Comparative effectiveness of the tumour diagnostics,

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1 Gut, 1987, 28, Comprtive effectiveness of the tumour dignostics, C 19-9, C 125 nd crcinoembryonic ntigen in ptients with diseses of the digestive system K SKMOTO, Y HG, R YOSHIMR, H GMI, Y YOKOYM, ND M KGI From the Deprtment ofsurgery II, Kummoto niversity Medicl School, Kummoto, Jpn SMMRY Serum concentrtions of C 19-9, C 125 nd crcinoembryonic ntigen (C) in 145 ptients with gstrointestinl crcinoms nd 89 with non-neoplstic diseses were determined to compre the clinicl usefulness of these tumour mrkers. Significntly fewer positive cses were obtined with serum C 19-9 (9%) nd C 125 (8%) tests thn the C test (22%) (both p<o-5) in ptients with benign diseses, while comprble sensitivities were chieved with the C 19-9 (44%) test, the C 125 (41%) test nd the C test (47%) in those with crcinom. High incidences of rised concentrtions of serum C 19-9 nd C 125 were observed in cse of cncer of the pncres (C 19-9: 87%, C 125: 67%) nd biliry trct (C 19-9: 63%, C 125: 48%). Combined tests of C 19-9 nd C 125 reveled increments in the sensitivity (61%) nd provided higher specificity (87%) thn tht of the single C test (78%). These combined tests were most useful for differentil dignosis of pncretic crcinom (97% positive) nd biliry trct crcinom (74%) from chronic pncretitis (4%) nd cholelithisis (%), respectively. Studies on the reltions of clinicl stging nd serum concentrtions of C 19-9 nd C 125 reveled significnt rises in cses of disseminted crcinom. These results clerly show tht serum C 19-9 nd C 125 tests re most pertinent for dignosing dvnced crcinoms of orgns in the digestive system. Conventionl tumour mrkers such s C nd lph-fetoprotein re used to monitor tretment nd detect recurrence'` of mlignncy. These tumour mrkers lso show non-specific rectivity in benign diseses' nd sometimes in even norml individuls.6` ttempts hve been mde to serch for monoclonl ntibodies which might be used s tumour mrkers. C 19-9, n ntigenic determinnt defined by murine monoclonl ntibody 1116NS19-9, ws generted by somtic hybridistion of the mouse myelom cell line nd splenocytes from mouse ddress for correspondence: Kiyoshi Skmoto. MD, Deprtment of Surgery II, Kummoto niversity Medicl School, Kummoto 86, Jpn. Received for publiction 2(1 June immunised with humn colorectl crcinom cell line, SW C 125 is n ntigenic determinnt defined by murine monoclonl ntibody C125 developed by hybridistion techniques fter immunistion of humn epithelil ovrin crcinom cell line OVC433."' These tumour mrkers hve dignostic vlue in cses of crcinoms of the digestive system, prticulrly of the pncres."' Clinicl dt on concomitntly mesured serum concentrtions of C, C 19-9 nd C 125, including their sensitivity nd specificity, hve pprently not been documented. We mesured serum C 19-9, C 125 nd C vlues in 145 ptients with mlignncy in the digestive system nd 89 with non-mlignnt diseses of the GI trct, the objective being to compre the clinicl utility for dignosis nd tretment. 323 Gut: first published s /gut on 1 Mrch Downloded from on 5 September 218 by guest. Protected by copyright.

2 - 324 Skmoto, Hg, Yoshimur, gmi, Yokoym, ndkgi Methods rdiologicl signs of pncretic clcifiction, exocrine dysfunction indicted by the pncreozymin-secretin SBJCTS test or by demonstrtion of moderte or high grde of Serum smples were obtined from ptients in the endoscopic retrogrde pncretogrphy (RP) findings, by the grding of Brgnz et l.' Deprtment of Surgery II, Kummoto niversity Medicl School nd ffilited hospitls. Serum smples were stored t -2 C nd used One hundred nd forty five ptients with histologiclly proven mlignnt disese nd 89 with benign within six months. diseses of the digestive system were studied. The SSY OF C 19-9 dignoses of benign diseses were estblished by C 19-9 ntigen concentrtion (/ml) ws mesured stndrd clinicl, rdiologicl nd lbortory by forwrd sndwich rdioimmunometric ssy methods. The mlignnt diseses included crcinoms of the pncres (3), biliry trct (23), liver (16), P, S). cutoff vlue of 37 /mi ws used.'2 using Centocor RI kit (Centcor Inc, Mlvern, colon nd rectum (19), stomch (45) nd oesophgus (12). To investigte the reltionship between the SSY OF C 125 clinicl stging nd tumour mrkers, ll ptients with C 125 ntigen concentrtion (/ml) ws mesured cncers of the pncres, colon nd rectum, nd by simultneous sndwich solid phse rdioimmunossy of Centocor C 125 RI kit (Centocor stomch were presumbly divided into three groups s follows. Group 1: loclised cncer without Inc, Mlvern, P, S). cutoff vlue of 32 /mi regionl lymph node metstsis, group 2: loclised ws used for women over 5 yers of ge nd ll men, cncer with regionl lymph node metstsis, group 3: nd 143 /ml ws used for women under 49, ccording to our previous investigtion.'7 spred to liver, lung, peritoneum or bone. ighty nine ptients with benign diseses included 27 with chronic pncretitis, four with cute SSY OF C pncretitis, 2 with chronic ctive heptitis, 14 with Crcinoembryonic ntigen vlues were mesured liver cirrhosis, 11 with peptic ulcer nd 13 with using the CIS RI kit (C IR SORIN, cholelithisis. Chronic pncretitis ws dignosed by Frnce) by the double ntibody method. The upper limit of norml C ws defined s 12-5 ng/ml, s Positivity (%/) obtined by Booth et l.8 p Vlues were determined by Student's t test. 8 Results 6 9 POSITIVITIS OF INDIVIDL TMOR MRKR TSTS * 4' s shown in Tble 1 nd Fig. 1, mong ll ptients L. with crcinoms, C, C 19-9 nd C 125 tests 2 showed comprble positivities (47%, 44%, nd 41%, respectively). In contrst, mong those with S &LX H\ non-neoplstic disese, the positivity of C (22%) Y X1 X I -14 ws significntly higher thn tht for C 19-9 (9%) C C19-9 C125 C 19-9 nd C 125 (8%) (both p<.5). The incidence of /C125 rised concentrtions of serum C 19-9 distributed mong 6-87% of those with mlignnt ) disese nd o1, high incidences were observed both in pncretic ) crcinom (26/3, 87%) nd biliry trct crcinom v)' (14/23, 61%). On the other hnd, mong those with benign disese, the incidence rnged from -25%. One of four ptients with cute pncretitis hd vlue of 29 /ml which reverted to norml fter 1 m tretment. Three (21%) of 14 with liver cirrhosis hd Fig. 1 Comprison ofpositivities oftumour mrkers C positive vlues. On the contrry, lower positivities 19-9, C 125 nd C in 145 ptients with digestive were found in those with chronic pncretitis (one of crcinoms nd 89 ptients with benign digestive diseses. 27, 4%) nd in two (1%) of 2 ptients with chronic Positivity ofc is significntly higher thn those ofc ctive heptitis. None of 13 with cholelithisis ws 19-9 nd C 125 in benign diseses. positive. Similrly, high incidence of elevted Gut: first published s /gut on 1 Mrch Downloded from on 5 September 218 by guest. Protected by copyright.

3 C 19-9, C 125, nd C in cncer Tble 1 Positivities ofindividul tumour mrker tests in ptients with diseses ofthe digestive system Diseses Ptients Positivities (%) (n) C 19-9 C 125 C Crcinoms Pncres Biliry trct Liver Colon/rectum Stomch Oesophgus Benign diseses Chronic pncretitis cute pncretitis CH Liver cirrhosis Peptic ulcer Cholelithisis 13 () 8 CH: chronic ctive heptitis. Serum concentrtions of the three mrkers were studied in the sme smple. vlues of serum C 125 ws observed both in cses of pncretic crcinom (19/3, 63%) nd biliry trct crcinom (11/23, 48%). In benign diseses, the incidence rnged from -29% nd high incidence of 29% (four of 14) ws observed in liver cirrhosis. No ptient with chronic pncretitis, cholelithisis or peptic ulcer hd rised concentrtions of serum C 125. High incidences of rised vlues of C were seen in ptients with colorectl cncer (13/19, 68%) nd pncretic cncer (2/3, 67%). Frequent positivities were observed in ptients with liver cirrhosis (seven of 14, 5%), peptic ulcer (three of 11, 27%) nd chronic pncretitis (seven of 27, 26%). POSITIVITIS OF COMBIND TMOR MRKR TSTS Dt obtined with three combintions of tests (C 19-9/C, C 125/C nd C 19-9/C 125) were compred. s shown in Tble 2, ll with crcinom showed similr sensitivities (C 19-9/C: 65%, C 125/C: 64%, C 19-9/C 125: 61%). On the other hnd, higher specificity ws found in C 19-9/C 125 tests (87%) thn those of C 19-9/C test (72%), C 125/C test (72%) nd even the single C test (78%). mong ptients with crcinom, C 19-9/C 125 proved positive in 97% of ptients with pncretic crcinom, 74% of those with biliry trct crcinom nd 15-58% of other crcinoms. In benign diseses, only one (4%) of 27 ptients with chronic pncretitis nd no ptient with cholelithisis were positive in these combined tests, lthough one of four ptients with cute pncretitis nd six (43%) of 13 ptients with liver cirrhosis showed rised concentrtions of serum C 19-9/C 125. CORRLTION OF SRM CONCNTRTIONS OF C 19-9, C 125 ND C The correltion between C 19-9 nd C 125 in 145 ptients with mlignnt disese is shown in Figure 2. No significnt correltion ws observed between serum levels of C 19-9 nd C 125 (r=.195). There ws lso no significnt correltion between those of C 19-9 nd C (r=.271) or between those of C 125 nd C (r=. 124). RLTIONSHIP OF SRM LVLS OF TMOR MRKR ND TMOR STGS IN PTINTS WITH CRCINOMS OF TH PNCRS, STOMCH ND LRG INTSTIN The reltion of tumour mrker levels nd tumour stges ws studied in the three groups previously defined. s shown in Figure 3, vlues of serum C 19-9 for group 3 were significntly higher thn those for groups 1 nd 2 in ll ptients with crcinoms of the pncres, stomch, nd lrge intestine (p<5). Vlues for groups 1 nd 2, however, were rised s well s those for group 3 in cse of pncretic cncer. This ws not observed with C 125 or C. s shown in Figure 4, C vlues for dvnced cncers (group 3) showed higher concentrtions in comprison with loclised crcinoms (groups 1 nd 2), lthough no sttisticl significnce ws obtined. Reltionship of serum C 125 concentrtions nd tumour stges mong the sme ptients ws previously studied.` It ws concluded tht in metsttic crcinoms, the C 125 vlues were higher thn in loclised crcinoms. Tble 2 Positivities ofcombined tumour mrker tests in ptients with diseses ofthe digestive system Diseses Ptients Positivities (%) (n) C 19-9 C 125 C 19-9 IC IC IC 125 Crcinoms Pncres Biliry trct Liver Colon/rectum Stomch Oesophgus Totl Benign diseses Chronic pncretitis cutc pncretitis CH 2( Liver cirrhosis Peptic ulcer Cholelithisis Totl CH: chronic ctive heptitis. Serum concentrtions of the three mrkers were studied in the sme smple. 325 Gut: first published s /gut on 1 Mrch Downloded from on 5 September 218 by guest. Protected by copyright.

4 326 Discussion >1 1 :3 * _.._ ) l! CD 4) LI) 1[ 1l 1- * o. S * o C Skmoto, Hg, Yoshimur, gmi, Yokoym, nd kgi * OO (D C.o,. ch. Cl.. n c r=195 (n=145) Serum C 125 levets ( I ml ) Fig. 2 Correltion between serum concentrtions ofc 19-9 nd C 125 in ptients with digestive crcinoms. : pncretic crcinom; *: stomch crcinom; : colorectl crcinom; : crcinom ofthe biliry trct; : heptocellulr crcinom; : oesophgel crcinom. To 1 Idn ; M We mesured serum vlues of the tumour mrkers C 19-9 nd C 125 in the sme smples from ptients with diseses of the digestive orgns, in order to evlute the clinicl utility, compred with the conventionl tumour mrker, C. C 19-9 nd C 125 tumour mrker tests reveled similr positivities to C in ll ptients with mlignnt disese, lthough ech mrker hd different positivity ptterns (Tble 1, Fig. 1). Interestingly, in oesophgel crcinom, lower positivities were found with ll the three tumour mrkers presumbly becuse this lesion rises in squmous epithelium. Importntly, C 19-9 nd C 125 tests hd significntly lower flse positivities for nonneoplstic diseses of the digestive system compred with C (Tble 1, Fig. 1). Mjor problems with the C test re high flse positivities mong ptients with vrious benign diseses nd even in pprently disese free hevy smokers.`7 Positivities of serum C 19-9 in ptients with chronic pncretitis vry in previous findings between nd 16% 19` ` Our findings resemble those of Del Villno et l, 2 but n incresed positivity ws reported by Schmiegel etll' (14%). Schmiegel et l my hve included ptients with severe chronic pncretitis such s the cute phse of chronic recurrent pncretitis. We found trnsient rises of serum C 19-9 concentrtions in ptients with cute pncretitis, thereby suggesting tht seril tests my be needed to exclude such conditions. recent study j Gut: first published s /gut on 1 Mrch Downloded from on 5 September 218 by guest. Protected by copyright.

5 C 19-9, C 125, nd C in cncer 4, c cs m 2 V.) 1- lol~ * -;-* n * ~~~~~~~~~~~~~ mn <6 S * Group 1 Group 2 Group 3 Fig. 3 Reltionship ofserum C 19-9 nd tumourstges in ptient.s with gstrointestinl crcinoms. Group 1: loclised cncer without regionl lymph node metstsis. Group 2: loclised cncer with regionl lymph node metstsis. Group 3: spred to liver, lung, peritoneum or bone. Horizontl line represents the cutoff vlue ofc 19-9 in seruim. : pncretic crcinom; *: stomch crcinom; : colorectl crciniom. by Schmiegel et l'9 reveled rised concentrtions of C 19-9 in pncretic juice from norml controls nd ptients with pncretitis s well s those with pncretic cncer. This would suggest tht trnsfer of C 19-9 ntigen from pncretic juice into the circultion my cuse trnsient rise of serum C 19-9 during the cute phse of pncretitis. Similrly, we found high concentrtion of C 19-9 (7- >1) in bile s well s pncretic juice from ptients with cholelithisis nd crcinom of the biliry trct nd pncres. s suggested by Jlnko et l, 9 stsis of bile with high concentrtion of C 19-9 my led to moderte rise of serum C 19-9 in _ 327 ptients with obstructive jundice. Furthermore, rised concentrtions of C 19-9, both in pncretic juice nd bile from norml controls nd ptients with benign diseses suggest tht C 19-9 in these juices my not hve dignostic vlue. Ptients with benign liver diseses, especilly liver cirrhosis, hd high flse positivities of C 19-9, C 125 nd C, thereby indicting tht those with benign liver diseses should be crefully followed. Combined tests of multiple tumour mrkers my provide both higher sensitivities nd lower specificities thn single test, hence we must consider the increment of flse positive rte in benign disese Gut: first published s /gut on 1 Mrch Downloded from on 5 September 218 by guest. Protected by copyright.

6 328 >1-1 c c 4, o C ' 1.. Pncres Stomch Cobon/rectum IL.I * Skmoto, Hg, Yoshimur, gmi, Yokoym, nd kgi ~eu woes * n m* Group 1 Group 2 Group 3 Fig. 4 Reltionship ofserum C concentrtions nd tumourstges in ptients with gstrointestinl crcinoms. Group 1: loclised cncer without regionl lymph node metstsis. Group 2: loclised cncer with regionl lymph node metstsis. Group 3: spred to liver, lung, peritoneum or bone. Horizontl line represents the cut-off vlue ofc in serum. C: crcinoembryonic ntigen. : pncretic crcinom; *: stomch crcinom; : colorectl crcinom. when evluting combined tests. Of importnce ws the finding tht combined tests of C 19-9 nd C 125 showed lower flse positivity (13%) thn did single C test (22%). Moreover, 97% of the ptients with pncretic cncer nd 74% of those with cncer of the biliry trct were defined positive by the combintion of C 19-9 nd C 125. In contrst, no ptient with cholelithisis nd only one ptient with chronic pncretitis ws positive by the sme combintion of tests (Tble 2). These results suggest tht this combintion will id in differentiting crcinoms of the pncres nd of the biliry trct from chronic pncretitis nd cholelithisis, n Tumour mrkers C 19-9, C 125, nd C hve proven to be useful in monitoring the effect of therpy nd re pertinent prognostic tools for clinicl use.'-5" 15M-21 In the present study, the vlues for C in disseminted cncer were higher thn in those with loclised cncer.5 The sme tendency ws noted with C 125, in our previous report.'5 The present work demonstrted the reltion of C 19-9 vlues nd tumour stges mong ptients with crcinoms of the pncres, stomch nd lrge intestine. In cses of pncretic crcinom, high vlues of C 19-9 were noted in loclised s well s disseminted cncer. The pncretic cncer ptients in our study were dvnced cses (except for two who on Gut: first published s /gut on 1 Mrch Downloded from on 5 September 218 by guest. Protected by copyright.

7 C 19-9, C 125, nd C in cncer 329 underwent curtive resection), s is usully the cse when these tumors re dignosed. Our previous nd present studies reveled, however, tht both C nd C 125 hd less utility thn C 19-9 in the sme ptient with loclised pncretic crcinom. These observtions indicte tht the C 19-9 test is more sensitive thn C or C 125 for detection of loclised cncer of the pncres. Two ptients with loclised smll crcinoms of the ppill of Vter showed respective serum C 19-9 concentrtions of 42 nd 48 /ml returning to norml (<13 /ml) fter pncreticoduodenectomy (unpublished dt). This result indictes tht the C 19-9 test my llow detection of resectble cncer. mong ptients with crcinoms of the stomch nd lrge intestine, C 19-9 vlues were significntly higher in disseminted cncer thn in cses of loclised cncer. Similr dt were reported by Kuusel et l,2' in ptients with colorectl cncer. Therefore the C 19-9 test my not be of use for detection of gstric or colorectl cncer in the erly stge. We thnk M Ohr (Kyushu niversity) for comments on the mnuscript. References 1 Herrer M, Chu TM, Holyoke D. Crcinoembryonic ntigen (C) s prognostic nd monitoring test in cliniclly complete resection of colorectl crcinom. nn Surg 1976; 183: Wnebo HJ, Ro B, Pinsky CM, et l. Preopertive crcinoembryonic ntigen level s prognostic indictor in colorectl cncer. N ngl J Med 1978; 299: Wnebo HJ, Sterns M, Schwrtz MK. se of C s n indictor of erly recurrence nd s guide to selected second-look procedure in ptients with colorectl cncer. nn Surg 1978; 188: Minton JP, Mrtin W. The use of seril C determintions to predict recurrence of colon cncer nd when to do second-look opertion. Cncer 1978; 42: Go VLW, Zmcheck N. The role of tumor mrkers in the mngement of colorectl cncer. Cncer 1982; 5: Ruoslhti, Seppl M. lph-fetoprotein in cncer nd fetl development. dv Cncer Res 1979; 29: Lurence DJR, Stevens, Bettelheim R, et l. Role of plsm crcinoembryonic ntigen in dignosis of gstrointestinl, mmmry, nd bronchil crcinom. Br MedJ 1972; 9: Booth SN, King JPG, Leonrd JC, et l. Serum crcinoembryonic ntigen in clinicl disorders. Gut 1973; 14: Koprowski H, Steplewski Z, Mitchell K, et l. Colorectl crcinom ntigens detected by hybridom ntibodies. Somt Cell Genet 1979; 5: Bst RC, Feeney M, Lzrus H, et l. Rectivity of monoclonl ntibody with humn ovrin crcinom. J Clin Invest 1981; 68: Herlyn M, Sers HF, Steplewski Z, Koprowski H. Monoclonl ntibody detection of circulting tumorssocited ntigen. I. Presence of ntigen in ser of ptients with colorectl, gstric, nd pncretic crcinom. J Clin Immunol 1982; 2: Del Villno BC, Brennn S, Brock P, et l. Rdioimmunometric ssy for monoclonl ntibody-defined tumor mrker, C Clin Chem 1983; 29: Bst RC, Jr, Klug TL, John, et l. rdioimmunossy using monoclonl ntibody to monitor the course of epithelil ovrin cncer. N ngl J Med 1983; 39: Klug TC, Bst RC Jr, Niloff JM, Knpp RC, Zurwski VR Jr. Monoclonl ntibody immunordiometric ssy for n ntigenic determinnt (C 125) ssocited with humn epithelil ovrin crcinoms. Cncer Res 1984; 44: Hg Y, Skmoto K, gmi H, Yoshimur R, Mori K, kgi M. Clinicl significnce of serum C 125 vlues in ptients with cncers of the digestive system. m J Med Sci 1986; 292: Brgnz JM, Hunt LP, Wrwick F. Reltionship between pncretic exocrine function nd ductl morphology in chronic pncretitis. Gstroenterology 1982; 82: Hg Y, Skmoto K, gmi H, Yoshimur R, kgi M. vlution of serum C 125 vlues in helthy individuls nd pregnnt women. m J Med Sci 1986; 292: Schmiegel WH, Kreiker C, berl W, et l. Monoclonl ntibody defines C 19-9 in pncretic juices nd ser. Gut 1985; 26: Jlnko H, Kuusel P, Roberts P, Sipponen P, Hglund C, Mkel, Comprison of new tumor mrker, C 19-9,"M with ct-fetoprotein nd crcinoembryonic ntigen in ptients with upper gstrointestinl diseses. J Clin Pthol 1984; 37: Sers HF, Herlyn M, Del Villno B, Steplewski Z, Koprowski H. Monoclonl ntibody detection of circulting tumor-ssocited ntigen. II. longitudinl evlution of ptients with colorectl cncer. J Clin Immunol 1982; 2: Kuusel P, Jlnko H, Roberts P, et l. Comprison of C 19-9 nd crcinoembryonic ntigen (C) levels in the serum of ptients with colorectl diseses. Br J Cncer 1984; 49: Gut: first published s /gut on 1 Mrch Downloded from on 5 September 218 by guest. Protected by copyright.