Document jmXne8m9dwOkGMppx42gv4KG2

x induced cures in patients with limited stage disease p0). For patients with disseminated diffuse histiocytic lymhorn;\. several drug combinations are available that as;lgh response rates. Table 1 of the paper by Lau- rence 2nd associates in this issue ( 11) summarizes results ,fcombination chemotherapy protocols in previously un- treated patients with advanced diffuse histiocytic lymphoma. Since 1969 the frequency of complete remission has Increased from 40% to over 70% using various ,gents in combination chemotherapy protocols. Not only are 60% to 80% of patients achieving complete remisdons, but 60% to 80% of those achieving complete remissions are disease-free for longer than 2 years (median sumivd) without maintenance therapy. Also, these newer dr,ii;s and new drug combinations have substantially rduL.-d the incidence of central nervous system involve- ment seen in-patients at high risk for such complications. With the cure of diffuse histiocytic lymphoma becom- ing a reality in many patients, we must begin to address five residual issues. First, diffuse histiocytic lymphoma is a heterogeneous group of disorders as shown by Lukes and Collins (12) and others, and recognized in the re- cently proposed "Working Formulation for Clinical Us- age" ( 13). Which histologic or immunologic subsets predict success or failure in response to current therapy programs (14-17)?Second, what are other characteristics of patier :s who do not respond to the current treatment progrzms? An analysis of this issue will require the iden- tification of risk factors such as age, sex, location of primary lesion, bulky disease, stage IV, systemic symptoms, previous therapy, biochemical markers, and other factors (16, 18). Third, when should additional central nervous system prophylaxis be offered separately from the systemic treatment program? Fourth, is there any role for maintenance chemotherapy when a pathologically proven complete remission has been induced? And fifth, what new treatment strategies can be devised for persons with pathclogic, immunologic, and clinical risk factors that predici the failure of current treatment programs to induce complete remission? Currently, 80% to 100% of patients with limited diffuse histiocytic lymphoma can be offered cure (with 5and 10-year actuarial disease-free survival rates established in a number of series) using radiotherapy, chemotherapy, or a combination of the two therapies. The actuanal 2- and 5-year survival rate of over 60% of patients with disseminated diffuse histiocytic lymphoma is within reach. The challenge is to identify, early in the course of their disease, those patients who will fail current initial 1nduc::on regimens and to devise treatment strategies and alternate programs to assure that these patients also will be cured. (JOHN E. ULTMANNM, .D.; Department of Medicine and Cancer Research Center, University of chicago; Chicago, IIIinois) Grant support: in part by grant CA-14599. US.Publrc Health Service, the Joanne Heppes Fund, the Goldblatt Brothers Employees Nathan Goldblatt Cancer Research Fund, and the Jean Heimdn Fund. ~EFERENCES I DEVITAVT. JR. The consequences of the chemotherapy of Hodgkin's Disease the 10th David A. Kamofsky Memonal Lecture. Cancer. * 19Fi 47:l-13. CAVTOR KP, FRAUMEJNF.IDtstnbution In the United States between 1950 and I97 E I, GAEKE M L . G o ULTMANNJE Survival of patients with-1- diffw histiocytic I LJ lymphoma. Blood 198I;JS:I 2 18-23. 4. SWEET DL. GOLOMBHM, ULTMANNJE. et al. Cyclophosphamide, vincristine, methotrexate with leucovonn rescue. and cytarabine (COM- LA) combination sequential chemotherapy for advanced diffuse histiocytic lymphoma. Ann Intern Med 1980;92:785-90. 5 . LEVIIT SH, BLOOMFIELD CD, FRIZZERAG, LEE CKK. Curative radiotherapy for localized diffuse histiocytic lymphoma. Cancer. 1980;31(su~plII):237-41. 6 . CABANILLAS F, BODY GP, FREIREICHU.Management with chemo- therapy only of stage I & I1 malignant lymphoma of aggressive histologic types. Cancer. 1980;46:2356-9. 7. MILLER TP, JONES SE. Chemotherapy or chemotherapy with adjuvant radiotherapy for localized diffuse lymphoma. In: JONES SE, SALMON SE. eds. Adjuvant Therapy of Cancer II. New York: Grune & Stratton; 1979: 155. 8. BONADONNA G , LATTUADAA. MONFARDINI s, MILANIF. BANFIA. Combined radiotherapy-chemotherapy in localized non-Hodgkin's lymphomas: $-year results of a randomized study. In: JONES SE,SALMON SE, eds. Adjuvant Therapy of Cancer IZ. New York: Grune & Stratton; 1979:145. 9. ROSENBERGSA. Current concepts in cancer: non-Hodgkin's lymphoma-selection of treatment on the basis of histologic type. N Engl J Med. 1979;301:924-8. 10. LESTER JN, FULLER LM. CONRAD FG, et al. The roles of staging laparotomy, chemotherapy, and radiotherapy in the management of 10calized diffuse large cell lymphoma: a study of 75 patients. Cancer. 1982;491746-53. 11. LAURENCE J, COLEMAN M, ALLEN SL, SILVER Rf. PASMANTIER M. Combination chemotherapy of advanced diffuse histiocytic lymphoma with the six drug COP-BLAM regimen. Ann Intern Med. 1982;97:190- 5. 12. LL`KESRJ.COLLINS RD. Immunologic characteristics of human malig- nan t lymphomas. Cancer. 1974;34:1488-503. 13. THE N O N - H O D G K I N .L~YMPHOMA PATHOLOGIC CLASSIFICATION PROJECT. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: summary and description of working formulation for clinical usage. Cancer. 1982;49:2112-35. 14. STRAUCHEN JA. YOUNG RC, DEVITA VT, ANDERSON T, FANTORE JC. BERARD CW. Clinical relevance of the histopathological subclassification of diffuse "histiocytic" lymphoma. NEngIJMed. 1978;299:1382- 6. 15. BLOOMFIELO CD, GAJL-PECZALSKAIu. FRIZZERGA, KERSEYJH. GOLDMANAI. Clinical utility of lymphocyte surface markers combined with the Lukes-Collins histologic classificafion in adult lymphoma. N ,Eng1 JMed. 1979;301:512-8. 16. KOZINERB, LITTLE C, PASSE S, et al. Treatment of advanced diffuse histiocytic lymphoma: an analysis of prognostic variables. Cancer. 1982;491571-9. 17. MILLER JB, VARIAKOJIDS . BITRANJD, et al. Diffuse histiocytic lymphoma with sclerosis: a clinicopathologic entity frequently causing superior venacaval obstruction. Cancer. 1981;47748-56. 18. FISHER RI. HUBBARDSM. DEVITAVT, et al. Factors predicting long- term survival in diffuse mixed, histiocytic, or undifferentiated lympho- ma. Blood. 1981;58:45-51. 01982 American College of Physicians Leukemia and Benzene :- 1 ESTIMATES OF-THE proportion of cancers attributable to occupational kxposures range from 1% to 38% (1). This quantification is hampered by many factors, including la- tency between past exposures and onset of disease, and difficulty in assigning the contribution of any single agent in the face of multifactorial causes. Knowledge .of the true contribution of workplace exposures to overall rates has obvious importance given the inherently nature of ohcupationally induced cancers. p.reventable While debates about cancer rates continue, ers continue to be exposed to known carcinogens. A specific instance is the case of benzene and leukemia as highlight- ed $I a.recent study published in the Amm`can Journal ofIndustrial Medicine. Rinsky and colleagues (2) report the findings of an epidemiologic investigation of workers exposed to benzene in the manufacture of rubber hydro- chloride. .This study is of unusual quality:.+The workers -. ....,. ..-_..- :. ..J..,there `was a'21-fold increased risk bf.deaths from.leuke-. .~Fe;icin.I -... _ ..-.-I., . . ,. .. ~- .-,.>... ... ., ....>. - .' by Rinsky and 1 ' ;:.:r..-- 9y-:"Tl c * o u & g,u e '( 2) ,> . & a t 8.+Q/',of leukemias in , I , . ; L . r &: wor*".I. k.eer.sas.:-. aar) .e ipe,c, o. .n.d,..a, j:t?l 5tEe.e exposure risk for leuk$mi& liad been' nalysis -published ?in :,1.977 Be..xep.c..oa.u*sus_ eIr,eosf.-m.b*ea..n,y,z`beenes'isg.,msu:. bfii-cqauin- tt`,o-..uw`s-.itnhataunree_s:tnimonaotcecdup7a5t%iono-af.l " when 'vi& -status of.75% of, the population was ascer- the population having been exposed (8). tained 43):.Some of the criticisms of this earlier remrt Calkins and associates (IO) have-proposed a two-stage (4) shoulh have been dismissed, because they were b k e d model for the control of potential human carcinogens. At on,faulty'reanalyses of the data. The ability of the findings to be generalized could have been fairly questioned, if the study population had had far greater exposures to benzene than present standards would allow; ,This latest r ~ p o ~ ~ : $ k c t i v eadl ydresses this concern: kinsky and col- stage I the identification and characterization of the risk of a carcinogen is made, based on scientific activity and judgment. In stage 11. choices are made among regulate. ry options for control of the recognized hazard, based on leagues (2) `provide extensive workplace-monitoring in- social and political judgment. In the case of benzene, the formation indicating that the exposures of the workers stage I risk has been well established and characterizd were, for'the most part, within limits permissible at the since at least 1977. Litigation by manufacturers has time. These limits are not greatly higher than the current legal'khdards. ` -` Benzene's myelotoxic properties, including its ability to cause aplastic anemia, have been long accepted (5, 6). Clinical reports of benzene-induced leukemia have been accumulating since the first case report in 1928 and in the past 2 decades reports of acute or subacute leukemia have exceeded,those of fatal pancytopenias (7). However, acceptance of the leukemogenic properties of benzene has been slow. This reluctance was due in part to the unusual block& implementation of the stage I1 regulatory r e sponse to the scientific evidence. Although it is important to continue to define the risk of benzene (stage I ) , unfortunately we are doing so while a significant number of workers continue to be exposed to unnecessarily high levels of a known carcinogen. (LINDA ROSENSTOCK, M.D., M.P.H.; The Robert Wood Johnson CIinical Scholars P m grant,and The Universityof Washington;SeattIe, Washington) difficulty in producing an animal model of benzene's car- cinogenicity; only in the last few years have investigators shown benzene to systematically induce malignancies in rats (8). Numerous studies have shown chromosomal damage in benzene-exposed workers, including increased damage in workers exposed to levels of benzene that are permissible by today's standards (6). Epidemiologic studies in the mid-l970s, even before the preliminary report of the study by Infante and colleagues (3). implicated benzene as leukemogenic to such an extent that in 1977 the National Institute for Occupational Safety and Health recommended that benzene be considered carcinogenic in humans and allowable occupational exposure to benzene be reduced (9). The Occupational Safety and Health Administration responded promptly to this recommendation by promulgating an emergency standard that was significantly more stringent than the 1971 consensus standard then in effect. The 1971 standard still stands, however, because in 1980 the Supreme Court overturned implementation of the more stringent standard (6). Thus, the standard in effect today is one that was is- sued without concern for the carcinogenic risk from ben- zene. The standard violates the principle of reducing ex- posure to carcinogens to the lowest possible level. Achievement of exposure levels far below the- cuI-yen_t standard is technologically feasible by enclosing produc- REFERENCES 1. PETO R SCHNEIDERMANM. eds. Banbury Report 9: Quantificationd Occupational Csnccr. Cold Spridg Harbor, N e w York: Cold Spring Harbor Laboratory;1981. 2. RINSKYRA. YOUNG RI, SMITH AB. Lcukcmia in benzene work- Am J Ind Mcd. 1981;2217-45. 3. INFANIT PF. RINSKYRA, WAGNONERJK.YOUNGRJ. Leukemia ia b c n m e workers. Lancel. 1977;2:76-8. 4. ~ABEFSHAW IR. LAMMSH. Benzene and leukemia [Letter]. h n d . 1977;2867-8. 5. NATIONAL IN5llTUTE FOR OCCUPATIONAL SAFETY AND HEALTH. CMwk for 8 Recommended Standard: Occup8tional Exposure to knzene. US.Department of Health, Education and Welfare. Public Health S e M c c Center for Disease Control; 1974:20-56. (HEW Publication No (NIOSH) 74-137). . 6. W H m MC. INFANTE PF. WALKER B. Occupational exposure tO zene: a review of carcinogenic and related hcalth effects following IhC U.S.Supreme Coun de5sion. Am J f n d Mcd. 1980;1:23343. 7 . VIGLIANEI C. Leukemia associatid with benzene exposure. .41m I*' A-d SC~.1976;271:143-51. 8. US.DEPARTMENT OF HEALTH A N D HUMAN SERVICES. Seton; .4mY a1 Report on Carinogms Washington. D.C.: U.S.Department of H a l * Md Human sen ice^; 1981:47-9. (NTP 81-43). 9. NATIONAL IN- FOR OCCUPATIONAL SAFETY A N D HEALTH. NIOSH Revised Recommendation for an Occupational BposuE st* d a d for Benrcne. U.S. Department of Health. Education and weifarc Pubtic Health Servics Center for Disease Control; 1977. (G.P.0. 757* M)9/8). IO. CALKINSDR. DIXONRL, GERBERCR, ZARIND.OMENNGS. Identi. fieation. characterization and control of potential human carcinogem:' ,. . framework 76. . . for : - :&: feder.:a.:l..decisI i, on-m. aking. J Natl Onnc fn5t. 1980,@:16e tion processes, prohibiting the occupational use of ben- zene in open-type operations, and substituting safer prod- `"From Other Pages": A New Feature ucts where possible (9). The significance of continued exposure to benzene is best understood in the context of THE EDITORS of this journal are as aware as the clini- benzene use today; it is a major raw material in the chem- cians who read it that those who practice medicine have ical industry, a solvent in common use. a gasoline addi- little time to scan the many clinical journals relevant to 2 7 6 August 1982 Annals of Internal Medicine Volume 97 Number 2