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FILE NAME Household Contact HC DATE 1993 Apr DOC HC019 DOCUMENT DESCRIPTION Journal Article - Natural History and Epidemiology of Malignant Mesothelioma  ^' t ^' ^' Natural Natural History and Epidemiology of Malignant Mesothelioma Karen H. Antman M.D. Asbestos exposure constitutes the primary pleouf prleaurlal and peritoneal mesothelioma in humans Risk relates to the duration and intensity of exposure Thus those exposed at younger ages are at higher lifetime risk Families of asbestos workers exposed to asbestos on hair and clothing as well as to asbestos items brought home from the workplace are also at risk as are employees working in the same vicinity as asbestos workers The public health significance of exposure from asbestos in public and private buildings , to diagnose and carries a poor prognosis Chemotherapy with single or multiple agents has thus far been disappoint- ing but or doxorubicin and cisplatin mitomycin and cisplatin are probably most active with response rates in measurable disease of 25 Palliative radiotherapy is also problematic since differences between tumor cytotoxicity and pulmo- nary tolerance are small and radiation pneumonitis may Chest 1993 3735-765 ASBESTOS AN OVERVIEW link between asbestos and asbestosis lung although ThTehe link asbestos asbestos asbestos well established although questions remain about the duration and intensity of exposure needed to initiate carcinogenesis Millions of Americans have been occupationally exposed to asbestos Although some uses of asbestos have been curtailed because of the characteristics that make it attractive industrially and its relatively low cost asbestos is still used widely Given the wide occupational exposure and the fact that until 1972 asbestos was sprayed in schools and other public buildings physicians should be aware of potential public health impli cations This article will briefly review asbestos use mineralogy and mechanisms of carcinogenicity and review the diagnosis and management of malignant mesothelioma Asbestos is the commercial name for a hydrated magnesium silicate fiber comprising 2 types the serpentine and the amphiboles The serpentine chrysotile fibers are curly and pliable whereas the amphiboles crocidolite amosite anthophyllite tremolite and actinolite are needle Asbestos Use Prized industrially for its resistance to heat and combustion asbestos was used abundantly in ships and other combat material during World War II When the war ended industrial and consumer use increased for insulation Asbestos was also sprayed on the interior structural surfaces of many public and private buildings between 1946 and 1972 including as many as 10 to 15 of the nation's schools The public health significance of this exposure as well as the cost From the Department of Medicine Farber Cancer Institute Harvard Medical School Boston effectiveness of asbestos removal are controversial." Asbestos continues to be used extensively in cement in ceiling and floor tiles and in automobile but not airplane brake linings Currently Canadian chrysotile accounts for about 90 of the asbestos used in the United States More carcinogenic types of asbestos continue to be used however Amosite for example is used in ships because it resists salt water and some fillers contain anthophyllite Carcinogenicity One of the most inert compounds known asbestos appears to provoke carcinogenesis through its physical rather than its chemical composition A 10 length fiber ratio is associated with carcinogenesis additionally the fibers musbte fairly fine Indeed fiberglass and other ^...bersmilled to this standard are also carcinogenic in laboratory animals although the fiberglass is commonly used in homes. Amphiboles are about 10 times as carcinogenic as chrys- otile The fibers with the highest carcinogenic potential are mined in South Africa and other countries whereas most chrysotile is mined in Canada Crocidolite has been associated with a high risk of malignant mesothelioma whereas amosite appears to carry an intermediate risk Chrysotile shows the weakest association with malignant mesothelioma Nonetheless chrysotile has been shown to cause mesothelioma in laboratory animals Whether human cases ofmalignant mesothelioma linked to past chrysotile exposure were caused by the serpentine fiber itself or by amphibole contamination"remains controversial since such contami- nation is common Mechanisms of Carcinogenesis Fibers enter the distal airway About two thirds of the daily dose is eliminated by coughing and swallowing which may be the mechanism for the development of peritoneal mesotheliomas As macrophages try to engulf the fibers remaining in the lung free radicals and lysosomal enzymes are liberated which probably accounts for the fibrosis that develops Regulatory Limits As the scope of asbestos effects on health became apparent attempts to limit permissible exposures grew By 1970 the Occupational Safety and Health Administration had established 5 fibers per cubic milliliter of air as the standard acceptable exposure which legally exposed asbestos workers to up to 4 million fibers a day By 1976 the standard had been reduced to 2 fibers and is currently 0.2 Gibers per cubic milliliter of air Above these limits respira- tors protective clothing and shower and changing facilities become mandatory Only exposures to fibers longer than 5 mare regulated currently however Present data do not allow conclusions regarding whether there is a safe threshold CHEST / 103 4 / APRIL 1993 / Supplement 3735 1111 ony . !!!! !!!! : , level for asbestos exposure ASBESTOS Cancer Risk Asbestos workers are currently at substantiallyhigher risk for cancer than they are for pulmonary disease About % of asbestos workers will die of asbestosis While the average American has about an 18 chance of developing and dying of any malignancy for an asbestos worker this risk is close the tumors the to 50 with most of involving lung Currently of an estimated % all cancers are asbestos most of which are primariyn the lung The incidence of lung cancer in the United States in nonsmoking non individuals is about one per million man years and the expected inciofdlue ng cn ancc ere in the population at large is about % In a cohort of asbeswotrokesrs howevethre risk of lung cancer increases to approximately 10.12 Asbestos which is directly cytotoxic efficiently adsorbs hydrocarbons which probably accounts for the higher risk of lung cancer in persons who have histories of asbestos exposure and cigarette smoking Interestingly there is no association between cigarette smoking and malignant mes- othelioma and they may even be negatively correlated most likely reflects earlier development of and death lung cancer in smokers removing them from the risk for mesothelioma As noted the risk of lung cancer in the nonsmoking general population with no asbestos is small This risk increases about fold in nonsmokers have been exposed to asbestos still a fairly small risk However conservative estimates of the lung cancer risk in almost fold smokers with a history of asbestos exposure suggest that their risk for lung cancer increases Table " The incidence of gastrointestinal malignancy is also whether asbestos is causally rheilgahteerd in asbestos workers but to these tumors is controversial Anecdotal reports also detail head and neck tumors and B cell malignancies such as myeloma and lymphoma Malignant MESOTHELIOMA Not until 1960 with the publication of a series of patients with mesothelioma by an astute internist in South Africa was the existence of malignant mesothelioma as a discrent clinical entity and its relation to asbestos exposure both occupational and bystander risk established The annual incidence of malignant mesothelioma in the United States is not known with certainty because cancer mortality in the United States is reported by site of the primary lesion not the morphology The incidence is estimated to be approxi- mately 2,200 cases per year or about 12.1 cases per million white men but in asbestos workers this risk rises to % to % The incidence appears to be increasing probably reflecting the long latency period from asbestos exposure to clinical disease and the high numbers of workers exposed to Table Standardized Death Rates per 10"Man Years Showing Synergism Between Asbestos Exposure and Smoking for Lung Cancer No Asbestos Asbestos 1 08 Nonsmoker 11 08 Smoker Data adapted from Hammond et al 3745 asbestos in the decades following World War II Risk of developing malignant mesothelioma varies de- pending on the duration and degree of exposure Because so many people have been exposed to asbestos the mathe , matic risk of developing malignant mesothelioma can actu- ally be calculated and equals a constant which comprises the intensity and duration of the exposure multiplied by the time since the first exposure to the fouorrfoturh th power Thus someone exposed at age 20 years has no higher risk per year for any given exposure but accumulates a higher lifetime risk than someone who is exposed to asbestos at age 50. In fact given the latency period which is 20 to more than 40 years moderate asbestos exposure would probably carry few medical consequences for asbestos workers 55 years or older Asbestos workers with heavy exposure have brief periods a higher risk of developing peritoneal mesothelioma whereas those exposed for relatively are at higher developing pleural primaries >. =~ developing Risks to Workers Families OT approximately of The families asbestos workers have an % risk of malignant mesothelioma In most cases this risk arises because of asbestos contamination of work clothes or less frequently manufactured articles eg textiles workers have brought home Projections based on the average family size in 1950 suggest that about up to one third of cases of malignant mesotheliomas may develop in family members of asbestos workers " Diagnosis and Management of Malignant Mesothelioma Patient History A comprehensive history for patients suspected of having malignant mesothelioma must focus on period of 20 to 40 years before and should include the a occupations offamily members living with the patient during this interval Even the most comprehensive history may fail to establish asbestos exposure in about 30 of cases For with example a cluster of cases of malignant mesothelioma no stated history of asbestos exposure was explained when 2 patients being treated at the Farber Cancer Institute realized they knew eachother Both had worked at a factory manufacturing asbestos paper filters for cigarettes When epidemiologists traced the histories of the approximately 50 people who had worked in that plant they found that most had already died of malignancies either lung cancers or mesotheliomas** Most Malignant mesothelioma is difficult to diagnose patients come to medical attention when they devewliolpl dyspnea chest pain or both symptoms Examination usually reveal a large unilateral effusion only about % of patients have bilateral disease at diagnosis Ray Findings Only about 20 of patients with pleural mesothelioma demonstrate characteristic signs of asbesto- low diaphragm interstitial fibrosis or even pleural plaques on chest films Since the development of both malignant peritoneal mesothelioma and asbestosis requires about 50 of patients with longer asbestos exposures evidence primary peritoneal tumors will demonstrate ray of asbestosis and pleural calcifications Other than being markers for prior asbestos exposure the calcifications are of no medical significance Patients with stage disease often develop a character- Natural History and Epidemiology of Malignant Mesothelioma Karen H. Antman or Estic scoliosis toward the side of the lesion as the lung is encompassed by tumor and cannot be fully expanded pulling the mediastinum to the ipsilateral side Other primary tumors almost always displace the mediastinum to the contralateral side with increased tumor volume Computed tomography is helpful in determining disease extent and in about 50 of patients will also reveal pleural calcifications not large enough to be visible on the chest x- ray Pathologic Verification Malignant mesothelioma remains a diagnostic challenge An adequate biopsy specimen must be obtained When pleural mesothelioma is suspected part of the sample should be placed in glutaraldehyde preserva- tive Pathologists may have difficulty differentiating mesothelioma from adenocarcinoma With a PAS periodic acid- Schiff stain both histologies stain pink However the distinction can be made after diastase digestion Adenocar- cinomas remain positive but mesotheliomas become negative By electron microscopy mesotheliomas characteristi- cally have lush microvilli that are helpful in diagnosis Prognostic Variables and Causes of Mortality Because malignant pleural mesothelioma is generally locally invasive eztensive work of other sites is usually unnecessary Fever of unknown origin and clotting abnormalities including an elevated platelet count are common and indicate a poor prognosis Patients generally die of local extension and respiratory failure Occasionally tumor extension below the diaphragm may result in death from sinall bowel obstruction In a series of patients at Farber about 10 had tumor invasion of the pericardium or cardium and died of arrhythmias or heart failure while % died of stroke Two early series of 69 patients from Mount Sinai and 40 patients from Farber suggested that women survived longer than men but a larger series of 180 patients at DanaFarber was unable to confirm this finding Similarly the Mount Sinai series identified stage I disease as an inde- pendent independent variable but the Farber series could not confirm this The presence of symptoms for more than 6 months before diagnosis indolent disease suggests slower disease progression Epithelial histology has been an independent variable in both series as have younger age and better performance status In the Farber experience recent patients with malignant peritoneal mesothelioma have had a better prognosis than those with pleural primaries which probably reflects the technical ease of administering intraperitoneal chemotherapy as well as the fact that multiple resections of a peritoneal mass are possible Four of a cohort of six carefully selected patients with malignant peritoneal mesothelioma treated in a phase I Farber trial 10 years ago are currently disease About one third of the 25 patients treated in a subsequent phase II series are disease at from 2 to 3 years Pleuropneumonectomy and chemotherapy were independent predictors of longer survival in both senes The response rate to single chemotherapy is gen- erally % to 20 with the highest single agent response rate for doxorubicin Mitomycin and cisplatin may be active in combination Only a few randomized trials have been conducted The Eastern Cooperative Oncology Croup assessed radiotherapy with or without doxorubicin but results have not yet been published When the Southwest Oncology Group tested doxorubicin and cyclophosphamide with or with dacarba- zine no benefit was found for the addition of dacarbazine The Cancer and Leukemia Group B assessed cisplatin combined with either doxorubicin or mitomycin but no difference was evident in the response rates 25 of patients with measurable disease However patients treated with cisplatin and doxorubicin lived somewhat longer Palliative radiotherapy with attempted delivery to the whole pleural surface is technically daunting and associated with a significant incidence of radiation pneumonitis Symp- tomatic improvement is documented in only a minority of patients Because surgery or radiotherapy alone have resulted in only a few anecdotal term survivors among mesothelioma patients intensive combined approaches have been studied at a few institutions Updated results will be covered in other papers in this issue Thus the etiology and natural history of malignant pleural mesothelioma has been well documented in the past 2 decades and initial trials are under way with some encour- aging preliminary data in selected subsets of patients References 1 Craighead JE Mossman BT The of asbestos- associated disease N EnglJ Med 1982 1446-55 2 Mossman BT B^>gnonJ Corn M et al Asbestos scientific developments and implications for public policy Science 1990 294-301 3 Stanton MF Layard M Tegeris A et al Carcanogenicity of fibrous glass pleural response in relation to fiber dimension ~fi Nati Cancer Inst 1977 589-603 Mesotheliomas 4 Wagner JC Berry G Polley FD and asbestos type in asbestos textile workers a study of lung contents BMJ 1982 603-06 Barras CE 5 Lee KP Griffith FD et al Pulmonary response and transmigration of inorganic fibers by inhalation exposure Am } Pathol 1981 314-23 6 Wagner JC Experimental production of mesothelial tumours of the pleura by implantation of dusts in laboratory animals Nature 1962 196 7 Rogers AJ Leigh J Berry G et al Relationship between lung asbestos fiber type and concentration and relative risk of mesothelioma a control study Cancer 1991 1912-20 8 Gibbs AR Griffiths DM Pooley FD et al Comparison of fibre tissues types and size distributions in lung of paraoccupational and occupational cases of malignant mesothelioma Br J Ind . Med 1990 621-26 9 McDonald JC Armstrong B. Case B et al Mesothelloma and asbestos fiber type evidence from lung tissue analyses Cancer 1989 1544-47 10 Selikoff ] Churg J. Hammond EC Asbestos exposure and neoplasia JAMA 1964 22-6 11 Seliko~ IJ Hammond EC Seidman H. Mortality experience of insulation workers in the United States and Canada 1943-76 Ann NY Acad Sci 1979 195-203 12 Hammond EC Selikoff IJ Seidman H. Asbestos exposure cigarette smoking and death rates Ann NY Acad Sci 1979 473-90 13 Wagner JC Sleggs EA Marchand P. Diffuse pleural mesothelioma and asbestos in the North Western Cape Province Br J Ind Med 1960 260 71 14 McDonald AD McDonald JC Epidemiology of malignant mesothelioma n Antman K Aisner J. eds Asbestos CHEST/ 103 4 APRIL 1995 / Supplement 375 1 alis _| sonnntg woe mete | a malignancy Orlando Fla Grune & Stratton 1987 31-55 15 Connelly RR Spirtas R. Myers MH et al Demographic patterns for mesothelioma in the United States J Natl CanceT Inst 1987 1053 60 .- 16 Talcott JA Thurber WA Kantor A et al associated diseases in a cohort of cigarette workers N Engl J Med 1989 1290-23 17 o Antman KH Clinical presentation and natural history of benign and malignant mesothelioma Semin Oncol 1981 313 20 18 Chahinian AP PajaTk Holland J et al Diffuse malignant mesothelioma prospective evaluation of 69 patients Ana Intern Med 1982 746 55 19 Antman K Shemin R Ryan L et al Malignant mesothelioma prognostic variables in a registry of 180 patients the Dana- Farber Cancer Instituatned Brigham and Women's Hospital experience over two decades 1965-1985 J Clin Oncol 1988 147-53 20 Antman K. Osteen R Klegar K et al Early peritonmeeasol- thelioma a treatable malignancy Lancet 1985 977-82 21 Weissmann L. Osteen R Corson J et al Combined modality therapy for intraperitoneal mesothelioma abstract Proc Am Soc Clin Oncol 1988 274 22 McCormack P Nagasaki F Hilaris BS et al Surgical treatment of pleuralmesothJ Tehol raciCao rdimovaasc Surg 1982 834- 42 23 Taylor RA Johnson LP Mesothelioma current perspectives We ] Ms ed 1t 981 379 83 oo, 4 ee| oa Natural History and Epidemiology of Malignant Mesothelioma X^,renH. Antman