Systematic review of actual 10-year survival following resection for hepatocellular carcinoma

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1 DOI: /j x HPB SYSTEMATIC REVIEW Systemtic review of ctul 10-yer survivl following resection for heptocellulr crcinom Annelise M. Gluer 1, Nichols Cocco 1, Jerome M. Lurence 1,2, Emm S. Johnston 1,2, Michel J. Hollnds 1,2, Henry C. C. Pless 1,2, Arthur J. Richrdson 1,2 & Vincent W. T. Lm 1,2 1 Deprtment of Surgery, Westmed Hospitl, Westmed, W, Austrlind 2 Discipline of Surgery, University of Sydney, Sydney, W, Austrli Abstrcthpb_ Bckground: Heptic resection is potentilly curtive therpy for heptocellulr crcinom (HCC), but recurrence of disese is very common. Few studies hve reported 10-yer ctul survivl rtes following heptic resection; insted, most hve used cturil mesures bsed on the Kpln Meier method. This systemtic review ims to document 10-yer ctul survivl rtes nd to identify fctors significnt in determining prognosis. Methods: A comprehensive serch ws undertken of MEDLINE nd EMBASE. Only studies reporting the bsolute number of ptients live t 10 yers fter first resection for HCC were included; these figures were used to clculte the ctul 10-yer survivl rte. A qulittive review nd nlysis of the prognostic fctors identified in the included studies were performed. Results: Fourteen studies, ll of which were retrospective cse series, including dt on 4197 ptients with HCC were nlysed. Ten yers following resection, 303 of these ptients were live. The 10-yer ctul survivl rte ws 7.2%, wheres the cturil survivl quoted from the sme studies ws 26.8%. Positive prognostic fctors included better heptic function, wider surgicl mrgin nd the bsence of stellite lesions. Conclusions: The ctul long-term survivl rte fter resection of HCC is significntly inferior to reported cturil survivl rtes. The Kpln Meier method of cturil survivl nlysis tends to overestimte survivl outcomes s result of censorship of dtnd subgroup nlysis. Keywords heptocellulr crcinom, primry liver tumour, heptectomy, liver resection, survivl, systemtic review Received 5 December 2011; ccepted 24 Jnury 2012 Correspondence Vincent W. T. Lm, Deprtment of Surgery, Westmed Hospitl, Drcy Rod, Westmed, W 2145, Austrli. Tel: Fx: E-mil: vincent.lm@sydney.edu.u Introduction This study ws presented t the Third Biennil Congress of the Asin Pcific Heptopncretobiliry Assocition, September 2011, Melbourne, Victori. Heptocellulr crcinom (HCC) is the fifth most common cuse of cncer worldwide nd is the fourth leding cuse of cncerrelted deth. 1 The incidence nd prevlence of HCC re highest in Southest Asind West Afric, but re rising in developed countries. 1 Both surgicl resection nd liver trnsplnttion re potentilly curtive tretments for resectble HCC, 2 lthough 95% of HCC ptients in Western popultions hve coexistent cirrhosis of the liver. 3 Even for smll nd resectble HCC, trnsplnttion is the preferred tretment option s it ddresses both the pprent tumour nd tumours tht re not yet pprent, nd the underlying cirrhosis. 4 However, its usge is limited by the lck of donor orgns. 5 Although it hs been recommended tht direct clinicl outcomes such s overll ctul survivl should be used s n endpoint in studies of HCC, 6 cturil survivl mesures remin the most often reported. The Kpln Meier method of cturil survivl nlysis ws first published in the 1950s s wy of estimting outcomes with incomplete dt. 7 The mjor risk for bis ssocited with this method is result of the process of censoring, whereby certin ptients re excluded from the finl nlysis. 8 The resons for exclusion my include loss to follow-up, periopertive

2 286 HPB mortlity or deth from other cuses. The Kpln Meier method lso llows subset nlysis to be used nd then pplied to the group s whole. When pplied to survivl dt, these pproches cn led to gross overestimtion of survivl, which is misleding for both clinicins nd ptients. The primry purpose of this study ws to estimte, by systemtic review of published dt, ctul 10-yer survivl following resection of HCC. The secondry im ws to estblish prognostic fctors ssocited with improved survivl. Mterils nd methods Literture serch A comprehensive serch of the MEDLINE nd EMBASE dtbses ws undertken in the first week of November The serch strtegy is provided in Appendix A1. A mnul serch of the references of the retrieved studies ws performed. In the cse of duplicte reporting of the sme study popultion, the report tht included the lrgest mount of outcome dt ws included. Inclusion nd exclusion criteri Studies were included if they exmined 10-yer survivl following resection of HCC in dults nd quoted n ctul number or percentge of survivors, or included sufficient dt for these to be determined. Studies were excluded if they reported dt for fewer thn five ptients, if 10-yer follow-up ws not complete, if the dt hd been previously published, or the informtion reported ws insufficient to clculte 10-yer ctul survivl. Outcome mesures In order to determine the primry outcome mesure of 10-yer survivl, the totl number of ptients live t 10 yers ws divided by the totl number of ptients included in the study. The secondry outcome mesures sought in ech study were the prognostic fctors ssocited with survivl. Becuse of the heterogeneity of the dt reported in ech study, forml met-regression ws not fesible. In ech study, the fctors reported to hve sttisticlly significnt ssocition with survivl were tbulted. Whether the fctor ws sttisticlly significnt using univrite or multivrite nlysis, or both, ws documented. These fctors were then qulittively described. Some fctors were reported in the originl studies with specific numeric cut-off vlue (such s level of lbumin or ge). In the review, these were brodly ctegorized (incresed lbumin or greter ge) to llow the otherwise heterogeneous dt to be presented nd nlysed coherently. Results Description of studies The serches of MEDLINE nd EMBASE yielded 966 nd 2327 publictions, respectively. The combintion of these serches produced 3293 mnuscripts for nlysis. No dditionl studies were identified fter reference serching. After excluding duplicte studies, studies tht repeted previously published dtnd studies tht did not include the bsolute number of survivors t 10 yers, 14 studies were suitble for inclusion in this review. All 14 studies were retrospective nlyses. Publiction dtes rnged from 1987 to Ptient chrcteristics Ptient chrcteristics re summrized in Tble 1. The totl number of ptients in these studies ws The medin ptient ge t study enrolment ws 60 yers (rnge: yers). Overll, 84.3% (2811 of the 3335 ptients for whom dt on sex were provided) of the ptients were mle nd 78.1% (2052 of the 2626 ptients for whom cirrhosis dt were provided) hd cirrhosis. Ptient chrcteristics were often collted fter censorship hd been pplied nd therefore were not reflective of the initil ptient popultion. Study heterogeneity There were significnt vritions in the popultions included in the studies. Mny of the studies included only ptients with wellpreserved liver function. Fukud et l. included only ptients with Child Pugh clss A liver function who underwent curtive resection, 9 wheres Lee et l. did not perform resection in ptients with evidence of heptic decompenstion. 10 The criteri for inclusion in the study by Pndey et l. were lesion of 10 cm nd Child Pugh clss A liver function. 11 Chen et l. exclusively studied people with lesions mesuring >10 cm nd Child Pugh clss A or B liver function; neither Chen et l. nor Ngsue et l. performed nlysis of prognostic fctors fter 10 yers. 12,13 The 2003 study by Zhou et l. ws limited to HCC tumours of > 10 cm, wheres their 2001 study referred to HCC mesuring > 5 cm. 14,15 Both Shimd et l. nd Hnzki et l. limited their nlysis to ptients who underwent potentilly curtive heptectomy, 16,17 but Shirbe et l. did not plce ny restrictions on ptient selection. 18 Primry study outcome The number of ptients in ech study nd the ctul nd cturil survivl percentges re summrized in Tble 2. Of the 4197 ptients included in the nlysis, 303 ptients were live t 10 yers, which equtes to n ctul 10-yer survivl rte of 7.2%. Acturil survivl figures in these studies rnged from 10.5% to 46.3%. 15,17 The overll rte determined cross the 14 studies ws 26.8%. Four studies 9,10,16,19 indicted the proportion of ptients whose fte t 10 yers (whether ded or live) ws known. These four studies included dt pertining to 862 ptients, the 10-yer outcome of 750 (87.0%) of whom ws known (Tble 2). Eleven studies stted the rte of periopertive mortlity within 3 months of surgery. In these, overll periopertive mortlity ws 5.0% (196 of 3912 ptients). The difference between ctul nd cturil survivl ws clculted for ech study (Tble 2) in order to determine whether ssocitions could be discerned between lrge difference in survivl mesures nd country of origin of study, prevlence of cirrhosis, periopertive mortlity or completeness

3 HPB 287 Tble 1 Ptient chrcteristics Study Yer City nd country of institution Ptients, n Gender, mle : femle Age, yers, medin Age, yers, men Cirrhosis, + : - HBs Ag, + : - HCV Ab, + : - Fortner & Fong New York, USA 70 Fukud et l Hiroshim, Jpn : : 112 b 68:41 b Pndey et l Singpore : :86 131:35 3:163 Hshimoto et l Fukuok, Jpn : 19 b 61 b 16:69 b 64:21 b Shimd et l Tokyo, Jpn : 98 b 60 b 75 : 406 b 286 : 144 b Chen et l Wuhn, Chin : : : 159 Zhou et l Shnghi, Chin 621 Zhou et l Shnghi, Chin : : : 218 b Hnzki et l Mtsumoto, Jpn : : : : 214 Shirbe et l Fukuok, Jpn : 15 b 56 b 72:31 b 16:87 b Lee et l Tiwn : : 8 Ngsue et l Izmo, Jpn : : 52 Choi et l Hong Kong : : 56 b 132:42 Sesto et l Clevelnd, USA 22 Totl : c : : : 583 This informtion ws nlysed fter the exclusion of some ptients nd therefore does not reflect the totl ptient number. b The nlysis of ptient chrcteristics ws either incomplete or mde fter the exclusion of some ptients nd therefore does not reflect the totl ptient number or the initil ptient popultion. c Men of men ges stndrd error of the men. HBs Ag+, positive heptitis B surfce ntigen; HCV Ab+, positive heptitis C ntibody. Tble 2 Survivl dtcross the 4197 ptients included in the 14 studies Study Ptients, n 10-yer survivors, n Ptients ccounted for t 10 yers, n (%) Periopertive mortlity within 3 months, n (%) Actul survivl, % Quoted cturil survivl, % Fortner & Fong (12.9) Fukud et l (100) Pndey et l (3.0) Hshimoto et l (97.8) 3 (3.3) 22.4 Shimd et l (80.9) 18 (3.1) Chen et l (2.7) c 2.9 Zhou et l (4.5) Zhou et l (1.5) Hnzki et l (7.0) d Shirbe et l (27.5) Lee et l (100) 31.0 Ngsue et l (10.5) c Choi et l (13.2) c 4.6 Sesto et l Totl % e Periopertive mortlity excluded from cturil survivl clcultion. b Acturil survivl not quoted. c Anlysis of periopertive mortlity with respect to cturil survivl clcultion not stted. d Periopertive mortlity included in cturil survivl clcultion. e Overll cturil survivl clculted from studies in which these dt were provided or could be clculted., not stted or cnnot be derived from dt presented. Difference between ctul nd cturil survivl, %

4 288 HPB Tble 3 Univrite nlysis of prognostic ptient fctors Study Inc ge Mle Cirrhosis Child A HBs Ag + HCV Ab + Lower Alb Higher ICGR15 Higher AFP Fukud et l. 9 N/A Pndey et l. 11 N/A Hshimoto et l. 19 Shimd et l. 16 Zhou et l. 14 Zhou et l. 15 Hnzki et l. 17 POS Shirbe et l. 18 Lee et l. 10 Anlysis not performed or not specificlly identified., not sttisticlly significnt; POS, positive prognostic fctor;, negtive prognostic fctor; N/A, not pplicble; Child A, Child Pugh clss A liver function; HBs Ag+, positive heptitis B surfce ntigen; HCV Ab+, positive heptitis C ntibody; ICGR15, indocynine green dye retention t 15 minutes; AFP, lph fetoprotein. Tble 4 Univrite nlysis of prognostic tumour fctors Study Number of tumours (multi) Tumour size (lrger) Differentition (less) Vsculr invsion (histopthology) Intrheptic metstses Cpsule invsion Portl vein invsion Cpsule presence Fukud et l. 9 (30 mm) Pndey et l. 11 (?limit) Hshimoto et l. 19 Shimd et l. 16 Zhou et l. 14 N/A POS Zhou et l. 15 POS Hnzki et l. 17 Shirbe 18 et l. Lee et l. 10 Anlysis not performed or not specificlly identified., not significnt; POS, positive prognostic fctor;, negtive prognostic fctor. of follow-up for 10 yers. However, the dt were insufficient to relibly describe ny such ptterns. Secondry study outcomes Univrite nlysis demonstrted number of ptient, tumour nd tretment prognostic fctors ssocited with survivl outcomes. Ptient fctors ssocited with survivl outcomes re described in Tble 3. Tumour nd tretment fctors re outlined in Tbles 4 nd 5, respectively. On multivrite nlysis the following fctors showed positive ssocition with survivl: the bsence of or less severe stge of cirrhosis; femle sex; lower serum g-glutmyltrnspeptidse (g-gpt); lower serum bilirubin; non-cncerous liver prenchym; higher serum lbumin; lower indocynine green retention rte t 15 min (ICG15), nd younger ge. 9 11,15,16,19 Significnt positive prognostic tumour fctors were: the bsence of stellite lesions; the bsence of intrheptic metstses, vsculr invsion or portl vein invsion, nd the bsence of cpsulr invsion. 9 11,15,16 The only significnt tretment fctor, on multivrite nlysis, ws resection mrgin, whereby mrgin of >10 mm ws ssocited with better prognosis. 10 Discussion This review identified n overll 10-yer ctul survivl rte following resection of HCC of 7.2%, which is lower thn the cturil figures quoted in the studies to which the review refers. The difference my be understood by considering the wy in which cturil survivl is clculted. It is result of subset nlysis nd censorship of outcomes for certin ptients. For exmple, in the study by Shimd et l., 578 ptients underwent potentilly curtive heptectomy for HCC. 16 Of these, 97 ptients were excluded from the finl nlysis s seven died in hospitl, 11 died within 1 month of surgery, 14 died from non-cncer cuses, eight were lost to follow-up nd 57 underwent pllitive resection. This gives surgicl mortlity of 3.1% (18/578 ptients). The number of ptients live t 10 yers fter resection ws 105, giving n ctu-

5 HPB 289 Tble 5 Univrite nlysis of prognostic tretment fctors Study Preopertive TACE Resection: limited vs. ntomicl Surgicl mrgin positive Blood trnsfusion Blood loss (higher) Resection intent: curtive vs. pllitive Fukud et l. 9 5 mm Pndey et l. 11 Hshimoto et l. 19 Shimd et l. 16 Zhou et l. 14 POS Zhou et l. 15 Hnzki et l. 17 >5 mm POS (>1500 ml) Shirbe et l. 18 Lee et l. 10 >10 mm POS Anlysis not performed or not specificlly identified., not significnt; POS, positive prognostic fctor;, negtive prognostic fctor; TACE, trnsrteril chemoemboliztion. ril survivl percentge of 21.8% (105/481 ptients). The ctul survivl s indicted by the number of ptients live t 10 yers divided by the initil number of ptients enrolled ws 18.2% (105/578 ptients). By excluding ptients who suffered postopertive mortlity nd those who died from other cuses, the survivl quoted in these mnuscripts reflects survivl probbility only if ptient did not die periopertively, did not die from other cuses nd did not undergo the conversion of curtive to pllitive procedure once the opertion hd commenced nd the extent of disese hd been discovered. The cturil survivl figure is thus not reflective of true 10-yer survivl in ll ptients who underwent initil resection. The ctul survivl outcomes in this study re reflective of worst-cse scenrio, s only ptients who were proven to be live t 10 yers were deemed to be ctul 10-yer survivors. Ptients who were lost to follow-up or who were live t the conclusion of the study but hd not been followed up for 10 yers were not included in the finl nlysis of ctul survivl, which my led to n overestimtion of mortlity. In the cturil survivl clcultions, these ptients re censored nd re ssumed to hve the sme survivl prospects s those who continued under follow-up. 7 This my led to n overly optimistic estimte of survivl. In only four studies ws the comprehensiveness of 10-yer follow-up stted. In these, the fte of 87.0% of ptients ws known t 10 yers. Given tht these dt were vilble for fewer thn one qurter of the cohort in this nlysis, the extent to which the difference between ctul nd cturil survivl cn be ccounted for by incomplete follow-up is unknown. Nevertheless, most studies censored dt for resons other thn incomplete followup, such s periopertive mortlity or deth from other cuses. It is likely tht the most ccurte survivl figure will lie somewhere between the pessimistic clcultion of ctul survivl nd the optimistic cturil survivl figures tht re more widely quoted. It ws not possible to perform met-nlysis of the dt in these studies becuse of the heterogeneous nture of the ptient popultions, differing qulities of outcome reporting nd the lck individul ptient dt provided in the mnuscripts. No relible conclusions could be drwn when the studies were nlysed ccording to the difference between ctul nd cturil survivl to determine whether there might be n ssocition with wide rnge in this outcome nd comorbid cirrhosis, periopertive mortlity or completeness of follow-up to 10 yers. This nlysis ws mde impossible by the incomplete reporting of dt in ech ctegory nd the smll number of studies. It my be tht lrge proportion of the difference reflects censorship resulting from incomplete follow-up. However, in the studies tht reported these dt, the vst mjority (87.0%) of ptients were followed until deth or 10 yers post-surgery. It should be noted tht there ws lck of greement regrding the prognostic significnce of mny ptient, tumour nd tretment fctors. In prticulr, fctors determined on univrite nlysis s not significnt in some studies were found by others to be significnt on multivrite nlysis. An exmple of this is femle sex. Fukud et l. 9 found it to be positive fctor on multivrite nlysis, but four studies deemed femle sex to be nonsignificnt on univrite nlysis. 10,11,18,19 These differences mke it difficult to ssess the true significnce of fctors in reltion to survivl. Further long-term follow-up nd multicentre nlysis re required to better define survivl outcomes nd fctors with prognostic significnce. In order to distinguish the effect of HCC from tht of its common comorbidity, cirrhosis, it would be necessry to perform cohort studies with ge- nd disese-mtched controls. Prognostic fctors could then be incresingly considered in plnning tretment for ptients. Actul long-term survivl fter resection of HCC is poorer thn the cturil figures reported imply. The significnce of the difference between cturil nd ctul survivl dt pertins to the expecttions of clinicins nd ptients when discussing tretment options. Although Kpln Meier survivl nlysis is legitimte nd necessry tool for providing survivl estimtes, especilly when compring groups in controlled clinicl trils, for most ptients nd mny clinicins it cn led to significnt overesti-

6 290 HPB mtion of the utility of tretment nd likely outcomes of surgery. A ptient who is informed tht she hs 20% chnce of survivl for 10 yers post-surgery is unlikely to interpret this s mening tht she hs 20% chnce of survivl only if she does not die periopertively, does not die from other diseses nd if her curtive procedure is not deemed pllitive once the opertion commences. The ctul survivl rte is the more intuitive nd pproprite mesure to use when discussing tretment options with ptients. Conflicts of interest None declred. References 1. Prkin DM, Pisni P, Ferly J. (1999) Globl cncer sttistics. CA Cncer J Clin 49: Llovet JM, Fuster J, Bruix J. (2004) The Brcelonpproch: dignosis, stging, nd tretment of heptocellulr crcinom. Liver Trnspl 10 (Suppl. 1): Bismuth H, Mjno PE. (2000) Heptobiliry surgery. J Heptol 32 (Suppl.): Mzzferro V, Regli E, Doci R, Andreol S, Pulvirenti A, Bozzetti F et l. (1996) Liver trnsplnttion for the tretment of smll heptocellulr crcinoms in ptients with cirrhosis. N Engl J Med 334: Llovet JM, Burroughs A, Bruix J. (2003) Heptocellulr crcinom. Lncet 362: Llovet JM, Burroughs A, Bruix J, Krmer BS, Lencioni R, Zhu AX et l. (2008) Design nd endpoints of clinicl trils in heptocellulr crcinom. J Ntl Cncer Inst 100: Kpln EL, Meier P. (1958) Non-prmetric estimtion from incomplete observtions. J Am Stt Assoc 53: Gudjonsson B. (2002) Pncretic cncer: cse in point. J Clin Gstroenterol 35: Fukud S, Itmoto T, Amno H, Kohshi T, Ohdn H, Tshiro H et l. (2007) Clinicopthologic fetures of heptocellulr crcinom ptients with compensted cirrhosis surviving more thn 10 yers fter curtive heptectomy. World J Surg 31: Lee CS, Sheu J, Wng M, Hsu HC. (1996) Longterm outcome fter surgery for symptomtic smll heptocellulr crcinom. Br J Surg 83: Pndey D, Lee K, Wi CT, Wgholikr G, Tn KC. (2007) Longterm outcome nd prognostic fctors for lrge heptocellulr crcinom (10 cm or more) fter surgicl resection. Ann Surg Oncol 14: Chen XP, Qiu F, Wu ZD, Zhng BX. (2004) Chinese experience with heptectomy for huge heptocellulr crcinom. Br J Surg 91: Ngsue N, Kohno H, Chng YC, Tniur H, Ymnoi A, Uchid M et l. (1993) Liver resection for heptocellulr crcinom. Ann Surg 217: Zhou XD, Tng Z, M ZC, Wu ZQ, Fn J, Qin LX et l. (2003) Surgery for lrge primry liver cncer more thn 10 cm in dimeter. J Cncer Res Clin Oncol 129: Zhou XD, Tng Z, Yng BH, Lin ZY, M ZC, Ye SL et l. (2001) Experience of 1000 ptients who underwent heptectomy for smll heptocellulr crcinom. Cncer 91: Shimd K, Sno T, Skmoto Y, Kosuge T. (2005) A longterm follow-up nd mngement study of heptocellulr crcinom ptients surviving for 10 yers or longer fter curtive heptectomy. Cncer 104: Hnzki K, Kjikw S, Shimozw N, Mihr M, Shimd K, Irguri M et l. (2000) Survivl nd recurrence fter heptic resection of 386 consecutive ptients with heptocellulr crcinom. J Am Coll Surg 191: Shirbe K, Shimd M, Kjiym K, Gion T, Iked Y, Hsegw H et l. (1998) Clinicopthologic fetures of ptients with heptocellulr crcinom surviving >10 yers fter heptic resection. Cncer 83: Hshimoto K, Iked Y, Koreng D, Tnoue K, Hmtke M, Kwski K et l. (2007) Ten-yer survivl of ptients with heptocellulr crcinom fter heptectomy. Heptogstroenterology 54: Fortner JG, Fong Y. (2009) Twenty-five-yer follow-up for liver resection: the personl series of Dr Joseph G Fortner. Ann Surg 250: Choi TK, Edwrd CS, Fn ST, Frncis PT, Wong J. (1990) Results of surgicl resection for heptocellulr crcinom. Heptogstroenterology 37: Sesto ME, Vogt DP, Hermnn RE. (1987) Heptic resection in 128 ptients: 24-yer experience. Surgery 102: Appendix A1 Serch strtegy for MEDLINE 1 exp heptectomy/ (19 350) 2 liver resection.mp. (4278) 3 exp crcinom, heptocellulr/ (51 560) 4 exp disese-free survivl/ or exp survivl/ or exp survivl rte/ ( ) 5 ten-yer survivl.mp. (640) 6 4 or 5 ( ) 7 1 or 2 (20 865) 8 3 nd 7 (3909) 9 6 nd 8 (968) 10 limit 9 to humns (966) Serch strtegy for EMBASE 1 exp liver resection/ (28 236) 2 exp liver cell crcinom/ (67 745) 3 exp overll survivl/ or exp survivl/ or exp event-free survivl/ ( ) 4 ten-yer survivl.mp. (705) 5 heptocellulr crcinom.mp. (45 885) 6 heptectomy.mp. (15 749) 7 1 or 6 (31 418) 8 2 or 5 (74 349) 9 7 nd 8 (6795) 10 3 or 4 ( ) 11 9 nd 10 (2566) 12 limit 11 to humn (2327)