Factors affecting screening for hepatocellular carcinoma

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1 204 Al Hsni F, et l., 2014; 13 (2): ORIGINAL ARTICLE Mrch-April, Vol. 13 No. 2, 2014: Fctors ffecting screening for heptocellulr crcinom Frh Al Hsni,* Mrin Knoepfli, Armin Gemperli, Attil Kollr, Vness Bnz, Jochim Kettenbch, Peter Jüni, Jen-Frnçois Dufour*, * Heptology, Deprtment of Clinicl Reserch, University of Bern. Switzerlnd. University Clinic for Viscerl Surgery nd Medicine, Inselspitl, University of Bern. Switzerlnd. Institut of Socil nd Preventive Medicine, University of Bern. Switzerlnd. Deprtment of Oncology, Inselspitl, University of Bern. Switzerlnd. Deprtment of Rdiology, Inselspitl, University of Bern. Switzerlnd. ABSTRACT Bckground nd im. Heptocellulr crcinom (HCC) is frequent cncer. Its prognosis is highly dependent on erly dignosis. Ptients t risk for developing HCC should be enrolled in surveillnce progrmme. Nevertheless, mny ptients t risk re not regulrly screened. We imed t exploring the chrcteristics tht ffect enrolment in surveillnce progrmme. Mteril nd methods. The chrcteristics of the ptients included in the prospective Bern HCC cohort between August 2010 nd August 2011 were nlysed ccording to their prticiption in surveillnce progrmme. Results. Among the 82 ptients included in the cohort during this period of time, 48 were in surveillnce progrm before the dignosis of HCC. Thirty five percent of cirrhotic ptients were not screened. Age, sex, level of eduction, Child-Pugh sttus nd MELD score were similr between the ptients who were screened nd those who were not screened. Ptients with privte insurnce nd ptients treted by liver specilist were more frequently enrolled in surveillnce progrm. Sixty seven percent of the screened ptients were eligible for curtive tretment wheres only 15% of the non-screened ptients were. Conclusions. In conclusion the surveillnce of ptients t risk for developing HCC increses their chnces to be dignosed t n erly stge to llow curtive tretment. More thn one third of cirrhotic ptients were not regulrly screened. Ptients with chronic liver disese should be referred to identify those t risk nd enrol them in surveillnce progrm. Key words. Cohort. Cirrhosis. Liver cncer. Risk fctor. Surveillnce. INTRODUCTION Heptocellulr crcinom (HCC) rnks fifth worldwide in terms of cncer incidence nd third in terms of cncer-relted mortlity. 1 The mngement of ptients with HCC is bsed on the ssessment of 3 prmeters: tumor burden, liver function nd ptient performnce sttus. This ssessment forms the bsis of the Brcelon Clinic Liver Cncer (BCLC) lgorithm, which is the most widely used. 2 Ptients with tumor less thn 2 cm re eligible for rdiofrequency bltion or surgicl resection. Ptients with 1 tumor less thn 5 cm or up to 3 tumors ech less Correspondence nd reprint request: Prof. Jen-Frnçois Dufour University Clinic for Viscerl Surgery nd Medicine Inselspitl, 3010 Bern, Switzerlnd. Tel.: Fx: E-mil jf.dufour@ikp.unibe.ch Mnuscript received: November 03, Mnuscript ccepted: December 14, thn 3 cm re eligible for trnsplnttion. Ptients with lrger tumors re not cndidtes for curtive pproches; they re treted with trns-rteril chemoemboliztion, selective internl rdiotherpy nd/or systemic trgeted therpy. Ptients with Child-Pugh C stge who re not eligible for trnsplnttion receive best supportive cre. If the medin survivl in cse of curtive pproch is more thn 5 yers, it is less thn 2 in cse of pllitive pproch. 3 Numerous guidelines recommend screening for heptocellulr crcinom. 3-6 The popultion t risk is well-defined, the screening test which is sonogrphy, is well ccepted nd widely vilble nd its intervl of ppliction hs been set to 6 month. 7 There is only one rndomized controlled tril showing benefit for HCC screening. 8 However, it ws criticized for not controlling for cirrhosis, for suboptiml dherence nd for incorrect sttisticl nlysis. Nevertheless numerous cost-nlysis studies hve shown tht enrolment in surveillnce

2 Screening nd HCC., 2014; 13 (2): progrm reduces HCC mortlity It is ssumed tht this benefit is due to dignosing ptients t n erlier stge. Despite these considertions, it is still unknown wht proportion of ptients dignosed with HCC is included in surveillnce progrm nd wht re the brriers to screening. The im of this work ws to investigte the prmeters tht could influence inclusion in surveillnce progrm for HCC using dt from the Bern HCC cohort, which prospectively collects stndrdized informtion on ptients ffected by HCC. MATERIAL AND METHODS Design of the study The HCC cohort strted in the 1st of August 2010 t the University Hospitl of Berne, one of the lrgest referrl hospitls in Switzerlnd. It is multidisciplinry prospective study including heptologists, rdiologists, oncologists nd viscerl surgeons. All the dult ptients with dignosed HCC in the lst 18 months were invited to prticipte. The dignosis of HCC ws bsed on the Americn Assocition for the Study of Liver Diseses (AASLD) prctice guidelines criteri. 15 The protocol ws pproved by the Bern ethics committee nd ech prticipnt hs to sign n informed consent. This mnuscript evlutes the chrcteristics of the ptients included during period of 12 months. Dt collection nd processing At inclusion ptients were evluted for the following vribles: demogrphic informtion (ge, sex, rce), dte of initil dignosis of HCC, methods of dignosis (CT, MRI, histology), context leding to the dignosis of HCC (finding in surveillnce progrm, new symptoms, lbortory results, incidentl rdiologicl finding), risk fctors for HCC nd comorbidities (cirrhosis, smoking, lcohol consumption, dibetes, elevted BMI), tumor burden, Child-Pugh stge nd its vribles (lbumin, bilirubin, prothrombin time, scites, encephlopthy), Brcelon Clinic Liver Cncer (BCLC) clssifiction, Model of End-Stge Liver Disese (MELD) score, α-fetoprotein (AFP) level, socio-economic prmeters (chieved eduction, professionl occuption, type of helth insurnce). The dignosis of cirrhosis ws bsed on histology nd/or indirect clinicl signs such s the presence of vrices or scites. With regrd to the cuse of liver disese multiple etiologies were possible. Anti-HBc denoted exposure to heptitis B virus. Positive viremi ws required for clssifiction s heptitis C virus. Alcohol ws retined in individuls who drnk more thn 60 g of lcohol dy. Non-lcoholic stetoheptitis ws considered in individuls with metbolic syndrome nd/or liver histology with the fetures of stetoheptitis in ptients drinking less thn 30 g of lcohol/dy. Ptients were considered in sur-veillnce progrm if they hd 2 liver sonogrphies t 6 month intervl in the 12 months preceding the dignosis of HCC. Sttisticl methods Continuous dtre expressed s the men ± SD. Fisher s exct test for comprison of ctegoricl outcomes nd Wilcoxon s test for comprison of continuous outcomes were used to compre screening nd the non-screening groups. Chrcteristics ssocited with HCC screening t p 0.20 in univrible nlysis were included in multivrible exct logistic regression model. Anlyses were performed with Stt IC 11.0 (SttCorp, College Sttion, TX). RESULTS From the 1st of August 2010 to the 1st of August 2011, 82 ptients were enrolled, no ptient declined to prticipte. Tble 1 shows the chrcteristics of these 82 ptients. The mjority were men (70/82, 85%). The mjority of mle ptients were included in surveillnce progrm (43/70, 61%), wheres the mjority of the femle ptients were not (7/12, 58%). The men ge ws 62 yers. Figure 1 shows the ge distribution in both, the screened nd non-screened group. The ge group yers ws the most frequent. Ptients older thn 80 yers old continued to be screened. The men vlue of the BMI ws Thirty-seven percent of ll ptients hd norml weight (BMI ) wheres 49% were slightly overweight (BMI 25-30). There ws no difference in BMI between the ptients who were screened nd those who were not screened. Fifty-one percent of ptients were retired, 24% were employees, 14% were independents nd 11% were on socil support. When exmining whether the level of eduction ffected the enrollment in surveillnce progrm, we found similr proportions of ptients with t lest 12 yers of eduction in those with nd without HCC surveillnce. There ws significnt reltionship between the

3 206 Al Hsni F, et l., 2014; 13 (2): Tble 1. Chrcteristics of ptients by HCC surveillnce. HCC surveillnce in the lst 12 months Yes (n = 48) No (n = 34) p-vlue Demogrphics Mle gender, n (%) 43 (90) 27 (79) 0.22 Age (yers, men ± SD) 63 (9) 61 (12) 0.29 BMI (kg/m2, men ± SD) 26.6 (4.6) 26.0 (3.6) 0.57 Socioeconomic fctors Eduction 12 yers, n (%) 15 (31) 9 (26) 0.81 Privte Helth Insurnce, n (%) 9 (19) 1 (3) Dignosis mde by heptologists, n (%) 30 (63) 6 (18) HCC risk fctors Cirrhosis, n (%) 46 (96) 25 (74) Alcohol, n (%) 20 (42) 12 (35) 0.65 NAFLD, n (%) 10 (21) 8 (24) 0.79 Hereditry hemochromtosis, n(%) 3 (6) 2 (6) 1.00 HCV positive, n (%) 10 (21) 11 (33) 0.31 HBc positive, n (%) 10 (21) 12 (35) 0.21 Co-morbidities Severe crdio-vsculr disese, n(%) 1 (2) 11 (32) Dibetes, n (%) 15 (31) 13 (38) 0.64 Smoking, n (%) 14 (29) 8 (24) 0.62 Wilcoxon test for comprison of continuous outcomes. Fisher s exct test for comprison of ctegoricl outcomes. Ptients (n) All ptients Surveillnce No surveillnce Age Figure 1. Age distribution in screening nd non-screening group. type of helth insurnce nd the likelihood of being in surveillnce progrm, however. Seventy-two ptients hd generl helth insurnce (88%) nd only 10 hd privte helth insurnce (12%). Nine out of the 10 ptients (90%) with privte insurnce were screened, but only 39 of those with generl helth insurnce (54%, p = 0.04). Inclusion in surveillnce progrm ws significntly more frequent for ptients who were followed by liver specilist. Thirty out of the 36 ptients treted by liver specilist nd dignosed with HCC were screened (83%), but only 18 ptients out of the 46 ptients not followed by liver specilist (39%, p < 0.001). Eighty seven percent of the ptients hd cirrhosis (71/82). Two ptients without cirrhosis but with dvnced fibrosis were subjected to screening. Alcohol ws the most frequent cuse of liver disese (32 ptients) followed by heptitis B (22 ptients) nd heptitis C (21 ptients). Eighteen ptients hd non-lcoholic ftty liver disese (NAFLD). Thirty four percent of the ptients hd dibetes mellitus nd 27% were smokers. As shown in figure 2 nerly qurter of the ptients (24%) cumulted more thn one cuse for their underlying liver disese. All combintions were present; 4% hd co-infection with heptitis C nd B, 4% hd combintion of lcohol nd HCV infection nd 2% combintion of lcohol nd HBV infection. Two percent hd even three different cuses for their underlying liver disese including lcohol, HCV nd HBV. Regrding prticiption in surveillnce progrm, the presence of cirrhosis ws significntly ssocited with regulr screening (p = 0.006): 65% of the screened ptients hd cirrhosis, wheres 35% of the nonscreened ptients hd liver cirrhosis. Neither the etiology of the liver disese, nor the presence of

4 Screening nd HCC., 2014; 13 (2): % HBV 19% HCV 4% HH 21% ASH 2% ASH + HBV 4% ASH + HCV 8% ASH + NASH 2% ASH + HCV + HBV 4% HCV + HBV Figure 2. Bseline liver diseses. 2% NASH + HH 2% NASH + HBV 17% NASH Tble 2. Assocition of ptient chrcteristics with HCC surveillnce in multivrible model. HCC surveillnce in the lst 12 months Odds-Rtio 95%-Confidence Intervl p-vlue Privte Helth Insurnce 12.8 (2.06 to ) Cirrhosis 5.62 (0.91 to 61.8) Severe crdio-vsculr disese 0.05 (0 to 0.24) Odds-rtio from multivrible exct logistic regression. A vrible ws included in the multivrible model if its p-vlue ws < 0.2 in univrible nlysis. Type of physicin who mde the dignosis (heptologist or other) not included in multivrible model, since this ws not ptient chrcteristic. Tble 3. Tumor clssifiction nd stging. Prmeter HCC surveillnce in the lst 12 months Yes No p-vlue N = 48 (100.0%) N = 34 (100.0%) Brcelon Clinic Liver Cncer (BCLC) clssifiction < (2.1%) 0 (0.0%) A 31 (64.6%) 5 (14.7%) B 13 (27.1%) 16 (47.1%) C 3 (6.3%) 13 (38.2%) Within Miln criteri < Yes 33 (68.8%) 7 (20.6%) No 15 (31.3%) 27 (79.4%) Child-Pugh Sttus 0.73 A 27 (56.3%) 22 (64.7%) B 17 (35.4%) 10 (29.4%) C 4 (8.3%) 2 (5.9%) Model for End-Stge Liver Disese (MELD) Score (men ± SD) 9.4 (4.0) 9.1 (5.1) 0.49 Wilcoxon test for comprison of continuous outcomes. Fisher s exct test for comprison of ctegoricl outcomes. 8 dibetes nd smoking ws ssocited with surveillnce. Ptients with dvnced crdiovsculr disese were significntly less likely to undergo surveillnce (p = 0.002). Tble 2 presents results from multivrible model including the three ptient chrcteristics tht were ssocited with HCC surveillnce in univrible nlysis t p Ptients with privte helth insurnce remined more

5 Al Hsni F, et l., 2014; 13 (2): likely to hve hd HCC surveillnce (odds rtio 12.8, p = 0.015), wheres ptients with severe crdiovsculr disese were significntly less likely (odds rtio 0.05, p = ). For ptients with cirrhosis there ws sttisticl trend towrds more frequent HCC surveilnce (odds rtio 5.62, p = 0.068). Tumor stging t the time of dignosis is described in tble 3. Ptients who were not in surveillnce progrm hd significntly more dvnced tumors s ssessed by the BCLC clssifiction (p < ). The mjority of the ptients who were screened were in BCLC clss A nd therefore were eligible for curtive tretments (65%), wheres the mjority of the non-screened ptients were in BCLC group B nd therefore were confined to pllitive therpies (47%). Ptients, who were in surveillnce progrm were more likely to hve tumor within the Miln criteri thn those who were not in surveillnce progrm (69 vs. 21%, p < ). These 2 groups of ptients were neither dif-ferent bsed on their Child-Pugh score (p = 0.73) nor on their MELD score (p = 0.49). Tble 4 shows tht inclusion in surveillnce progrm ws ssocited with less mcro-vsculr invsion (2 vs. 21%, p = 0.032), nd tended to be ssocited with less extr-heptic locliztion (4 vs. 18%, p = 0.061). Three ptients hd extr-heptic metstsis or vsculr involvement t dignosis even though they were in screening progrm prior to the dignosis of HCC. These 3 ptients were mle, cirrhotic nd older thn 50 yers of ge. As bseline liver disese, one ptient hd n lcohol-induced liver disese, one ptient hd NASH nd the third one chronic heptitis B. As comorbidity, 2 of these 3 ptients hd n insulin-dependent dibetes mellitus. Figure 3 shows the eligibility of ptients for curtive nd pllitive tretments ccording to their enrollment in surveillnce progrm. Only 15% of the ptients not included in surveillnce progrm were eligible for curtive therpy. DISCUSSION These results identify sttisticlly significnt nd cliniclly relevnt differences in ptients dignosed with HCC depending on their prticiption in surveillnce progrm or not. Ptients who benefited from regulr screening were dignosed t n erlier stge nd were eligible more frequently for curtive tretments. These ptients did not hve higher eduction thn the ptients not enrolled in surveillnce, but they did more often hve privte helth insurnce. Cre-givers hve strong impct on screen-ing; ptients treted by liver specilist were much more often enrolled in surveillnce progrm. The demogrphic chrcteristics of our ptients showed strong mle predominnce with rtio of 6:1. It is well known tht HCC ffects men more frequently thn women nd similr rtio hs been reported in Spin. 16 In the Swiss Heptitis C Cohort we found rtio 3:1. 17 This suggests tht other etiologies such s lcohol, NASH nd heptitis B re more predominnt in mles thn in femles. The mjority of the ptients were dignosed in their erly sixties, which explins why hlf of our ptients were retired. In line with the Spnish experience, dvnced ge ws not discrimintory fctor ginst screening. 16 Actully, ge should not be fctor since rdio-frequency bltion nd TACE re prticulrly successful in smll tumors nd cn be dministered in older ptients. Severe crdiovsculr co-morbidity did influence screening. Ptients with this co-morbidity re likely not to benefit from screening nd were not included in surveillnce progrm. Obesity hs been linked to HCC. Mles with BMI bove 35 increse their risk for HCC by fctor of 4.5, much more thn for ny other kind of cncer. 18 The BMI in our cohort cn be considered norml with medin of However, we cn not exclude tht overweight ptients lost weight before inclusion in the cohort. Our results identify fctors tht ffect screening some of which re ptient-relted nd some of which re physicin-relted. For ptients, neither the level of eduction nor the type of occuption influenced inclusion in surveillnce progrm. In contrst, the type of insurnce did. Ptients who contrcted privte insurnce were lso those who prticipted more frequently in surveillnce Figure 3. Difference in distribution of ptients eligible for curtive nd pllitive tretments ccording to surveillnce. Ptients (%) Curtive Pllitive Surveillnce No surveillnce

6 Screening nd HCC., 2014; 13 (2): Tble 4. HCC chrcteristics. HCC surveillnce in the lst 12 months Prmeter Yes No p-vlue N = 48 (58.5%) N = 34 (41.5%) Extrheptic metstses 0.06 Yes 2 (25.0%) 6 (75.0%) No 46 (62.2%) 28 (37.8%) Vsculr involvement Yes 1 (12.5%) 7 (87.5%) No 47 (64.4%) 26 (35.6%) Unknown 0 (0.0%) 1 (100.0%) Fisher s exct test for comprison of ctegoricl outcomes. progrm. This prmeter likely identifies ptients with interest in their helth who re seeking dequte mngement. The type of physicin (whether ptients were followed by liver specilist or not) ws lso strongly ssocited with surveillnce. Despite guidelines recommending surveillnce of ptients t risk, 3-6 nd dt supporting the costeffectiveness of regulr screening, 9-14 these mesures re insufficiently implemented by non-liver specilists. The importnce of screening ptients t risk should be better recognized. Progresses in this re will improve the outcome of ptients dignosed with HCC. Inclusion in surveillnce progrm ws ssocited with dignosis t n erlier stge. Our dt confirm other publictions tht show tht screened ptients re more likely to be eligible for curtive tretment Ptients in surveillnce progrm were more frequently BCLC 0 or BCLC A, were more frequently dignosed within the Miln criteri nd hd less mcro-vsculr involvement. This ws independent from the clinicl stge of cirrhosis ssessed by either Child-Pugh score or MELD score. Severl studies hve shown tht dignosis of HCC t n erly stge trnsltes into longer survivl. 20,22 Only rndomized controlled trils could ssure this is not due to led time bis. The only study tht hs been performed supports periodic screening, but it presents some weknesses. 8 However, it is unlikely tht nother tril will be conducted nd the vilble evidence is considered sufficient to recommend surveillnce of the ptients t risk. 23 Our study hs severl limittions. We do not know whether ptients who were not included in surveillnce progrm were offered screening nd refused to prticipte. Similrly, we do not hve dtbout the dherence to screening nd cnnot evlute the cceptnce of ptients for screening. We re not considering ptients who hve screening to detect erly recurrence of HCC, these ptients form specil collective which cn benefit from specific predictive tools. 24 These dt hve been cquired prospectively with one-center cohort, it is uncler to wht extent they re relevnt for other centers nd other countries. In conclusion, we found tht 35% of ptients with cirrhosis nd t risk of developing HCC re not regulrly screened. Not surprisingly, ptients who were regulrly screened were dignosed t n erlier stge of the disese. Although the level of eduction of the ptients did not influence inclusion in surveillnce progrm, the type of helth insurnce did. Ptients mnged by liver specilist were more frequently included in surveillnce progrm nd hd therefore more opportunities to be dignosed t n erlier stge. This stresses the importnce of referring ptients who re t risk to centers with expertise in liver diseses. ACKNOWLEDGMENTS We re thnkful to the philnthropic committee of the Firmenich Fmily, which supported this HCC cohort from its strt. This project ws lso supported by the Swiss Foundtion ginst Liver Cncer nd the Bern Legue ginst Cncer. JFD hs received founding from Oncosuisse. We thnk Ms N. Sollberger for ssistnce in mnging the dtnd to Dr. B. Sr for contributing to the initition of this project. FINANCIAL SUPPORT Swiss Foundtion ginst Liver Cncer, Philnthropic Committee of the Firmenich Fmily, Bern Legue ginst Cncer.

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