Synchronous Colorectal Liver Metastasis: A Network Meta-Analysis Review Comparing Classical, Combined, and Liver-First Surgical Strategies

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1 Journl of Surgicl Oncology 2015;111: Synchronous Colorectl Liver Metstsis: A Network Met-Anlysis Review Compring Clssicl, Combined, nd Liver-First Surgicl Strtegies M.E. KELLY, BA, MB, BCh, BAO, MRCS, 1 * G. SPOLVERATO, MD, 2 G.N. LÊ, BA, MB, BCh, BAO, MRCP, 1 M.N. MAVROS, MD, 2 F. DOYLE, PhD, 3 T.M. PAWLIK, MD, PhD FACS, 2 AND D.C. WINTER, MD, FRCS 1 1 Deprtment of Surgery, St Vincent s University Hospitl, Dublin, Irelnd 2 Deprtment of Surgery, Johns Hopkins, Bltimore, Mrylnd 3 Division of Popultion Helth Sciences, Royl College of Surgeons Irelnd, Dublin, Irelnd Bckground: In recent yers, the mngement of synchronous colorectl liver metstsis hs chnged significntly. Alterntive surgicl strtegies to the clssicl colorectl first pproch hve been proposed. These include the liver first nd combined resections pproches. The objectives of this review were to compre the short nd long term outcomes for ll three pproches. Methods: A systemtic review of comprtive studies ws performed. Evluted endpoints included surgicl outcomes (5 yer overll survivl, 30 dy mortlity, nd post opertive complictions). Pir wise nd network met nlysis (NMA) were performed to compre survivl outcomes. Results: Eighteen studies were included in this review, reporting on 3,605 ptients. NMA nd pir wise met nlysis of the 5 yer overll survivl did not show significnt difference between the three surgicl pproches: combined versus colorectl first, men odds rtio (OR) 1.02 (95% CI , P ¼ 0.93); liver first versus colorectl first, men OR 0.81 (95% CI , P ¼ 0.37); liver first versus combined, men OR 0.80 (95% CI , P ¼ 0.41). In ddition NMA of the 30 dy mortlity mong the three pproches lso did not observe sttisticl difference. Anlysis of vrince showed tht men post opertive complictions of ll pproches were comprble (P ¼ 0.51). Conclusion: There re considerble differences in the peri opertive mngement of synchronous CLM ptients. This met nlysis demonstrted no cler sttisticl surgicl outcome or survivl dvntge towrds ny of the three pproches. J. Surg. Oncol. 2015;111: ß 2014 Wiley Periodicls, Inc. KEY WORDS: surgicl strtegies; surgicl outcomes; long term survivl; surgicl oncology; colorectl resection; heptobiliry resections; synchronous colorectl liver metstses INTRODUCTION Colorectl cncer is the second most common cuse of cncer relted deths in the United Sttes nd in the United Kingdom [1,2]. The most common metsttic site is the liver [3], with 15 25% of ptients hving colorectl liver metstsis (CLM) t the time of dignosis [4,5], nd nother 30 50% of ptients developing CLM during their tretment course [5 7]. The presence of CLM is poor prognostic fctor conferring medin survivl of 6 12 months in untreted ptients [8]. A complete surgicl resection is considered the best chnce for long term survivl, however unfortuntely only 20% of ptients with CLM re eligible for rdicl resection [9,10]. Recently, with dvnces in chemotherpy regiments nd liver directed therpy, s well s with the improvement of opertive techniques, the 5 yer survivl of ptients who underwent surgicl resection for CLM hs risen to 40 58% [11 13]. The optiml surgicl mngement of ptients with colorectl cncer nd synchronous liver metstsis is still controversil. Trditionlly, colorectl cncer ptients with synchronous liver metstsis would undergo stged pproch [14], consisting of the resection of the primry tumor followed by heptectomy t lter dte (colorectl first pproch). The rtionle is tht the primry neoplsm should be mnged first becuse it is both the source of further metstsis nd potentil complictions, including intestinl obstruction, perfortion, or mssive gstrointestinl bleeds [15]. The stged pproch lso provides the opportunity for recovery fter the initil surgery nd for commencing chemotherpy erlier. In ddition, this pproch enbles nturl selection of ptients. Those with less fvorble disese typiclly hve either progression of metstsis or significnt morbidities fter their primry surgery, nd therefore re deemed unsuitble for heptic resection [16]. More recently, in order to prevent delys in liver directed therpy or in systemic tretment, some uthors hve dvocted the liverfirst pproch [15]. Alterntively, when techniclly fesible nd clinicl pplicble, some centers hve shifted to combined pproch. The potentil benefit of performing combined resection of both the primry colorectl nd the liver metsttic tumor includes single opertion nd nesthetic induction with n overll reduction in the totl hospitl length of sty [1,17]. In contrst, this pproch my increse the complexity of the surgicl procedure nd the length of the opertion, rising concern on sfety nd the long term outcomes [1,5]. Severl studies hve compred the different surgicl pproches in n effort to identify whether one confers survivl dvntge over the others, but the evidence so fr hs been inconclusive [18 21]. In this context, we sought to systemticlly review the existing evidence relting to clinicl outcomes of ptients with synchronous CLM depending on the surgicl pproch, nd synthesize the dt using the methodology of met nlysis. All uthors hve seen, edited nd pproved the finl version of this pper. *Correspondence to: Mr. M.E. Kelly, BA, MB, BCh, BAO, MRCS, Deprtment of Surgery, St Vincent s University Hospitl, Dublin, Irelnd. Fx: E mil: kellym11@tcd.ie Received 28 July 2014; Accepted 7 September 2014 DOI /jso Published online 31 October 2014 in Wiley Online Librry (wileyonlinelibrry.com). ß 2014 Wiley Periodicls, Inc.

2 342 Kelly et l. METHODS A systemtic review ws performed ccording to the guidelines nd recommendtions from the preferred reporting items for systemtic reviews nd met nlyses checklist (PRISMA) [22]. Institutionl review bord pprovl ws not required. Serch Strtegy An electronic serch for relevnt publictions ws performed using the following resources: PubMed, Embse, Ovid, nd the Cochrne collbortion dtbse from Jnury 1998 to November The following serch hedings were used: colorectl liver metstsis surgery, resectble synchronous colorectl liver metstsis, synchronous colorectl liver metstsis surgery, liver first pproch surgery synchronous colorectl liver metstsis, stged surgery synchronous colorectl liver metstsis, nd combined surgery synchronous colorectl liver metstsis. Subsequently, we repeted the serch on PubMed using the following medicl subject hedings (MeSH); surgicl procedures, opertive AND colorectl neoplsm AND neoplsm, synchronous. All titles were initilly screened nd pproprite bstrcts were reviewed. Ech of the relevnt publiction reference section nd Google scholr ws lso screened for other pplicble publictions. The lst dte of serch ws November 12th, Inclusion Criteri To be included in the nlysis, the studies hd to meet the following criteri: () report on ptients with synchronous colorectl liver metstsis (CLM); (b) compre the pproches for synchronous CLM (either colorectl first pproch vs. combined, combined vs. liver first pproch or compre ll three pproches); (c) report on surgicl nd outcomes mesures mentioned below; (d) hve cler reserch methodology; (e) hve the longest follow up or the lrgest smple size when two or more studies were reported by the sme institution. Exclusion Criteri Studies were excluded from the nlysis if: () they did not specify tht CLM were synchronous to primry disese; (b) they did not compre the surgicl pproches; (c) outcomes of interest were not reported; (d) the methodology ws not clerly reported; (e) the dt were overlpping mong uthors; (f) the ptients in the studies hd plnned two stge heptectomy or hybrid pproch to define the CLM dignosis. Dt Extrction Two reviewers (M.K. nd G.S.) independently reviewed the literture ccording to the bove predefined strtegy nd criteri. Ech reviewer extrcted the following dt vribles: title nd reference detils (first uthor, journl, yer, country), study popultion chrcteristics (number in study, number treted by ech pproch, gender nd ge), disese chrcteristics (loction of the primry lesion, loction of heptic metstsis, number nd size of CLM), type nd pproch of surgicl intervention, nd outcome dt. All dt were recorded independently by both literture reviewers in seprte dtbses nd were compred t the end of the reviewing process to limit selection bis. The dtbse ws lso reviewed by third person (D.W.). Duplictes were removed nd ny disprities were clrified. Outcomes of Interest The following outcomes were used in the met nlysis to compre the three pproches in mngement of synchronous CLM: Primry outcome: 1. Survivl outcome: 5 yer overll survivl Secondry outcome: 2. Surgicl outcomes: Post opertive complictions nd 30 dy mortlity Other res of interest, but not included in the met nlysis were: length of hospitl sty, durtion of surgery, volume of blood loss, nd trnsfusion requirements. Sttisticl Anlysis Descriptive sttistic ws used to report the chrcteristics of ll eligible trils, describing the types of surgicl modlities, totl ptients numbers, men ge, durtion of surgery, mount of blood loss, nd medin length of sty. Sttisticl nlysis ws conducted using STATA softwre (Version 13, SttCorp LP, TX). Anlysis of dichotomous vribles ws performed using odds rtio (OR), reported with 95% confidence intervl (CI). First, we utilized pir wise met nlysis to compre the overll 5 yer survivl between the three surgicl pproches, using the rndom effects model with the ssumption tht there is vrition between studies. The test for heterogeneity ws investigted by visul inspection of the forest plots nd I 2 sttistic, which provides the percentge of vribility ttributed to heterogeneity rther thn smpling error. The OR ws considered to be sttisticlly significnt t the P < 0.05 level if the 95% CI did not include the vlue of 1. Second, we performed network met nlysis (NMA) using STATA to compre the three surgicl pproches simultneously. NMA synthesizes dt from network of trils involving multiple interventions nd therefore hs the potentil to rnk the tretments ccording to the studied outcome [23]. This method integrtes direct nd indirect comprisons of interventions. In NMA, common heterogeneity vrince is ssumed cross ll pir wise comprisons. The NMA results re represented grphiclly in forest plot with the men ORs together with their 95% confidence nd predictive intervls. The predictive intervls provide n estimted intervl within which the results of future studies re expected to be. Within the frmework of NMA, we rnked the evluted surgicl interventions bsed on the mortlity outcome. The surfce under the cumultive rnking curve (SUCRA) ws used to provide rnking probbilities. The lrger the SUCRA vlue, the better the rnk of the intervention. We lso performed network met regression ccounting for smll study effects (using the vrince of the log ORs s covrite) [23]. This ws grphiclly represented together with the SUCRA. One wy nlysis of vrince (ANOVA) ws used to nlyze the differences between the men numbers of complictions of ech surgicl pproch. The F rtio ws used s test for the null hypothesis of equlity of the mens. A sttisticlly significnt result is denoted by P < The qulity of the studies included in this systemtic review ws ssessed by the Newcstle Ottw scle (NOS) [24], to evlute ptient selection methodology, comprbility nd ssessments of outcomes. The qulity score rting ws determined for ech publiction, with eight or more strs representing studies of higher qulity. RESULTS Eligible Studies A totl of 1,929 rticles were initilly identified using the forementioned serch strtegy. On full text screening, 18 Journl of Surgicl Oncology

3 Synchronous Colorectl Liver Metstsis 343 Fig. 1. PRISMA flow digrm demonstrting results of literture serch. publictions tht met the inclusion criteri were included in the metnlysis (Fig. 1). All studies were retrospective, nd were published between Jnury 1998 nd November All studies were comprtive, reporting on t lest two surgicl pproches for synchronous CLM. On review of the extrcted dt, there ws 100% greement between the two reviewers. Numbers, chrcteristics nd qulity of the studies ssessed by the Newcstle Ottw scle (NOS) re outlined in Tble I. TABLE I. Demogrphic nd Study Chrcteristics of the Studies Included in the Met Anlysis Study Journl Yer Study period Country Totl number Clssicl group Combined group Liver first group Qulity score (NOS) Slesser et l. [39] Eur J Surg Oncol UK Andres et l. [40] Annls of Surg Countries Myo et l. [20] J Am Coll Surg USA, Itly, 1, Portugl, Switzerlnd Brouquet et l. [21] J Am Coll Surg USA vn der Pool et l. [41] Br J Surg Netherlnds Kibori et l. [42] Dig Dis Sci Jpn Moug et l. [43] Eur J Oncol 2010 NS UK de Hs et l. [32] Br J Surg Frnce, Netherlnds Slupski et l. [44] Cn J Surg Polnd Theln et l. [45] Int J Colorectl Dis Germny Yn et l. [46] World J Surg 2007 NS Austrli Cpussotti et l. [47] Ann Surg Oncol Itly Turrini et l. [33] Eur J Surg Oncol Frnce Vssiliou et l. [48] World J Gstroenterol Greece Chu et l. [49] Dis Colon Rectum USA Tnk et l. [50] Surgery Jpn Tnii et l. [51] J Nippon Med Sch Jpn Weber et l. [52] Br J Surg Frnce Journl of Surgicl Oncology

4 TABLE II. Clinicopthologicl nd Opertive Chrcteristics of the Ptients Included in the Met Anlysis No. of ptients Men ge (medin) Gender brekdown (mle, femle) Colorectl distribution (colon, rectum) Heptic distribution (unilobr, bilobr) Medin no. of CLM (men) Type of liver resection Study C S L C S L C S L C S L C S L C S L C S L Slesser et l. Andres et l. Myo et l. Brouquet et l. vn der Pool et l. Kibori et l. Moug et l. de Hs et l. Slupski et l. Theln et l NS (62) NS (55.5) , , 24 23, 13 41, , , 30 17, 19 25, , , 26 15, 19 16, 41 NS (4.8) 30 right hep, 7 ext. R hep, 13 left hep, 4 ext. L hep, 2 cudte, 4 segm, 7 section, 6 trisegm, 3 wedge NS (4.2) NS NS (61) NS (60) NS (58) 396, , , , , 91 13, , , , bisegm, 145 hemihep, 105 ext. hep, 44 NS 12 right hep, 4 ext R hep, 6 left hep, 4 segm, 4 section, 1 trisegm, 5 wedge 230 bisegm, 53 hemihep, 25 ext. hep, 21 NS NS (56) NS (58) NS (48) 44, 28 23, 20 10, 17 37, 35 25, 18 19, 8 29, 43 30, 13 10, >triseg, 3NS NS Yn et l Cpussotti et l Turrini et l. Vssiliou et l. Chu et l Tnk et l NS (63) NS (64) 27, 15 17, 15 21, 11 18, , 66 28, 27 34, 27 18, 10 96, 84 24, 16 15, 15 33, 40 35, 22 40, 30 28, 34 25, 32 47, 31 15, 10 18, 14 39, 25 NS 20, 19 28, 14 27, 5 20, 12 20, , 29 43, 12 47, 14 18, , 72 34, 6 18, 12 58, 15 37, 20 43, 27 42, 20 33, 24 70, 8 22, 3 19, 18 24, 15 22, 20 25, 7 91, 75 37, 18 91, 88 25, 15 20, 10 23, 50 41, 16 55, 15 25, 37 43, 14 66, 12 23, 2 19, 13 48, 16 13, 24 25, 14 NS (3.8) NS (2.9) NS (3) NS (4) (5.3) NS (2.2) 7 subsegm, 9 segm, 9 bisegm, 6 left hep, 1 right hep 13 right hep, 2 ext. R hep, 12 ext. L hep, 2 trisegm, 15 bisegm, 9 segm, 8 non nt 60 right hep, 28 ext. R hep, 17 left hep, 17 ext. L hep, 12 right trisect, 3 left trisect, 5 bisegm, 7 segm, 6 left lt, 24 non nt 7 subsegm, 9 monosegm, 9 bisegm, 6 left hep, 1 right hep 4 right hep, 4 ext. L hep, 1 trisegm, 2 bisegm, 6 monosegm, 11 non nt 9 right hep, 2 left hep, 2 ext. R hep, 2 R trisect, 6 left Lt, 19 non nt 17 hep, 6 ext. hep, 7 segm 25 hep, 28 ext. hep, 20 segm 233 segments, 55< 3 segments 10 right hep, 2 ext. R hep, 1 left hep, 2 left lt, 12 wedge, 5 non nt 14 right hep, 3 left hep, 3 segm, 6 section, 2 trisegm, 3 prtil 7 >trisegm, 18 <trisegm 35 wedge, 9 right hep, 1 left hep, 7 leftlt, 12 non nt 23 prtil, 3 segm, 8 section, 4 left hep, 1 right hep NS 13 bisegm, 6 hemihep, 4 ext. Hep, 5 NS 344 Kelly et l. Journl of Surgicl Oncology

5 TABLE II. (Continued) Heptic distribution (unilobr, bilobr) Medin no. of CLM (men) Type of liver resection Colorectl distribution (colon, rectum) Gender brekdown (mle, femle) No. of ptients Men ge (medin) C S L C S L C S L C S L C S L C S L C S L Study NS 42, 25 20, 42 27, 8 NS (1.86) NS (2.36) NS (3.7) NS (1.9) 6 right hep, 2 ext. R hep, 1 left hep, 2 trisegm, 8 bisegm, 6 monosegm, 10 non nt 12 right hep, 5 ext. R hep, 7 left hep, 11 trisegm, 17 bisegm, 8 segm, 2 non nt Synchronous Colorectl Liver Metstsis , 27 25, 42 38, 34 25, 10 25, 16 35, 32 31, 31 18, Tnii et l Weber et l C, colorectl first; S, simultneous/combined; L, liver first; Hep/Hemi hep, heptectomy/hemi heptectomy; Ext. hep, extended heptectomy; Segm, segmentectomy; Triseg, tri segmentectomy; Section, sectionectomy; Lt, lterl; Non nt, non ntomicl resection; NS, not specified. No results. Demogrphics Anlysis ws performed on 3,605 ptients, of which 2,439 (67.7%) hd clssicl colorectl first resection, 133 (3.7%) hd liver first resection nd 1,033 (28.6%) hd combined resections. The studies spnned men time period of 14.3 yers, with ptients operted from 1982 to 2012 (Tble I). Across ll studies, mle gender ws more common, ccounting for 58.9%, 60.1%, nd 54.7% of ll ptients treted s colorectl first, liver first, nd combined pproch respectively (Tble II). Sixteen studies reported colorectl distribution of primry tumor. Colorectl first pproch hd 71.2% (n ¼ 1,696) colonic primries nd 23.8% (n ¼ 684) rectl primries. Liver first pproch hd less colonic primries t 50.4% (n ¼ 57) nd more rectl primries t 49.6% (n ¼ 56). Combined pproch hd 67.8% (n ¼ 652) colonic primries nd 32.2% (n ¼ 309) rectl. Fourteen studies reported heptic distribution of CLM. The colorectl first pproch hd 48.3% (n ¼ 1,091) unilobr nd 51.7% (n ¼ 1,167) bilobr CLM. The liver first pproch hd 33.9% (n ¼ 38) unilobr nd 66.1% (n ¼ 74) bilobr CLM. The combined pproch hd 64.7% (n ¼ 623) unilobr nd 35.3% (n ¼ 340) bilobr CLM (Tble II). Surgicl Outcomes There ws considerble heterogeneity in the methods of reporting surgicl outcomes nd complictions mong the studies. Only nine studies reported on the durtion of surgery with no informtion pertining to liver first strtegy. Seven studies reported the medin blood loss, nd eight studies reported on blood trnsfusion requirements. Sixteen studies reported post opertive complictions, with only 7 ctully specifying the types of compliction. Ten studies reported on the length of sty, including only 1 study from liver first strtegy (Tble III). Overll Results of Met Anlysis Met nlysis of 5 yer overll survivl (primry outcome). Fifteen studies reported on the 5 yer overll survivl (OS). However, only 3 studies compred the 5 yer OS for ll three pproches; while 11 studies included 5 yer OS for combined versus colorectl first, nd one study reported 5 yer OS for colorectl first versus liver first. Pir wise met nlysis did not show significnt difference between the three tretment pproches (P ¼ 0.93 for combined vs. colorectl first; P ¼ 0.37 for liver first vs. colorectl first; P ¼ 0.41 for liver first vs. combined; Fig. 2). There ws significnt heterogeneity mongst the studies involving the liver first versus colorectl first pproches (P ¼ 0.019, I 2 ¼ 69.8%). This significnce ws due to one study finding higher OS in the liver first group (Tble IV). The finding of no significnt difference between the three tretment pproches ws concurred by the network met nlysis. The forest plot depicting the estimted summry effects in the form of men ORs long with their confidence intervls nd corresponding predictive intervls is presented in Figure 3. All confidence intervls crossed the line of no effect [combined vs. colorectl first: men OR 1.02 (95% CI ); liver first vs. colorectl first: men OR 0.81 (95% CI ); liverfirst vs. combined: men OR 0.80 (95% CI )]. Within the frme work of this network met nlysis, the SUCRA probbility ws highest for combined pproch t 69.8%. However, when djustment for smll study effects ws mde, the liver first pproch ws preferred t 78.9%. Met nlysis of post opertive outcomes. Only five studies reported 30 dy mortlity for the different surgicl pproches. Network met nlysis did not find significnt difference mongst the three groups s ll confidence intervls crossed the line of no effect [combined vs. colorectl first: men OR 1.26 (95% CI ); liverfirst vs. colorectl first: men OR 0.56 (95% CI ); liver first vs. combined: men OR 0.44 (95% CI ; Fig. 4)]. Journl of Surgicl Oncology

6 TABLE III. Opertive Outcomes nd Complictions After Combined Versus Stged Resection for Synchronous Colorectl Liver Metstsis Medin (rnge) durtion of surgery in minutes (men) Medin (rnge) blood loss (ml) No. of ptients trnsfused (%) Compliction rte nd type Medin (rnge) length of sty in dys Study C S L C S L C S L C S L C S L Slesser et l. 420 ( ) 400 ( ) 900 (600 1,200) 1,200 (400 2,000) 16 (21.1%) 8 (22.2%) 34 complictions NS 9 complictions NS 18.5 (16 23) 14 (12 18) Andres et l. NS NS Myo et l. NS 124 complictions NS 78 complictions NS 2 complictions 2 (2.7%) 7 (16.2%) 2 (7.4%) 37 complictions NS 20 complictions NS 10 complictions Brouquet et l. vn der Pool et l. Kibori et l. NS 600 (100 3,300) 300 (50 3,300) 500 (200 2,200) NS 14 complictions NS 18 (13 95) 9 (7 15) 15 (7 30) Moug et l. de Hs et l. Slupski et l. 200 ( ) 250 ( ) Theln et l. NS (208.6) NS (260.4) Yn et l. NS (180) NS (300) Cpussotti et l. Turrini et l. NS (256) NS (325) Vssiliou NS (340) NS (260) et l. Chu et l. 392 (427) 370 (430) Tnk et l. 480 ( ) 510 ( ) Tnii et l. Weber et l. NS (290) NS (313) 425 (50 1,700) 475 ( ) 620 (0 1,170) 950 (0 3,000) 1,070 (300 5,000) 1,300 (70 6,300) 15 (35.7%) 11 (34.3%) NS (21%) 14 (35%) NS 2 (3.5%) 35 (56%) NS 6 complictions 1 bile lek, 3 intr bdominl bscess, 1 pneumoni, 1 pleurl effusion 19 complictions 5 LRTI, 3 UTI, 3 ileus, 2 wound, 2 bile lek, 1 A. Fib, 1 myocrdil infrction, 1 renl impirment, 1 trnsfusion 44 complictions 9 bile lek, 4 hemtom, 3 scites, 5 bdominl collection, 3 trnsient liver filure, 12 sepsis, 4 LRTI, 1 bronchitis, 1 UTI, 1 delirium, 1 cholecystitis 12 complictions 3 bile lek, 4 intr bdominl bscess, 3 cute colitis, 2 pleurl effusion 9 complictions 2 bile lek, 2 wound infections, 1 ileus, 1 urinry infection, 3 new onset A. Fib 6 complictions 1 hemtom, 1 bile lek, 1 heptic filure, 1 sepsis, 1 pneumoni, 1 LRTI 8 complictions NS 4 complictions NS 45 complictions 16 bile leks, 10 trnsient heptic filure, 10 wound infection, 4 pleurl effusion, 2 pneumoni, 1 reintubtion, 1 stroke, 1 PE 20 complictions 7 wound infection, 3 peri heptic collections, 5 other bdominl collection, 3 respirtory issues, 1 bile lek, 1 sepsis 7 complictions 1 bile lek, 3 wound infections, 1 trnsient liver impirment, 1 pneumoni 41 complictions 14 wound infections, 9 intrbdominl collections, 10 heptic collections, 5 LRTI, 1 sepsis, 1 crdic compliction, 1 bile lek 21 complictions NS 24 complictions NS 19 complictions NS 12 complictions NS 59 complictions 3 wound, 20 LRTI, 18 pleurl effusion, 7 bile lek, 8 subphrenic collection, 1 splenic bleed E, 1 nstomotic lek, 1 intr bdominl bleed 19 complictions 2 bile lek, 2 wound infections, 3 subphrenic collections, 4 LTRI, 5 pleurl effusions, 1 bleed (NS) 13 complictions NS 34 complictions NS 6 complictions 3 biliry fistul, 1 post opertive bleed, 1 trnsient liver filure, 1 intestinl obstruction 11 complictions 2 bile lek, 2 wound infections, 1 intr bdominl bscess, 2 subphrenic bscess, 2 trnsient liver impirment, 1 biliry fistul, 1 pneumoni 20 complictions NS 8 complictions NS 20 (7 51) 12 (8 21) 6(5 14) 12 (10 26) 15 (9 27) 7 (5 19) (11 107) 10 (5 40) 20 (11 48) 22 (12 58) C, colorectl first; S, simultneous/combined; L, liver first; NS, not specified; UTI, urinry trct infection; LRTI, lower respirtory trct infection; PE, pulmonry embolism; A. Fib, new onset tril fibrilltion. 346 Kelly et l. Journl of Surgicl Oncology

7 Synchronous Colorectl Liver Metstsis 347 Fig. 2. Forest plots of pir wise stndrd met nlysis of the three surgicl pproches. OR, odds rtio; CI, confidence intervl. TABLE IV. Overll Survivl After Combined Versus Stged Resection for Synchronous Colorectl Liver Metstsis 30 dy mortlity (%) Medin follow up in months (Men) 5 yer overll survivl (%) Medin survivl in months Study C S L C S L C S L C S L Slesser et l. 1 (1.3%) 2 (5.5%) Andres et l. NS NS 55% 42% NS NS Myo et l % 42% 44% 40.9 Brouquet et l. 2 (2.7%) 2 (4.6%) % 55% 39% vn der Pool et l. NS % 73% 67% NS Kibori et l. 31 NS Moug et l % 21% de Hs et l. 0 0 NS (39) NS (45) Slupski et l. 1 (1.6%) 0 38% 45% NS 51.2 Theln et l % 53% Yn et l % 36% Cpussotti et l. 0 1 (1.4%) % 30.80% Turrini et l. 3 (5%) 2 (3.5%) % 32% Vssiliou et l. NS 0 31% 28% Chu et l % 28.90% Tnk et l % 53% Tnii et l (31) % 26.70% Weber et l. 0 0 NS (32) NS (37) 22% 21% Not ssessed. Journl of Surgicl Oncology

8 348 Kelly et l. Fig. 3. A: Network met nlysis predictive intervl plot for the three surgicl pproches. The blck lines represent the confidence intervl (CI) for men odds rtio (OR) for ech comprison. The red lines re the predictive intervls (PrI). The blue line denotes the line of no effect (OR ¼ 1). B: Plots of the surfce under the cumultive rnking curves (SUCRA) for three tretments. The tble presents the SUCRA hierrchicl vlues (in percentge) for ech surgicl pproch. The grphs show tht smll study effects lter the rnking of tretments putting liver first s the most fvorble pproch. Sixteen studies reported the post opertive complictions. From ANOVA, there ws no difference found between the men number of compliction events of the three surgicl pproches [colorectl first men 37.4 (SD 19.0), combined men 33.0 (SD 17.9), liver first men 22.1 (SD 21.1), P ¼ 0.51]. For the colorectl first group, the compliction rte ws 29.3% (n ¼ 489), within which respirtory events (sepsis nd pleurl effusions, 12.2%, n ¼ 60), bile lek (7.9%, n ¼ 39), nd intr bdominl collection/bscess (5.9%, n ¼ 29) were the most common. The compliction rte of the combined group ws 30.7% (n ¼ 294) with the most common types of complictions being intrbdominl collection/bscess (9.8%, n ¼ 29), wound infection (7.8%, n ¼ 23) nd respirtory sepsis/pleurl effusions (6.8%, n ¼ 20). Comprison of high qulity studies (NOS 8) to those of lower qulity (NOS < 8) yielded similr compliction rtes. For the colorectlfirst group, 11 high qulity studies tht reported compliction events hd n overll rte of 27.8%, while the rte of the five low qulity studies ws 31.1%. Similrly in the combined group, the compliction rtes for the high nd low qulity studies were 30.6% nd 31.0%, respectively. As for the liver first group, only two studies reported complictions with n overll rte of 16.5% (n ¼ 12). DISCUSSION This systemtic review nd met nlysis compred the three surgicl pproches in the mngement of ptients with synchronous colorectl liver metstsis, with specific im to ssess which pproch conferred the best chnce for long term survivl. Despite the dvncements in chemotherpy regimens nd the use of biologicl gents, no tretment other thn surgery hs shown survivl plteu for the mngement of synchronous CLM [25]. There is cler evidence from rndomized control trils tht resection of heptic metstsis hs significnt vlue in improving survivl outcomes nd qulity of life with 5 yer survivl between 25% nd 40% post CLM resection in selected ptients [25,27,28]. The timing of surgery for ptients with synchronous CLM is currently hot topic, since there is no consensus on the pproch strtegy or contrindictions to resection of CLM yet. Moreover, studies Journl of Surgicl Oncology

9 Synchronous Colorectl Liver Metstsis 349 Fig. 4. Network met nlysis for 30 dy mortlity of the three surgicl pproches. The blck lines represent the confidence intervl (CI) for men odds rtio (OR) for ech comprison. The red lines re the predictive intervls (PrI). The blue line denotes the line of no effect (OR ¼ 1). hve observed tht the potentil for CLM resection is often underestimted [26], with mny ptients deemed unresectble too soon without being referred to specilized hepto biliry centers [1]. This lck of consensus emphsizes the need for cler interntionl guidelines nd referrl pthwys to optimize long term clinicl outcomes in ptients with CLM. Those in fvor of the clssicl colorectl first or delyed pproch postulte tht the intervl between primry resection nd CLM resection provides the opportunity to delinete those ptients with unfvorble cncer biology, nd therefore prevent them from undergoing mjor surgicl resection with potentil relted morbidity [10]. In ddition, there is the worry tht delying primry resection my increse the rte of complictions from the primry including perfortion, obstruction, nd bleeding. Studies hve reported this rte s high s 20% but some rgue tht this my be over stted [29,30]. Alterntively, proponents of both combined or liver first (reverse) strtegies rgued tht the presence of synchronous CLM lredy indictes tht the ptients hve poor cncer biology. Therefore it is resonble tht these ptients should receive chemotherpy upfront, nd then be ressessed to determine which surgicl pproch is pproprite if t ll. Colorectl cncer is predominntly chemo sensitive, nd therefore erly chemotherpy is logicl. Lm et l. [31] hd shown tht neodjuvnt chemotherpy resulted in down stging nd conversion of unresectble disese in 22.5% of ptients. Centers tht strongly fvor this pproch contend tht post immunodeficiency stte occurs fter primry resection which drives the rte of metsttic growth, nd tht chemo therpy is typiclly delyed due to recovery from the primry resection [32,33]. Advoctes of combined resection ssert tht its gretest dvntge is tht ptients receive one generl nesthetic, nd one opertion. This pproch offers reduction in totl hospitl length of sty, risk of morbidity nd helthcre cost overll [10,19,34]. Liver first (reverse strtegy) is invribly misleding term s ptients undergo neodjuvnt tretment prior to surgicl resection. This strtegy does fcilitte erly control CLM by erly heptic resection hoping to optimize ptient s survivl [35]. However, studies reporting on this tretment strtegy hve been highly selective, nd therefore re not representtive of the spectrum of synchronous CLM ptients. Moreover, concerns over the dverse effects of neodjuvnt chemotherpy hve been rised. Reports of liver chnges including stetosis, non lcoholic stetoheptitis, sinusoidl chnges nd centrilobulr necrosis hve been cited, potentilly delying surgery [36]. Despite these reports, recent studies hd observed nd speculted tht bevcizumb my protect the liver from sinusoidl dmge from chemotherpy gents such s oxlipltin [37]. Of note, there ws considerble heterogeneity in the 5 yer overll survivl rtes reported for ptients treted with the liver first pproch, rnging from 39% to 67% in this review. Mny surgeons consider tht liver first strtegy is highly selective strtegy, which should be reserved for ptients with high burden of CLM, but with low risk of the primry neoplsm cusing complictions [38]. Our review observed tht liver first ptients hd the highest number of bilobr disese t 66.1%, compred to tht of the combined resection group t 35.3%. This ws expected s the rtionle for the liver first pproch is to fcilitte erly control of CLM in the hope to offer ptients down stging therpy nd curtive resections. In ddition, the colorectl first pproch hd substntilly more colonic primries (71.2%) wheres, the liver first pproch hd n evenly distribution between colonic nd rectl neoplsm (50.4% nd 49.6% respectively). This ws likely due to trditionl emphsis for erly resection of colonic neoplsm to prevent compliction, wheres in recent yers the role of neo djuvnt therpy for rectl tumors hd been strongly dvocted. Though 15 studies reported on 5 yer overll survivl, only 3 studies compred ll three surgicl pproches. Brouquet et l. [21] were the first uthors to retrospectively compre ll three tretment strtegies for mngement of synchronous CLM. They found comprble surgicl outcomes, morbidity nd mortlity between ll three tretment pproches. In concordnce, our systemtic review nd met nlyses found no significnt difference between those surgicl pproches. Interestingly though, upon further nlysis, our network met nlysis surfce under the cumultive rnking curve showed tendency towrds better outcomes in ptients treted with the liver first pproch (78.9%) when djusted for smll study effects. This finding could be ttributed to the highly selective nture of the liver first ptient cohort nd smll smple size. We lso noted tht the combined surgicl pproch hd higher, though not sttisticlly significnt, rte of intr bdominl collection/bscess most likely due to the fct tht this pproch evolves more extensive resection. This study is the first systemtic review nd met nlysis compring ll three surgicl pproches for synchronous CLM, nd s such it bers importnt clinicl implictions. Unfortuntely, due to non vilbility of more detiled time to event dt in the originl studies, it ws impossible to use the idel method of survivl met nlysis to compre hzrd rtios insted of ORs of 5 yer survivl; however stndrd met nlysis hs been routinely used for comprison of survivl dt when detiled timeto event dt re not vilble. Our review lso highlighted severl limittions to the current dt vilble. Currently, there re no rndomized control trils compring ll three surgicl pproches; insted, there re only limited retrospective studies tht hve mostly compred two surgicl pproches. In ddition, there remin vst differences in chemotherpy regimens, especilly in reltion to the role nd use of biologicl gents. The evolution of surgicl nd nesthetic technology hs dded more vrition over recent yers. Current studies hve considerble disprity in the ge of ptients, site of primry neoplsm, size, number nd distribution of heptic metstsis. All these spects dd substntil heterogeneity to the current dt skewering ny possible inference. Therefore, there is need for prospective comprtive trils (idelly rndomized nd including ll three pproches) with stndrdized reporting of surgicl outcomes including the length of surgery, blood trnsfusion nd intensive cre requirements, ssocited morbidities, length of hospitl sty nd both 3 nd 5 yer disese free nd overll survivl to properly ssess the superiority of one surgicl pproch over the others. Nevertheless, our review nd met nlysis suggests tht ll surgicl pproches hve comprble outcomes. Therefore, the im of surgicl Journl of Surgicl Oncology

10 350 Kelly et l. cre could be to ssess ech cse individully with multi disciplinry input nd select the pproprite pproch vilble to ech ptient. Those ptients with high burden of liver disese my be more likely to benefit from erly surgicl intervention vi liver first pproch, wheres the clssicl colorectl first pproch my be more pproprite for ptients who do not require down stging therpy. CONCLUSION The mngement of colorectl cncer with synchronous CLM is evolving. The decision for timing of the primry nd CLM resection should be individulized for ech ptient bsed on technicl, oncologicl nd ptient considertions, with multi disciplinry tem input. Our network met nlysis showed no significnt difference in the 5 yer overll survivl of the three surgicl pproches. There is growing need for rndomized controlled trils to further investigte differences in clinicl outcomes of the three different pproches. REFERENCES 1. 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