Factors Associated With Cancer of the Esophagus, Mouth, and Pharynx in Puerto Rico 1,2

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1 Factrs Assciated With Cancer f the Esphagus, Muth, and Pharynx in Puert Ric 1,2 ISIDRO MARTiNE, M.D.,s Directr, Central Cancer Registry, Cancer Cntrl Prgram, Department 1 Health, San Juan, Puert Ric SUMMARY-A case-cntrl, cmmunity-based study f 4 patients with cancer f the esphagus, muth, and pharynx was undertaken t explre the assciatin f envirnmental and dietary factrs and familial aggregatin. Twelve hundred age- and sex-matched cntrls were interviewed and asked the same questins as were the cancer patients. Bth cntrls and patients had diets deficient in fresh Fruits, vegetables, meat, eggs, and milk, but high in beans and carbhydrates in the frm f rice, bread, and such starchy rts as ptates and sweet ptates. Patients differed significantly frm cntrls in that they used mre alchl, tbacc, ht beverages (mstly cffee), and spices. Their meals were Fewer, scantier, and mre irregular, served very ht and withut beverage.-j Nat Cancer Inst 42: ,1969. THE INCIDENCE f cancer f the esphagus and its assciated mrtality in Puert Ric are amng the highest in the wrld. Cancer f the muth and pharynx als ranks higher than in many ther cuntries (1-3, 6, 8, 18-2,26,27,29,4-42). The increasing number f cases and the upward trends f age-adjusted rates (6, 26, 27) fr these particular cancer sites justified the explratin f factrs assciated with the disease in Puert Ric. Because f the relative islatin and stability f the ppulatin, the reliable Cancer Registry data (28), and the reasnably gd medical care services perating n the Island, this cmmunity-based, retrspective study was made. The peple f Puert Ric still are quite receptive t surveys by the interview methd, a cnditin which favrs reliable answers. This cmmunity-based, case-cntrl study reprts n epidermid carcinmas f the esphagus, muth, and pharynx diagnsed in Puert Ric during It explres differences between cases and cntrls in relatin t envirnmental factrs, diet, and familial clustering. The fllwing hypthesis was tested: Upper alimentary-tract epidermid carcinmas are assciated with an interplay f 1 Received January 22, 1969; accepted March 5, Supprted by Public Health Service grant I-R-OI-CA 818 frm the Natinal Cancer Institute. 3 I wish t express my appreciatin t the fllwing individuals fr their cllabratin in this study: the persnnel f the Central Cancer Registry f the Cmmnwealth f Puert Ric; all the pathlgists f the Island wh lent the slides f cancer cases fr review; the Pathlgy Department f the Schl f Medicine fr the review f the slides; Dr. Oscar Garda Ramire. Directr f the Cytlgy Prgram, Cancer Cntrl Prgram, Puert Ric Department l Health; and Dr. Luis Keith, Assistant Prfessr, Obstetrics and Gyneclgy, The Chicag Medical Schl, fr the revisin f English in the manuscript. 169 Dwnladed frm at Pennsylvania State University n May 11, 216

2 17 MARTINE sme factrs perating in undernurished epithelium secndary t a diet mildly, but chrnically, deficient. MATERIALS AND METHODS Included are all cases f malignancy f the esphagus, muth, and pharynx diagnsed and histlgically cnfirmed as epidermid carcinma in all hspitals and clinics in Puert Ric during Since 195, cancer must be reprted t the Central Cancer Registry f the Department f Health. T cmply with the law, all pathlgists must send carbn cpies f reprts f psitive bipsies fr malignancy t this Registry. In additin, the Central Cancer Registry cnducts a yearly systematic search fr thse cases nt reprted. Fr this study, all pathlgists n the Island supplied us with carbn cpies f the bipsy reprt and slides f each tumr. These slides were reviewed by the same pathlgist frm the Department f Pathlgy f the Schl f Medicine f the University f Puert Ric. A ttal f 548 malignant tumrs f the esphagus, muth, and pharynx [crrespnding t the rubrics f the Internatinal Classificatin f Diseases and Injuries (ICD), Wrld Health Organiatin, 1955] were diagnsed in bth sexes during Frm these 548 cases, 4 (73%) were cnfirmed histlgically as epidermid carcinmas. Fr each cancer patient, 3 cntrls were matched by age (within 5 years) and sex. One cntrl, frm the same hspital r clinic at which the patient was diagnsed, was selected wh had been admitted immediately after the patient and was free f any f the carcinmas under study. The ther tw cntrls were selected frm the same cmmunity as the patient and had lived there fr a t least 1 years. In searching fr these cmmunity cntrls, we started at the huse t the left f the patient's dwelling. If n matched cntrl was fund, we prceeded t the nearest huse t the right, alternating until 2 age- and sex-matched cntrls were fund. Interviewers had 2 years f cllege educatin and had been trained by prfessinals f the Divisin f Research f the Department f Health. They had n knwledge f the prevalent hypthesis f the etilgy f these carcinmas r f the specific primary site f the cancer in the particular cases. When the questinnaire was tested in the field, interviewers were supervised by a prfessinal interviewer. All interviews were revised systematically, and a 5% sample was repeated by the supervisr and checked against the riginal nes. The average interview lasted l hurs. Questinnaire tpics related t religin, educatin, birthplace, places f residence, ccupatin, and use f tbacc. There were als queries abut eating habits, special diets, kind, amunt, and time f fd cnsumptin, and the predminant methd f preparing fd in the fllwing categries: spices, fats, fruits, cereals, vegetables, salads, meats, seafds, "Puert Rican fds," cheese, nnalchlic beverages, alchlic beverages. The questinnaire requested infrmatin regarding lss f mlar and premlar teeth and the length f time withut prsthetic replacement. Lastly, it cntained questins relating t the family histry f cancer f the esphagus, muth, and pharynx. If the patient r cntrl died r was physically r mentally incapacitated, a member f the family wh had lived fr n less than 1 years with the patient r cntrl was interviewed. T insure cmparability f interviews, if a family member f a matched grup were interviewed, infrmatin frm the ther members f the grup was als btained frm their family members. Of the 4 patients, nly 43 (12%) members f their family were interviewed, and the crrespnding cntrls were als interviewed thrugh their family members. The same persn interviewed the patient and his crrespnding cntrls. Hspital and neighbrhd cntrls were very hmgeneus fr mst variables. Mrever, levels f differences between cancer patients and hspital cntrls were very similar t thse between patients and cmmunity cntrls. Frm the 4 cases and 1,2 cntrls matched by age and sex, 346 pairs were matched n tbacc use and 349 pairs n alchl cnsumptin, t determine independence f assciatin. Cnventinal chi-square tests with Yate's crrectin were used t determine statistical significance fr difference between patients and cntrls. The Dwnladed frm at Pennsylvania State University n May 11, 216 JOURNAL OF THE NATIONAL CANCER INSTITUTE

3 FACTORS IN CANCER OF ESOPHAGUS, MOUTH, AND PHARYNX IN PUERTO RICO 171 cnventinal methd fr relative risk calculatin was used. RESULTS Lcatin f Lesins Of the 4 lesins, 179 were in the esphagus (12 in males and 59 in females), 153 in the muth (115 in males and 38 in females), and 68 in the pharynx (55 in males and 13 in females). The verall male-female rati was 2.6: l. Of the esphageal carcinmas, 52% were in the middle third f the esphagus in bth sexes. Of the muth carcinmas, 4 and 5% were in the tngue in males and females, respectively. Of the pharyngeal malignancies, 45% were in the hyppharynx in bth sexes (table 1). Backgrund Infrmatin Age.-The age distributin f bth patients and cntrls was very similar amng bth sexes. Mst subjects (35%) were in the 6- t 69-year-ld grup. Other carcinmas and jamily histry j cancer. Amng the patients, 18 had had previus carcinmas. Of 1 male patients, 5 had lesins in the upper alimen tary tract. Of 8 female pa tien ts, 4 had lesins in the genital tract. Amng the cntrls, 6.2% were healthy, 1.1 % had malignant tumrs in sites ther than the muth, pharynx, and esphagus (almst half f them in the breast and genital rgans), 3.7% had diabetes mellitus, 4.6% had digestive diseases, 2.4% had diseases f urinary system, and 6.% had diseases f the bnes and rgans f mvement (mstly arthritis, table 2). Almst 11 % f the patients and 8% f the cntrls had family histries f cancer in similar anatmic sites. This difference was nt significant. Place j birth and residence.-ninety-eight percent f the patients and 99% f the cntrls were brn in Puert Ric, and 7 and 72%, respectively, were brn in the rural areas (table 3). This latter figure was in cntrast t the 196 census which shwed that nly 56% f the ttal ppulatin was brn in the rural areas. The residences f patients and cntrls, befre and after they were 21 years ld, were determined. Over 5% f them lived in rural areas befre and after the age f 21 years; 64.3% lived in rural areas r twns befre and after 2l. Only 6% f the patients and 5% f the cntrls lived in large cities during bth perids (table 4). In 196, 55% f the ttal ppulatin lived in rural areas (46). Educatin and ccupatin.-in ur study, 33.3% f the pa tien ts and 3l. 7 % f the cn tris were illiterates, in cntrast t 12.8% fr the ttal ppulatin 1 years f age r mre (36); 25.3% f the patients and 29.1 % f the cntrls had less than a TABLE I.-Lcatin f epidermid carcinmas f the esphagus, muth, and pharynx by sex, Puert Ric, 1966 Site Bth sexes Males Females N. % N. % N. % Esphagus: Upper third Middle third Lwer third Ttal Muth: Lips Tngue Flr f muth Other parts f muth Ttal Pharynx: Naspharynx Mespharynx Hippharynx Unspecified Ttal Dwnladed frm at Pennsylvania State University n May 11, 216 VOL. 42, NO.6, JUNE

4 172 MARTINE TABLE 2.-Diseases amng the age- and sex-matched cntrls by sex, Puert Ric, 1966!CD N. Site Bth sexes Male Female N. % N. % N. % N disease reprted Other malignant tumr frm: Digestive system except esphagus Respiratry system Breast and genital urinary rgans Other and unspecified sites 2-25 Lymphid and hematpietic tissue Benign tumrs Infective-Parasitic disease Allergic disrders Diseases f endcrine glands 26 Diabetes mellitus Diseases f bld and bld rgans Mental disrders Diseases f nervus system Diseases f circulatry system Diseases f respiratry system Diseases f digestive system Diseases f genital urinary system Diseases f skin and cellular tissues Diseases f bne and rgans f mvement Cngenital malfrmatins Senility and ill-defined cnditins N8-999 Accidents, pisn, and vilence Ttal furth-grade grammar schl educatin. Only 3% f the patients and 4.7% f the cntrls finished the furth year f high schl r mre. Of the patients, 35.% were agricultural wrkers expsed t the sil in cntrast t 19.4% f the ttal labr frce (46). Anther significant aggregatin f patients was fund amng indr wrkers withut specific expsure t the sil, husewives included (32.2%). In general, mst patients were in the lwest salary ccupatins (table 5). Similar ccupatin distributin was fund amng the cntrls as result f matching. Marital status.-amng the cancer patients, 4% were single, widwed, r divrced, as cmpared with 29.9% f the cntrls. This difference is significant at less than the.1 level. The male grup accunts fr the difference f bth sexes cmbined. Race and religin.-the race was very difficult t evaluate due t the intermixed ppulatin in Puert Ric. Hwever, interviewers reprted 85% as Caucasians and nly 13% as clred persns. Eightyeight percent f the patients and 85% f the cntrls stated they were Cathlic. Other special gruping f patients by different religin preference was nt O O O. 5 5 O. 6 1 O O. 4 3 O O O O O O , fund. N difference was nted between cases and cntrls. Dental status.-frty-fur percent f the patients and 42% f the cntrls lacked 8 r mre mlars withut prsthetic replacement fr at least 1 years. The difference between cases and cntrls was nt significant. Eating Habits Diet.-All items f diet in the questinnaire had three alternatives: 1) never part f regular diet, 2) frmerly used but discntinued fr 1 years r mre, r 3) used befre present time. The last alternative was investigated fr apprximate amunt, time f cnsumptin, and methd f use. Fr analysis, high r lw amunts were cnsidered in terms f 1 years r mre f cnsumptin r use f the item. Amunt f fd.-the amunt ffd ingested by the patients was cnsistently less than by the cntrls (18.7 vs. 13.9%). This difference was significant at the.5 level. Number f meals during the day.-the percent f patients eating nly ne daily meal was signifi- Dwnladed frm at Pennsylvania State University n May 11, 216 JOURNAL OF THE NATIONAL CANCER INSTITUTE

5 r'!>- S'" TABLE 3.-Place f birth f patients with epidermid carcinmas f the esphagus, muth, and pharynx and age- and sex-matched cntrls by site!:l and ne, Puert Ric, 1966 vo> '-< Bth sexes Male Female I'2j c::: Place f birth* > i:':! Cases % Cntrls % Cases % Cntrls % Cases % Cntrls %,., ;a > :<l t '" The 3 Cancer Sites P.R., rural P.R., twn P.R., small city i:':! P.R., large city :<l Other cuntries r unknwn O. 9 I'2j Ttal , M Cancer f the Esphagus '" 'ti :I: P.R., rural > P.R., twn P.R., small city JI' P.R., large city i!:: Other cuntries r unknwn O O. 6 Ttal c::,., Cancer f the Muth P.R., rural P.R., twn 'ti P.R., small city :I: > c::: v:i: > tl P.R., large city > :<l Other cuntries r unknwn ><: Ttal Cancer f the Pharynx 'ti P.R., rural c:: M P.R., twn :<l,., P.R., small city P.R., large city Other cuntries r unknwn :<l Ttal 'Rural, less than 2,5 inhabitants. Twn, 2,5-25, Inhabitants. Small City, 25,-1, luhabitants. Large city, 1, r mre Inhabitants.... e" " <: Dwnladed frm at Pennsylvania State University n May 11, 216

6 '--< ;. t"" "l ;.- ;.- t"" 51 I - ;t TABLE 4.-Residence f patients with epidermid carcinma f the esphagus, muth, and pharynx and age- and sex-matched cntrls by ne and sex, Puert Ric, 1966 Residence after 21 years f age' Residence befre Rnral 21 years f age Twn Small city Large city U.S. Varied Unknwn Ttal Cases Cntrls Cases Cntrls Cases Cntrls Cases Cntrls Cases Cntrls Cases Cntrls Cases Cntrls Cases Cntrls M F M F M F M F M F M F M F M F M F M F M F M F M F M F M F M F :s: ;.-.., Rural ' Twn t'l Smal\clty Large city U.S Varied Unknwn Ttal nO N *Rural, less than 2,5 Inhabitants. Twn, 2,5-25, inhabitants. Small city, 25,-1, Inhabitants. Large city, 1, r mre inhabitants. Dwnladed frm at Pennsylvania State University n May 11, 216

7 FACTORS IN CANCER OF ESOPHAGUS, MOUTH, AND PHARYNX IN PUERTO RICO 175 TABLE 5.-ccupatin f patients with epidermid carcinmas f the esphagus, muth, and pharynx and age- and sex-matched cntrls, Puert Ric, 1966 Occupatin THE THREE CANCER SITES Bth sexes Cases % Cntrls % Agricultural wrkers (sunlight and sil expsure) Indr wrkers with n specific expsure, including husewives Outdr wrkers except agriculture Cement dust expsure Mtr vehicle driver Sawdust expsure Tbacc expsure White cllars, clerk secretaries, ffice wrkers, etc Grease and gasline expsure Acids and ther chemical expsure Dyes and dust expsure O. 6 Paint fume expsure O. 3 Alchl expsure O. 5 Pliceman guards Prfessinal executive, managers, prprietrs 3 O Prfessinal athletes 3.2 Nt stated Ttal , 2 1. cantly different (.1 level) frm the percent f cntrls (3.3 vs. 1.2%). The difference was als significant in the male grup (.5), but nt in the female grup. Regularity f meals.-fifty-tw percent f the patients and 41.8% f the cntrls ate meals irregularly. This difference was significant at the.1 level fr the "bth sexes" grup and fr males in the 3 cancer sites cmbined. Temperature j meals.-thirty-seven percent f the patients and nly 31.2% f the cntrls preferred ht and very ht meals. This difference is significant at the.5 level fr bth sexes and 3 sites cmbined. Beverages during meals.-five percent f the patients and 2.4% f the cntrls never drank liquid with meals. This difference was significant at the.5 level fr bth sexes. Similar difference was fund fr males. Rapidity f eating.-only 29% f the patients and 28% f the cntrls ate faster than the rest f adults in their families. This difference was nt significant. Specific Fds Each fd was investigated in terms f apprximate r grss estimate fr amunt, quality, methd f cking, and time f cnsumptin. Fruits and vegetables.-except fr ranges, bananas, and mangs, eaten nly in seasn, fruit cnsumptin by patients and cntrls was chrnically deficient. In general, fr the 3 cancer sites and bth sexes cmbined, 75% f the patients and cntrls never had fresh fruit in their regular diet. There was n significant difference in amunt, time, r methd f preparatin f fruits between patients and cntrls by sex r cancer sites. Vegetables were cnsistently insufficient in the diet f bth patients and cntrls fr each cancer site. Eighty-seven percent f patients and cntrls had nly tw prtins r less per week during their lifetime. There was n significant difference between cases and cntrls. Meat.-In bth patients and cntrls, meat cnsumptin was lw fr each cancer site grup. There was n significant difference between patients and cntrls. Fr the 3 cancer sites and bth sexes cmbined, 9% f the cancer patients and 88% f the cntrls had 3 prtins f meat per week r less during their lifetime. N particular cnsumptin f smked meat was fund. Similar findings were nted fr sausages, smked and nt smked. Only 2% f patients and cntrls had sausages in their regular diet. N significant difference was fund between patient and cntrls. Seajds.-Seafds in general were nt part f the regular diet amng bth patients and cntrls, Dwnladed frm at Pennsylvania State University n May 11, 216 VOL. 42, NO.6, JUNE 1969

8 TABLE 6.-Use f spices in fd by patients with epidermid carcinma f the esphagus, muth, and pharynx and age- and sex-matched cntrls, by sex, Puert Ric, J O'l Bth sexes* Male* Female* Use f spices in Cases Cntrls Cases Cntrls Cases Cntrls fd R.R R.R. R.R. N. % N. % N. % N. % N. % N. % Ht Pepper (Chile) Nne A B B Light Mderate B BB D 6 6.9D Heavy B 11.9B B 7.8B B B Nt stated O. 8 1 O. 9 Ttal , Black Pepper Nne B B B B 1. Light D D Mderate C C C C Heavy 8 2.A 3.3A O >,l Nt stated O O. 3 ' t'l N t..., Ttal , c:: Capper Bush )- t'" Nne Light "l Mderate Heavy >,l 1 2.5B 8.7B O O :Il Nt stated t'l Ttal , > >,l (5 Criander > Nne t'" Light O n )- Mderate O Heavy 12 3.A 7.6A C 5.6C O n t'l Nt stated O. 9 2 O. 6 Ttal , fj'l >,l ::J c:: *R.R.: relative risk. A: significant at.1 level. B: significant at.1 level. C: significant at.2 level. D: significant at.'5 level. >,l t'l )- Dwnladed frm at Pennsylvania State University n May 11, 216

9 FACTORS IN CANCER OF ESOPHAGUS, MOUTH, AND PHARYNX IN PUERTO RICO 177 except fr dried cdfish cnsumed regularly by 86% f the patients and 85% f the cntrls 3 r 4 times a week during their lifetime. Milk and cheese.-thirty-nine percent f the cancer patients and 41% f the cntrls had never drunk fresh milk. Sixty-seven percent f the patients and 68% f the cntrls had never had cheese in their regular diet. These differences were nt significant. Eggs.-Thirty-five percent f the patients and 39% f the cntrls cnsumed fewer than 3 eggs per week during their lifetime. This difference was nt significant. Cereals and starchy fds.-eighty percent f bth patients and cntrls reprted a high cnsumptin (3 times a day r mre) f cereals and starchy fds such as rice, beans, bread, ptates, sweet ptates, etc. Fats.-The predminant fat used was lard. Patients and cntrls used the same type f fat, refried with the same frequency. Spices.-Table 6 shws thse spices which patients and cntrls used differently. Three percent f the patients and less than 1 % f the cntrls used spices in quantity. Differences varied particularly with spices, but were generally significant at a.1 level. The breakdwn by cancer site gave a few cases fr analysis. "Puert Rican fds".-these cnsist f fried mixtures f cereals (crn, flur, etc.) with meat, cheese, r cdfish. Others are prtins f grund green plantains with spices and prk meat, packed in plantain leaves and biled. These fds were cnsumed nly during certain perids f the year, and n significant difference between patients and cntrls was fund. Ht beverages.-a significant difference (at the.1 level) was nted between patients and cntrls in regard t drinking ht beverages. The greater difference was in cnsumptin f black cffee (table 7). Alchl Cnsumptin Thirty-tw percent f the patients, but nly 1.9% f the cntrls, were heavy drinkers (5 units f alchl r mre per day). This difference was significant at much less than the.1 level. A similar difference existed fr each cancer site when bth sex grups were cmbined. The male grup shwed a similar difference in each cancer site, except fr cancer f the muth, where the difference was significant at the.1 level. The female grup had a difference significant at less than.1 level when the 3 cancer sites and mderate level f cnsumptin were cmbined (2-4 units per day). The breakdwn f female cases by cancer site shws a difference, but the number f cases was t small t test fr significance (table 8). Mixed drinking was the mst cmmn type f alchl cnsumptin amng bth sexes and fr each cancer site. It was fllwed in frequency f preference by males f cmmercial rum, hmeprcessed rum, and beer. The secnd preference f females was beer, wine, r hme-prcessed rum (table 9). Distilled alchlic liqurs (rums, whiskey, etc.) were drunk "straight" mre frequently by patients than by cntrls. The difference was significant at less than.1 level in bth sexes fr the 3 sites cmbined, in the male grup fr each separate cancer site, and in the female grup fr cancer f the esphagus (table 1). Fr the 346 pairs matched by age, sex, and use f tbacc, the prprtin f heavy drinkers was always greater amng patients than amng the cntrls. Relative risks increased with the increasing alchl cnsumptin, becming 2-6 times higher amng the heavy drinkers than amng the nndrinkers (table 11). Tbacc The use f tbacc per day is shwn in table 12. Amng the patients, 25.5% were heavy smkers (5 units f tbacc r mre per day), in cmparisn with nly 1.2% f the cntrls. This difference was significant at less than the.1 level in bth sexes and the three sites cmbined. Similar differences fr heavy smking exist fr each cancer site when bth sex grups were cmbined. The male grup had significant differences fr each cancer site. Female differences were significant nly when the number f cases f mderate use (3-4 units per day) were cmbined with thse with heavy use f tbacc fr cancer f the muth and pharynx. Dwnladed frm at Pennsylvania State University n May 11, 216 VOL. 42, NO.6, JUNE 1969

10 - TABLE 7.-Beverages usually drunk ht by patients with epidermid carcinma f the esphagus, muth, and pharynx and age- and sex-matched cntrls by sex, Puert Ric, 1966 Beverages Bth sexes* Male* Female* Cases Percent Cntrls Percent Cases Percent Cntrls Percent Cases Percent Cntrls Percent Black Cffee Ht 4 1O.A A B B Warm r cld Nne D D Nt stated O. 7 2 O Ttal , t!:: ;I> :<1 Cffee With Milk >-l 51' Ht D D l'l N Warm r cld , '- Nne ;I> t"' Nt stated O Ttal , Chclate With Milk "l i Ht Warm r cld B B Nne B B D D Nt stated ;I> ::l Ttal , ;I> t"' A: significant at.1 level. B: significant at.1 level. C: significant at.2 level. D: Significant at.5 level. ;I> l'l :<1 51 CIl ;l Dwnladed frm at Pennsylvania State University n May 11, 216

11 <: TABLE 8.-Alchl cnsumptin by patients with epidermid carcinma f the esphagus, muth, r' cntrls by sex and site, Puert Ric, 1966 and pharynx and age- and sex-matched yro Units* f alchl per Bth sexest Malet Femalet day p Cases % Cntrls % Cases % Cntrls % Cases % Cntrls % va> '- The 3 Cancer Sites q Nne B B OA A ;I> 1 r less B B A A ;;; }A 4 a> 1. 2}A < 5 r mre A A A A O. 6 Discntinued 1 yr r '" "" mre A A A la Nt stated O ;I> Ttal , Cancer f the Esphagus Nne B B 1 8.3B B r less B B "C 5 r mre A A A A :c Discntinued 1 yr r q mre D D 1 8.3B B q Nt stated JI' i!:: Ttal Cancer f the Muth Nne ;I> 1 r less D D 9 7.8D D t) "C 5 r mre A A B B O. 9 :r: Discntinued 1 yr r ;I> :; mre C C C C >< Nt stated Ttal "" Cancer f the Pharynx Nne 1 r less :; >-l :; 5 r mre A A A A Cl Discntinued 1 yr r mre 4 5.9D D Nt stated "1 >-l :; :; >">j '" ;I> q >-l y:c "C q Ttal 'Unit f alchl: 2 unces f liqur r 18 unces f beer r 8 unces f wine.... t A: significant at.1 level. B: significant at.1 level. C: significant at.2 level. D: Significant at.5 level. <i Dwnladed frm at Pennsylvania State University n May 11, 216

12 - TABLE 9.-Type f alchl drunk by patients with epidermid carcinma f the esphagus, muth, and pharynx and age- and sex-matched cntrls by sex and site, Puert Ric, 1966 Bth sexes* Male* Female* Type ;:: Cases % Cntrls % Cases % Cntrls % Cases % Cntrls % :> :>:!... '"'l, The 3 Cancer Sites t<l N... Nne A A OA A Wine nly O :>:! Beer nly D D :> Brandy nly t"' Whiskey nly O. 6 1 O. 3 Cmmercial rum nly "'l Hme-prcessed rum nly '"'l Mixed A A A A :r: Nt stated t<l 1.8 :> Ttal , ::l Cancer f the Esphagus :> t"' Nne B B 1 8.3B B C Wine nly O :> Beer nly O c Brandy nly 1 O. 2 1 O. 6 t<l Whiskey nly 1 O. 2 1 O. 3 :>:! Cmmercial rum nly Hme-prcessed rum nly til Mixed C C C C ::l '"'l Nt stated '"'l t<l Ttal Dwnladed frm at Pennsylvania State University n May 11, 216

13 r Cancer f the Muth u"" Nne IS Wine nly 1 O O !:l Beer nly uo"> Brandy nly... Whiskey nly 1 O c::: Cmmercial rum nly "1 Hme-prcessed rum nly >- l':i n -j Mixed : Nt stated "> )ti <&J '" Ttal Cancer f the Pharynx Nne Wine nly Beer nly "1 Brandy nly Whiskey nly t<l '" Cmmercial rum nly 'ti Hme-prcessed rum nly ::= Mixed D D B B >- Cl Nt stated c::: J" Ttal is:: c::: A: significant at.1 leve!. B: significant at O.Olleve!. C: significant at.2ieve!. D: significant at.5 leve!' -j u::= >- tl n >- n t<l )ti 'ti ::= >- )ti 51 'ti c::: t<l )ti -j )ti a -g < Dwnladed frm at Pennsylvania State University n May 11, 216

14 .- OJ I\:) TABLE 1.-Methd f drinking alchlic distillates by patients with epidermid carcinma f the esphagus, muth, and pharynx and age- and sex-matched cntrls by sex and site, Puert Ric, 1966 Methd Bth sexes* Male* Female* Cases % Cntrls % Cases % Cntrls % Cases % Cntrls % The 3 Cancer Sites Nne A A OA A Straight A A A A 11 1.A A Diluted 2 5.B B Discntinued 1 yr r mre A A A la Nt stated O Ttal , Cancer f the Esphagus Nne B B B Straight A A A A A A a:: Diluted :> Discntinued 1 yr r mre D D IE >-l Nt stated ' l'l Ttal N C Cancer f the Muth Nne :> Straight A A A A t"' Diluted Discntinued 1 yr r mre B B ':rl Nt stated >-l ::t: l'l Ttal :> Cancer f the Pharynx ::l Nne Straight A A A A :> Diluted t"' Discntinued 1 yr r mre C'l Nt stated :> 1. C'l l'l Ttal *A: significant at.1 level. B: significant at.1 level. C: Significant at.2 level. D: significant at.5 level. ::l '" d ;l Dwnladed frm at Pennsylvania State University n May 11, 216

15 r <: TABLE n.-alchl cnsumptin amng patients with epidermid carcinma f the esphagus, muth, and pharynx and cntrls matched by age and sex and use f tbacc by sex and site, Puert Ric, 1966 Bth sexes Male Female P Units* f alchl per day Cases Cntrls Cases Cntrls Cases Cntrls C"l R.R.t R.R.t R.R t '--< N. % N. % N. % N. % N. % N. c:: % "1 :> trl '" a> i<:i The 3 Cancer Sites.., Nne '" til 1. 1 r less r mre :> Discntinued 1 yr r mre Nt stated trl i<:i Ttal "1 Cancer f the Esphagus trl U> Nne "C :t: 1 r less O :> O r mre c:: J" Discntinued 1 yr r mre Nt stated , c:: Ttal :t: Cancer f the Muth :> t:l Nne 'ti 1 r less :t: O. :> 5 r mre ><: Discntinued 1 yr r mre Nt stated Ttal "C Cancer f the Pharynx.., i<:i Nne r less i<:i O r.; 5 r mre Discntinued 1 yr r mre Nt stated Ttal *One unit: 2 unces f liqur (rum, whiskey, gin, etc.) r 18 unces f beer r 8 unces f wine. g tr.r.: relative risk. t;.:l Ii:: Dwnladed frm at Pennsylvania State University n May 11, 216

16 - TABLE 12.-Use f tbacc by patients with epidermid carcinma f the esphagus, muth, and pharynx and age- and sex-matched cntrls, by sex and site, Puert Ric, 1966 Bth sexest Malet Femalet i!:: Tbacc in units* per day Cases Cntrls Cases Cntrls Cases Cntrls N. % N. % N. % N. % N. %... The 3 Cancer Sites ::l, N. % t'ii N Nne A A B B t"' < D SD ':r:i r mre A 122 1O.2A A A A A := Discuntinued fr 1 yr r mre 2 5.A A B B tj Nt stated Ttal , ::l Cancer f the Esphagus t"' Nne B B D D C'l < S C'l tj S r mre A A B 36 1.B Discntinued fr 1 yr r mre 8 4.5C C Nt stated c: ;J Ttal Dwnladed frm at Pennsylvania State University n May 11, 216

17 r Cancer f the Muth ft Nne < ucfl '-4 5 r mre A A B B q Discntinued fr 1 yr r mre 7 4.6D 47 1O.2D trj Nt stated ;:;; Cfl 1. Ttal Cancer f the Pharynx Nne D D < O r mre A 2 9.8A A A Discntinued fr 1 yr r mre D D Nt stated }A }A "l > a >-l a O trj 4 3.8}B 4 :: 1.3}B Ttal One uuit: 4 cigarettes r 2 pipes r 1 cigar r 2 "pieces" f chewing tbacc. fa: significant at O.OOlleve!. B: significaut at O.Olleve!. C: significant at O.2Ieve!. D: significant at O.5Ieve!. :: til... a > "l trj en 'tl :rl > q q sn i!:: > t;; '1:1 :rl > '1:1 6 :: n U1 <: Dwnladed frm at Pennsylvania State University n May 11, 216

18 ..- TABLE 13.-Type f smking by patients with epidermid carcinma f the esphagus, muth, and pharynx and age- and sex-matched cntrls by sex and site, Puert Ric, 1966 I::: Bth sexes* Male* Female* > Type f smking.., Cases % Cntrls % Cases % Cntrls % Cases % Cntrls % St N '-< The 3 Cancer Sites c:: Nne A A C C B B 2: ;r. Cigarettes nly t"' Cigars nly C C Pipes nly O O. 9 "l Chewing nly , Mixed B B B B II: Nt stated r discntinued 2 yr r mre : > ::l Ttal , ;r. Cancer f the Esphagus t"' C'l Nne B B D D ;r. Cigarettes nly : Cigars nly &1 Pipes nly 5 O Chewing nly Mixed D D '" Nt stated r discntinued ::l.., 2 yr r mre Ttal Dwnladed frm at Pennsylvania State University n May 11, 216

19 <: t"' Cancer f the Muth v Nne '(' Cigarettes nly D D C C -l Cigars nly B 32 7.B Pipes nly O I a> c,-< Chewing nly O O. 6 '" C Mixed D D C C Nt stated r discntinued I<> _ 2 yr r mre I c <C a> <C Ttal Cancer f the Pharynx Nne D D Cigarettes nly Cigars nly Pipes nly O O. 6 Chewing nly Mixed Nt stated r discntinued 2 yr r mre B 3 2.6B "1 ;I> )d rn t" t"1 rn Ttal *A: significant at O.OOlleve!. B: significant at O.Olleve!. C: significant at.21eve!. D: significant at.5 level. a::..., > )d "1 "C :I: > C S" c..., :I: > t:i "C :I: > )d ><: ::.<... "C C t"1..., )d )d 8... g "'-J Dwnladed frm at Pennsylvania State University n May 11, 216

20 188 MARTINE Tbacc was used in the fllwing rder f ppularity: 1) cigarettes, 2) cmbinatins f cigarettes with ther types f tbacc, and 3) chewing. Patients with cancer f the muth did nt ften use chewing tbacc disprprtinately nr did patients with cancer f the pharynx smke cigars mre ften than usual. The mst cmmn mixed use f tbacc was cigarettes and cigars (5%), fllwed by cigarettes and chewing tbacc (15.2%), and cigars and chewing tbacc (11.4%) (table 14). The breakdwn f mixed uses f tbacc by cancer site grups gave a very small number f cases. F r the 349 pairs matched by age, sex, and alchl cnsumptin, the prprtin f heavy smkers was always greater amng patients than cntrls. Relative risks increased with the increasing amunts f tbacc used. The risk was frm times higher fr heavy smkers than fr nnsmkers (table 15). DISCUSSION The study agrees with mst f the previusly published incidence data in terms f distributin f these cancer sites by sciecnmic levels, age, sex, ccupatin, etc. (7,9,16,17,21,26,27). It als validates sme clinical impressins and prevailing hyptheses f assciated factrs derived frm studies f hspital series. We are aware f the pitfalls and bias f sme data btained by interview, especially n diet, alchl cnsumptin, and ther items. We tried t minimie these factrs by training the interviewers well and by questining clsely, but the interviewees' recall ability is still a prblem. We believe that with the exceptinal matching btained by age, sex, hspital, residence, educatin, place f birth, etc., at least the biases are equally distributed in bth grups. This study shws a very lw cnsumptin f fruits, vegetables, milk, eggs, and meat by bth patient and cntrl grups. Additinal evidence f undernurishment f similar ppulatin grups was fund cnsistently in six previus studies (clinical, dietary, and bichemical) cnducted in rural cmmunities in Puert Ric. The specific and cmmn findings have been: "diet deficient in gd quality prteins, calries, vitamin A, ribflavin, and calcium; the mst imprtant clinical findings were retarda tin f grwth, skin xersis, and hyperkeratsis assciated with vitamin A deficiency; bichemically, a cnsiderable number f individuals shwed lw serum vitamin A and cartene bld levels" (1-14, 37). The staple diet f ur study grups was high in carbhydrates btained frm rice, beans, and such starchy rts as ptates and sweet ptates. The mst imprtant surce f animal prtein was cdfish, supplemented during the last decade with pultry. These nutritinal studies actually shw the present dietary picture when the ecnmy f the Island is much better than it was 2 r mre years ag. We must assume that nutritinal deficiencies were mre accentuated in the first three decades f this century, when it is likely that the peple began t develp cancer. Rural residency, agricultural ccupatin, and lw educatinal level are factrs usually assciated with a lw sciecnmic level. Pverty, in turn, means fasting perids between meals, irregularity f meals, small amunts ffd, and a diet deficient in such mre expensive nutrients as meats, vegetables, fruits, milk, and eggs. Perhaps these cnditins have als influenced the cnsumptin r use f large amunts f alchl and tbacc f lw quality. Single, divrced, and widwed males in this sciecnmic stratum may be mre susceptible t bth alteratins: deficiency in quality and regularity f diet fr bvius reasns, and prir r cncmitant emtinal disturbances that accentuate the use and cnsumptin f high amunts f stimulants. The factrs fund in different prprtins between patients and cntrls are in descending rder f magnitude: cnsumptin f alchl, use f tbacc, cnsumptin f ht beverages, irregularity f meals, cnsumptin f spices, reduced number f meals during the day, absence f beverages during meals, small amunts f fd, and higher temperature f meals. The utstanding factrs assciated with these particular cancer sites are the use f alchl and tbacc, which apparently perate independently. Similar assciatins have been fund in several hspital-based studies (5, 15, 22, 23, 31, 32, 35, 39, 45, 48-5). The smaller difference between female patients and cntrls fr alchl cnsump- Dwnladed frm at Pennsylvania State University n May 11, 216 JOURNAL OF THE NATIONAL CANCER INSTITUTE

21 <: r' v'?$ va>... ['6 TABLE 14.-Mixtures f tbacc use by patients with epidermid carcinmas f the esphagus, muth, and pharynx and age- and sex-matched cntrls, Puert Ric, 1966 Mixtures Bth sexes Male Female Cases % Cntrls % Cases % Cntrls % Cases % Cntrls % Cigarettes and cigars Cigarettes and pipe Cigarettes and chewing tbacc Cigars and pipe Cigars and chewing tbacc Pipe and chewing tbacc Cigarettes, cigars, and pipe Cigarettes, cigars, and chewing tbacc Cigarettes, pipe, and chewing tbacc Cigars, pipe, and chewing tbacc O Cigarettes, cigars, pipe, and chewing tbacc 1 O. 3 1 O. 4 Ttal n >-i :c '"» ttl :c '%l ttl '" "d ::t:» q J" E:: v» ti "d ::t: :> :c x "d q ttl :c >-i :c g <.D Dwnladed frm at Pennsylvania State University n May 11, 216

22 - TABLE 15.-Tbacc cnsumptin amng patients with epidermid carcinma f the esphagus, muth, and pharynx and cntrls matched by age and sex and uses f alchl by sex and site, Puert Ric, 1966 '-< Bth sexes Male Female il:: >.., Unit* f tbacc per day Cases Cntrls Cases Cntrls Cases Cntrls..., N. % N. % R.R.t N. % N. % R.R.t N. % N. % R.R.t c:: The 3 Cancer Sites :: ;I> Nne t'" < "l 3-5.., r mre :t: t'l Discntinued 1 yr r mre Nt stated ;I>.., Ttal ;I> Cancer f the Esphagus t'".., j C'} Nne ;I> < C'} t'l r mre Ii Discntinued 1 yr r mre til Nt stated c:: Ttal (%j N Dwnladed frm at Pennsylvania State University n May 11, 216

23 t"' Nne v'" "'" < O s;, r mre Discntinued 1 yr r mre '-< c: Nt stated Ttal :: '> '"' Nne < r mre Discntinued 1 yr r mre Nt stated Cancer f the Muth O Cancer f the Pharynx Ttal Unit f tbacc: 4 cigarettes r 1 cigar r 1 "piece" f chewing tbacc r 2 pipes. tr.r.: relative risk "'1 )-?O '" )- t%l?o "'1 t%l 'ti II: )- ffi ;;:: v ) 'ti II: )-?O... 'ti?o Cl,... <: Dwnladed frm at Pennsylvania State University n May 11, 216

24 192 MARTINE tin may be an underestimate due t strng scial attitude against alchlism in females in Puert Ric. The reductin in number f cancer patients in this sex grup may als reduce the significance f the difference, since the gruping f patients accrding t the three cancer-site categries and/r adding patients wh cnsume alchl mderately t thse wh cnsume it heavily make the difference significant. A larger series f cancer cases in the female grup might well reveal mre significant differences. We cannt prve the exclusive assciatin f the highly suspected hme-prcessed rum in ur study. But we cannt deny it. We may assume that we did nt btain the cmplete histry in relatin t this type f rum. This particular alchlic liqur is prcessed by uncntrlled fermentatin f sugarcane mlasses in barrels f different surces like crude petrleum drums, and distillatin smetimes in primitive stills like car radiatrs. This prduct is sld illegally. It csts ne-fifth t ne-tenth the price f cmmercial rum. Standard chemical analysis f this rum has shwn cnsiderably greater amunts f isamylic alchl, isbutylic alchl, prpylic alchl, fusel il, and furfural than thse fund in cmmercial rums. Since mst f these cancer patients are frm the lwest scial strata, it makes sense t assume that they drink the cheapest liqur and in greater amunts than they reprted, n matter hw clse the questining. Per capita cnsumptin f alchlic beverages and smking f cigarettes n the Island have increased at the same rate as cancer incidence in the esphagus, muth, and pharynx (4, 26). Chemical analysis and animal experimentatin are indicated fr this particular substance. Tbacc use is secnd t alchl in the magnitude f difference between patients and cntrls. This factr has been fund assciated in previus studies (24, 25, 3, 33, 34, 38, 43, 44). Heavy drinkers are usually als smkers. In this study, statistical prcedure has been used t test assciatin independent frm alchl. Uncmmn types f tbacc use, such as smking cigarettes with the burning end in the muth, nasal applicatin f tbacc, r the mixing f tbacc with ther substances, are nt practiced in Puert Ric and were nt fund thrughut the study. Chewing tbacc was mixed with a mlasses slutin t imprve the taste and t preserve it frm drying. We expected t find a high frequency f tbacc chewing amng patients with cancer f the muth, cigar smking amng patients with cancer f the pharynx, and cigarette smking amng patients with cancer f the esphagus, but cigarettes predminated in each cancer site. Hwever, smking cmbinatins ranked secnd t cigarettes, the mst frequent being cigarettes with cigars. The difference fr tbacc use between patients and cntrls amng females by cancer site presented the same type f difficulty as did alchl cnsumptin, i.e., lwer values f significance, mstly due t reductin f the number f cases by the breakdwn by cancer site. The greater relative risk fund fr heavy smkers matched by age and sex and alchl cnsumptin, and vice versa, strengthened the assciatin f these factrs with the disease. The data f this study lead t the cnclusin that patients and cntrls cnsumed diets deficient in fresh vegetables, fruits, milk, eggs, and meat. Beans, rice, ptates, and ther starchy rts predminated in their diet. The develpment f epidermid carcinmas f the esphagus, muth, and pharynx was assciated with a high cnsumptin f alchl, heavy use f tbacc, and high cnsumptin f ht beverages and spices. Experimental and labratry studies shuld be fcused n the interrelatin f unbalanced diet and the cnsumptin f these prducts. REFERENCES (1) BERNARD, F., HANDY, V. H., GERHARDT, P. R., and SOLOMON, M.: Cancer in New Yrk State A review f incidence, mrtality, prbability and survivrship. Bureau f Cancer Cntrl, N.Y. Department f Health, (2) BOULLE, J. R., and KARK, A. E.: Oesphageal cancer in Africans: Nte n incidence in Durban area. Univ Natal, Durban, Med Prc 6: , 196. Abstr in Excerpta Med 9: 128, (3) BRAS, G., WATLER, D. C., and ASHMEADE-DYER, A.: The incidence f malignant neplasm in Jamaica. BritJ Cancer 19: , (4) BUREAU OF ALCOHOLIC BEVERAGE TAXES: Dept f Finance, Gvt f Puert Ric. Persnal cmmunicatin, (5) BURRELL, R. J. W.: Esphageal cancer amng Bantu in the Transkei. J Nat Cancer Inst 28: , Dwnladed frm at Pennsylvania State University n May 11, 216 JOURNAL OF THE NATIONAL CANCER INSTITUTE

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26 194 MARTINE (39) SCHWART, D., et at.: Alchl et cancer, Resultats d'une enqute retrspective. Rev Franc Etud Clin Bii 17: 59-64,1962. (4) SEGI, M., et at.: Cancer Mrtality fr Selected Sites in 24 Cuntries ( ). Sendai, Japan, Dept Public Health, Thku Univ Schl Med 196. (41) SEGI, M., and KURIHARA, M.: Cancer Mrtality fr Selected Sites in 24 Cuntries, N.2 ( ). Sendai, Japan, Dept Public Health, Thku Univ Schl Med (42) ---: Trends in Cancer Mrtality fr Selected Sites in 24 Cuntries, Sendai, Japan, Dept Public Health, Thku Univ Schl Med (43) SMOKING AND HEALTH: Reprt f the Advisry Cmmittee t the Surgen General f the U.S. Public Health Service. USPHS Pbl 113: , (44) STEINER P. F.: Etilgy and histgenesis f cancer f esphagus. Cancer 9: , 1956; (45) THE EPIDEMIOLOGY OF GASTROINTESTINAL CANCER WITH SPECIAL REFERENCE TO CAUSATION: Wrld Organiatin f Gastr-enterlgy, Reprt f Internatinal Wrking Party, Hunt, T. C., president. Lndn, Ciba Fundatin, (46) U.S. 196 CENSUS POPULATION: U.S. Dept f Cmmerce, Bureau f Census, vl I, part 53, tables 52, 73-75, (47) VINCENT R. G., and MARCHETTA, F.: The relatinship f the use f tbacc and alchl t cancer f the ral cavity, pharynx r larynx. Amer J Surg 16: 51-55, ( 48 ) WATSON, W. L.: Cancer f esphagus; sme etilgical cnsideratins. Amer J Rentgen 41 : , (49) WYNDER, E. D., BROSS, I. J., and FELDMAN, R.: A study f etilgical factrs in cancer f the muth. Cancer 1: , (5) WYNDER, E. L., and BROSS, I. J.: Study f etilgical factrs in cancer f the esphagus. Cancer 14: , Dwnladed frm at Pennsylvania State University n May 11, 216