present with pleural masses, chest-wall pain, effusions, or tracheal deviation, there is currently no well-validated blood test for malignant mesothelioma, and the diagnostic reliability of pleural fluid analysis involving cytologic evaluation, cell counts, various special stains, and measurement of hyaluronic acid content, as well as other tests touted in the past, is erratic.5 Irrespective of the potential for aggressive treatment of the disease, most patients ultimately require some type of biopsy — thoracoscopic, closed-needle, or open — for diagnosis, and there is anecdotal evidence that this approach may complicate subsequent management by seeding tumor cells.
In the light of these issues, the report by Pass et al. regarding the use of serum osteopontin levels as an index of the risk of disease offers some basis for optimism. As this group demonstrates,1 the blood test appears to be reliable and straightforward, and depending on the cutoff value chosen, the sensitivity and specificity of this approach allow mesothelioma to be identified among workers with similar degrees of exposure to asbestos, many of whom have asbestosis, benign pleural lesions, or both. Overall, results are better than or rival those of any other available test, of which several have now been described.6,7 The practical value of this approach as a diagnostic test overall, however, must await the assessment of serum osteopontin levels in other disorders common after extensive exposure to asbestos, such as diffuse pleural thickening with or without benign effusion, advanced carcinoma of the lung with pleural involvement, and rounded atelectasis, from which mesothelioma must commonly be differentiated.
Any recommendation regarding the measurement of serum osteopontin as a screening test for workers exposed to asbestos will require further study and more data. For one thing, the risk among most patients with limited disease in the thorax is far lower than the lifetime risk of 5 to 10 percent quoted by Pass et al. or the risk among crocidolite (blue asbestos) miners in Australia and South Africa and, in earlier studies, among asbestos insulators exposed to amphibole fibers — crocidolite and amosite (brown asbestos) — in the 1940s and 1950s. Amphibole asbestos is now recognized to confer a higher risk of mesothelioma, dose for dose, than the more commonly used chrysotile (white asbestos), although the latter is no less potent at causing lung cancer.8 For example, in the cohort of 4060 heavily exposed men recruited for the Beta-Carotene and Retinol Efficacy Trial, a group of older men with exposure histories that sound quite similar to those of the exposed control subjects studied by Pass et al., the cumulative risk during 12 to 19 years of prospective follow-up was 0.9 percent (38 cases as of December 31, 2004), as opposed to the 6.9 percent rate of incident lung cancers (282 cases) (Goodman G: unpublished data). In those with briefer or less intense contact with asbestos or those exposed after the imposition of modern controls, the risks will surely be lower, but even at a rate of 1 percent, on the basis of the data presented, the predictive value of the osteopontin level would be very low, leading at a minimum to needless testing and worry in far more people than would potentially benefit from early detection of disease.
What we would need to know before embarking on any form of population screening for mesothelioma is whether early detection would, in fact, change the outcome. Although there are data to support the view that surgery or combined treatment lengthens survival among those with limited disease in the thorax — to as long as 34 months in one series,9 as compared with 10 months among patients with more extensive disease — the difference could well be accounted for by the lead time afforded by early diagnosis, leaving the actual date of death unchanged. Alternatively, tumors that are currently identified at earlier stages may be, on average, more indolent, and hence destined to have a better response to treatment at whatever stage. Pending more encouraging news, the prospects for successful early intervention for mesothelioma in this population as a result of an efficient, noninvasive diagnostic strategy appear far worse than those for lung cancer, for which there is new hope, and other, more treatable cancers associated with exposure to asbestos, such as colorectal cancer. Given current knowledge, these more prevalent end points should remain the focus of active surveillance among people with an extensive history of exposure to asbestos. That said, the findings of Pass et al. do offer at least a faint glimmer of hope that the fate of future patients with mesothelioma will be better than that of their predecessors.
Dr. Cullen reports that he is medical director of Alcoa.
Source Information
From the Yale University School of Medicine, New Haven, Conn.
References
Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 2005;353:1564-1573.
Weill H, Hughes JM, Churg AM. Changing trends in US mesothelioma incidence. Occup Environ Med 2004;61:438-441.
Steele JP. Prognostic factors in mesothelioma. Semin Oncol 2002;29:36-40.
Ceresoli GL, Locati LD, Ferreri AJ, et al. Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma. Lung Cancer 2001;34:279-287.
Hughes RS. Malignant pleural mesothelioma. Am J Med Sci 2005;329:29-44.
Marukawa M, Hiyama J, Shiota Y, et al. The usefulness of CYFRA 21-1 in diagnosing and monitoring malignant pleural mesothelioma. Acta Med Okayama 1998;52:119-123.
Robinson BW, Creaney J, Lake R. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003;362:1612-1616.
Cullen MR. Chrysotile asbestos: enough is enough. Lancet 1998;351:1377-1378.
Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122:788-795.(Mark R. Cullen, M.D.)
Success in the primary prevention of pleural mesothelioma has sadly not been paralleled by success in identifying even a single viable strategy for secondary prevention or any substantial progress in treatment; the mean survival after diagnosis remains 6 to 10 months.3,4 Even differential diagnosis remains problematic: for at-risk patients who present with pleural masses, chest-wall pain, effusions, or tracheal deviation, there is currently no well-validated blood test for malignant mesothelioma, and the diagnostic reliability of pleural fluid analysis involving cytologic evaluation, cell counts, various special stains, and measurement of hyaluronic acid content, as well as other tests touted in the past, is erratic.5 Irrespective of the potential for aggressive treatment of the disease, most patients ultimately require some type of biopsy — thoracoscopic, closed-needle, or open — for diagnosis, and there is anecdotal evidence that this approach may complicate subsequent management by seeding tumor cells.
In the light of these issues, the report by Pass et al. regarding the use of serum osteopontin levels as an index of the risk of disease offers some basis for optimism. As this group demonstrates,1 the blood test appears to be reliable and straightforward, and depending on the cutoff value chosen, the sensitivity and specificity of this approach allow mesothelioma to be identified among workers with similar degrees of exposure to asbestos, many of whom have asbestosis, benign pleural lesions, or both. Overall, results are better than or rival those of any other available test, of which several have now been described.6,7 The practical value of this approach as a diagnostic test overall, however, must await the assessment of serum osteopontin levels in other disorders common after extensive exposure to asbestos, such as diffuse pleural thickening with or without benign effusion, advanced carcinoma of the lung with pleural involvement, and rounded atelectasis, from which mesothelioma must commonly be differentiated.
Any recommendation regarding the measurement of serum osteopontin as a screening test for workers exposed to asbestos will require further study and more data. For one thing, the risk among most patients with limited disease in the thorax is far lower than the lifetime risk of 5 to 10 percent quoted by Pass et al. or the risk among crocidolite (blue asbestos) miners in Australia and South Africa and, in earlier studies, among asbestos insulators exposed to amphibole fibers — crocidolite and amosite (brown asbestos) — in the 1940s and 1950s. Amphibole asbestos is now recognized to confer a higher risk of mesothelioma, dose for dose, than the more commonly used chrysotile (white asbestos), although the latter is no less potent at causing lung cancer.8 For example, in the cohort of 4060 heavily exposed men recruited for the Beta-Carotene and Retinol Efficacy Trial, a group of older men with exposure histories that sound quite similar to those of the exposed control subjects studied by Pass et al., the cumulative risk during 12 to 19 years of prospective follow-up was 0.9 percent (38 cases as of December 31, 2004), as opposed to the 6.9 percent rate of incident lung cancers (282 cases) (Goodman G: unpublished data). In those with briefer or less intense contact with asbestos or those exposed after the imposition of modern controls, the risks will surely be lower, but even at a rate of 1 percent, on the basis of the data presented, the predictive value of the osteopontin level would be very low, leading at a minimum to needless testing and worry in far more people than would potentially benefit from early detection of disease.
What we would need to know before embarking on any form of population screening for mesothelioma is whether early detection would, in fact, change the outcome. Although there are data to support the view that surgery or combined treatment lengthens survival among those with limited disease in the thorax — to as long as 34 months in one series,9 as compared with 10 months among patients with more extensive disease — the difference could well be accounted for by the lead time afforded by early diagnosis, leaving the actual date of death unchanged. Alternatively, tumors that are currently identified at earlier stages may be, on average, more indolent, and hence destined to have a better response to treatment at whatever stage. Pending more encouraging news, the prospects for successful early intervention for mesothelioma in this population as a result of an efficient, noninvasive diagnostic strategy appear far worse than those for lung cancer, for which there is new hope, and other, more treatable cancers associated with exposure to asbestos, such as colorectal cancer. Given current knowledge, these more prevalent end points should remain the focus of active surveillance among people with an extensive history of exposure to asbestos. That said, the findings of Pass et al. do offer at least a faint glimmer of hope that the fate of future patients with mesothelioma will be better than that of their predecessors.
Dr. Cullen reports that he is medical director of Alcoa.
Source Information
From the Yale University School of Medicine, New Haven, Conn.
References
Pass HI, Lott D, Lonardo F, et al. Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 2005;353:1564-1573.
Weill H, Hughes JM, Churg AM. Changing trends in US mesothelioma incidence. Occup Environ Med 2004;61:438-441.
Steele JP. Prognostic factors in mesothelioma. Semin Oncol 2002;29:36-40.
Ceresoli GL, Locati LD, Ferreri AJ, et al. Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma. Lung Cancer 2001;34:279-287.
Hughes RS. Malignant pleural mesothelioma. Am J Med Sci 2005;329:29-44.
Marukawa M, Hiyama J, Shiota Y, et al. The usefulness of CYFRA 21-1 in diagnosing and monitoring malignant pleural mesothelioma. Acta Med Okayama 1998;52:119-123.
Robinson BW, Creaney J, Lake R. Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 2003;362:1612-1616.
Cullen MR. Chrysotile asbestos: enough is enough. Lancet 1998;351:1377-1378.
Rusch VW, Rosenzweig K, Venkatraman E, et al. A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001;122:788-795.(Mark R. Cullen, M.D.)