Document jmL8LXRzOD42jzNRkRNV33Z85

Ca-ACancerJournal for Clinicians Published by the : \; S American Cancer Society. March^pril1978 , / Asbestos*associated Disease in United States Shipyards SCF-ALLF-07120 SC-ALL-20995 H FM - 003505 Editor in Chief Arthur I. Holleb, M.D. Executive Editor Sidney L. Arje, M.D. Associate Editor Michael Mannion Assistant Editor Donna M.M. Herman Managing Editor John Aschemeier Advisory Editors Dominic Do-Van-Quy, Ph D. Lawrence Garfinkel, M.A. E. Cuyler Hammond, Sc.D. George Manner, Ph.D. William Market, M.D. JackW. Milder, M.D. Louis H. Muschel, Ph.D. Frank J. Rauscher, Jr., PhD. Herbert Seidman, M.B.A. Margaret M. Sharkey, Ph.D. Philip Terman, D.D.S. StefanoVivona, M.D. G. Congdon Wood, Ph.D. Medical Librarian Sourya Henderson, Ph.D. Designer Thomasina Webb Production Director William Negro Production Manager Marvin Taub Circulation Ronald Daddea Cover Design William Behnken Professional - Education Committee _ Hugh R.K. Barber, M.D. : James G. Bassett, M.D. ' Carl W. Bpyer, Jr., M.D. Daniel Burdick, M.D. Florence Chu, M.D. y Mrs. Josephine Craytor, RJ|. Gerald D. Dodd, M.D. William M. Dugan, Jr., M.D. Robert J. Faulconer, M.D." John R. Hartmann, M.D; ff, William H. Hartmann, M.D. Robert V.P. Hutter.M.D. Richard H. Jesse, M.D. B.J. Kennedy, M.D, y Robert M Kretzschmar, M.D. Louis A. Leone, M.D. if: Edward F. Lewison, M.D. f Claude Organ, M.D. 7 John D.Pigott, M.D. f E.C.H. Schmidt, M.D. : Charles R. Smart, M.D. ' Willis J. Taylor, M.D. f t Donald T. Waggener, D.O.S. Winston H. Weese, M.D.3 Willet F. Whitmore, Jr., M.D. John P. Wilson, M.D. , 7 Articles in Ca are Indexed in Index Medicus and Current' Contents/Clinical Practice: Some are abstracted in " ' Chemical Abstracts, Biological Abstracts, Excerpta Medica, . Abstracts of World Medicine, Medical Socioeconomic Research Sources, Public^ tion does not constitute ;' f endorsement by the American Cancer Society. Circulation: over 400,000 Address manuscripts to :' Arthur I. Holleb. M.D. y Editor in Chief Ca--A Cancer Journal for Clinicians ,. 777 Third Avenue '. New York. N.Y. 10017 . , Bl.'O 3 0 B9 A Ca-A Cancer Journal for Clinicians Published by the American Cancer Society March/April 1978 Vol. 28, No. 2 Features . 66 Epidemiology of Thyroid Cancer David Schottenfeld,MD: and Susan T. Gershonan, M.PiH. V 87 ] Asbestos-associated Disease In N:__ ' United States Shipyards Irving J. SeBkoff, M.D. and E. Cuyler Hammcnd, Sc.D. 100 CTScan-- . It& Use and Abuse Robin Caird Watson, M.D. 104 Prostate Cancer: ; 7 . Progress and Change Gerald P. Murphy, M;p.,D.Sc. . Departments ; 116 Questions and Anavrers on Cancer 118 Interview: Oral Contraceptives and Cancer v"f f::S Robert M, Kretzschmar, M.-D.: 124 Opinion: Warning: False Cancer ; Claims May be Hazardoos to your . ;' Health . ' 7-ff ... ' John H. Weisburger. Ph.D. 127 Editorial: A Personal Tribute to ' Robert M. Taylor, M.D. 197(5, American Cancer Society. Inc. NewYork, N Y HFM - 003506 Epidemiology of Thyroid Cancer David Schottenfeld, M.D., and Susan T. Gershman, M.P.H. Thyroid cancer mortality in the United Survey (1969-1971) were 5.2 in white wonj- States in 1976 has accounted for approxi en, 3.2 in black women, 2.2 in white mat mately 1,150 deaths, or 0.5 percent of all and 1.1 in black men. The age-specific cancer deaths in women and 0.2 percent incidence in white women peaks initially in men.1 Hie age-adjusted mortality per at the interval 30-34 years (9.6/100,000), 100,000 in 1967 was 0.9 in non-white wom and then again after 65 years (9.2-10^4/ en, 0.6 in white women, and 0.3 in white 100,000). The age-specific incidence^m -. men and 0.2 in non-white men. *The time white men tends to fluctuate,' but the over trend analysis for age-adjusted mortality all pattern is one of gradually increasing (1950-1967) indicated significantly de incidence with increasing age (Figure 2). creasing mortality in white women and A similar pgttem suggesting bimodality men. For non-whites, there were no sig- is evident in the curve for age-specific mV nificant trends in age-adjusted mortality cidence in black women (Figure 3).5 ; f (Figure 1). The femaletmale ratio of age- Although secular or temporal trends adjusted mortality rates was 2.0 in the in the incidence of thyroid cancer are not whiteand 4.5 inthenon-whitepopulations.> available for the entire United States, they For 1976, the American Cancer Society are provided by the population-based regV has estimated that there were 5,900 new istries that are maintained by state health cases of thyroid cancer in women and departments. The age-adjusted incidence 2,200 cases in men. The-average annual in women, reported by the Connecticut; age-adjusted incidence rates per 100,000 Tumor Registry, increased from an aver as determined by the United States Public age annual rate of 1.4/100,000 (1940-1949) , Health Service Third National Cancer to 4.0/100,000 (1970:1973), almost a threes fold increase, The age-adjusted incidence in men increased from 0.6 (1940-1949) tin Epidemiology of Thyroid Cancer--Parts 1 and II are reprinted from Clinical Bulletin, 7:2, 47-54, and 7:3, 98-104, 1977. Tables I-VI, fig ures 1-7 and references 1-29, as well as Table VII and references 30-95 were included. ' Dr. Schottenfeld is Attending Physician; Chief, Epidemiology and Preventive Medicine Ser vice, Department ofMedicine, Memorial Sloan- Kettering Cancer Center, New York, New York. Ms. Gershman is Research Assistant, Epi demiology and Preventive Medicine Service, Department of Medicine, Memorial SloanKettering Cancer Center, New York; New York. 1.5/100,000(1970-1973), arelative increase of 2.5 and similar to die trend: noted in women (Figure 4). In both women and men, the increasing incidence during the; past .25 years has been limited to persons under .age 50 years (Figures 5 and 6).4 Carroll et al.5 reported in New York State that the age-standardized incidence rates for thyroid cancer more than doubled be tween 1941 and 1962. When the age-specific incidence rates were examined, the in- eg R00I > :R JOURNAL FOR CLINICIANS creases between 1941 and 1962 were limited to persons under age 55: Cohorts bora after 1910 and before 1949 demonstrated a doubling of age-spetific incidence with eachsuccessivedecadeqfbirth.Thechange in the cohort pattern after 1910 coincided vri the administration of x-ray for thy- mic enlargement, oropharyngeal lymph- VOL 28, NO. 2 MARCH/APRIL If : . : 8901 (H97 67 HFM - 003507 oid hyperplasia and cervical lymphadeni apparent thyroid cancer by country ^td tis in infancy and early childhood, and race may -reveal important interacti^is was consistent with the hypothesis that between host and environmental fadttjffs. ionizing radiation was a cause of thyroid However, such comparisons must be^i- cancer in children and young adults. terpreted cautiously since they are sub Whetherincreasing incidence rates are ,, ject to variations in the procedures used:. real or artifactual depends upon the de for neoplastic classification and registra gree to which they have been influenced tion and in the quality of diagnostic ahd by changing diagnostic criteria and com therapeutic services. The pattern of geo pleteness of reporting. For example, the graphic and racial differences in the: in occult sclerosing non-encapsulated papil cidence of clinical thyroid cancer should lary carcinomas and intraglandular en be distinguished from that observed for capsulated follicular carcinomas with occult thyroid cancer. ' minimal vascular invasion have received In 5,636 consecutive autopsies on can increasing recognition during the past 20 cer patients at Memorial Hospital, the years. In their review of thyroid cancer in prevalence ratio of occult thyroid cancer Olmsted County (1935-1965), Verby et al.6 as an independent primary cancer was 6,4 attributed the observed substantial in per 1,000 autopsies. The method of exam crease in incidence to the greater recog ination consisted usually of a single section nition of occult papillary tumors during from each lobe when no tumor was grossly the 1955-1965 decade. visible. The peak prevalence in women Variations in the incidence of clinically was 19.6 per 1,000 at 20-29 years of age, N 0 U i Of.'X'.i A CANCER JOURNAL FOR CLINICIANS and 10.4 per 1,000 in men at 30-39 years. Unlike most eai^nomas, there was rip indication that std&linical thyroid cancer increases with iirigeesii$ age.? Sampson et al. 8 arrived at a similar conclusion in their autopsy study in Hiroshima arid Nagasaki. In autopsy studies conducted in the United States where the thyroid gland was examined meticulously, the ob served prevalence ofoccult thyroid cancer varied between 1.0V5.7 percent. Whereas the prevalence due to clinically apparent thyroid carcinoma predominates in wom en, occult thyroid cancer occurs almost as frequently in men.*-!0 The prevalence oflatent thyroid cancer (i.e., 1.5 cm. or less'in maximum dimen sion) diagnosed at autopsyip the Hawaiian Japanese and native Japanese (17.9-24 percent) is at least four times that observed in comparable autopsy studies from Can ada and the continental United States iweyer, clinically apparent thyrpitf can- Incidence rates in the Hawaiian Japa nese and the native Japanese are not sig nificantly different from those in the Hawaiian whites and the continental Unit ed States whites (Table i.l'^The:age- adjusted incidence in theHawaiian .Chi- npse women is greater than that observed in the Japanese and Caucasian groups in Hawaii and is almost 18 times that re ported in Singapore Chinese women, X MOre recent information on this-find ing has been furnished by Koloriel and Rdlahan from the Hawaii Tumor Regis try (Table II). N These rates were based upon a total of 110 patients in 1960-1964 and 184 patients in 1968-1972.The small number of cases in each racial ' lowed for wide sampling fl The rates in the Chinese and women were in contrast to those the Japanese and Caucasian ,w< VOL. 28, NO. 2 MAI R O^l, 0 S -JL- A 69 HFM - 003508 example, between 1960 and 1964 the Chi- carcinoma, develops from the parafollicnese women (six percent of all women) ular cells. The biologic behavior of thy* incurred almost nine percent of all incident cancers and 20 percent of incident thyroid cancers; the Japanese women (36 roid cancer is extremely variable, and any:'' system of histologic classification should serve to ideittify important differences in: percent of all women) incurred 35 percent of all cancers and 32 percent of thyroid . cancers. The proportional incidence would suggest that the Chinese women in Hawaii epidemiology, natural history, prognosis and the ratiohale of therapy. At Memorial Hospital, we have classifiedthe epithelial tumors into papillary, , occult sclerosing, may be at high risk for thyroid cancer, follicular, Hurthle cell, medullary, and The age-standardized morbidity ratio in- spindle and giant cell, dicated a 43 percent excess of thyroid can- The occult sclerosing carcinoma may cer in the Chinese women, but the 95 percent confidence limits were not statistically significant for a Poisson distribution, Austin provided incidence data by race be classified as a subtype of the papillary carcinoma; it is a small (commonly less than 1.5 cm. in diameter), unencapsulated low grade carcinoma, showing marked for the San Francisco-Oakland Standard desmoplasia. The Hurthle cell carcinoma Metropolitan Statistical Area (Figure 7.p1 represents a varietyof follicular carcinoma The age-adjusted rates were computed by and is composed of large cells with small the direct method using the 1950 popula- hyperchromatic nuclei and relatively large tion of the continental United States as the standard. The incidence in the Chinese women was similar to that registered in white United States women, and exceeded amounts of pink cytoplasm. The resulting simplified taxonomy of thyroid carcinoma--papillary, follicular, medullary and anaplastic--is currently in common use. the rates seen in Japanese and black ^ pe^ge distribution by cell women. type will vary by age, sex, geographic The female:male ratio of age-adjusted incidence rates in the Hawaiian Chinese is 5.9 and, in the Hawaiian Chinese men, area, and source of pathologic material, Surgical materials tend to select the djfferentiated carcinomas (i.e., papillary aqd the age-adjusted incidence is seven times follicular), whereas mortality studies tend that noted in the Singapore Chinese men. >> to select the anaplastic carcinomas (i.e., Fraumeni and Mason19 reported that thy- spindle and giant cell).*? roid cancer mortality in the Chinese re- |n the Third National Cancer Survey, siding in the United States during 1950- papillary carcinoma was the most com- 1969 was increased, particularly in males, when compared with the United States white and black populations. The geographic and racial patterns for thyroid cancer incidence and mortality should be mon form, accounting for 64 percent of all primary malignant tumors (Table II{). This type of tumor has a peak incidence in the third and fourth decades, and occurs three times more frequently in wonitn studied carefully for differences in histo- than in men. The disease is distinctly less pathology and natural history, and par- malignant in children and young adults, ticularly among different generations of jn 0ur experience at Memorial Hospital, Chinese immigrants to the United States. not more than 10 percent of these tumors It is possible that the complex of host and may be classified as pure papillary cardenvironmental factors that promote clini- .nomas. The remainder of these tumors cal expression pf disease are distinctive variously contain follicular, trabecular, from those that initiate tumorigenesis. Hurthle cell, epidermoid or spindle and Pathology giant cell features. The finding of foci of giant or Spjn<ue ceji anaplastic carcinoma The majority of thyroid tumors arise from interspersed throughout the papillary and, the epithelial elements of the gland. Most follicular structures is considered a poor tumors originate from the follicular (aci- prognostic sign.21 . ,j : nar) cells, and at least one type, medullary The percentage relative frequency of 70 ^t'Ul 091)0 JCER JOURNAL FOR CLINICIANS Femalu Mein United Statu Hawaii: Chinese. Hawaii: Filipino Hawaii: Hawaiian Hawaii: Japanese Hawaii: Caucasian Connecticut ' California, Alameda: White California, Alameda: Black 20.7* 14.3 10.1 6.5 5.4 3.0 1A 23 14.1t 18.7 16.0 7.8 9.2 3.7 6.5 1.9 3.5* 4.5t` 5.0 4.7 5.7 3A 1.7 3.2 4.4 3.1 0.8 1.5 2.8 23 0.6 13 Israel AH Jews ' Jaws born in Africa or Asia - Jews bom in Europe.or America Jews born in Israel Nondews Japan ~ Okayama Prefecture Miyagl Prefecture 4.2 3 4.6 6.7 4.0 6.4 2.0 6.1 2.0 1.8 3,3 2.4 2.0 2.1 13 43 1.6 2A 2.0 4.2 0.3 43 1.2 131 1.1 0,8 n: New Zealand Maori " !' European . ,. ; 5.5 2.3 2.6 2.0 0.4 03 0.9 1.0 . South Africa ' Natal: African:: . Natal: Indian'. Capa Province: White Cape Province: ' Bantu .. \ Cape Province:/Nqnrvyhite ' 3.3 3.0 3.6 2.7 1.1 0.2 1.0 1.2 ^ . 0.0 03 Norway All Urban Rural V : . ... Columbia, Cali . 2.4 3.7 2.6 3.1 2A 43 6.6 5.5 1.1 1.6 . 1.0 1;7 1.1 I-4 3.5 ' ' 2.7 Canada, Quebec Finland 2.6 " 2.4 2.7 2.9 0.9 1.0 1.0 India, Bombay Denmark :. . 1.5 1.8 .1.4 1.8 -7 0.7 0.8 0.8 U.K., England and Wales (Liverpool Region) ' 1.3 Sources: *See reference! 3. tSea reference 14. 1.2 0.6 6.6 - :`:.V' VOL 28, NO. 2 MARCH/APRIL 1978 pool OVO j HFM - 003509 Race 1960-64 1969-72 :: ---------------:----------------- .---------------------------- !________ Chinese Hawaiian Filipino Japanese Caucasian 19.9 11,8 8.8 6.1 4.9 12.3 17.0 18.4 6.3 9.4 -*v- the remaining ceil types was follicular (18 percent), medullary (three percent), anaplastic (three percent), sarcoma (less than one percent), lymphoma (two per cent) and other (11 percent) (Table III). Follicular carcinoma has a peak incidence in the fifth decade of life, and occurs with greater frequency in women. Anaplastic carcinoma tends to be diagnosed at a later age than the differentiated carcinomas, ' and occurs about equally in men and women. Russell et al.22 found a differen tiated component in all anaplastic carci nomas, and concluded that the undiffer entiated foci were derived from the more differentiated papillary and follicular elements. It is reasonable to assume that in the bimodal age-incidence curve evi denced by women, the first mode is com prised predominantly of papillary and, to a lesser extent, follicular carcinomas, and the second mode is comprised of predom inantly anaplastic and, to a lesser extent, papillary and follicular carcinomas. The prognosis in patients with thyroid carcinoma is variable and correlates with histologic type, extent of disease, age at diagnosis and sex. The survival rate for papillary carcinoma is significantly higher than for follicular carcinoma, and is low est for the spindle and giant ceil carcino mas (Table IV).22-22 In follicular carcino- ma, the encapsulatedsubtype with minimal vascular and capsular invasion is charac terized by a 10-year survival rate that is almost twice that of non-encapsulated, primary, operable follicular carcinoma. The survival rate in women as reported by the End Results Group of the National Cancer Institute was consistently better than that noted in men (Table V). During 1955-1964, 54 percent of women as con trasted with 39 percent of men were diag nosed as having localized disease. Relative survival rates at five and 10 years in men and women decreased with increasing age (Table VI). Women and the younger age groups are characterized by a higher prev alence of papillary and follicular carci nomas and earlier stage of disease.24 Rel ative survival rates at three and five years for women and men have improved sub stantially between 1940-1949 and I9601964: If these data can be generalized, then the declining age-adjusted mortality in the face of increasing age-adjusted in cidence since 1950 in the United States has occurred because of more significant gains in survival and in average duration of disease. Medullary carcinoma or solid carcino ma with amyloid stroma is typified by a , lack of follicular and papillary differen tiation; colloid formation and radioiodine ' ' a.Qfl'l tV9H? .-A CANCER JOURNAL FOR CLINICIANS Type Total No. % AH races Male No. % Female' No. % Papillary carcinoma Follicular carcinoma Medullary carcinoma Anaplasticcarcinoma Lymphoma. Sarcoma ' Othert ..... Total number of patients 1434 403 . 59 55 34 4 236 2225 84 18 3 3 2 <1 11 100* 364 61 96 16 28 5 21 4 11 2 1 <1 74 12 596 100 1070 307 31 34 23 3 162 1630 66 19 2 2. 1 <1 10 . 100 Type Papillary carcinoma Follicular carcinoma . Medullary carcinoma Anaplastic carcinoma Lymphoma . Sarcoma ' Othart Total number of patients Total No. % 1334 358 56 55 33 4 218 65 17 3 3 2 <1 11 2058 100* White Mala No. % 344 62 85 15 28 6 21 4 11 2 1 <1 67 12 557 100 Female No. % 990 66 273 18 28 2 34 2 22 2 3 <1 151 10 1501 100- Type Total No. % Black Male No. % Female No. % PapBlary carcinoma Follicular carcinoma - Medullary cardRoma . Anaplastic carcinoma Lymphoma .: .,/ Sarcoma : , Othart 1 63 . 2 .' 11 41 40 33 11 41 3 3 ' ' '" -- .-- '----- : ' 1 1' -- ` -- ---- ---- 14 12 5 19 52 r 55 29 31 3 '3 -- . v- 1 . 1 . "* .. ~ 9 10 Total number of patient* 121 100* 27 100* 94 100 : TOth#f inciuaos carcinoma yr SOnocrcmma mm vumnnB spewniwii vwwihwh.h Implex, dear cell adenocarcinoma, squamou* carcinoma and malignant neoplasm (not otherwise specified). 'Does not total'-.100 percent because of rounding. . . VOL. 28. NO. 2 MARCH/APRIL197 . *30i 0903 W: 73 .0h:: HFM -003510 uptake. Its biologic behavior is of an in termediate grade of severity when com pared with the differentiated and anaplas tic carcinomas. 23 Medullary carcinoma originates from the parafollicular C cells. The epithelial follicular cells, which are concerned with the iodination of thyroglobulin and the release of thyroxine and triiodothyronine, arise from foregut endoderm and give rise to the differentiated (papillary and follicular) and anaplastic (giant and spindle cell) carcinomas. The parafollicular C cells, have a neuroecto dermal (neural .crest) origin, presumably derived from the ultimobranchial body, and synthesize the peptide hormone, cal citonin. The tumor may appear either in a single member or in multiple members of a family! Experimental Thyroid Tumors Thyroid neoplasia develops predictably in experimental animals exposed to ionizing radiation or to any procedure that induces prolonged, excessive thyroid-stimulating hormone (TSH) secretion. Excessive TSH secretion may be produced through die tary iodine deficiency, sub-total thyroid ectomy, implantation- of autonomous thyrotrophic hormone-secreting pituitary tumors, or by the administration of chem ical goitrogens. Augmentation of neo plasia, as evidenced by shortening of the latency period or increasing tumor inci dence, or both, is achieved by .the prior administration of a carcinogen such as 2 . acetylamiriofluorene or ionizing radiation followed by experimental induction of . . increased TSH stimulation. How does TSH-induced hyperplasia lead to neoplasia, and to what degree does rapid proliferation of the follicular cells independently initiate the neoplastic pro cess? The number of cytogenetic abnor malities within the thyroid epithelium apparently increases with the duration of increased' TSH stimulation. Various in vestigators have interpreted experimental thyroid neoplasia as being analogous to the Berenblum-Shubik2* 2-stage hypoth esis of carcinogenesis in mouse epidermis. The 2-stage hypothesis presumes two con secutive processes: initiation which occurs quickly and is irreversible, and promotion which occurs slowly, is reversible, and for which ceil proliferation may be a nepe^. sary although not sufficient conditit^; Initiators may include ionizing radiation, chemical or biologic agents and generic factors. The major promoting factor may reside within the hypothalamic-pituitary- thyroid axis and be triggered by an exceg- sive secretion of TSH.23 : . The 2-stage hypothesis is particularly applicable to neoplasia in tissues in which a high rate-of cell renewal or mitosis is normally present. Experimental carcind- genesis in the thyroid is correlated with the effect of a sustained growth stimulus on a tissue in which the normal rate ofcell renewal is negligible. It would appear, therefore, that the mechanism of carcind- genic promotion of thyroid tumors by TSH is somewhat different from the mod el for experimental skin tumors in mice. Doniach23 suggested that experimental thyroid neoplasia results from the chro mosomal and. mutational abnormalities induced by the imposition of accelerated mitosis-in a tissue in which the noringl rate of cell renewal is minimal, Christoy has shown that irradiation of the thyroid gland in adult rats achieved the highest incidence of tumors when administered after treatment with a goitrogen and qt the time of peak cellular proliferation. The experimental manipulation of TSH secretion has its clinical counterpart ip patients with endemic goiter due to iodine deficiency and in the genetic disorders of the thyroid that lead to hypothyroidism, Genetic Factors :f ' The multiple endocrine adenomatosis syt" dromes (MBA I and II) are genetically distinct neoplastic endocrinopathies pre sumably arising from faulty differentia-,, tion of the neuroectoderm 3-" (Table VII). Both WeichertJ2 and Pearse33have ad vanced the concept that the C cells of the thyroid and extrathyroid tissue share a* common embryologic origin in the neural crest with the enterochromaffin serotonin, producing cells of the gastrointestinal tract, the islet cells of the pancreas, the neurochromaffin cells of the adrenal mfc H - 10 l OA-A CANCER JOURNAL FOR CLINICIANS w Histologic . 5 " 10 15 20 type years S.E.** years S.E,** years S.E.** years s.E,*# ; All histologic typos PapBlary Occult sclerosing Follicular Hurthle ecH Medullary Spindl* and' giant call Lymphoma 70.4 82.7 too.ot 65.6 60.8 49.1 3J6 31 Jt 1.6 1.6 ... 4.2 6.9 6.6 . 2.4 11.6 639 2.1 78.2 2.1 -t 47.0 42.5 37.6t 6.6 11.1 11,7 O.Ot. ' -- -t ' ^ _ 73.6 1.9 40.6 8.8 _ V. 70.8 3.6 40.5 14.9 *Tha oburved nat survival ratat ara calculated try the dlract method and exclude doaths from other causat. . "Survival rsm rnd standard errors ara sxprassad asparcantagea. . '. tLassthan 20ptlant*. dulla and the ceils of the anterior pituitary - chromaffin paraganglioma, although it that secrete ACFH. these polypeptide- rarely produces catecholamines. In con- secreting neuroendocrine cells share func- trast to the phebchrotnocytom%htcdul- tiohally the AJPl3x> mechanism and the lary carcinoma in the thyroid syndrome, propensity for ectopic hormone produc- the. chemodectoma-papillary and follicution by neoplastic tissues. The letters iar carcinoma of the thyroid syndrome is APUD describeithe process of amine and . rarely familial or characterized bytnulti- precursor uptake and decarboxylation of centricity and;bilaterality.-i various endocrine substances such as do- There are several reports withjta fam- pamine and its precur&or, 3,4-dihydrxy- ilies pf muitiple cases of differentiated pVi^nyiaianinf and gprotnnin and its pre- carcinomaof the thyroid in association cursor, 5-hydroxytryptophah.34-3* with goiter and neurosensory deafness A syndrome of papillary and follicular (Pendred syndrome). In this disorder, an carcinoma of the. thyroid and chemodec- inborn error of iodinejorganification im- toma, a non-chromaffin paraganglioma pairs the ability to synthesize thyroidhor- of the carotid body, aortic body or glomus mones, resulting in excessive secretion of jugulare has been described in humans.39 abnormal iodoproteins.42 ;; The carotid and aortic bodies, like the Papillary carcinoma ofthethyroid has adrenal medulla, are of neuroectodermal, been described in siblings with Gardner's origm/Thechempdectomais histological- syndrome, an autosomal dominant dis- ly similar to the pheochromocytomai a order*associated with multiple polyposis . .. v VOL. 28. NO. 2 MARCH/APRIL197B ^,001 09$S' /! HFM -003511 No. of patients 1940-1949 1960-1959 1960-1964 1965-1969 ^ Male Female Male Female Male Female Male Female -: 197 600 674 1803 416 989 392 1053 J Percent at 3 years 54 72 73 84 80 87 80 88 > Percent at 6 years 61 69 73 83 78 87 - '-i Percent at 10 years 48 68 73 83 Percent at 16 years 48 68 ' '' Source: End Results In Cancer, Report No. 4, End Results Section, Biometry Branch, National Cancer Institute, 1972, p. 162. - and carcinoma of the colon, osteomas pathogenic events which include intense and sebaceous cysts.45 The multiple ham follicular hyperplasia, hypertrophy and artoma syndrome (Cowden's disease) is nodule and adenoma formation. The evi an analogous disorder first described by dence in man for an etiologic association Lloyd and Dennis in 1963. **45 Patients between severe iodine deficiency and thy- . with this autosomal dominant disorder roid cancer has consisted of increased exhibit some form of thyroid neoplasia, thyroid cancer incidence and mortality^ most often as goiter or multicentric ade particularly of the follicular and anaplaS nomas, bt|t in some cases as carcinoma. tic types, in geographic areas considered Other prominent familial features of this to be.at high risk for adenomatous or syndrome include mucocutaneous papil- nodular goiter. Hie foci of carcinoma . lomas, lichenoid keratoses of the face, have usually been located in otherwise neck, hands and forearms, angiomas, normal parenchyma rather than within subcutaneous and retroperitoneal lipo hyperplastic nodules.4*-41 Ithas even been mas, ovarian cysts, fibrocystic disease suggested that the frequency of goiter and and carcinoma of the breast. Adenoma thyroid cancer in Switzerland diminished tous, metaplastic or inflammatory polyps after the introduction of iodized table saifi and ganglioneuromas of the gastrointes Those who argue against a direct causal tinal tract have been described. relationship between endemic goiter and thyroid carcinoma point to prior studies' Iodine Deficiency as a Co-factor In Thyroid Carcinogenesis in geographic areas where, there wasno correlation (i.e., Australia,. Austria, Firi: land and the United States), or where the In experimental animals such as rats, frequency of goiter was low and thyroid mice, and. Syrian hamsters, chronic io cancer was high (i.e., Hawaii, Iceland and dine deficiency may eventuate into carci Newfoundland).48 Other reports from noma of the thyroid after a succession of Switzerland subsequent to. the introduce HG01 0906 CA-A CANCER JOURNAL FOR CLINICIANS , All Ages Under 25 26-44 . Male Female Male Female Male Female Percent at 6 years Percent at 10 yens 76 85 96 74 ;86- V 96 99 99 45-54 65-64 Male Female Mala Fenrale 92 98 91 96 65+ :r'v " Male Female Percent at 6 yean Percent at 10 years : 76 . . 91 70 .: so ... 61 . 49 67 65 39 . 33 46. 44 \ Source: End Results In Cancer, Report No. 4, End.Results Section, Biometry BranchNational Cancerinstitute, 1972, p. 164. ; tion of iodized table salt do not substanti ate a continuing trendVof decreasing frequency of thyroid cancer, but rather emphasize the stable rates of thyroid can cer mortality, decreasing incidence- of goiter, and increasing proportion of thy roid cancers that are classified as papillary.^-^The observation of increased thyroid cancer mortality in ah endemic goiter area, i.e., where the prevalence of goiter is 10 percent or greater, may be due to the higher proportion of anaplastic carcinomas.* In addition, thyroid en largement due to iodine deficiency may obscure the. existence of a cancer, ahd because of delay in seeking medical care, the majority of malignant tumors are diagnosed at more advanced stages. " In studies conducted in the United States during 1939-1951, the average annual age- *It has also been suggested that the highly ma lignant hemangioendothelioma of the thyroid occurs in geographic areas where iodine is de ficient. and particularly in older patients with chronic goiter. (Cubilla, A.: PersonaI Com munication, 1977.) : adjusted mortality due to thyrotoxicosis (secondary to toxic nodular goiteiriand the diffuse hyperplasia of Graves* ^disease) diminished significantly in relation to the decreasing prevalence of endemic; goiter; during the same period of time, the age- adjusted mortality due to thyroid cancer increased slightly.52 To summarise, the epidemiologic evidence that endemic io dine; deficiency may serve as a necessary and sufficient cause of the follicqjsr type of thyroid carcinoma is unconvincing, although iodine prophylaxis mayJlter the histologic pattern of thyroid cancer, and ultimately diminish the mortality due to thyrotoxicosis. : Gtrave'Disease and-Hashimoto's Thyroiditis The coincidence of thyrotoxicosis and thyroid cancer was considered tp be ex tremely rare. In more recent statistical surveys, the prevalence of thyroid carci. noma in patients with toxic goiter has been reported variously as being between 0.2 and 5.0 percent.51 The average prevalence VOL 28, NO. 2 MAR&VAPRIL 1978 PO'Oi 0907 HFM -003512 of 2.5 percent for thyroid carcinoma in patients with toxic goiter is similar to the 2.8 percent reported by Mortensen and colleagues m in their study of subclinical thyroid cancer in 1,000 consecutive routine autopsies. In the Olen and Klinck study of toxic goiter and carcinoma3', 50 percent of the carcinomas were "occult sclerosing" or papillary in type, and in no instance did carcinoma arise from a preexisting adenoma. It is now accepted that Graves'disease, myxedema and Hashimoto's thyroiditis are closely related immunogenetic disorders. Two of these diseases may co-exist in the same patient, aggregate in the same family, or demonstrate a high concordance rate in monozygotic twins. The incidence of each disease is at least four times greater in women than in men. Hashimoto's disease tends to be uncommon in American blacks and increases in incidence with age, whereas Graves' disease (diffuse toxic, goiter) is not uncommon in blacks, tends to peak during the third and fourth de cades, and is distinctly uncommon after age 60. Hashimoto's thyroiditis and Graves' disease are significantly associated with a number of other diseases characterized by abnormal immune reactivity to autologous antigens such as pernicious anemia, primary (Addison's) adrenal insufficiency and myasthenia gravis. The prevalence, of thyroid carcinoma in pa- . tients with the diffuse chronic lymphocytic thyroiditis of Hashimoto has been reported variously as being; between 1.5 and 3.0 percent. Focal lymphocytic thyroiditis is commonly seen in association with papillary and'follicular carcinomas, The frequency and significance of these focal lymphocytic infiltrations are not known precisely, although they may represent secondary immune responses to . *00 '. 0 A-ACANCER JOURNAL FOR CLINICIANS. #. * . ' proliferating parenchymal tissues.56-38 In the National Cancer Institute's Veterinary Medical Data Program, it was observed that the beagde, boxer andgolden retriever breeds were at increased risk of developing ctinicsdly; apparent thyroid cancer. Severalbeagle colonies used in laboratory researchhave exhibited a familial, ptedisposition to lymphocytic thyroiditis, indistinguishable, from Hashimoto's disease.39 Although thyroid neoplasia was not identified in these colonies, further follow-up beyond six years and careful pathologic study may serve to describe the incidence; of thyroid cancer in dogs. with antecedent thyroiditis. A prospective epidemiologic study would determine whether Hashimoto's thyroiditis is a specific precursor of thyroid carcinoma. The diagnosis of struma lymphomatosa may beestablished through a biopsy or a combination of immunolag- ic tests and thyroid scintiscans. Crile and Hazard60 did not observe a single.case of clinically apparent thyroid cancer in 222 patients with Hashimoto's thyroiditis after follow-upofmorethanl,000person-years. vMost of these patients were maintained on daily doses of two-three grains of des- iccated thyroid, which may have dimin- ished any inherent risk of their developing subsequent neoplasia. ' Human Radiation Exposure and Thyroid Cancer : From the 1920's through the 1950's, many ..infants, children and young adults re ceived X-ray therapy to the head, neck and mediastinum for cervical lymphadenitis, mastoiditis, enlarged palatine and naso- pharyngeal lymphoid tissues, pertussis, acne, hemangiomas or keloids, orto shrink . an allegedly enlarged thymus gland that VOL28,NO.ZMARCH/APRIL 1978 , 80Q1 0909 . HFM -003513 was thought to cause acute respiratorydistress and sudden death. Duffy and Fitzgerald*1 made the important observa tion in 1950 that more than one-third (36 percent) of children with papillary and follicular carcinomas of the thyroid had received radiation therapy to the upper mediastinum or neck. Subsequent publi cations in the United States reported that from one-third to three-fourths of all children and young adults with benign and malignant thyroid neoplasia received prior irradiation to the head, neck and/or me diastinum during the first five years of life. 6J-69 in a recent publication from Israel by Modan et al.,7the risk of thy roid cancer was significantly enhanced in children 12-23 years after receiving X-ray epilation treatment of the scalp for tinea capitis. In New York City, Shore, Albert and Pasternak71 observed an increasing, incidence ofthyroid adenomas 15-30 years after X-ray epilation for tinea capitis. Radiation-induced thyroid cancer may be characterized. by multi-focal malignant lesions. It is evident from all. such studies that irradiation to the thyroid in infants, chil dren and young adults up to 20 years of age carries a far greater risk of inducing neoplasia than does similar exposure in adults. This increased risk is probably due .to the1 far greater rate of mitosis in the young thyroid and, as a consequence, the greater likelihood of inducing cytogenetic abnormalities in viable cells. Hempelmann and co-workers72 noted that following irradiation of the thymus in infancy, the incidence of thyroid cancer in women 15-29 years of age increased five times over that of the rest of the irradiated population. In contrast, the incidence of thyroid cancer in irradiated women young er than age 15 or older than age 30 years was almost identical with that found in the irradiated men. The age period 15-29 years coincides with the onsetof ovulatory men strual cycles and maximal reproductive activity. During pregnancy, the thyroid gland frequently undergoes physiologic hypertrophy, presumably secondary to an increased renal loss of iodide and height ened secretion of thyroid-stimulating hor mone..In areas of endemic goiter second^ ary to low dietary intake of iodine, the' prevalence of thyroid hypertrophy during gestation is further enhanced. These observations are particularly pertinent when we recall that in animal experimen tation, increasing amounts of thyroid? stimulating hormone after radiation exposure are associated-with an increasing incidence of thyroid cancer. On the assumption of- linearity in the dose-response curve, the National Acad emy of Sciences has estimated that the risk of thyroid cancer developing in irra-* diated children- was within die range of 1.6-9.3 cases/year/million exposed chil-dren/rem.73 (In terms of biologic damage, the rem is equivalent to 1 rad of 250 KVP X-rays.) The assumption of linearity was questionable under 20-50 rads-until Mo-.. dan's study which suggested a mean ex posure dose to the thyroid of 6.5 rads. . In terms of a clinical approach to en suring early diagnosis, all children aid young adults who have had X-ray treat ment to the chest, neck, faceor scalp shoirid be kept under continuing surveillance. The thyroid gland, cervical lymph nodes and salivary glands should be examined meticulously. When there is a history of irradiation and particularly when palpable. - thyroid disease is suspected, the clinical examinationshould berfellowed by a thy roid scan using 9901 Technetium pertech- netate. The 99111 Tc thyroid scan delivers 0.1 rad to the adult thyroid, as compared with the '311 scan which delivers. 100-200 rads. Although information on past X-ray exposure may not be known by a young patient, nor readily volunteered by parr ents, the.examining physician should pur sue any uncertain'aspect of the past medi cal history by securing copies of pertinent medical records. ' The optimal therapeutic approach to the young adult with no currently detect able abnormality but with a past history of irradiation is less clear. The efficacy of thyroid hormone to suppress thyroid stim ulating hormone (TSH) in preventing malignant neoplasia is unproven although: suppressive therapy has been used in the evaluation of a thyroid nodule.74 *00) 0910 CA-A CANCER JOURNAL FOR CLINICIANS The tumorigenic effect of irradiation on the thyroid has also been documented through a prospective study by the Atomic Bomb CasualtyCommission and the Japr anese National Institute ofHealth (ABCCJNIH). The ABOC-JNIH Adult Health- Study Program commenced in 1958 and includes standardized biennial medical examinations of about 20,000 persons selected from the 1950 cohort of 109,000 atomic bomb survivors. Prior to 1955',excessive mortality due to -leukemia was the only evidence of radiation carcino genesis among the atomic bomb survivors. When compared with a risk of 1.0 in age and sex-matched controls with little or no exposure, the relative risk of clinically, diagnosed thyroid cancer in the high ex posure subgroup was increased signify candy to 5.0 m women and 9.4 in men. Whereas the relative risk of clinically ap parent thyroid cancer in men who were exposed within 2,000 meters from.the hypocenter of the. bomb explosion was increased significantly only during the examination period 1958-1962, the risk in women with similar exposure continued to be excessive, even after 25.years of fol low-up. The cumulative risk of thyroid cancer was highest in subjects who were under 20 years of age in 1945 and were exposed to at least 50 rads of gamma and neutron radiation.75-76 There have been isolated case reports of thyroid cancer occurring between four and 12 years after 1511 therapy for thyro toxicosis.77 A prehminary analysis of the Cooperative Thyrotoxicosis Follow-up Study indicated that theinddence of thy roid cancer or leukemia was not signifi cantly different between 22,000 patients treated with mi and 14,000 patients treat ed with surgery or antithyroid medica tions.78 In this comprehensive study, the mean follow-up time was 15 years, and most of the patients examined were over ' 40 years of age when first treated. The report concluded that children and young adults treated with lower dose mi therapy for hyperthyroidism appeared more sus ceptible to the development of adenomas. Higher ablative doses of5,000-10,000 rads of mi will lead to a higher inddence of of thyroid parenchyma which may pre dude all replication and tumorigeaesis. Since the latency period for radiationinduced thyroid cancer may be as long as 20 to 40 years, the final chapter on the treatment of thyrotoxicosis in children with radioactive iodine has not yet been written. In 1954, the population of the Rongelap Atoll in the Marshall Islands wds 'ex posed to radioactive fallout from a ther monuclear bomb.79The inhaled and in? gested beta - and gamma radionuclides included the short-lived isotopes of.radio activeiodinewhichresulted in an estimated exposure dose to the thyroid-.of between 700-1,400 rads in children and 220-450 rads in adults. The highest incidence of benign and malignant thyroid nodules Was recorded clinically in the heavily ex posed groups who were under 10 years old at the time of exposure. The annual inci dence of thyroid cancer was estimated to be 2.1 per million children per rad. Thyroid and Breast Cancer-- la There a Common Etiology? In a review of the Connecticut experience between 1935-1964, Schoenberg8*) failed to observe a statistically significant inr crease in the incidence of thyroid cancer in breast cancer patients. Therisk Ofbreast- cancer was increased 1.8 times to expecta tion in thyroid cancer patients, but this was not determined to be. statistically significant. '' During the brief-interval of. follow-up obtained in the Third United States Can cer Survey (1969-1971), the inddence of histologically diagnosed thyroid cancer was increased significantly in women with breast cancer, but the converse rdationship, i.e., an increased incidence ofbreast cancer in women with thyroid cancer, was not observed.81 ' , In a survey ofmultiple primary cancers at Memorial Sloan-Kettering Cancer Cen ter, Schottenfeld and Berg observed that the incidence of clinically diagnosed pap illary and follicular thyroid carcinomas in 9,792 women with previously diagnosed breast cancer was 0.2 per year per 1,000 VOL 28, NO. 2 MAHCH/APRIL1978 8001 091i I ' Inheritance Clinical and pathological feature* Thyroid . Adrenal medulla Adrenal cortex Parathyroid Pancraat Pituitary Other phenotypic features B G 01 Type 1 (Warmer!3 Type II (Sipple)31 ? Autosomal dominant with high degree of penetrance. Thyroid disorder In 20% usually adenoma, but may include differentiated cardnoma (not medullary), col loid goiter, thyroiditis or thyrotoxicosis. Autosomal dominant with high degree of penetrance. " Medullary carcinoma, frequently multifocal. Elevated serum calcitonin with exaggerated response to calcium or glucagon infusion may facilitate . : diagnosis of carcinoma or C-cell hy- ; perplatia. Increased serum and tissue hlstaminase activity can serve as bio-. chemical marker for primary and mar" tastatic carcinoma. (Hlstaminase Is found normally in human intestine, : kidney and placenta.) Ectopic pro- ; ductlon of serotonin and prostaglan dins may give rise to carcinoid end dirrheal syndromes, respectively. . Pheoehromocytoma may be bF lateral. Diffusa or local hyper- plasia may precede tumor forma- . tion. ' Adenoma, diffuse hyper- piasla or carcinoma. Cushing's syndrome may be secondary to ectopic secre tion of.ACTH. Aldosteronoma. . Diffuse hyperplasia secondary to ? ACTH secretion by medullary thy roid carcinoma. Hyperparathyroidism due to adenoma or hyperplasia in most patients. Less common and characterlstical- :' ly hyperplasia rather than adeno- . ma. More likely a secondary re- > sponse to the hypocalcemfc action of calcitonin, than an expression of genetic plelotropism. Adenoma, hyperplasia (microadenomatosis) or car cinoma of non-beta islet cells. Accompanied frequently by elevated fasting serum gastrin and intractable peptic ulcer diathesis (Zollinger-Ellbon syndrome). Glucagon and in sulin-secreting adenomas have also.been described. Adenomas In about 65% of patients. Frequently non functional, but may give rise to acromegaly or FoibesAlbrlght syndrome (amenor rhea and galactorrhea)! Bronchial and intestinal car Multiple mucosal neuromas of lips, cinoid tumors, multiple tongue, eyelids, segmental gang- - lipomas, schwannomas and lloneuromatosls of large intestine thymomas. resulting in megacolon, neurofibro mas, cafe au leit spots and marfBn- old body habitus. These pheno typic features in conjunction'with medullary carcinoma and pheo- -, 0912 chromocytoma are' now designa- - i _ tedMEA III. -> patients, or four times that expected. The: ence TRHsecretion.Mittra88-*8 described observed risk of thyroid cancer in women a prolactin-thyroxin antagonism in the with breast cancer was statistically signi- rat whereby, in the absence ,of thyroid ficant at the one percent level. The inci- hormones, the mammotrophic effect of dence of breast cancer in g27 patients with endogenous prolactin was enhanced;; thyroid cancer, ai^>ugh not statistically Prolactin is a sustaining factor in the significant, was 0.9 per year per 1,000 patients or 1.5 tunes expectation. The magnitude of increase in. the incidence growth of mammary carcinoma in some laboratory animals. For example, in the absence of the ovaries and adrenals, pro of thyroid cancer in our breast cancer iactjn alone can maintain the growth of patients did not exceed that observed an existing mammary carcinoma in the throughout our population of hospital rat. The role of prolactin to human breast cancer registry patients. We observed a cancer is less certain. Significant prolactin 5.7-fold excess of second primary cardnomas of the thyroid in 41,341 cancer, patients and after 123,531 person-years of stimulation occurs during pregnancy and lactation, yet .pregnancy before age 30 is relatively protective against breast cancer follow-up. Because the incidence of breast cancer was not seen to increase significantly in thyroid cancer patients, and because of the generally observed increase of second primary thyroid cancers, we were unable to determine if a common etiology for both breast and thyroid can- when compared with the risk noted in nulljparous women or in women whose first pregnancy is after age 30, and neither the duration nor the frequency of lactation is significantly correlated with the risk of breast cancer. Blood prolactin concentrations are not consistently aberrant in cer might have exited. ' . . .. women with breast cancer, although ele- Experimentally, ionizing radiation and vated prolactin, estradiol and estrone hypothyroidism augment'tumorigenesis : levels have been detected in the daughters in the thyroid and breast. Previous case r breast cancer patients, control studies of women with breast can- Mittra and Hayward86 studied the role cer that used conventional tests of thyroid of the thyroid in breast cancer by assessing function failed to provide unequivocal the adaptive alterations in the hypothai- evidence that hypothyroidism predisposes . amic-pituitary-thyroid axis. By measuring to breast cancer.88 Although a positive levels of TSH before and after TRH: stim- correlation has been suggested for coun- illation, they observed evidence of hypo- tries at increased risk of endemic goiter and breast cancer mortality, a simitar correlation is not evident between thyroid thyroidism in 10 percent of women with early breast cancer, 14 percent with advanced breast cancer, and in none of their cancer and breast cancer incidence. For example, the Chinese women living in Hawaii do not exhibit an increased risk of breast cancer. Although a study in Japan suggested that the risk of breast cancer was significantly increased in women with Hashimoto's thyroiditis, this was not con- age-matched hospital controls. The plasma concentration ofTSH was significantly higher in patients with breast cancer, These recent studies.are of interest if we recall that Sommers in 1955 reported in a controlled necropsy study that pituitary amphophil hyperplasia ("thyrotropic firmed, at least in the population studied basophils") and thyroid atrophy were at the Mayo CUnic. present with significantly greater frequen- Thyrotropin-releasing hormone (TRH) from the hypothalamus is not only in breast cancer patients. Thyroid,atro^.interpreted as the most significant required for the normal synthesis and anatomical alteration m explaining ap secretion of thyroid stimulating hormone: endocrine imbalance that predisposed to (TSH), but also stimulates the secretion breast cancer. of prolactin. The concentration ofplasma- ' The role of the thyroid in breast cancer free thyroxine regulates the responsive-- is a question that has been pursued since ness of TSH to TRH and may also influ- at least the time of Beatson in VOL SB. NO. 2 MARCWAPRIL1978 -. *00.1 0913. HFM -003515 There is now an apparent renewal of in terest in thyroid dysfunction as an etio- logic factor in cancers of the breast, ovary and endometrium, and in invoking com mon factors within the hypothalamus arid anterior pituitary to explain a presumed association of breast and thyroid can cer. w-w In our view, the multiple primary cancer studies that have been described previously do not substantiate the infer ence of a common cause for thyroid can cer and breast cancer. (3 References________________ 1. Cancer Statistics, 1976. CA 26:14-29, 1976. 2. Burbank, F.: Patterns in Cancer Mortality in the United States: 1950-1967. National Can cer Institute, Bethesda, Maryland, 1971. 3. 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McKenzie, J.M.; Zakariga, M.,.and Bon- dectoma. Am. J. Surg. 116:887-890,1968. nyns, M.: Graves' disease. Med. Out. North 40. Sato, T., et.al.: Concurrence of <roud Auri. 59:1177-1192,1975. VOL 28. NO;2MARCH/APRH.1978 B ? 0 1 0 915 HFM -003516 38. Bastenie, P.A.; Ermans, A.M., and Deles- 76. Parker, L.N., et al.: Thyroid carcinoma pessc, G.: Chronic lymphocytic thyroiditis and after exposure to atomic radiation. Ann. Intern.- cancer of the thyroid. In: Bastenie, P.A., and Med. 80:600-604,1974. ft. Ermans, A.M. (eds.): Thyroiditis and Thyroid 77. Hayek, A.; Chapman, E.M., and Craw Function. Oxford: Pergamon Press, 1972. ford, J.D.: Long-term results of treatment of Pp. 139-170. thyrotoxicosis in children and adolescents with; 59. Hayes, H.M., Jr., andFraumeni, J.F., Jr.: radioactive iodine. N. Engl. J. Med. 283:949k' Canine thyroid neoplasms: epidemiologic fea 953,1970. .. -ft; ' . tures. J. Natl. Cancer..Inst. 33:931-934,1973. 78. Dobyns, B.M.,etal.: Malignant and benign' 60. Crile, G., Jr., and Hazard, J.B.: Incidence neoplasms of the thyroid in patients treated for . of cancer in struma lymphomatosa. Surg., hyperthyroidism: a report ofcooperative thyro- . Gynecol., Obstet. 113:101-103,1962. toxicosis therapy follow-up study. J. Clin. 61. Duffy, B.J., Jr., and Fitzgerald, P. J.: Can Endocrinol. Metab. 38:976-998,1974. ftftft cer of the thyroid in children: a report of 28 79. Conard, R.A.: A 20-year review ofmedical ft cases. J. Clin. Endocrinol. 10:1296-1308,1930. findings in a Marshallese population accident 62. Clark, D.E.: Association of irradiation tally exposed to radioactive fall-out. Upton,' - with cancer of the thyroid in children and ado New York: Brookhaven National Laboratory, lescents. JAMA 159:1007-1009,1955. 1973. ; 63. Pincus, R.A.; Reichlin, S., and Hcmpel- 80. Schoenberg, B.: Multiple primary malignant mann, L.H.: Thyroid abnormalities after neoplasms: the Connecticut experience, 1935k; radiation exposure in infancy. Ann. Intern. 1964. New York: Springer Yerlag. (In press.) ft Med. 66:1154-1164,1967. 81. Horm, J.W.: Personal communication. ft- 64. Winship, T., and Rosvoli, R.V.: Thyroid 82. Schottenfeld,D.,andBerg,J.W.:Incidence,. . carcinoma in childhood: final report on a 20- of multiple primary cancers. IV: Cancers of the;' year study. Clin. Proc. Child. Hosp. 26:327 female breast and genital organs. J. Natl. Can-. - 348,1970. cer Inst. 46:161-170,1971. 65. DeGroot, L.J., and Paloyan, E.: Thyroid 83. Schottenfeld, D.: The relationship ofbreast' carcinoma and radiation: a Chicago epidemic. cancer to thyroid'disease. J. Chronic Dis. 21:' JAMA 225:487:491,1973. 303-313,1968.: ftft! 66. Consequences of thyroid radiation in chil 84. Itoh, K., and'Maruchj, N.: Breast cancer in.s dren. (Editorial) N. Engl. J. Med. 292:204-203, patients with Hashlmoto's thyroiditis. Lancet ; 1975. 2:1119-1121,1975. ft' % 67. Refetoff, S., et al.: Continuing occurrence 85. Maruchi.N,; Annegers, JJF., and Kurland,!' of thyroid carcinoma after irradiation to the L.T.: Hashimoto's thyroiditis and breast can-: heck in. infancy and childhood. N. Engl. J. cer. Mayo Clin. Proc. 51:263-265,1976. Med. 292:171-173, 1975. 86: Mittra, I., and Hayward, J.L.: Hypotha?/ 68. Becker, F.O.; Economou, S.G.; South- lamk-pituitary-thyroid axis in breast cancer, ft wick, H.W., and Eisenstein, R.: Adult thyroid Lancet 1:885-888; 1974. ft " .ftvj:.' cancer after head and neck Irradiationininfancy 87. Mittra, l.; Hayward, J.L., and McNeiUy, ft and childhood. Ann. Intern. Med. 83:347-351, A.S.: Hypothalaituc-pituhary-prblactin axis m 1975. . ': ' breast cancer. Lancet 1:889-891,1974. ft- 69. Favus, M.J., et al.: Thyroid cancer oc 88. Mittra, I.:Mammotropiceffectofprolactin y curring as a late consequence of head and neck enhanced hy .thyroidectomy. Nature 248525 irradiation. . N,, Engl. J. Med. 294:1019-1025, 526,1974. ft ft 1976. 89. Schottenfeld, D.: Epidemiology of breastiV 70. Modan, B., et al.: Radiation-induced head caitcer. Clin. Bull: 5:135-143(1975. ' 'ft' and neck tumors. Lancet 1:277-279,1974. 90. Henderson.B.E., et al.: Elevated serumft 71. Shore, R.E.; Albert, R.E., and Pasternak, levels of estrogen and prolactin, in daughters of ft ' B.S.: Follow-up study of patients treated by patients with breast cancer. N. Engl. J. Med.ft: X-ray epilation for tinea capitis. Arch. Environ. 293:790-795, 1975. ft ft -- Health 31:21-28,1976. 91. Sommers, S.C.: Endocrine abnormalities-.. 72. Hempelmann, L.H., et al.: Neoplasms in : in women with.breast cancer. Lab. Invest. 4: ft! persons treated with X-rays in infancy: fourth 160-174,1955. ft ft survey in 20years. J. Nad. Cancer Ink. 55:519 92. Beatson, G.W.: On the treatment of inopft 530,1975. erable cases of carcinoma of the mamma-- - 73. Silverman, C., and Hoffman, D.A.: Thy suggestions for a new method of treatment with roid tumor risk from radiation during child illustrative cases. Lancet 2:104-162,1896. ft hood. Prev: Med. 4:100-105.1975. 93. Stadd, B.V.: Dietary iodine and risk of : 74. Information for physicians on irradiation- breast, endometrial, and ovairian cancer. Lan related thyroid cancer. Report of Workshop on cet 1:890-891,1976. ' ' the Late Effects of Irradiation to the Head and 94. Edington, G.M.: Dietary iodine and risk of Neck in Infancy and Childhood. CA 26:150 . breast, endometrial, and ovarian cancer. Lan-.: 159,1976. cet 2:1413-1414,1976. , 75. Jablotr, S.; Belsky, J.L.; Thchikawa, K., 95. Williams, R.R.: Breast and thyroid cancer and. Steer, A;-. Cancer in Japanese exposed as and malignant melanoma promoted by alcohol- . children to atomic bombs. Lancet 1:927-932, induced pituitary secretion of prolactin, TSH k and MSH. Lancet 1:996-999,1976. ftft 00 1 ISII'3 ' " . ' CA-A CANCER JOURNAL FOR CLINICIANS ' United States Shipyards Irving J. SetikoM, M.D. and E Cuyler Hammond, Sc.D. CLINICAL LATENCY OF for example, where individuals simply ASBESTOS-ASSOCIATED CANCER working near "asbestos workers*' are ex posed to the same dusts. Riskextendseven During the past 15 years the important disease potential of asbestos exposure has been clarified, The principal hazards have been demonstrated to be cancer of a numher of sites; ^ndasbestosis. Among ashestos workers. Approximately 20 percent of all deaths are due to lung cancer, six per cent or seven percent to pleural and/or peritoneal mesogielioma, and there is an excess found in cvend other categories (e.g., cancer of the esophagus, stomach, colon-rectum, oropharynx, lafynx, kid ney). Table 1 provides asanalysis ofcauses of death among 17,800 asbestos insula tion workers , in , the United States and Canada followed prospectively from January 1,1967 to January 1,1977. ft Risk of asbestos-associated disease hasalso beenobserved in workers in other trades where asbestos exposure occurs-- to individuals not employed in an asbes- tos-contamlnated environment; mesothe lioma has been found among family con tacts of asbestos workers residing in the same households, as well as amqpg people living witmri a quarter of a mile or so of asbestos plants or other facilities which have' used asbestos-containing materials. Althongh mesothelioma is not neces sarily the most commondisease resultjug , from asbestcis expostire, it provides a very useful index of such problems, 'Since it is only uncommonly seen as a result^ex posure to other agents or without iden tified cause. Large scale investigations of - series of cases of mesothelioma in France, Great Britain, the Netherlands `-'andelse- where have demonstrated that the large majority of these cases can be traced to : prior asbestos exposure. ft For these neoplasms, as for all can cers due to asbestos exposure (and, in deed, for extensive asbestosis as.well), a ( Dr, Selikoff is Professor of Medicine, and rather uniform characteristic has been Director, Environmental Sciences Laboratory, Mount Sinai School of Medicine, City Univer ft found: the disease usually'does not be sity of New YorkiNewYtirk, New York. come clinically evident for 15, 25, 35 or Dr. Hammond isVice President, Epidemiology more years from onset of asbestos ex Cand Statistics, American Cancer Society, Inc., New York, New York, ft posure. The initial decades are periods of grace with no illness or disability. While This is a special report from the Environmental some early X-ray changes may be seen Cancer - Research . Project,1 American Cancer Society and the Environmental Sciences Lab-' after five to 15 years, they are limited in oratory of the Mount Sinai School of Medicine extent and not usually accompanied by ofthe City University of New York.: ' significant symptoms. They merely dem- VOL 28, NO, 2 MARCHIAPRIL1978 soci C 717 HFM -003517 : - ' ' TABLE 1 ' \ ' . Deaths among 17,800 asbestos insulation workers . in the United States and Canada January 1, T067-Jamiary 1,1977 . ' "5 ; > f Number of men Man-years of observation ' 17,800 166.856 Expected* Observed Total deaths, all causes Total cancer, all shas Lung cancer Pleural mesothelioma Peritoneal mesothelioma Cancer of esophagus Cancer of stomach Cancer of colon-rectum All other cancer - Asbestos)* All other causes 1,660.96 319.90 105.97 7.01 14.23 37.66 164.83 1,351.06 2,270 994 485 66 109 18 22 69 235 162 1.114 . 'Expected deaths are based upon white male age specific mortality data of the U.S. National Canter for Health Statistic! for 1967-1975 and extrapolation to 1976. "These are rare causes of death In the general population. The membership of the International Association of Heat and Frost Insulators and Asbestos Workers, AFL-CIO, CLC, was enrolled onJanuary 1, 1967, and has been observed since. oiutrate that enough asbestos exposure has occurred to produce such changes. In this sense, they are harbingers of future risk of clinical disease. Thbles 2-5 illustrate the characteristic latency of asbestos disease. In one group o? 1,117 asbestos insulation workers in the New York metropolitan area, most of 725 workers with less than 20 years from on set of exposure (Thble 2) had normal Xrays. When changes were present, they were minimal in extent. On the other hand, after the 20-year point, most X-rays were found to be abnormal, frequently exten sively so.4 Tables 3-5 show that few mesotheljomas and little excess cancer of the',, lung occurred less than 20 years from on-" set. Most occurred 30 or mote years from: onset of exposure. A young man may be gin work at the age of 18; his risk of as bestos-associated cancer does not become, substantial until he Is 40,50 or older. : EARLY STUDIES: MESOTHELIOMA IN SHIPYARDS In 1968, the first warning that asbestos 8&01 6^18 VA CANCER JOURNAL FOR CLINICIANS Onset of (vrs.) 40+ 30-39 20-29 10-19 0-9 , y/ ' TABU2 X-ray changes in asbestos infglatipn workers4 No. 121 194 77 379 346 Norma} 5.8 12.9 27.2 55.9 89.6 Abnormal 94.2 : 87.1 72.8 44.1 10.4 Asbastosif (grade) 1 23 35 51 28 102 49 18 35 17 4 158 9 0 36 0 0 . Total 1,117 51.5 48.5 366 126 60 disease might be a serious problem in of 1946rl976, total employment remained shipyards was sounded by Harries Jin in this range, fluctuating with economic Great Britain and Stumphius6intheNeth- conditions and the country's shipbuilding erlands when they reported instances of program. The 200,000-250,000 figure mesothelioma among shipyard workers. characterized the total number in the What was worrisome was that the men yards at one time; however, there was were not "asbestos workers" but rather,- much turnover, and the total number of individuals employed in other trades. At different individuals was much larger. the Devonport shipyard of the Royal There are no accurate data readily avail Navy, for example, mesothelioma in a able which could tell us how many differ boilermaker, a fitter, a shipwright, a weld ent people--.carpenters, riggers;-; electri er and a laborer were described. cians, draftsmen, welders, etc.---were so This raised the important qumtion of employed. Nevertheless, the early obser whether asbestos use in shipyards might;, vations (soon augmented, by later stud result In the exposure of the workers em- . ies7-*) pointed to a potentially serious ployed in many trades, to dust derived problem. from the few "asbestos workers" in their \ Harries has recently published his fur midst. In 1943; in the United States, for ther observations at Devonport, through example, approximately one in 500 ship 1973.'By the end of the year, he had ob yard workers was an insulator. The other served 55 cases of mesothelioma in that 499 included welders, shipfitters, machin shipyard alone. Again, trades other than ists, pipefitters, electricians, boilermakers ``asbestos workers'' gave evidence, of the and painters (Thble 6). The significance of hazard. Only two of the 55 worked directly this question is made apparent by the fact : with asbestos (lagger, sprayer). The other that during World War II, approximately 53 included 14 shipwrights, nine boiler 4,500,000 men and women worked in our makers, eight fitters and eight electricians shipyards, many of them under conditions (Tfcble 7). - ; -- in which exposui-e to asbestos was possible. John Edge of High Carley Hospital After World War II the total number of has published similar data-from shipyards shipyard workers rapidly decreased from in Barrow (Table 8)10; his most recent a high of 1,700,000 in the last months of observations are particularly disturbing. 1943 to 200,000 or so; During the period In Barrow, 429 individuals were seen, be- VOL 28, NO. 2 MARCH/APRIL 1978 ooi my HFM -003518 TABLE 3 Deaths among 17,800 asbestos insulation workers in the United States and Canada January 1,1967-January-.I-, 1977: Analysis ,by v duration from onset of employment 4 :. - Total man Man-year* of observation ` 12.683 89,466 12,061 77,389 Before 20 years from onset 20 or more years from onset Expected* Observed Expected* Observed Total death*, all cairns 283.93 324 1,377.01 1,946 Cancer, all sites 42.65 83 277.25 911 Lung cancer Pleural mesothelioma Peritoneal mesothelioma . Cancer of esophagus Cancer of stomach - Cancer of colon-rectum 1Z03 .. ** 0.66 1.56 4.07 36 2 3 1 1 4 93.94 * ** 6.35 12.67 33.79 449 64 106 17 21 55 ; Asbestosis ** 8- 164 :r. * Expectad deaths ara bated upon whfto malt age specific mortality data of the U.S. - . National Center for Health Statistic* for 1967-1976 and extrapolation to 1976. ' . These are rare causes of death In the general population. .. ' - tween 1964 and 1971, with radiologically evident pleural plaques; these plaques were considered to signal prior.shipyard employment. Controls were 429 men from a neighboring city (Carlisle), matched for age and date of X-ray; they had no plaques on their roentgenograms. Both groups were observed through 1976, i.e., for a minimum of five years. Among the 429 men with pleural plaques, there were 127 deaths; those with no plaques suffered 74 deaths. The excess was primarily in two categories, lung cancer and mesothelioma. There were T9 deaths from lung cancer and 23 from mesothelioma among the former shipyard workers. As for the com trols, four died of lung cancer and none, died of mesothelioma. 4f ' . Findings of an extraordinary increase -, of mesothelioma were also reported last , year from the French shipyard area ih Western Brittany. Lajartre et'al. analyzed cases of pleural mesothelioma in Nantes; In the period 1957-63, there were two cases; from 1964-1970 there were 12; and from 1971-1974 there were 24.12 This was interpreted as consistent with the mark edly increased shipbuilding program dur ing and after World War II, and with its ' attendant risk of asbestos exposure. / aooi. e t' CA-A CANCER JOURNAL FOR CLINICIANS. ` TABLE# 4 Deaths among 17,800 asbestos insulation workers in the United States and Canada, ,1*0.1,1967-4an 1,1977: 1 Analysis by dotation froiii onset of emptoymant ' * - Duration Numfrom bar onset of (years) men - Person- . ' yetre: . of observation Lunge Expected* Observed Pleura! mesothelioma No./IOOO parson-years Peritoneal mesothelioma No./1OO0 , . persorvyaars <10 10-14 15-19 20-24 25-29 30-34 36r39 40-44 45+ 5,552 . . 2RJ383 9,063 29,003 9,948 4 34,069 8,887 -.314269 6,596 20#67 ; 3,547 4 11.698 2,019 5,401 . 1,108 ' 3,160 1,030 5,305 0j69 2.77 8.57 17.03 21.04 18.48 11.47 8.12 17.82 0 7 - 29 69 104 112 - 66 ' 39 : 69 0 0 0^6 0.19 0.73 0,86 2:96 1.27 2.45 0 0 ; 0.09 , 0.10 0.87 - 1.90 3.33 5.06 5.47 ; 'Expected deathsare based upon whits male ega specificmortality data of the U.S. National Cerrt^rfor H^alth Sttrtlstles for 1967-t97B end extrapolation to 1976: . Smoking h*bit*?t teken Into account. ` ' ' --- - ASBESTOS DISEASE IN U S; SHIPYARDS employed in shipyards had unhappy dis ease experience, with markedly increased, death rates of cancer (lung cancer, pleural mesothelioma, peritoneal mesothehpma, There has been comparatively little writ gastrointestinal cancer) and asbestos.14 ten concerning thepotential for asbestos- These observations, however, were,con- disease hazards hi U.S. shipyards. In part, fined to insulation workers, and jwhile;' this may have been. due to the fact that in they painted to a possible accompanying the latter part of World War II a survey difficulty among other shipyard trades, ' directed to this question failed to demon expedally In view of British experience, strate the prevalqace of significant asbes detailed observations concerning. 4pther tos disease. At thitTime, 1,074 insulation workers werenot available. - workers employUd"in TJiS: yards were " The potential for asbestos disease in; examined and, with few exceptions, no U.S. shipyards was further iughiigh|^d by evidence of dfceaspikas found. ''Unfortu* accumulatingknowledge that the workers nately, the significance of the fact mat the who manufactured the asbestos insulation very large majority, of men had begun, materials used in U.S. yards during and working only a shoj* time before was not afterWorld War II were themselves found appreciated; neither was it understood to suffer serious asbestos disease. Inyesti-. that X-ray evidence of disease could not gatiops of the employees at one such plant be expected to appear until one or two de showed markedly increased risk of neo cades later. plastic disease and asbestosis, including During the 1960's, evidence accumu - increased risk of death of cancer with as lated that "asbestos workers" (insulation) little as one month of employment; *5; *6 VOL: 28, NO. 2 MARCH/APRIL 1978 8C01 921 Fie-1 S.P.&J.M. Extensive bilateral pleural calcification In former shipyard workers. Asympto? mafic. No part of pleura is immunecostal; diaphragmatic, mediastinal, pericardial. Bilateral calcifi cation of this sort rarely seen except with prior asbestos exposure. Fig. 2 J.B. Both fibrQtlp plaques and pleural Fig.. 3 J.W- Age 49, 1975. Trud< drJver.,until calcification in x-ray of former shipyard worker. . 1 WO, wh$Rhe became "pipe covered In aato- . Asymptomatic. Thek presence ls merely evl- yard-'.X-ray, Afteen.years fater, shows reneular . dence of prior asbestos exposure and not In- (Irregular) opacfttes of moderate profuston(2/2 dlcative that mesothelioma will necessarily In the ILO U/C Classification). Some shortness follow ' of breath on exertion. Note: Infiltrate Intower lung fields, upper lobes clear. This Is common. ... Even'wives and children of the employed workers showed evidence of asbestos dis ease, indicating that exposure of lesser, intensity might be seriously hazardous as well, n RECENT SURVEY OF SHIPYARD WORKERS, GROTON, CONNECTICUT Cases of asbestos-associated disease among workers employed in a shipyard in Groton, in 1974-1975, were brought to our attention. Against the background ofwhat was already known concerning the poten tial for asbestos disease in shipyards, it appeared useful to obtain information concerning whether there was the likeli-, hood of a high incidence of such disease or whether the cases seen were isolated, random exceptions. Lung cancer, mesothelioma, extensive asbestosis and other serious complications of asbestos exposure are late findings. Limited X-ray change (parenchymal, with in the lung, or pleural) often precede these serious consequences. While such change may occur to an extent visible by X-ray without subsequent cancer or disabling asbestosis, their appearance among a group of workers provides evidence of prior significant asbestos exposure. Ab- setice of such X-ray changes is no guar-, antee that important asbestos exposure has not occurred. Many workers may have, had asbestos exposure sufficient to cause, death from mesothelioma, for example, without showing X-ray change. Neverthe less, taken as a whole, absence of X-ray change in a group of workers suspected1qf; having been exposed to asbestos provides some evidence that the exposure was lim . ited. On the other hand, the presence of characteristic asbestotic X-ray abnormal ities is pritna facie evidence that, overall, there was important asbestos exposure in the group. ;'v' In light of this, we sought to ascertain whether there was significant prevalence of asbestotic X-ray abnormalities among Groton shipyard workers. Examinations HO 01 092 2 CA-A CANCER JOURNAL FOR CLINICIANS were largely limited to those whose em- . present in 274 of 636 workers with less ployment had begun 15 or more years be^ than 20 years from onset of exposure (43.1 fore; all were volunteers. A caveat is in percent) and among 185 of 364 shipyard . order: there is no way of knowing, under workers 20 or more years from onset (50.8 these circumstances, whether those who percent). Parenchymal disease was seen in volunteered were necessarily represen- 29.6 percent of the former group and 36.8 tative of the entire work force, or even of percent of the latter. Pleural changes tyere their specific employment category. Al- found in 23.1 percent of the less experi- together, 1,000 men were examined, in- enced workers and in 29.7 percent of the eluding 157 boilermakers, 121 pipefitters, men with longer experience. The high ' 73 insulators, 82 painters, 69 carpenters, ; prevalence of pleural changes was not un- 117 welders, 104electricians, 108 outside expected, having been found previously : machinists, as welLas laborers, raolders, among shipyard workers in Britain and lead bonders, office workers, draftsmen, elsewhere.1* .; . guards, and decontamination technicians. The importance of duration from on- Films werecatejfprizedusingthelnter- setofexposureisclearlyseenin TablelO, national Classification of Radiographs of where it is found that among 303 workers Pneumoconioses (ILO U/C)(Appendix 1). who began work only in 1961 or later, 115 Overall, approximately half of the (38.0 percent) had abnormalities onX-ray. workers examined showed X-ray evidence In contrast, among 166 workers Whose of pulmonary and pleural changes of the employment began in 1950 or before, 85 sort regularly seen following direct or in- (51.2 percent) were abnormal, direct occupational exposure to asbestos.. :: No trade was immune to changes, (pulmonary asbestosis, pleural asbesto- Thbles 11 and 12 indicate that this was as sis). The findings are outlined in Tables 9 ; true for painters as if was for electricians, and 10. One or another abnormality was for carpenters as for machinists, and for VOL.26,NO.2MARCHIAPRIL T978. a 0 p 1 r. ", . > . ...... ....... HFM - 003520 TABLE 5 Deaths among 17,800 asbestos insulation workers in the United States and Canada, Jan. 1,1987-Jan. 1,1977: Analysis by duration from onset of employment -T - ' y Yean onset employment <10 10-14 10-20 20-24 26-29 30-34 36-39 40-44 46+ Total deaths 61 85 188 320 388 340 263 203 442 . cancer 0 8.24 16.43 18.44 26.80 32.94 26.09 19.21 15.61 Percent of all deaths Mesothelioma Pleural Peritoneal 0 0 1.06 1.88 3.86 2.94 6.32 1.97 2.94 0 0 1.60 0.94 4.64 6.47 7.11 7.88 6.66 '`^ Total :y.t. V--.: 0 V- 2-60|; ' 2.82 8.40; 9.41 13.43/. 9.86': 9-60/ Total 2270 21.37 2.90 4.80 7.70 boilermakers as for welders. Review of changes raises the question of increased work practices makes this quite under- risk of asbestos-associated neoplasms* in standable, of course. The conditions of the future. Those to be considered include shipyard , work have been such that it is . - cancer of the lung, pleural mesothelioma, likely that asbestos exposure would have ' peritoneal mesothelioma, and esophageal* occurred among all individuals at a work stomach, colorectal, oropharyngeal.' m- site where the material was being installed, ryngeal and renal cancer. The extent nf repaired or removed. Data are less certain ; this risk is not now known. .5 for the less common crafts, where fewer workers were examined. Although evi- CURRENT SITUATION dence of asbestotic changes was found/ : :' - . among some of these men and women as In terms of public health, the overwhelm- well, one can estimate a proportion only ing problem is the undoing, ameliorating with less assurance. or modifying of both current and anrici- Thus, exposure to asbestos under past pated results of past mistakes. Theprob- conditions, of an intensity sufficient to fans are straightfprward and, siinujjm- cause significant asbestotic X-ray change, neously, complex. To a considerable, $e- was common at the shipyard in Groton, gree, the complexity derives from the filet As a result, a large number of workers that we have had little experience to guide now have pulmonary changes associated us in such matters, especially on the scale with such exposure. The prevalence of found in the present situation. ' ' ;' such a high proportion of asbestotic X-ray The following recommendations -- 8001 CA-A CANCER JOURNAL FOR CLINICIANS necessarily incomplete and tentative--are; offered: '; ' \ : TABLE S ' ' ` 1. Knowledge concerning asbestos expo Percentagedistribution pf trades sure: .' ; .V Dissemination of information: under-:: standing the disease potential of asbes tos exposure (past and future) would be valuable for both worker and manager ment. /. : ' `. Avoidance of additional exposure:' appropriate engineering and industrial ' in private shipyards, June 194|: Trad* ' . Welders . Shiptitters Machinists . Percentage 16J ; 11.0 , , 8.1 hygiene methods are crucial; removal or repair of asbestos materials now in place presents a problem for the future. Pipefitters Electricians Carpenters 7.2 ; 6.6 6.1 2. Medical surveillance programs: Asbestosis: awareness of the presence of this disease bit both the patient and; the treating. physician would be im portant, since most deaths of asbestosis are due to interburrent respiratory in fections, rather than to progressive pul monary fibrosis. Pulmonary infections can be well treated, and experience has shown that many lives can be saved. /.Laborers. Burners Painters Sheatmstal workers ' Risers - . Chippers and caulkers . Boilermakers Crane operators 5.5 . 3.8 . . 3.1 . 3.0 . 2.8 2.8 2.3 1-3 ' ...... ' Lung cancer:' early diagnosis: can in crease the likelihood of successful treat Plpecoverers 0.2 ment to some extent (by no means as much as we would like). It is not known whether more energetic surveillance (as with frequent spt^um cytology examin ation) will increase the percentage of those successfully treated. Studies are . All other. ' 21.1 Source: Bureau of. Labor Statistic* Bulletin 824 now in progress to investigate this pos sibility. //- . multiplied by asbestos exposure.19 It is Colorectal cancer; early'diagnosis in*'- urgent that this information become creases the likelihood of cure. : available to workers who have beep, ex Oropharyngeal, laryngeal or renal car? posed to asbestos, and that every assis cinoma: awareness of theincreased risk. tance be afforded themtohelp in their of'these cancers Smproves chances for;: efforts to control and eliminate smok early study and/diagnosis of the pres- ing, espedally cigarette smoking: Sq:me ' ehce of these conditions, which can be itata are ako`available suggesting/that cured in many raises. ' . ' . cessation of smoking will, after a hum- a Pleural and/or peritoneal mesothelio- her of years, reduce the risk of lung rria: effective therapy is not now avail cancer, even with a history of prior cig able and early diagnosis does not sig arette smoking, Should these experi nificantly increase the likelihood of ences be confirmed, it will be even more survival. However, research concerning urgent to identify and alert former ship- therapy is now-underway in the United ` yard workers,- to acquaint them 'with States, Great Attain and France, and it '. the important risk of lung cancer should may be hoped that improved treatment they continue cigarette smoking- Cigar methods will become available. ' ' * ette smoking also increases the risk of m Education programs: ' serious disability associated with pul Smoking: lungcancer risk is greatly monary fibrosis, and of the develop- VOL 28, NO. 2 MARCH/APRIL1978 BO01 0925 HFM - 003521 TABLE 7 Mesothelioma tumors in Devonport Dockyard, England, 1964-1973* Asbestos!* (disability) No. % 16 10.3 36 23.1 15 9.6 4 Z6 16 9.6 11 7.1 6 3.8 6 3.2 48 30.8 156 Occupation Sprayers Laggers Shipwrights Boilermakers Engine fitters Electricians Caulkers-R (voters Welders All others Mesothelioma (deaths) No. ' 1 1.0 1 1,8 14 25.5 9 16.4 8 14.6 5 9.1 . 3 5.6 . 3 6.5 11 20.0 55 Marries, P.G., Envlr. Rai. 11:261-267,1976. TABLE 9 ; X-ray abnormalities among workers employed in shipbuilding and ship repair: TYPE OF ABNORMALITY Less than 20 years from onset of shipyard amploymant (636) 20 or more years from onset of shipyard amploymant (364) Total 'V Number % Number % Number % V_i;- Any abnormality All parenchyma Parenchyma only Parenchyma & pleura All pleura Pleura only 274 188 127 61 147 86 43.1 29.6 20.0 9.6 23.1 13.6 185 134 77 57 108 51 50.8 36.8 21.1 15.7 29.7 14.0 459 322 204 118 255 137 46.9 32.2 ' ' 20.4 116 25.6 : ; 13.7 \ 3001 Wdo CA-A CANCER JOURNAL FOR CLINICIANS. ' ; . TABLE8 Mortality experience of 429 shipyard workers in Barrow, England with pleural plaques on x-cay (1984-1971) compared with control men in Carlisle, without pleural plaques Tracing to Decembar.31,1976 Plaques .j t : Controls Alive Dead Not traced Causes of dsuth'. Lung cancer .: Mesothelioma G. 1. cancer . . . .. All othar cancer Ischemic hean disease Chronic bronchitis All other Muses 299 127 ( 30%) . 3(0.7%) ' : 429 ' ' 347 74 (17.2%) 8( 1.9%) 429 . : Plaques . Contrails :v > ' .' : > 19 23 ' 7 . - 13 34 ' 9 22 , - .. , . '. . jit-/:.'1 ' 0 ' 4. /; 7 -V ' 29 '- 9 21 . table 10 v - - X-Ray ataormalitiftfeijiupiig workers employed in shipbuilding onid ship repair: analysis by duration from onset of work V . NORMAL ABNORMAL Onset of work Total . No. % ; No. . ' % <1950 1951-1955 1956-1960 >1961 166 198 333 303 1000 81 48.8 98 49.6 174 52.2 188 62.0 541 64.1 85 61-2 100 50.6 159 47.8 115 38.0 459 45.9 VOL 28, NO. 2 MARCHWPRIL1978 flOOl 6927 H FM - 003522 TABLE 11 X-Ray abnormalities among shipyard workers employed in shipbuilding and ship repair: major crafts : 1 rATcnriRV All crafts Painters Machinists (outside) Pipefitters Insulators Electricians Boilermakers Welders Carpenters Years from onset of shipyard work All groups 20 or more years Abnormal Abnormal Number Number % Number % 1000 459 46.9 185 50.8 82 108 121 73 104 1B7 117 69 831 44 53.7 58 53.7 66 54.5 3S 52.0 55 52.9 80 51.0 42 35.9 38 55.1 10/26 12/32 25/34 2/7 23/34 41/84 25/48 12/33 40.0 37.5 73.6 28.6 67.8 48.8 52.1 36.4 Total 1000 459 45.9 185/364 50.8 ment of cancer of the esophagus. Again, educational programs wouldbe ofvalue. information is required for proper clin ical surveillance. 3. Assessment of the potential for ship yard asbestos disease: Household contact asbestos disease: while families of asbestos workers are at risk, it is not known whether ship yard workers tended to contaminate their homes with appreciable amounts of asbestos in the past, and whether this has resulted in disease risk. Such Necessary additional data: appropriate _ studies of mortality experience, status of retired workers and effects of mini; mal exposure are required for complete evaluation of the potential for future shipyard asbestos disease. Nevertheless, enough is now known to warrant rapid development of effective medical sur- veiUance programs. Further research can proceed apace. @ CA-A CANCER JOURNAL FOR CLINICIANS - '% .' ' TABLE 12 ' . "' X-Ray abnormalities ampng workers employed in thipbuildingandship repair: less common crafts Heavy equipment operators Laborers . Inside machinists Molden Lead bondets Decontamination technicians Guards w/o previous job in yard Office workers -- Draftsmen w/o previousjob in yard No. 13 7 30 12 21 12 12 37 Abnormal . 8/13 1/7 15/30 4/12 7/21 5/12 3/12 16/37 % 62 14 50 33 33 42 26 43 References 1. Bientz, M.; DiMenza, L.; Nebut, M., and Bignon, J.: Registre des mesotheliomes malins de ta pleure et du peritoine. Premiere resul- tats. Nouvelle PresseMed. 6:3114,1977. 2. Greenberg, M., and Davies, T.A.L.: Meso thelioma Register 1967-68. Brit. J. Indust. Med. 31:91-104,1974. 5 Zielhuis, R.L.;.Versteeb, J.P.J., and Plan- tejdt, H.T.: Pleural mesothelioma and exposure to asbestos. Int. Asia. Occup. Envir. Health 36:1-18.1975. 7 4. Selikoff, I.J.; Churg, J., and Hammond, E.C.: The occurrence of asbestosis among in sulation workersintheUnited States. Atm. N.Y. Acad. Sci. 132:139-155,1965. 5. Harries, P.G:: Asbestosis hazards in naval -dockyards. Ann. Occup. Hyg. 11:135-145,1968. V6;) Stumphius, J.i Epidemiology of mesothe lioma on Walcheren Island.' Brit. J. Indust. Med. 28:59-66,1971. v McEwen, J.; Finlayson, A.; Mair, A., and Gibson, AJid.M.: Asbestos and mesothelioma in Scotland. Int. Arch. Arbeilsmed. 28:301-311, 1971.- 8. Fletcher, D.E.: A mortality study of ship yard, workers with pleural plaques. Brit. J. Indust. Med. 29:142-145,1972. : 9. Hturies, P.G.: Experience with asbestos disease and its control in Great Britain's Naval dockyards. Envir. Res. 11:261-267,1976. 10. Edge, J.R.: Asbestos-related disease in Barrow-in-Furness. Envir. Res. 11:244-247, 1976. 11. Edge, J.R.: Personal communication, December 16,1977. ' 12. Lajartre, M,, et al.: Mesotheliomes pleurauxdCffus etamiante. Ouest Med. 29:615-621, 1976. 13. Fletcher, W.E.; Viles, F.J., Jr.; Gade, R.L., and Drinker, P.: A health survey of pipe covering operations in constructing naval ves sels. J.Ind. Hyg. Toxicol. 28:9-16,1946. ' 14. Selikoff, ;I.J.: Disease prevention in as bestos insulation work. Int. Symp. on Safety and Health in Shipbuilding and Ship Repairing, Helsinki, Finland, 1971. Occupational Safety and Health Series 827, ILO, Geneva, 1972. 15. Selikoff, I.J.; Hammond, E.C., and Churg, J. : Carcinogenicity of amosite asbestos. Arch. Env. Health 25:183-186,1972. CJ>) Seidman, H.; Lilis, R., and Selikoff, I.J.: Sfiort-term asbestos exposure arid cancer risk. Proc. Third Inti; Symp. Detect. Prev. Cancer, . 1977. .. . ' 17. Anderson, H.A., etai.: Household-contact asbestos neoplastic risk. Ann. N.Y. Acad. Sci. 271:311-323,1976. ? 18. Sheers, G., and Templeton, AR.: Effects of asbestos in dockyard workers. Brit. Med. J. 3:574-579,1968. 19. Selikoff, I.J.; Hammond, E.C., and Churg, j.: Asbestos exposure, smoking and neoplasia. JAMA 204:106-112,1968. VOL. 28, NO. 2 MARCH/APRIL 1978 i i/Qrfu 99 HFM - 003523 CT Scan-- Its Use and Abuse Robin Caird Watson, M.D. concept of computerized transaxial tomography (CT scan) was Hist envisaged by both Oldendorf in America and Hounsfield in England. It was Hounsfield who produced the first marketable unit, with the backing of the English Musical Instru ment Corporation (EMI), in 1971. This early unit was specifically de signed for intracranial examination and, although 'cumbersome, proved to be an effective diagnostic tool. Then, in 1975, machines capable of scanning the entire body were developed. Since that time, CT scanner manufacturers have proliferated --at a recent meeting of the Radiological Society of North America, some 20 dif ferent brands were exhibited--and rapid technological improvements have ren dered the CT unit an unparalleled diag nostic instrument. Using the CT machine, we are now able to accurately locate a disease process anywhere in the body, determine the na ture of the process (cystic, solid or inflam matory) and ascertain its extent, including any involvement with adjacent organs. The CT scan is infinitely more sensitive than many other tests, and the type of information gleaned is invaluable in the Dr. Watson is Chairman, Diagnostic Radio logy, Memorial Sloan-Kettering Cancer Center, New York, New York, and Professor of Radio logy, Cornell University Medical College, New York, New York. diagnostic workup of patients. Surgeons, for example, have benefited enormously : from the information provided preopera-. tively by the CT scanner. Ultimately, of course--and this should be our primary/ : "Clearly, we have not yet explored all the possible uses of the CT scanner... we must carry put extensive research in order to realize the potentials and determine the limits of CT use." interest--it is the patient who gains from, such diagnostic advances. Unlike many.*4 elaborate diagnostic procedures, the scan can be performed on an outpatient basis. Further, it is noninvasive and therefore entails minimal trauma and risk for the patient. '. Diagnosis, however, is not the only ./ application of the CT scanner--its great/?/ est effectiveness may well be in its use as a treatment tool for patients with cancer. In radiation therapy, pretreatment plan ning and posttreatment evaluations are being increasingly determined by CT scans. ; Similarly, the tean is being incorporated into chemotherapy protocols, both for* baseline and follow-up assessments. . Clearly, we have not yet explored all the possible uses of the CT scanner. In , addition to performing routine case exam- H 0 0 1 69 3 0 CA-A CANCER JOURNAL FOR CLINICIANS A inatipns, we must cany out extensive re not been replaced by CT scanning, since search in order to.- realize the potentials tl different methods provide different and determine the limits of CT use* :. sorts ofinformation. / -/A discussion of contemporary <tiag- Present Uses . Current applications of the CT scan are numerous; in some cases it has replaced long-used, standard procedures. Certain nostic techniques cannot ignore ultraso nography; significant technological advarices have made it a diagnostic modality of utmost importance. Indeed, it is even applications remain controversial, how ever, and one can-only seek guidelines and attempt to benefit from others' ex periences. CT examination of the head has been possible long enough that we can compare it to other diagnostic modalities. Based "Though a helpful adjunct, the CT scan has by no means eliminated / * explorative surgery." on our experience/it would seem that rou tine screening of patients with headaches is not indicated. However, since the intro duction of the scan there has been a dra matic diminution in the number of ar teriograms andpneumoencephalograms performed at most institutions, and this is a very positive development, as these tests are expensive, time-consuming and?, highly unpleasant for the patients. Certain ' other: examinations, such as skull X-rays and nuclide brain/scans, have also been replaced, to a largeextent, by CT scans. Generally, abdominal exploration should include.standard, routine examin- ations--upper GI. series, barium enema and I.V. P. -- before CT scanning. less invasive than CT screening, as no ra diation and no intravenous contrast are used. In obstetrics, therefore, ultrasonog raphy is vastly preferable to other tech niques, and it is also very effective in de lineating hepatic, pancreatic and renal tutnors, as well as the portal-hepatic re- gipn. Major vessels are also clearly seen with ultrasonography, which has the ad vantage of being multidirectional. In the investigation of pericardial and valvular problems, echocardiography is the tech- tuque of choice. / In the chest, routine PA and. lateral views or stereo films, decubitus views and CT Policy Criteria ' overpenetrated films should be obtained before CT scanning is ordered. In somemedical centers chest tomography has been replaced by CT scanning, based on ; the opinion that-scans are more sensitive. / With the large selection of diagnostic tests available, it is clear that this aspect of medical practice must be considered in physician education. Careful screening, by radiologists, of requisitions for CT . Within the thorax, the CT scan can scannings are of primary importance, in accurately localize and delineate medias Order to eliminate unnecessary examin- ; tinal, pleural and" parenchymal tumors, ations. The scanner is not a diagnostic and for examination of osseus or paraos- panacea and it must be usedwith-intel- seus soft tissue masses, the CT scan re iigenceand restraint. - // mains the test of choice. However, many ' * In establishing diagnostic justification centers use both ultrasonography and CT for CT scans, other considerations also scanning in such cases, as they are com enter into the decision. One such consider- plementary procedures. adon is time. Since the body scanner was ? Though a helpful adjunct, the CT scan first introduced, some two-and-a-half has by no means eliminated explorative years ago, immense technological im surgery, despite some claims to this effect. provements have been made. Prototype In fact, speaking generally, most invasive models, although unquestionably a tech techniques--such as angiography--have nological breakthrough, provided images VOL. 28, NO. 2 MARCH/APRIL 1978 ; . noi 0931 ` ' HFM - 003524 that can be likened to Dr. Roentgen's ear ly attempts. In addition, the early models required between two and four minutes to render an image of each slice. This time has been considerably reduced and a bet ter image can now be obtained in two to five seconds. However, it must be remem bered that a considerable amount of time is usually expended positioning the pa- "The scanner is not a diagnostic panacea and it must be used with intelligence and restraint." the market. Most patients undergo exam*, (nation only once; however, repeated ex aminations of the brain over a prolonged period of time can result in damage to the:cornea, and it is the responsibility of the radiologists to see that this sort of trauma does not occur. Future development env tails reduction of the amount of radiation while preserving the quality of the image. In sum, the criteria for formulating policy regarding CT scans are diagnostic reliability and superiority over other tech niques, time and cost considerations, and the safety and well-being of the patient. Governmental Regulation =' tients on the table and injecting them with contrast material. Thus, even with the improved scanning time, studies may take 10 to 20 minutes for each patient, as many examinations require evaluation before and after the injection of contrast materi al. In addition, reproduction of the image on the screen may take an appreciable amount of time, and this in itself can re duce the daily quota of patients. Another important factor is patient cost. Though fees charged for CT scan ning have been reduced during the last year, the cost to the patient--$100 to $400--remains high, relative to most other diagnostic tests. Some centers have separate charges for examinations with and without the use of contrast material, and patients must pay the double rate if both examinations are performed. The amount of radiation delivered during a CT scan is an aspect which has provoked little comment. The older, slow er units deliver a dose of approximately two rads per slice, which is in the range of acceptability, but the newer models de liver a significantly larger amount of radi ation to the patient. In an age in which we are all sensitive to the amount of radiation exposure patients receive, we must make a hard appraisal of our present practices.. It would seem appropriate for medical physics departments to play a dominant role in this matter and compare the doses incurred by various machines currently on In reality, CT policy is affected by devel opments that have little to . do with real needs. Distribution of CT scanners is a major problem currently facing the medical com munity. The scanner unfortunately made; its appearance just at a time when rising medical costs had caught the attention of federal agencies; the scanner itself was blamed for the increase in health care costs, though this assertion actually has no merit. The' federal government none- "In an age in which we are all sensitive to the amount of radiation exposure patients receive, we must make a hard appraisal of our present practices." theless felt compelled to involve itself in CT planning policy, and the certificate of need concept, making all equipment purchases over $100,000 subject to federal approval, grew out of these economic concerns. To further complicate the situ ation, recent HEW recommendations sug gest that before a hospital can acquire a CT scan, neighboring units must conduct 4,000 examinations per year. Again, this is not founded upon a realistic assessment,' as no CT unit can accomodate this many examinations. While the basic intent of aooi nv.i'i ;a-a cancer journal for clinicians these federal regulations is to prevent du plication of service and ensure adequate backup in terms of facilities and person nel, this sort of legislated distribution ap plies more logically to treatment modali ties than to diagnostic techniques--and the scanner is primarily a diagnostic tool. The unfortunate result of this govern mental intereferenpe is a battle over the control of scanning equipment and, par ticularly where head units are concerned, a source of conflict between radiologists and neurologists. Another potential prob-. lem related to government involvement is the complete loss of quality control--for example, making CT units available to untrained practitioners and encouraging mistakes and unnecessary examinations by inciting centers to perform more scans than good policy would dictate. Further, government-imposed restrictions on pur chases will depress the market and obviate research incentives among manufacturers. Hospital Expanse being used, and a physician is required to monitor the tests and inject contrast material. ' Space requirements--these are cqnsid- erable, as the equipment is bulky. ' Depredation of the equipment. Utilities--the system houses its own air conditioner. a Servicing costs. ,, aCharges for contrast material, syringes and other supplies. The impulse at many centers is to max imally utilize such a marvelous and costly piece of equipment. However, running a : scanner on a 24-hour basis only serves to magnify the costs involved--and these costs are ultimately passed to the patient "The medical and lay communities must act together to prevent this very important achievement from becoming a political football." The cost of CT scanning units is very high,; with prices ranging up to $750,000 for the newest and most sophisticated units. It Is.-', hoped that over the years prices will be reduced, although this has not been the case with other types of X-ray equipment, where prices havesteadily increased. Ohio Nuclear recently marketed a dedicated head scanner at $95,000, presumably to circumvent the certificate of need stipula tion. The drawback to this otherwise com mendable unit is . that it can accomodate . --by the requirement for several teams of. physicians and technicians and inevitable overtime payments. Examinations con ducted at odd hours are inconvenient for patients, and especially so for outpatients who may travel long distances to obtain , the test. In addition, it is apparent that excessive use of CT equipment induces an increase in breakdown time. : only a relatively small number of patients. Most medical centers have managed to Tho Task of the Future scrape together the necessary funds for a In the CT scanner we have a remarkable CT unit, recognizing it as a diagnostic tool whose potential has hardly been ap necessity, though no one views such a pur proached. The medical and lay communi chase lightly. ' ties must act together in preventing this The.cost of maintaining a scanner is very important achievement of modern extraordinarily high (at our. institution it medicine from becoming a politicalfoot- runs to $300,000 per year); the claim that ball. Federal agencies are faced with solv scanners are money-making devices is ing the very pressing problem of increas patently false. This maintenance, figure ing medical costs; we in the medical pro includes various elements: fession are faced with keeping bureau Salaries for medical, technical and sec cratic intervention at a minimum. Above retarial assistance---we have found it all, we cannot allow our accomplishments necessary to have two technicians on to go unused, nor our future to be subject hand at all times that the machine is toirrational restrictions. @ VOLZ8.NO. 2 MARCH/APRIL 1978 . **01 b933 : HFM - 003525 Prostate Cancer: Progress and Change Gerald P. Murphy, M.D., D.Sc. ' : . V-; vi For several years it has been recognized that prostate cancer constitutes a signif icant oncologic problem. The relative constancy of both the numbers of new cases and the recorded numbers of deaths have been the subject of numerous re views and reports.1 However, we have recently experi enced a period of substantial clinical change in the overall approach to prostate cancer: new methods of diagnosis; em phasis on primary care; assessment of histologic, prognosis; clinical classifica tions for prognoses reflecting the extent of disease; and the availability of new therapeutic interventions. With change hopefully comes progress, and there is significant documentation of this progress (Fig. 1). Current national figures on pros tate cancer reveal--in terms of population groups, for localized cancers--that there is improvement in the five-year survival rates (Fig. 1). These results, of course, must be followed closely for longer pe riods of time and can only be evaluated when the specific factors responsible are identified, and when further follow-u] and This observation times is not the case at the maroemaefnfto.rdable' Epidemiology There is no question that there are ing cancer death rates by age and the United States. Prostate cancer remains a serious problem among blacks. 2At- tempts to identify other high risk groups* possible sexual or transmissable factors and socioeconomic factors involved have; been instituted and preliminary reports given.J-5 These areas must be watched; closely since there may be a particular:; group of individuals who, with further. identification, coujd benefit from im proved methods of screening and preven tion of prostate cancer. It should be noted that even this limits ed amount of information has not been previously available.1 Careful case controlstudies of blacks in Washington, D.C. compared with those in Africa have sug gested that external, environmental fac-y tors other than original racial origin may be affecting prostate cancer growth rates. ? This is a significant epidemiological ad vance.2 Morphology and Histological Prognosis; The morphology of prostate'cancer has: , been described by individual experts and. collaborative groups for some time. This area has been recently reviewed and there- is excellent information available for stu- .. dents concerned With this perplexing problem.6 .' All available evidence suggests that, generally, prostate cancer exists as a multi focal carcinoma, as Mostofi and his asso-. Dr. Murphy is Institute Director, Roswell Park Memorial Institute, Buffalo, New York. - "in.- ft9.}* CA-A CANCER JOURNAL FOR CLINICIANS tiates have pointed out; 7 Some investigators believe that these multiple foci of prostate cancer represent intraglandular metastases, but this has not yet been resolved.7 No matter how early prostatic cancer is detected, it seems to exist at more than one cellular site. There have been a number of attempts to indentify those factors in systems espoused by Gleason, Mostofi and others, that could provide a single, system for histological prognostic use.7 Such a venture represents change and change is usually difficult to apply widely. In 1978, the American Cancer Society National Prostatic CancerIhsk Force will undertake this difficult effort. The comparison of proven systems inthe United States and elsewhere will be helpM. The. assimilation of all factors that are found reproducible and that can be adapted by many pathologists will alter and significantly affect our current thinking about aggressive approaches and other alterations in early or late treatment of prostate cancer. Since this appears to be possible, it is a most important event. VOL. 28. NO. 2 MARCH/APRIL 1978 900 1 0V 35 HFM - 003526 '' TABLE ia DIFFERENT CLASSIFICATIONS OF ADENOCARCINOMA OF THE PROSTATE ' ' American System Stage Description A 1,0 At *2 B It, A Occult Cancer Flistologic: wall differentiated, < 3 slides Histologic: > 3 slides or not well differentiated Cancer confined within prostate capsule ' Lc B1 b2.b Tumpr occupying <1.5 cm. in 1 lobe only Tumor occupying >1.5 cm. In one or both lobes, not invading capsule . C III Cl C2 D D1 Cancer with extracapsular extension, no nodal or distant metastases < 70 gm. > 70 gm. Cancer with demonstrable metastases Pelvic lymph node metastases or ureteral obstruction causing hydronephrosis . . 2 Bony or distant lymph node or organ metastases Chemical Diagnosis For some time, acid phosphatase deter mination has been essential to the diag nosis of prostate cancer. Unfortunately, its elevation, as determined indirectly by substrate assay has usually been clinically associated with extension or metastasis-- that is, the prostate cancer is no longer confined to the- gland. Within the past few years, several new assays have been developed by a number of investigators, and are currently under a nationwide field trial by the American Cancer Society Task Force on Prostate Cancer. Radioimmunoassay Radioimmunoassay (RIA) techniques8 Mf'01 693 A CA-A CANCER JOURNAL FOR CLINICIANS ---- ^ TABLE IS D1F F t r: t t\i T CLASS; r iCATiONS OF AOF\JGCArtCir\iOf\/tA OF THE FBOSTATE '4"* \ ^ uicc -1 ; ; ' '1 , .1,1.' Classification Description T* Incidental finding of cancer in operative specimen 1 1 ;. Ti Tumor occupying less than half of prostata. surrounded by normal gland t2 Tumor occupying more than half of prostata, but not producing enlargement or deformity . t3 Tumor confined within prostata but producing . ' enlargement or deformity of gland Tumor extending beyond prostate Mp No evidence of distent metastases Nn (L) M0 M, M1a M1b n2 Regional nodes No evidence of distant metastases Distant metastases only Bony metastases only Other metastases with or without bony metastases Fixed regional.nodes palpable in abdomen . for prostate cancer can provide immuno logic Specifie prostatic acid phosphatase assays^ It is hoped that improved RIA will identify the extent of disease in patients earlier and more accurately. Radioim munoassay, now undergoing a national screening test, is an expensive test, and therefore other alternatives have been re ported and are similarly under trial. Counter-immunoelectrophoresis Counter-immunoelectrophoresis (CIE)' can provide an immunochemical method for the detection of. prostatic acid phos phatase. Early tests demonstrate that it is relatively inexpensive and can b.e performed in any hospital laboratory equipped with commonly available equip- VOL. 28, NO. 2 MARCH/APFIIL 1978 . f>917 H FM - 003527 ment. The counter-immunoelectrophoresis method may provide a more widely usable test, with equal specificity and ac- . curacy. ClE is also currently under a na tionwide American Cancer Society field test. Further Chemical Assessment primary tumor from former methods, Past remits using other techniques cannot be applied to present circumstances. Cur rently, bone marrow acid phosphatase measurement by these new techniques appears to only minimally improve the diagnosis of metastatic disease. ;^ One must not overlook further chemical Staging Claaslfleatlons v; assessment and determinations of prostat ic fluid. In most patients, continuing eval uations of this substance are warranted upon urologic examination. Early tests suggest that certain isoenzymes may be altered.1? In fact, elevations in LDH in prostatic cancer patients seem to support the concept that the prostate cancer may not only be multi-food in its histologic origin, but also may exert a general meta bolic effect upon the gland. ><> In the past, there have been differences in both the staging and end results reporting for a variety of tumors. The American Joint Committee for cancer staging and classification has used Roman numerals I through IV to correspondwithWhitmore's A through D.6 The International Union Against Cancer (using the TNM classifi cation) has a slightly different approach to clinical staging. These systems are cur rently under evaluation by several groups. The most current and comprehensive com parison of these classifications was de "Within the past few years, several rived from that prepared by Boxer6 (Table new assays have been developed... and are currently under a nationwide field trial." 1). The most significant difference in all of these approaches seems to occur with the early focal or occult cancer. In the United States, further definition and fur ther subclassification is occurring and ,,fs a result, other recommendations are bring Bone marrow acid phosphatase deter made for therapy. The so-called focal lo minations have been utilized as well as calized nodule of the prostate frequently lymph node biopsy in the neck and other occurs in the B stage. However many be areas to detect metastatic disease where it lieve that its frequency is less than Had is not thought to be clinically present. The been thought. ^Localized pelvic prostate goal and philosophy of therapy can be cancer, stages C or D, or D t, are how substantially changed by such tests. Newly more frequently defined as a result of purified acid phosphatase determinations bilateral pelvic lymph node dissection. To previously.referred to8-9 have been used date, no one can precisely define when a recently to assess the value of bone mar pelvic node dissection is diagnostic, when row acid phosphatase in staging prostatic it is therapeutic, or even when it conisti- cancer but the results are still tentative. tutes a procedure acceptable to all. There These tests, appear to be more accurate are extensive procedures performed in the than those used previously and upon which course of some interventions; lymph node clinical recommendations havebeen made. sampling is done in others. The numbers' At present, it would appear that such de of sections of the lymph nodes considered terminations will confirm the unexpected necessary for.the detection of microscopic presence of microscopic prostatic cancer; cancer cells is a problem of institutional further tests and triald will determine how variation. Moreover, lymphangiograms often this occurs. The preliminary results " have recently been substantially used for from such new tests suggest that it does preoperative staging with some modifica not occur frequently: One must again sep tion in technique. >* The advent of CT arate the newly available methods of stag scanning will doubtlessly provide further ing for the extent of disease beyond the changes, additional refinement and more *0 0) <) - Ja CA-A CANCER JOURNAL FOR CLINICIANS assistance in the determination of the ex of prognoses reflected, improvementmay tent of disease without surgical interven come from other areas of biology. Tnmor tion. Implicit in alljof these factors is that ' markers or hormonal (androgen aigl es- the degree of diff^entiation of the pri trogen)'receptor sites have been fbimd to. mal? prostate car&noma may affect the be useful for therapeutic treatment and survival regardless of the therapeutic in also for clinical treatment trial stratifica tervention. This has beat previously not- tion. Work on a variety of receptors is underwayand promising results havdbeen reported in terms of estrogen receptor* in human prostate cancer.14 While final re "One must not forget Lord Batson's plexus andtfaeprostatic venous drainage! It may prove of continued importance." . suits will not be available in the near fu ture, current data suggest that some hor monal markers may be useful in the future in clinical classification and further thera peutic stratification. r Physical examination has not been extensively mentioned in this particular ed1 and has been most carefully deter mined in a recent study by Whitmore and; associates.12 Important determinants of metastases subsequent toa particular form of therapy probably do indeed seem to relate to: .: -P"; ' report. It remains, however, an essential part of any program of complete evalua tion and initial and continuing inspection. Biopsy techniques likewise have not been reviewed since they have been extensively repented upon.4 The use of roentgeno grams and other forms of scanning are n The large size ofjthe primary tumor; helpful and reports are also available. Poor histological differentiation; Prostatic echography is a new topi, and n Volume of lymph node metastases; initial promising results have been re- o Lack of local prostatic response to viewed.6 The scanning of bone marrow in radiation; A. .: prostatic cancer may also be usefupfpr a n Possible seminal vesicle invasion. >* ; varietyof staging purposes.butmateim- Such careful studies provide important new factors that will affect the further classification, staging arid assessment of our end results. - ; \;v Randoraized selection of cases from institutions doing one form of treatment compared to others who-have performed lymph node dissections have been report ed. ^ While thesb cmphasize the impor tance of lymph node drainage and lymph node assessment iii'the staging of extent portantly, for therapeutic decisiohs re garding the efficacy of adjuvant treat ment, i.e., chemotherapy. Other immuno logic markers and assessments of immunocompetence of status of the host, rsipsain the subject of intensive and widespread individual research studies. They ahimld be watehed for futher promising reports but at present cannot he translateq ihto widespread therapeutic or diagnostic recommendations. of disease, they abb document that even today there are stjjl unanswerable ques tions or at least instances of clinical vari Primary Treatment ance. One must not forget Lord Batson's . As in the past, perineal.prostatectomy and plexus and the prostatic venous drainage! radical retropubic prostatectomy are be It may prove to be of continued impor ing performed today (Table 2). The per tance. The possibility that the interruption: ineal approach has not changed and is of lymph node drainage may have non- bring used by some for more selected cases; beneficial immunological effects has been or patients with other medical life-threat raised but not resolved. ening complications. As is reflected in In addition to the factors mentioned recent reviews . (Thble 2),? there are some for staging prostate cancer and the variety patieng who are now benefiting from ret- VOL. 28, NO. 2 MARCHAAPRIL1978 8001 6939 HFM - 003528 ropubic prostatic removal combined with lymph node intervention. Recent reviews and summaries1 of the results of this ap proach appear to justify its use. However, longer follow-up is needed. Interstitial therapy for localized pros tate cancer has been introduced using Il23. Extensive results have been described by Whitmore and associates and are being followed closely.u Thus, one has a variety of surgical approaches to early or local ized stages of disease combined with vari ations in lymph node dissection, with or ".. .There are some patients who are now benefiting from retropubic prostatic removal combined with lymph node intervention." without the addition of interstitial opera tive applications. * The techniques, the numbers and the degrees of lymph nodes are .currently subjects of dispute and-debate. There are at present no randomized studies, nor should there necessarily be any. However, it is important to note that . these results are promising,and, in and of themselves, they afford a therapeutic option. Bagshaw's observations with external radiation for localized disease indicate that short-term, disease-free survival is possible in over 87 percentof patients with negative lymph node biopsies. Patients in an intermediate phase, with positive lymph node biopsies only in the pelvic region following extended field radiation therapy also have an improved survival rate, near ly 72 percent. Patients with positive peri aortic node and pelvic node biopsies have a diminished survival. The randomized trial conducted by Bagshaw and associates has been recently reported and continued promising results are seen.15 There are other features of radiation therapy re ported and described that cannot be ig nored. The question of the use of exogen ous estrogens as a form of endocrine ther apy, has been most recently reported; a 0 (; ] 0<f6.o those interested in reviewing the divergent opinions may wish to consult a recent review.*Hormones should be considered essentially palliative and should not be- confused with primary treatment. % Surgery and radiation therapy as pri mary treatment afford a reasonable op? portunity for disease-free interval and possible cure. The author does not prefer' ; surgery, interstitial therapy or external radiation therapy on the basis of any ipS:. suits currently available. In the author's^ present viewpoint, no one mode is defi-` ' nitely proven to be superior to any other, Urologic surgeons and others should aff; ford patients the opportunity for the se-. lection of treatment best suited to them, particular needs, depending upon a variety;; of interpersonal factors and possible med-t>. . ical conditions. In terms of primary ther-- apy, it must be remembered-that lymph?, , node dissection is not without its possible complications. Moreover, lymphangio- grams may or may not be desirable. Radi~ ation therapy has an important role to' play as does primary surgery. An attempt ed resume of the current status of the; therapy as employed today by radiothera-. pists and urologists is reflected in Table 3; ; The biggest problem with the interpreta tion of Thble 3 is that many of the stages depend upon precise surgical staging.' They are not. clinical stages.' Whether of, not node dissection or node sampling is done remains an important and irresolVv able distinction. ' ;? ' .- . . '' Palliation Therapy ^ Palliation, or hormonal, therapy is neithf er intended nor claimed to be curative. Whether one uses a different doseofestro;; gen combined with the presence or absence; of orchiectomy, remains a source of occa sional concern. It is appropriate to restate- results from our. own institution as an ex? ample of full term follow-up and high percentage autopsy examination of pa-/ tients with widespread or metastatic pros*- tatic cancer who are treated with either orchiectomy or combination treatment (Thble 3). Without question, prostate;; carcinoma remains the all-time and major'- cause of death in all such patients. There; '' ' - 'r'. CA-A CANCER JOBRNAl F8R CLINICIANS' 1 A r` L . CuF.REr.T STA7.;, " r MOST COfvT.`;OI\JL V ciV)PLOYED Me. ; OF PRIMARY TKLriAr r Stage Example* of TherapauticChoices Currently Being Employed *1 Some prefer surgery, others observation. ' ** t 1) Radical prostatovestadectomy (either retropubic or perineal approach*) a lymph node bisection ! 21 Radiation therapy : , '/ . Ba 1) Radical retropubicprostatpvesiculectomy with pelvic ' . lymphadenectomy ' . 2) Radiation therapy t node sempljng ' c ' ,1) Radical retropubic prostetoveslculectomy with pelvic . . ; lymphadenectomy : ./ : ; 2) Interstitial radiation with pelvic lymphadenectomy - 3) Radiation therapy lymph node sampling , .' - 4) Some prefer observation endocrine treatment ' - ' 0l ' .. ; ' D:MSee text ' ' .'V'. - " ' - ;- - _ _ 77- .' ~: - - - - 7--'--- . .. A few canters employ cryour8lcl destructlontlymph node,dissection In all the rtagei depicted In this table. . are no significant statistical differences in of well being, weight, appetite, etc. A vathis particular hormonal program. We are , riety of doses are useful and have been aware of the ability to measure dihydro- found adequate. Levels of .hormones in . testosterone (DHT):and other substances one partition of the total body compartin the serum, but these should not be used ,. ment cannot possibly be of predictive.val-: as a guide to the adequacy of palliation . ue, although some may feel that is'-the therapy. The patient himself, will inform case. Only extended metabolic studies over the clinician regarding pain relief, sense 24 hours includingall possiblecomponpnts VOL. 28. NO. 2 MARCHfAPRIL t978 - SOOl Q4) H FM - 003529 TABLE 3 CAUSE OF DEATH BV PRIMARY TREATMENT" Cause of Death ' Orchiectomy Estrogen + Orchiectomy Prostatic carcinoma Other neoplasms ' Cardiovascular dteas8s Other, mainly respiratory diseases 47.4% 32.8% 13.2% 6.6% 64.7% 6.0% 22.9%A 6.4% * Excluding patient* who are alive or have died.from unknown cause*. ANot itatlttlcally significant. -. : may lead to a valid endocrinologic coo-' fectiveness of these two procedures has elusion. In our own experience, this does been established and need not be repeated not justify a change in clinical judgment at this time. Occasional long-term results and is a research project only. The follow from this form of extensive hormonal ing viewpoints for conventional hormonal therapy have been described.'.6However,; palliation with advanced, untreated pros following new forms of chemotherapy for tatic carcinoma are restated: patients-relapsing after conventional hor- Withhold therapy until the patient's symptoms or general condition warrant treatment. Generally, use castration alone although "Hormones should be considered J-. many physicians also administer stil- essentially palliative and should bestrol either with or without castra not be confused with primary tion. a When stilbestrol is administered follow treatment." ing symptomatic or clinical relapse after castration, limit the dose to one mg. daily. There is some suggestion, how ever, that three mg./day may provide better androgen suppression in certain patients. a High-dose estrogen therapy (natural or synthetic source) is not recommended except for selected use in short-term, acute situations. Hypophysectomy and adrenalectomy have been discussed previously.1 The ef monal therapy, it has been found that chemotherapy is generally superior.IT Non-steroidal anti-androgens and other agents that have suppressive effects upon the adrenals have undergone some clinical study.. ''They do not, however, appear to afford a practical or useful alternative; for palliationat this time. Metastatic pro?, static cancer that has relapsed following conventional hormonal therapy can be <4 managed usefully according to the results results have been documented.20-2*!! is of the National Prostatic Cancer Project, fahportant to emphasize that the criteria The National Prostatic Cancer Project and. evaluation of the response parimeparticipants (see box on page XX) have tiers selected by this particular national demonstrated that a variety of forms of group have beat found reproducible and chemotherapy in such patients who have tisefbl in the hands of others.23 Moreover, had previous radiotherapy or who have they too, even in dealing with widespread not been treated with, radiotherapy, can metastatic disease in patients who have . be effective in controlled randomized clin- relapsed after all forms of conventional ical T values. Although these agents are therapy, have found a relationship shetoxic, under a carefully controlled pro- twe^p priinary tumor histologic gradej|hd gram they can be used successfully. Their die tpsppnse to chemotherapy.24 This im- RtjOl 094? CA-A CANCER JOURNAL FOR CLINICIANS VOL. 28, NO. 2 MARCH/APRIL 1978 L 1 C94! ' . /. H FM - 003530 portant viewpoint will be puisued and further studied. In addition to the ability of these new treatments to provide an altemative for the relief of pain, other ob jective and measurable partial responses have been observed. Some of these were first described in 1973 in terms of one agent, and further follow-up has now shown this to be true of still others, rs Ster oidal complexes combined with chemo therapeutic agents do have direct effects on human prostate cancer. "Phase 1 and "Palliation, or hormonal, therapy is neither intended nor claimed to be curative." Phase II trials currently underway will pro vide opportunities to develop alternatives. As a result of this interest in extensive disease, patients with metastatic prostate cancer at Various sites other than bone are now receiving careful clinical evaluation and the assessment. of their measurable responses is being documented.21'"It is recognized that chemotherapy in the ad vanced stage of disease will not be the final answer but rather an alternative to. treat ment which already has proved useful and at this point justifies our earlier optimism in 1973. cures, it will also assure the quality ofjhfe and the maintenance of our high cliH&al standards. In the very near future, adju* vant chemotherapy in patients with pos itive periaortic nodes or other advanced stages of surgical disease will be undfct- taken, expanding parameters and know ledge. This is the basis for reasonable ^nd justifiable optimism and may wellprodufce future reports from the National Cancer Institute reflecting improvement in sur vival rates for greater durations and for larger numbers of patients. It is unfortu nate and regretful that we cannot separate our goal of primary therapy from thatbf palliative therapy..On the one hand jve must have a concern for the welfare of bur patients30but this should be tempered with the realization that many require treat ment and many present with advanced prostate cancer despite our current highly developed medical facilities and technol ogy.31 This, however, can be altered ;as demonstrated by the alternatives' of chemotherapy. ,: We are defining metastatic disease in new ways: it is being defined by surgical intervention, by lymphangiogram andiby "Multidisciplinary treatment remains most important... Hormonal palliation is still a mainstay." Future Perspectives other external means to a degree never Combination chemotherapy of selected done before. As a result, we have larger agents and other new, single agents has numbers of patients at an earlier phase&f. been proved active under national rain-: .. their disease, compared to the early 1970,'s. domized trial conditions. Under this af Multidisciplinary treatment remains most fordable and desirable parameter, patients important; so-called surgical staging, uro- newly diagnosed, or ihose with stable stage ' logical-operative intervention and radio D prostate metastatic cancer, , are being logical treatment have established their afforded the opportunity for treatment abilities to provide significant and sub with these drugs. The studies are underway stantial improvements in survival of pri and will take some time before complete mary tumors. Hormonal, palliation is still evaluation. At no time in their conduct a mainstay and will unquestionably re- will the patient be denied an opportunity main.so for the future. The role of adju for exposure to conventional or hormonal vant chemotherapy has, since 1973, pro therapy. While this may complicate the gressed to the point of being appropriately evaluation of possible chemotherapy . considered for controlled trials in th^se 80 01 CA-A CANCER JOURNALFOR CLINICIANS patients with early diagnosed, microscop ic, occult or progressive disease. Com paring their results with palliative ther apy will be a fruitful endeavor and should provide us with a basis for optimism and hope. i @ l5,Bagshaw, MA et aL: Evaluation of ex-. tended-field radiotherapy for prostatic neo plasm: 1976 progress report. Cancer Treatment Rep. 61:297-306.1977. ' 16. Martin, C.; Murphy, G.P.; Chu, T. M:, and Miuetman, A,: Carcinoma of the prostate, long-term survival after bilateral adrenalecto my-Urology 3:223-225,1974. 1 17.-Welvaart,K.; Merrin, C.E.; Mittelman, A., and Murphy, G.P.: Stage D prostatic candbo- References new fonts of palliation TJrology 4:283,28f>! __________ 1974. ' " 1. Murphy, G.P.: Prostate cancer. CA 24:282 288,1974. 7.- ' 2. Jackson, M.S. et al.: Characterization of prostatic carcinoma among blacks: A continu ation report. Cagccr Treatment Rep. 61:167 172,1977. : 3. Rotkin, I.D.: Studies in the epidemiology of prostatic cancer: Expanded sampling. Cancer Treatment Rep. 61:173-180,1977.' : 4. Schuman, L.M. et.aL: Epidemiologic study of prostatic cancer: Preliminary report, Cancer; Treatment Rep. 61:181-186,1977. ; 3. Emster,. V. L. etal.: Race, socioeconomic lB. Varkarakis, M.J.; Williams, P.D.; Chu, T.M., andMUiphy, O.P.: The effects ofaminoglutethimide on prostatic function. Res. Comm. Cbem. Pathol. Pharmacol.9:J61-574,19W.. 19. Varkarakis, M.J. et al.; Prostatic eff&ts of a nonsteroidal antiandrogen. Invest. Urtfl. 12; 273,284,1975. :v' 20. Murphy, G.P. et al.: A comparison of estramustipe phosphate and streptozonin in. patients -with - advanced prostatic carcinoma who have had extensive irradiation. J..Urol. 118:288,291,19T7. 21. Murphy, G.P. etaL: Chemotherapy of ad status, andprostatic cancer. Cancer Treatment vanced prostaticcancer bythe national prpstav Rep. 61:187-191,1977. ^/ ^ tic cancer grow, Semin. Oncol. 3:103-103,1978. 6. Boxer, R.J.: Adenocarcinoma of the pros 22. Scott, W.W. et at.: The continued mlua- tate gland. Urol. Surv. 27:75-94,1977. ; .: tionof the effects of chemotherapy in patients 7. Harada, M. et al.: Preliminary studies of with advanced carcinoma of the prostate. J. histologic prognosis in cancer of the prostate. Urol. 116:211-213,1976. r Cancer Treatment Rep. 61:223-225,1977: / 23. Schmidt, J.D. et al.: Chemotherapy of ad 8. Choe, B.K.; Pontes. E.J.; McDonald, I., vanced prostatic cancer. Evahiation ofresponse and Rose, N.R.: Immunochemical studies of parameters. Urology 7:602-810,1976. ' ^ prostatic acid phosphatase.' Cancer Treatment 24. Gibbons, -R.P. et al.: Prostatic carcinoma: Rep. 61:201-204,1977. Relationship betweenprimary tumoT.histo- 9. Chu, T.M. et al.: Immunochemical detec : lode grade, and response to chemottagapy. tion of serum prostati&add phosphatase meth Urology 8:222-226,1978. odology and clinical evaluation. Invest. UroL 25. Murphy, G.P.et al.: A clinical.pharmaco In press. - :'V:' logic . study of oral estramustlne phosphate 10. Grayhack, J.T.; Wendel, E.F.: Lee, C., and (estracyt) in patients with adenocarcinoma of Oliver, L.: Analysis ofprostatic fluid inprostat ' the prostate. in: XVleCongrcs de la Spciete ic disease. Cancer Treatment Rep. 61:205-210, Internationale d'Urologie 2, Paris: Doig.Edi- 1977.' - . ".r teurs, 1973, Pp. 235-242. ; 11. Pontes, J.E.; Cheje, B.K., and Rose, N.R.; 26. Kadohiuna, N.; Kirdani, R.Y.; Murphy, Bone marrow arid phosphatase in staging of . G.P., and'Sandberg, A.A.: Hydrolysis arid me prostatic cancer. Mow reliable is it? J. Urol. In . tabolism of estracyt by human prostatic cancer. press. !' " ' ' ' ' Urology. In press, ; 12. Barzell, W.; Bean,M.A.;Hilaris, B.S.,and 27. Catane, R. et al.: Brain mestastasesifrom Whitmore, adenbeud- prostaticcarcinoma. Cancer 38:2583-2S8T1976, noma: Relationship Qfgrade and local extent to 28. Varkarakis, M.J. et al,: Lungmetastases in the pattern of raetastases. J. Urol. 118:278-282, prostaticcardnoma. Clinical significance,Urol 1977.' ; v:" w ` - ogy 3:447HtS2,1974. T ' 13. Varkarakis, M.J. et al.: Lymph node in .- 29.': Murphy. G.P.: Proceedings: Cancer .of the volvement in prostatic carcinoma. Urol. Clin! : prostate: Cancer 32:1089-1091,1973. . ;; North Am. 2:197-212,1975. 30.' Primary treatment of prostatic canocr. (Ed, 14. Sufrin, C.; Kirdani, R.Y.; Sandberg, A.A., hmiaD Br. Med. J. 2:781-782,1977. ' and Murphy, O.P.: Estrogen binding and es 31: Murphy, G.P. etal.: TresUment ofprostatic trogen receptors in the prostate. Surg. Forum cardnoma in western New York. N.Y. State J. 26:584:586,1975. : Med. 76:869-873,1976. VOL. 28. NO. 2 MARCH/ARRIL1978 6601 Q945 HFM - 003531 Questions and Answers on Cancer Phenyl-beta-naphthylamine Hodgkin's Disease Recent investigations have disclosed that phenyl-beta-naphthylamine can undergo N-dephenylation in humans, with recovery ofsmall amounts of beta-naphthylamine, a potent carcinogen, in the urine of ex posed subjects. Has bladder cancer or any otherform ofcancer been associated with exposure to phenyl-beta-naphthylamine? M.D., Peoria, Illinois Phenyl-beta-naphthylamine is manufac tured in this country by BASF Wyandotte Company. In the past it had been used in the manufacture of rubber tires. Accord ing to the company only 10 lbs. was used in the U.S. last year. There are a number of chemicals used in rubber manufacture, notably benzene, and occupationally exposed workers in the rubber industry have been reported to have excess rates of bladder cancer and leukemia. But it is not possible to attribute any of the higher risk to use of phenylbeta-naphthylamine. Lawrence Garfinkel Assistant Vice President for Epidemiology and Statistics American Cancer Society New York, New York My patient is a 2I-year-old auto mechan ic with theproved diagnosis ofHodgkin's disease, stage III/B of mixed ceUularity, discovered in May of 1977. He was com pletely staged and retroperitoneal nodes were negative, as was the spleen. During thefirst cycle ofMOPP chemotherapy he developed an unquestionable allergy''to procarbazine, and a small re-challenge brought back the anaphylactoid reaction. / was thenforcedto use theABVD regimen ofDr. Bonnadonna. After three cycles of ABVD, he received irradiation of up to 3000 rads to the bulky sites, according to the suggestion ofDr. Leonard R. Prosnifz (Ca 26:2826, 1976). Soon he will complete his sixth and last cycle ofABVD. Most reports state that ABVD is com parable to MOPP; one exception is a short abstract that appeared in the Proceedings ofthe Society ofHematology meeting hgld in San Diego , last December. This report prompts me to askyou two questions: 1) Do you give much credence to this recent assertion that AB VD is not as ef fective as MOPP? 2) Ifyou agree with this report, would you recommend that this man (stage III/B ofmixed cellularity) befollbwed by a total nodal irradiation in the usual manner, as suggested by the Stanfordgroup? M.D., San Clemente, California RflQl 094* ' CA-A CANCER JOURNAL FOR CLINICIANS The MOPP program remains the standard and most proven chemotherapy regimen for the treatment of Hodgkin's disease, There are a number of other combinations which have been reported to produce com- benefit from adjuvant chemotherapy if total nodal radiation is given. If, ip fact, the patient had pathologic Stage III/B disease then radiation therapy is an inadequate treatment program and chemo- plete response rates comparable to those therapy should be the primary approach. ofMOPP, but none has shown the quality If, as has been described, there has been or duration of the MOPP response, at an allergy to procarbazine one can sub least as reported by DeVita and confirmed stitute for procarbazine in the MOPP at Stanford. - regimen, utilizing a nitrosurea or adria- The MOPP program can produce 80% myadn. As stated, the ABVD regimen complete response, on the average, for all may be equivalent, but would not be the patients treated; two-thirds of the com- first choice in a primary treatment pro- plete responders remain free of disease at gram. There are experimental and chemo- fiveand 10 years on an actuarial basis. therapy for Stage III/B disease but the The ABVD program of Dr. Bonna- role of radiation therapy has not yet been donna has been compared to the MOPP established. If the patient has pathologic regimen; the ABVD treatment is a com- Stage II/B disease and has received 3,000 bination modality in which radiation is rads to known sites of disease as well as 6 also given. To date these two approaches, cycles of ABVD, this can be considered a show equivalent results. However, there very acceptable treatment program since, are not enough data in the literature to in this case, the ABVD will be given as an demonstrate how ABVD, used alone as a adjuvant and the radiotherapy is the ma primary treatment, compares with MOPP. jor form of disease control. With regard to the patient with clinical Stage III/B, but pathological Stage II/B ' Hodgkin's disease of mixed ceUularity type, the following comments can be made: The Stanford study shows that patients with pathologic Stage II/B disease do not Saul A. Rosenberg. M.D. professor of Medicine and Radiology Chief, Division of Oncology Stanford University Medical Center Stanford, California VOL. 28, NO. 2 MARCH/APRIL 1978 ROfil -I'-'h ? HFM - 003532 Oral Contraceptives and Cancer The Editor Interviews: Robert M. Kretzschmar M.D. Associate Professor of Obstetrics and Gynecology University of Iowa- Editor: There are about 10 million American women and 50 million women world-wide who now take oral contraceptives. In the IS years since the Pill was first marketed, more and more has become known about its potential health hazards, arid fear has arisen about a possible link to cancer. Is there any con vincing evidence that oral contraceptives are associated with breast cancer, for example? Dr. Kretzschmar: No, there isn't. There is no evidence that the Pill increases the risk of breast cancer and in fact, it has been shown that oral contraceptives may offer some protection against benign: breast disease. For example, when Vessey and his group com pared 345 women admitted to Urndon teaching hospitals with breast lumps (90 malignant and255 benign) against a matched control group admitted for acute medical or surgical condi tions, it was found that oral contraceptives were in no way related to the risk .of breast cancer. It was discovered that the risk of admission to a hospital for a breast biopsy among Pill;, users was reduced by about 75 percent, compared to those women who had never usedthe Pill at all. The Boston Collaborative Drug Surveillance Program did another retrospective study, and had similar findings. One hundred twenty-one patients with breast disease (cancer, fi brocystic disease, fibroadenoma and miscellaneous problems such as fibrolipoma or benign duct ectasia) were compared to: 842 patient controls. Among the.women with newly diagnosed breast cancer, three of 23 (13 percent) had'received oral con traceptives, compared to 20 percent who had received oral contraceptives among the controls: Of the patients with benign breast tumors, six percent had received oral contraceptives!; compared to the 20 percent among the controls; When these findings were analyzed for the patients' ages, it was revealed that at each age level, Pill usage was less common in those with benign breast tumors. According to their data, hospital admissions in the Boston area for breast diagnosis were reduced by almost half for those women using oral contraceptives. 3001 0940 CAA CANCER JOURNAL FOR CLINICIANS The prospective study bring done by the Royal College of General Practitioner^in Gnat Britain has also ruled out an association betimsa ineast-caiicer and oral cbntraceg^on. Their 1974 interim report showed that of 46,600 womenw- 50 . percent using the Pill rontinuously, and 50 percent not --11 , cases of malignant neoplasm of the breast were found in Pill- takers, four cases in ex-takers, and 16 among the non-taking control group. A lower incidence of benign breast neoplasm became apparent after two years of continual Pill usage. Editor: - Aside from causing cancer de novo, is there any evidence that the Pill might exacerbate existing tumors? Dr. Kretzschmar: As far as the belief that women with benign breast turnors have a higher risk of developing breast cancer, the apparent protective effect of oral contraceptives against benign hjjpast tumors could be considered a protection against subsequent development of breast malignancy as well. Also, prolonged use of oral contraceptives simulates pregnancy in some ways, " and we know that, relative to other women, those who become pregnant early in life are at a lower risk of developing breast cancer. . There is some evidence that women who have fibroids may have enlargement oftheir fibroidsrelated to the Pill. Ofcourse, women with a strong family history of breast cancer should be followed with caution, and should have careful breast e^tpi- nations at frequentintervals; women with known pr suspected carcinoma of the breast should choose another form of con traception. But I am quite convinced that oral contraceptive intake is in no way responsible for breast carcinoma, de novo or otherwise. ; Editor: Have oral contraceptives[been linked.to ovarian cancer? . Dr. Kretzsctupar: No. There is no relationship; If anything, the Pill has an in . ; hibitory effect on the development of ovarian cancer. In the * British study of 46,000 women, there have been fewer deaths r from both breast and ovarian cancer among those wdinen using the Pill than amopg those who did not: Editor: ' '; Is there a relationship between the Pill and uterine cervical: cancer? " y-' ' ' ' Dr. Kretzschmar: No. Among women receiving estrogen from a combinationtype oral contraceptive, no convincing relationship to cancer of the uterine cervix has been established. In a case-control study done at the State University of New. York-Dowrisitate , Medical Center in Brooklyn between 1969 and 1975, 689 con secutive patients with cervical carcinoma were interviewed and. compared with a control group of 1,300 with normal cervical smears. Each case subject was matched with a control subject for age, ethnic origin, age at first coitus, age at first pfegnancy, and socioeconomic status. The findings: no significant VOL. 28. NO. 2MARGH/nPHIt. 197 ' . RdOi - ;118 difference between the case and control subjects in the use of oral contraceptives. This conclusion duplicates the results of many other stud ies as well. Worth and Boyes. compared the use of oral contra ceptives among 310 women, 20 through 29 years of age, who had carcinoma in situ of the cervix with 682 control subjects matched for age who had negative smears. Again, there was no significant difference in the use of oral contraceptives. Thomas compared 324 women who had positive cervical smears showing dysplasia or carcinoma in situ of the cervix with 302 women from the same locality. No difference was found in their use of the Pill. Although there has been a significant increase in recent years in pre-invasive lesions of the uterine cervix, this increase has been found in both users and non-users of the Pill. : This brings out one of the more positive-aspects of the Pill. Just think of the. number of women who routinely see their., physicians now and obtain a Pap smear because they are on the Pill. Womenwho are.on the Pill have a much better chance for earlier diagnosis of changes in their cervical epithelium than those who are not -- and that's certainly a plus factor in the relationship of cancer to oral contraception. Editor: You discount a link between oral contraceptives and uterine cervical cancer. But if a Pap test reveals cervical dysplasia in a patient, would you advise her to stop taking the Pill? '[ Dr. Kretzschmar: No, I would manage the dysplasia with selective biopsies and... appropriate treatment. I would not advise her to stop taking the Pill. Editor: Are oral contraceptives associated with endometrial cancer in your view? Dr. Kretzschmar: No, there is no relationship. The sequential tablets', which provided estrogen alone for 14 days, and then estrogen and progestogen in combination for seven more days, were taken; off the market when controversial evidence Unking estrogen with possible cancer of the uterus came to.Ught. In 1973, 21 cases of endometrial cancer among Pill-taking women under the age of 40 had been recorded, but in eight of the cases, fac tors were found which militated against a close relationship between oral contraceptives and carcinoma, and of the re maining 13 cases, 11 had taken sequential agents. So, there is absolutely no evidence to Unk endometrial cancer with com-' bination or progestin-only oral contraceptives-. In fact, since only about eight percent of women taking oral contraceptives' at that time used sequential agents, the unduly high incidence of sequential agent therapy in these 21 cases might suggest that women who are predestined to develop this tumor are actually protected against it by the combination pills . If you wish to discuss replacement estrogen, exogenous long-term estrogen for menopausal women, that's controver-y sial. According to an article pubUsbed in the New England RU01 OVM' CA-A CANCER JOURNAL FOR CLINICIANS Journal ofMedicine in 1975, the use of these exogenous estro gens in menopausal and post-menopausal women was assod- : ated with a 4.5 dmes greater risk of endometrial cancer; Hovir: ever, some physicians do not believe that there is a connection, and there are many knowledgeable people on both sides of the fence. Women taking estrogens should have frequent''pelvic cancer-screening examinations and physicians should be on guard if abnormal bleeding develops. I would point out,' in tins respect, that the Pap smear is not a totally effective screen ing device for endometrial cancer; in fact, 40 to 60 percent of patients with adenocarcinoma of the uterus will have negative Pap results. An .evaluation of the endometrial cavity with a suction curette, or an endometrial biopsy should be performed on all patients at high risk, or on those with a suspicious his tory. If a physician then feels he has not gotten a sufficient sampling, a dilation and fractional curettage should be done under local or general anesthesia. Our diagnostic procedures in this area should be further developed. Editor: Would you comment on the evidence linking oral contracep tive use to benign liver Humors? Dr. Kretzschmar: Yes, this was looked at carefully, and in April 1977, the Ajner- ican College of Surgeons released documented evidence on the increased incidence of benign hepatomas related to oral con traceptives. Their survey material consisted of 543 casts of primary liver tumors among both sexes; 378 in females and 165 in males. Among the males, 8.5 percent were benign, while - among the females; 56,1 percent were benign. A positive his tory of oral contraceptive use was reported in 49,5 percent of the female patients, and in 29 percent the contraceptive history was unknown. However, it is reasonable to assume that a cer tain number of these "unknowns" included Pill-users; there fore, among the female patients in this study, more than 50 percent of primary liver tumors occurred in users of oral contraceptives. The majority (73.8 percent) of the liver tumors diagnosed in Pill-users were benign. On the other hand, among non-users, the percentages of benign and malignant tumors were roughly equal. This difference in the proportion of benign to malig nant tumors among users and non-users is substantial,: and further supports the association between Pill use and the occurrenceof benign liver tumors. Also, the frequency of ma lignant tumors in this study increased with age, and resembled the distribution of malignant liver tumors in the various age groups of the general population. But the distribution of be nign liver tumors peaked in the age group of 26-30 years. and this parallels the age distribution of oral contraceptive use in the general population. Editor: What were, the histologic, types of these benign liver tumors? Dr. Kretzschmar: The survey showed that among non-users, the benign tutors wereproportionatejy divided ampng four histologictypes.Siut VOL. 28, NO. 2 MARCH/APRIL1978 ' <3001 005) among users, there was a preponderance of hepatic cell adehpmas and focal nodular hyperplasia; together, these two types represented 82.6 percent of all benign tumors in users. So. it appears that the association between oral contraceptives and benign liver tumors applies only to these two types.Theincidence of adenomas peaked significantly in the 26-30 yearold group, and then declined sharply; the incidence of focal nodular hyperplasia peaked in the 31-35 year-olds and then remained rather constant in the older groups. Editor: Do the statistics vary with different types of oral contra ceptives? Dr. Kretzschmar: Two synthetic estrogens are used in oral contraceptives: ethinyl estradiol and mestranol. (Mestranol is demethylabed in the liver to ethinyl estradiol.) Where information was avail able on the type of synthetic estrogen used, 66.7 percent of the tumors were found in women who had used mestranol. But that correlation should be interpreted rather cautiously, since mestranol was marketed first, and until 1970, was used more frequently than ethinyl estradiol by the general population. Editor: What were the most common presenting symptoms, and how were these tumors treated? Dr. Kretzschmar: Many presented with symptoms of intraperitoneal bleeding, although masses and pain were, generally the most frequent presenting symptoms in the survey. It would appear that coif? traceptive users had highly vascularized tumors, and this might suggest that oral contraceptives exacerbate clinical symptomatology of these tumors. But it should be noted that' . a high proportion of these benign liver tumors were asympto matic and were discovered incidentally. I think clinicians should be especially aware of this diagnostic possibility when examining young women who appear otherwise healthy. Most hepatic cell adenomas studied in this survey were treated by surgical resection, but 13 percent were untreated! and of the cases of focal nodular hyperplasia, 14 percent were untreated. There may be a spontaneous regression of these:, tumors once oral contraceptive use has been discontinued. v- These two types of benign liver tumors have not been shown to be precursors of hepatocellular carcinoma, and there is no evidence that because of different pathogenic mecha nisms, the benign tumors in patients on oral contraceptives have any proclivity for malignant degeneration. But benign hepatic lesions can suddenly and unexpectedly rupture, and: hemorrhage into the abdominal cavity. Emergency resection of the tumors has not always prevented fatalities. Clinicians should be aware that oral contraceptive users are at risk in relation to these benign liver tumors, and should follow their patients accordingly. Editor: Do you recommend the use of DES as a morning-after pill, given its proven correlation with vaginal carcinoma in female } Ri'jOl 09 Si CA-A CANCER JOURNAL FOR CLINICIANS ' children of women who received the drug early in pregnancy? Dr. Kretzactimar: I think that for any patient who is fully aware of the controV versies about it, DES is an appropriate management for the morning-after situation, as is menstrual extraction. Editor: . What are the major contraindications to the use of oral con traceptives? Dr. Kretzschmar: Women with present or past thrombophlebitis or thromboem bolic disorders should hot take the Pill. Similarly, patients with a history of cerebrovascular and coronary artery disease should use another form of contraception. Impaired liver function, known or suspected carcinoma of the breast or e$trogen-dependent cancers are other contraindications. The Pill should not be used when pregnancy is suspected, and any undiagnosed abnormal genital bleeding should be investigated and treated before an oral contraceptive is prescribed. Editor: In your experience, what is the most common side effect of thePill, and how should it be treated? Dr. Kretzschmar: The most common side effect is breakthrough bleeding, and this should be treated withan increased dosage of estrogen. As a general principle, a patient should begin with the lowest level of estrogen that will prevent ovulation. If breakthrough bleeding persists, the estrogen dosage can be gradually in creased. And I'm sure the physician can find another oral contraceptive-assuming the patient is healthy--that will not cause this side effect. ` . Editor: ShouldthePillbeprescribedforusesotherthan contraception? Dr. Kretzschmar: This is done, and I think it's acceptable. For example, it's effective and relatively safe in the management of severe dys- ... mennorrhea. A Oral contraceptives also provide an effective control of prolonged or excessive bleeding. When there is no pathologic basis for the menorrhagia-^such as leiomyomas, polyps| and the like--combination agents are very successful in reducing the blood flow. The advantage of this is obvious. Editor: To sum up, for whom is it safeio prescribe the Pill? Dr. Kretzschmar: A safe candidate for the Pill is any healthy young woman who wishes to have temporary control of her fertility. And I em phasize the word temporary. Neither patients nor physicians should avoid the Pill out of fear of carcinogenicity. There is simply no convincing evidence that the Pill causes cancer. Editor: 9 Thank you Dr. Kretzschmar . VOL 28. NO. 2 MARCH/APRIL 1978 . C 95"' i HFM - 003535 Medicine as an art demands constant evaluation, weighing new treatments against oldpractices, benefits against ' risks, successes againstfailures. On occasion, the evidence,' leads to different conclusions. Nowhere is this more : f- evident than in the management ofthe cancerpatient. -y OPINIONS willpresent the views ofspecialists on a wide spectrum ofcontroversial subjects. It is hoped that the ? frank expressioniofideas willprovide aframework within' which our readers mayform their own opinions. .=' Publication does not constitute endorsement by the v American Cancer Society. " V---------- ----- ----- -I-.' -- i - ------ ------------------------- -- .' - John H. Welsburger, Ph.D. experimental data. The major human can Vice President for Research Naylor Dana Institute For Disease Prevention American Health Foundation Valhalla, New York cers are due to our lifestyle, among which cigarette smoking and diet, especially high-fat, low-fiber foods and mode of cooking, are key elements. When the public is informed of newly found environmental cancer hazards/ it is WARNING: FALSE imperative that the information be slip- CANCER CLAIMS MAY ported by definitive documentation. Scare BE HAZARDOUS TO tactics are counter-productive. If baseless YOUR HEALTH assertions continue, society will only be come deafened to bona fide evidence of In the fall'of 1974, a rash of newspaper real carcinogenic hazards. Valuable re and magazine headlines claimed that con search funds and time will be diverted in taminants discovered in the lower Missis useless investigations, and efforts to focus sippi Valley drinking water were associat on the key causes and prevention of major ed with a grave risk of cancer. One ac human cancers will be neglected for lack companying illustration, playing upon the of resources. . ' ;K . story's shock-value, showed the face of a . The stories dealing with the "carcino man drinking a glass of water, and was genic" contaminants in the Mississippi captioned: "Will he get cancer?" ' ; River were spun before any scientific evi It is highly unlikely that the trace con dence had even established what tijjat taminants of drinking water would pose drinking or river water contained. Sciigi- specific risks of cancer iii the general pop-' tists in the fields Of chemical carcinogen ulation. Yet these unfounded claims, sen esis and cancer etiology were left wonder sationalized in the media, have greatly ing as to the nature and basis of the prob alarmed the public. We can say that envi lem. Months after the announcements ronmental factors cause about 80 percent had alarmed the general public, a paper of all human cancers, and this knowledge appeared in Science, but it merely listed is grounded in both epidemiologic and the chemicals found in the water of that region; its tables gave no information concerning the amounts of those chemi This review is an adaptation of a paper entitled cals. The carcinogenicity of the agents "Social and Ethical Implications of Claims for Cancer Hazards", published in Medical and Pediatric Oncology 3:137-140 (1977) by Alan R. was implied, but not specifically discussed, in relation to the publicly announced can Liss, Inc., 150 Fifth Avenue, New York, New . cer hazard. Buried in the text was a state York 10011. ment that the salient contaminant was &U0 1-6954' CA-A CANCER JOURNAL FOR CLINICIANS chloroform, and that it was present at the even for powerful carcinogens. level of three parts per million. Chloro form had beeaabown to induce livef tu mors in mice in about 1945. While I was fhe other question is whethaf chesncali/whicharecarcinogenic in dqjferimental animals at high dose levels cajiactufdly at the National Cancer Institute, addi tional tests on jhis and Other chlorinated hydrocarbons had beat started under my lead to cancer in man in trace amounts even when present for an entire life span. Ail known chemical carcinogens have a direction; however, detailed and carefully evaluated results of these tests were not available at the time of the publicity. classical pharmacological dose response. The higher the dose, the higher the cancer yield and the shorter the latent period, Most chemical carcinogens have one or more specific target organs. No agent is known which! leads to a generalized in and/yice versa. To be sure, there are syner gistic effects like inhalation of asbestos and smoking of cigarettes where the as- crease in diverse tissues. Yet, the implica bestps enhances manyfold the rigidueto tion of the publicity about contaminants smoking alone. Nevertheless, it is most in water was that these contaminants unlikely that the. trace contaminants of served to increase the cancer risk at di-, drinking water or river water would be verse sites for people using such water! associated with specific carcinogenicity in This is scientifically unsound extrapola the general population. In this instance, tion. Afiatoxin, for example, causes can the press reports thoroughly frightened cer mainly in the liver, in many expert- the public. This does not mean we should mental species and is strongly suspected not clean up our rivers and water. This is of doing so in than. Aromatic amines in an urgent aim, meritorious for its own an occupational setting have led to cancer sake. But we should not have to use a can in the urinary bladder in man and in most; cer scare to reach this goal. ; experimental species in which these same Misguided concern about therelation- chemicals were'tested, although in mice shipjof certain food additives to cancer is they also led. to tumors, of the liver. The yet another case where facts were grossly fact that this is so probably stems from misrepresented and funds needlessly the specific biochemical transformation spent. When a study performed abroad required to convert procarcinogens to the , found that the food dye Red #2 had a ultimate active forms. The required en "carcinogenic effect," well-meaning but zymes are probably similarly located in ill-informed lay groups exerted pressure organs across species lines, although ad on the United States Food and Drug Ad mittedly, more research in this area' is ministration (FDA) to re-examiriefhe data necessary. Nonefheless/.if chloroform and in their hands. The foreign investigation other such chlorinated hydrocarbons did claimed to have qbtiiihedevidence i;for cause cancer in man, the preferred site carcinogenicity in a test where the treated would be the liyer or kidney. These are animals developed cancer in different tar 'among the rare cancers of man in the get sites, mostly intheendocrine-sensitive United States. '/ organs such as pituitary, gonads akd uter Not all carcinogens are alike. The mold us. In a lifetime study, the control animals toxin and afiatoxin Bt causes liver cancer reportedly had no cancer. This is a most in rats even at one part per billion in the unusual finding: the cancers seen in the ' diet; the flavoring agent safrole requires experimentally treated group were the 2000 to $000 parts per million, a consider ones normally present in aged untreated able difference!/Yet the FDA has banned controls. Yet these were the results;which safrole, but has set a tolerance of 15 parts apparently caused the FDA to set up an per billion for afiatoxin B|. The latter is other expensive research project to re-test a sound practical decision, for setting a this dye, even though in the mid^1950's, "zero tolerance," for foods with afiatoxin - FDA scientists of excellent standing and B; would require a ban pit many of our ' repuif hid conducted a test sertes|inyolvfoods! Thus, the FDA also tacitly under jpg large numbers of/mice and i^s; and writes the existence of "no effect" levels had concluded that this dye presented no VOL 28. NO. 2 MARCH/APRIL1978 "v 'HHiV H FM - 003536 cancer hazard. But these were discounted, in favor of clearly specious findings in an attempt to assuage the fears that unfounded publicity had aroused in the American people. In the field of azo dye carcinogenesis, a considerable number of studies on structure-activity correlation have been performed by many scientists and, in particuiar, in the laboratory of the Millers at the University of Wisconsin. The general conclusion was drawn that substitution of polar groups or of solubilizing groups like hydroxy, carboxy, and especially sulfonate, uniformly decreased, and in the latter instance abolished, the carcinogenic effect. Pure Red Dye #2 has the structure of an azo dye with sulfonic acid substitution oil the aryl rings on both sides of the azo bond. On the basis of what is known in the Held, it seems unlikely, therefore, that this polar, water-soluble azo dye or its metabolites should be carcinogenic, This was also the conclusion of the extensive FDA studies performed in 1954-1956. However, the FDA went to the trouble of performing one more test series. For various reasons, this series was inadequately supervised and poorly conducted, Yet, the data generated were evaluated mathematically and the conclusion was drawn that excess cancers were seen in female animals. These cancers were not at specific target sites. They were not in organs affected by known carcinogenic azo dyes for which many structures have been examined. They were, instead, in organs where neoplasms are often seen in aged animals. Given such random distribution of cancers, one is entitled to ask: Why does if affect only female rats and not males? In fact, males treated with Red #2 had a lower disease incidence than untreated males. Yet, all of this information taken together was used by administrative and legislative authorities, and boards ofscientists and physicians, to rule that insuffident evidence existed to declare Red Dye #2 a safe dye. It was, therefore, banned, The public must have been relieved that government authorities had protected it from a grave risk of cancer! ' & Dr. F. Ingelfinger, the editor-emeritus of the New England Journal ofMedicine, in an editorial on the "cancerophobia" being induced in the public, indicated that too many claims for cancer hazards, which eventually are found wanting, immunize and make the public resistant to what might be valid, proper and real cancer hazards. Thus, the efforts to control can- cer, which are the concern of all in the field of cancer and medical research, are rendered ineffective. The public will ignore any statements if they come too often and do not discriminate between claims ba$ed on sound evidence and those which $re flimsy. It is important that when the publiois alerted, the alert have the backing of au- thoritative, reliable documentation. Itfs important that when scientists go to Fed- end or State agencies in order to modify the environment through regulatory and legislative action, that their evidence be strong and irrefutable. It is important that interpretation of the existing literature rest on a sound foundation and not repre sent frivolous imagination. It is important to construct protocols for new studies, which consume a good fraction of our limited resources for medical research, so that such studies, if successful: and prop- erly conducted, will actually contribute knowledge which can be used to reduce human cancer risk. Finally, it is important that we emphasize and deliberately foster public action on those cancer risks which are already well defined, such as those seen in occupational settings and, most urgently, those due to our lifestyle, such as the smoking of cigarettes, the cpn- sumption of diets high in fat and lovbjn fiber, and other conditions which are epidemiologically and experimentally ful- ly documented as real cancer hazards, Let us not waste time and effort, apd delude the public and ourselves through irrelevant busybody actions. Let us, rath- er, concentrate on what is important .'ip all mankind--the effective prevention and control of cancer. @ 8 0 '11 CA-A CANCER JOURNAL FOR CLINICIANS EDITORIAL A Personal Tribute to Robert M|Taylor, M.D. When Robert Mackay Taylor began his tioh in international cancer programs. long and distinguished career in cancer rie- Last September Dr. Taylor retired as search and treatment, the prognosis for : Executive Vice President of the Canadian patients with cancer was poor. Recently, in Cancer Society and Executive Director of a spedal lecture, he recalled his first year the National Cancer Institute of Canada, of graduate medical training in the cancer a dual post he had held since 1955..During ward at the Toronto General Hospital: "At that time the surgeon had no antibi otics with which to control infections... he had no bloo4;bank on which he could call for massive support when carrying out radical procedures?' In Dr. Taylorls early experience,physicians' efforts were; directed primarily to alleviating pain and "It is misleading to hold up mortality as the only criterion for , ^determining success or failure of the effort directed against cancer." controlling infection and bleeding. Since that time, there has been remark able progress in the understanding and his tenure, these two related organizations management of cancer; Improved survival grew stronger both financially and philo statistics of certain cancers and the in sophically, and the scope of their research, creasing sophistication of diagnostic and education and service activities expanded treatment capabilities are gratifying in considerably. !; deed to a man who has focussed his pro- . V Dr, Taylor can be justifiably prpud.of fessional energies on the prevention and the growth of the Canadian Cancer Soci early detection of cancer, as well as on ety, and of its sponsored, research and management and rehabilitation. Dr. Tay treatment programs. He can speak with lor has contributed enormously to these knowledge and confidence of the quality developments through' his role in the Ca of his Canadian colleagues' workffdr he nadian Cancer Society and his participa- has a long and thprough'familiar}ty with VOL. 28, NO 2 MARGH/APRIL1978 ?BQ l e957 HFM - 003537 international cancer activities. His travels bued the field of cancer research will) a have included many lectures, seminars deeply humanitarian perspective. In tiis with oncologists, and site visits to labora view, "It is.. .misleading to hold up mor tories throughout the world. From 1966 tality as the only criterion for determining to 1974 Dr. Taylor served as Secretary- success or failure of the. effort directed General of the International Union against cancer." The improvements! in Against Cancer (UICC). Prior to that ap cancer management and the quality!of pointment he was chairman of the UICC's survival are extremely important in his Cancer Control Commission. assessment of progress, reflecting a sincere Among his many other accomplish- concern for. people. Dr. Taylor has always been a realist about the promises of cancer research be "The fight against cancer will fail unless the people accept their responsibility to participate." cause the vicissitudes often make it a dis couraging endeavor. Its history has bfen punctuated by false leads and subjected to various fads and fancies. Dr. Taylor un derstood and accepted this inevitability, all the while retaining an unwavering con ments and appointments were: five years viction thht "... this scourge will be lied of overseas service in theCanadian Army; from us...I am optimistic." ' a five-year directorship at the Medical Dr. Taylor considers cancer "a peo Division of the Atomic Energy of Canada ple's disease" because he has always be Limited at Chalk River (where, in 1950, lieved that a number of cancers are catted he participated in the first cobalt treat by personal habits and lifestyles. Accord ment experiments); a long-term clinical ingly, he has placed a fair share of the teaching appointment at the University cancer burden squarely on the public's of Toronto Department of Medicine; at shoulders: "The fight against cancer,.ylriil the same University, an appointment as fail unless the people accept their respon Lecturer in the Department of Medical sibility to.participate." This holistic ap-* Biophysics; and a general medicine con proach to the problem of cancer, with the sultancy at Princess Margaret Hospital in insistence upon mutual responsibility; is Toronto. Dr. Taylor has also served on, one of Dr. Taylor's great contributions to governmental agencies and is a member our understanding of, and our successful of many professional organizations. effort against, this disease. $ To all the institutions and the causes We are grateful to Dr. Taylor for all he has served, Dr. Taylor has demonstrat his efforts and we can assure him that his ed magnificent leadership and has been an fine example will be followed by all of. us exemplar for his co-workers^ He has im- who have learned so much from him. : @ i l4o(ltn. SCO) f'9u'S CA-A CANCER JOURNAL FOR CLINICIANS Ca--A Cancer.Journal forCdnicians is iumisbad through following Divisions o the Anwrtcah Capper Society. : Alabama Oblslort, tne. ' Main*OMalon, Inc. 2926 Centra; Avenue' ' Federal and Green Streets . Birmingham, ASbama 35209 . Brunswick, Maine 04011 Ohio Written, tne. " 453 Urtcokt Budding . 1367 Ess! Sixth Street r Alaska Dlatfiaa, foe. .. ' 1343 G Street:A Anchorage. 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"The program will . include psycho-social, educational; and economic aspects of childhood cancer as well as treatment and rehabilitation. There will be an opportunity for discussion '' " of the medical, nursing, and related health professions. ' There is no registration fee. r Advance registration is requested. Accredited for continuing education. For further information write: . Sidney L. Arje, M.D; American Cancer Society National Conference on the Care of the Child with Cancer 777 Third Avenue New York, New York 10017 : .. J: \ 8001 0960 Ca is provided to you as an educational service of your local Division of the American Cancer Society. For other professional education publications, contact the office of your local Division at the address on the inside back cover. HFM - 003538