Prophylactic effect of neoadjuvant chemotherapy in gastric cancer patients with postoperative complications

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1 Gstric Cncer (2018) 21: ORIGINAL ARTICLE Prophylctic effect of neodjuvnt chemotherpy in gstric cncer ptients with postopertive complictions Kojiro Eto 1 Noki Hiki 1 Koshi Kumgi 1 Yoshiki Shoji 1 Ysuo Tsud 1 Yosuke Kno 1 Itru Ysufuku 1 Ysuhiro Okumur 1 Mshiro Tsujiur 1 Stoshi Id 1 Souy Nunobe 1 Mnbu Ohshi 1 Tkeshi Sno 1 Toshihru Ymguchi 1 Received: 4 April 2017 / Accepted: 19 November 2017 / Published online: 29 November 2017 The Interntionl Gstric Cncer Assocition nd The Jpnese Gstric Cncer Assocition 2017 Abstrct Bckground The occurrence of postopertive complictions my hve significnt negtive impct on the prognosis of ptients with gstrointestinl cncers. The inflmmtory response releses systemic cytokines, which my induce residul cncer cell growth. Recently, neodjuvnt chemotherpy (NAC) ws found to improve the prognosis of dvnced gstric cncer (GC). We hypothesize tht when postopertive complictions occur fter gstrectomy, NAC tretment of micrometstses cn prevent residul cncer cell growth. Methods This study included 101 ptients who underwent curtive resection fter NAC for GC from 2005 to Clinicl dt, including intropertive prmeters, were collected retrospectively. Overll survivl (OS) nd relpse-free survivl (RFS) were compred between the ptients with complictions nd those without complictions. Results Of the 101 ptients, (34.7%) hd grde 2 or higher complictions. Among those with complictions, the 3- nd 5-yer OS rtes were 63.5 nd 58.2% nd the 3- nd 5-yer RFS rtes 41.7 nd 41.7%, respectively. Among those without complictions, the 3- nd 5-yer OS rtes were 65.9 nd 56.3% nd the 3- nd 5-yer RFS rtes 51.1 nd 43.9%, respectively. There ws no significnt difference in prognosis between the ptients with complictions nd those without complictions. Conclusion Our study is the first to demonstrte the potentil of NAC to bolish the poor prognosis induced by postopertive complictions fter curtive resection for GC. Keywords Neodjuvnt chemotherpy Gstric cncer Postopertive compliction Micrometstses Inflmmtory cytokines Prophylctic effect Introduction Gstric cncer (GC) is the fourth most commonly dignosed mlignncy nd the second leding cuse of cncer deth worldwide [1]. Despite the recent progress in cncer tretment, the prognosis of ptients with dvnced GC remins poor. Gstrectomy nd regionl lymph node dissection re the most powerful tretments for ptients with Electronic supplementry mteril The online version of this rticle ( contins supplementry mteril, which is vilble to uthorized users. Noki Hiki noki.hiki@jfcr.or.jp 1 Deprtment of Gstroenterologicl Surgery, Cncer Institute Hospitl, Arike, Koto ku, Tokyo , Jpn GC; however, recurrence nd metstsis cn be observed in 20 60% of ptients even fter curtive surgery for GC [2 4]. Approximtely 10 20% of ptients with GC who re considered for potentilly curtive resection hve invisible peritonel seeding t the time of surgery, nd even ptients treted with curtive intent experience invisible metstsis not long fter resection [5]. Despite significnt dvnces in surgicl skills nd medicl instruments such s lproscopic or robotic devices, surgery is not cpble of treting invisible micrometstses in blood nd other orgns nd thus cnnot prevent ll cses of recurrence. Previous studies reveled tht the occurrence of postopertive complictions, especilly inflmmtory complictions, could hve significnt negtive impct on the prognosis of ptients with colorectl cncer, esophgel cncer, nd GC [6 13]. The ssocition between postopertive complictions nd negtive prognosis is considered to result Vol.:( )

2 704 K. Eto et l. from the relese of systemic cytokines during inflmmtory responses, nd these fctors my induce residul cncer cell growth [10, 14]. Adjuvnt chemotherpy with S-1 demonstrted significnt survivl benefit over surgery lone in ptients with GC, nd it ws successful in treting invisible micrometstses [15, 16]. Recently, dministrtion of neodjuvnt chemotherpy (NAC) ws found to improve the prognosis of ptients with dvnced GC by downstging the tumor, eliminting micrometstses, nd rpidly improving tumorrelted symptoms [17 23]. We hypothesized tht eliminting micrometstses by NAC before postopertive complictions occur fter gstrectomy my suppress the growth of residul invisible cncer cells nd control metstsis. The im of this study ws to evlute whether NAC bolishes the poor prognosis induced by postopertive complictions fter gstrectomy. Ptients nd methods Dt collection From Mrch 2005 to December 2015, totl of 101 ptients with GC underwent curtive (R0) gstrectomy fter receiving NAC t the Cncer Institute Hospitl of the Jpnese Foundtion for Cncer Reserch, Tokyo, Jpn. The eligibility criteri for NAC were bulky N GC, pr-ortic lymph node swelling, nd type 4 nd lrge type 3 GC (clinicl tril: JCOG0501, 1002). Surgery ws performed within 3 5 weeks from the lst chemotherpy tretment. Gstrectomy nd lymph node dissection were crried out ccording to the recommendtions of the Jpnese Reserch Society for GC [24]. Ptients underwent open gstrectomy with stndrdized extended lymphdenectomy (D2). Moreover, we performed pr-ortic lymph node dissection if prortic lymph node swelling persisted fter NAC. If prortic lymph node swelling did not persist fter NAC, we performed pr-ortic lymph node smpling. Tumor stging ws evluted ccording to the seventh edition of the Interntionl Union Aginst Cncer tumor, node, metstsis (TNM) clssifiction system. Informtion including ptient chrcteristics, surgicl records, nd pthologicl dt were obtined from dtbse of the Cncer Institute Hospitl. The dtes nd cuses of deth were determined from followup dt collected during clinicl exmintions performed every 3 6 months fter dischrge. Evlution of complictions During the postopertive period, ll ptients were observed for ny complictions, nd only those occurring within 1 month fter surgery were recorded. The severity of postopertive complictions ws evluted ccording to the Clvien Dindo clssifiction system. We considered complictions of grde II or higher s postopertive complictions in this study, nd we divided the ptients into two groups: those with complictions () nd those without complictions (). When two or more complictions occurred in one ptient, the higher-grde compliction ws used. We considered inflmmtory complictions such s pneumoni, ctheter infection, cholecystitis, nd infection t the surgicl site (SSI), including wound infection (superficil nd deep incisionl SSIs) nd orgn spce SSIs cused by bscess, lekge, nd pncretic fistul. Additionlly, to evlute the postopertive inflmmtion sttus, we obtined blood smples from ptients on dys 1, 3, 5, nd 7 fter surgery nd mesured relevnt prmeters including white blood cell (WBC) counts nd C-rective protein (CRP) levels. Body temperture (BT) ws mesured every dy, nd the pek BT for ech dy ws recorded. Sttistics Overll survivl (OS) ws defined s the intervl from surgery to the dte of deth from ny cuse, or the lst followup in living ptients. Recurrence-free survivl (RFS) ws defined s the intervl from surgery to either the first recurrence or deth from ny cuse. Clinicopthologicl chrcteristics nd lbortory dt were compred between the C nd s using the chi-squre test for ctegoricl vribles nd the Mnn Whitney U test for continuous vribles. Cumultive survivl ws plotted using the Kpln Meier method, nd differences were compred using the log-rnk test. P vlues < 5 were considered sttisticlly significnt. The Cox proportionl hzrds model ws pplied to ssess the effects of covrites on RFS in both univrite nd multivrite nlyses with the ctegoricl covrites listed in Tbles 3 nd 4. We conducted multivrite nlysis using fctors tht were < 0.10 in univrite nlysis (ge, gender, ypn, histologicl response, opertion time, nd blood loss). Ptients with missing covrite vlues were excluded. All tests were nlyzed using JMP softwre (SAS Institute Inc., Cry, NC, USA). Results Ptient chrcteristics A totl of ptients (34.7%) were included in the nd totl of 27 ptients (26.7%) were included in the inflmmtory complictions group. The complictions experienced were nstomotic lekge (3 ptients, 3.0%), pncretic fistul (7 ptients, 6.9%), intr-bdominl infection (10 ptients 9.9%), pneumoni (3 ptients, 3.0%), wound

3 Prophylctic effect of neodjuvnt chemotherpy in gstric cncer ptients with postopertive 705 infection (2 ptients, 2.0%), ctheter infection (1 ptients, %), nd cholecystitis (1 ptients, %). Of these, 18 (17.8%) ptients hd grde 3 complictions requiring surgicl, endoscopic, or rdiologicl intervention. Tble 1 summrizes the bseline chrcteristics before surgery of the 101 ptients who underwent curtive resection for GC ccording to the presence of complictions. The incidence of complictions ws only significntly ssocited with sex. Tble 2 summrizes the intropertive fctors nd postopertive pthologicl fctors. The hd significntly longer opertion time nd tendency towrds n extent lymphdenectomy rte. However, the pthologicl stge nd Tble 1 Ptient chrcteristics Fctors Number of ptients P vlue (N = 66) (N = ) Age, yer Gender 2 Mle Femle 28 7 Body mss index, kg/m ASA score Tumor loction 0.16 Upper Middle 23 9 Lower 24 8 Preopertive lbumin, g/dl Preopertive CEA, ng/ml Preopertive CA19-9, U/ml ycstge 0.53 I 0 0 II 10 3 III IV 11 9 NAC regimen 9 S-1 nd cispltin S-1 nd oxlipltin 3 1 Cpecitbine, cispltin nd 2 3 trstuzumb Others 5 2 Effectiveness of NAC b 1 PR SD 17 8 PD 1 1 According to the seventh edition of the Interntionl Union Aginst Cncer tumor, node, metstsis (TNM) clssifiction system b According to the RECIST guideline proportion of the ptients who received djuvnt therpy were not significntly different between the two groups. Moreover, the dt on the durtion of djuvnt chemotherpy were not significntly different between the two groups. Survivl outcomes The medin follow-up time for the 101 ptients ws 33.7 months. Of the 41 ptients (4%) who died within this period, 33 died of GC. During the follow-up, 50 ptients (49.5%) developed recurrence (24 in the lymph nodes, 15 in the peritoneum, 10 in the liver, nd 7 in other sites), while 6 ptients (5.9%) died from other diseses. Among ll ptients, the 3-yer OS rte ws 65.5% nd the 3-yer RFS rte ws 45.8%. In the, the 3-yer OS rte ws 61.9% nd the 3-yer RFS rte ws 41.7%. In the, the 3-yer OS rte ws 65.7% nd the 3-yer RFS rte ws 47.0%. The OS nd RFS results re represented grphiclly in Fig. 1, b, respectively, nd the resultnt curves strtified by inflmmtory complictions re shown in Fig. 2, b. There were no significnt differences between the two groups. The only risk fctor for 3-yer OS ws the histologicl response of the primry tumor. The risk fctors for 3-yer RFS were histologicl response of the primry tumor nd gender. The presence of complictions ws not risk fctor for survivl in this cohort (Tbles 3, 4). Postopertive chnges in the WBC count, CRP level, nd BT Figure 3 shows the chnges in clinicl nd lbortory dt ccording to the presence of inflmmtory complictions over the postopertive period. The men BT peked on dy 1 nd then decresed. The men WBC count nd CRP level peked on dy 3 nd then decresed. The men WBC count, CRP level, nd BT were ll significntly higher in the C group thn in the. The RFS tended to be worse for high-pek CRP groups thn for low-pek CRP groups (Fig. S1, b in the Electronic supplementry mteril, ESM). However, univrite nlysis for RFS ws performed, there ws no significnt difference in postopertive infectious complictions or pek CRP level (Tble 3). Discussion The present study reveled tht the prognosis of the 101 ptients with GC who underwent curtive gstrectomy fter NAC ws not significntly ffected by the occurrence of complictions. We demonstrted the possibility tht NAC bolishes the poor prognosis induced by postopertive complictions.

4 706 K. Eto et l. Tble 2 Intropertive fctors nd postopertive pthologicl fctors Fctors Number of ptients P vlue (N = 66) (N = ) Surgicl procedure 0.13 Distl gstrectomy Totl gstrectomy Opertion time, min Blood loss, ml Extent of lymphdenectomy 9 D D ypstge I 6 3 II 16 9 III IV 5 6 Histologicl response of primry lesion b Adjuvnt chemotherpy 0.76 Present Absent Durtion of djuvnt chemotherpy (dys) According to the 7th edition of the Interntionl Union Aginst Cncer tumor, node, metstsis (TNM) clssifiction system Fig. 1 Kpln Meier nlyses of overll survivl () nd relpse-free survivl (b) in ptients with nd without complictions fter resection of GC with curtive intent Survivl rte No. t risk p=7 Months fter surgery b Survivl rte No. t risk p=0.70 Months fter surgery Fig. 2 Kpln Meier nlyses of overll survivl () nd relpse-free survivl (b) in ptients with nd without inflmmtory complictions fter resection of GC with curtive intent Survivl rte No. t risk p=0.53 Months fter surgery b Survivl rte No. t risk p=0.72 Months fter surgery

5 Prophylctic effect of neodjuvnt chemotherpy in gstric cncer ptients with postopertive 707 Tble 3 Univrite nlysis of the fctors ffecting RFS in ptients who underwent curtive resection fter NAC for gstric cncer Fctors HR rtio 95% CI P vlue Age < 70 yer 0 70 yer Gender Mle 0 Femle Body mss index < 25 kg/m kg/m Preopertive lbumin < 3.5 g/l g/l Tumor loction Upper 0 Middle/lower NAC response PR 0 SD/PD ypt T1/2 0 T3/ ypn Absent 0 Present Histologicl response of primry tumor 1 0 1b/2/ <1 Opertion time < 273 min min Blood loss < 600 g g Compliction grde 2 or higher Absent 0 Present Inflmmtory compliction grde 2 or higher Absent 0 Present Durtion of djuvnt chemotherpy 1 yer 0 Less thn 1 yer Pek CRP level < 13.4 mg/dl mg/dl Tble 4 Multivrite nlysis of the fctors ffecting RFS in ptients who underwent curtive resection fter NAC for gstric cncer Fctors RFS P vlue HR rtio 95% CI Age < 70 yer 0 70 yer Gender Mle 0 Femle ypn Absent 0 Present Histologicl response of primry tumor 1 0 1b/2/ Opertion time < 273 min min Blood loss < 600 g g Kubot et l. reveled tht postopertive complictions prolonged inflmmtion nd negtively impcted prognosis in 1395 ptients who underwent curtive resection for GC [12]. Their finding tht survivl ws different between ptients with nd without complictions ws especilly remrkble in those with pstge III GC. Our study enrolled similr cses with loclly dvnced or extensive lymph node metstsis. In such cses, the occurrence of postopertive complictions my ffect prognosis more dversely becuse there is high probbility with dvnced GC tht residul nd circulting cncer cells will remin. However, in our study, the prognosis ws not significntly different between the C nd s. We consider tht NAC is cpble of treting invisible micrometstses nd bolishing the poor prognosis induced by postopertive complictions. Next, we focused on the postopertive inflmmtory response. The meditors nd cellulr effectors of inflmmtion re importnt constituents of the locl tumor environment. The inflmmtory cells nd meditors in tumor tissues induce tissue remodeling nd ngiogenesis [25]. The long-term follow-ups performed in rndomized trils hve shown tht spirin reduces the risk of colorectl cncer fter dely of severl yers, possibly vi inhibition of COX-2, which is one of the mjor inflmmtory cytokines [26]. It ws shown recently tht postopertive peritonel fluid from infected ptients fter surgery for colorectl cncer enhnced both the migrtion nd invsion of residul tumor cells, thus fcilitting their growth into recurrent tumors [27]. These

6 708 K. Eto et l. WBC(/µl) b CRP (mg/dl) Dys fter surgery < Dys fter surgery <5, <05 c Body temperture ( C) Dys fter surgery <5, <05 Fig. 3 Chnges in the white blood cell count (), C-rective protein level (b), nd body temperture (c) in ptients with nd without complictions fter resection of GC with curtive intent. For the nlysis, we used the pek body tempertures for ech dy evluted. Brs show stndrd errors. P < 5, P < 05 findings suggest tht inflmmtion cused by postopertive complictions leds to the relese of systemic cytokines nd immunosuppression, which cuse metstsis nd recurrence. In the present study, the postopertive inflmmtory response (s defined by BT, WBC count, nd CRP level) ws significntly incresed nd prolonged in the ; however, the prognosis ws not significntly different between the C nd s. Moreover, we evluted the prognosis of the ptients with inflmmtory complictions within the. There ws no significnt difference in prognosis between the ptients with nd those without inflmmtory complictions. The RFS tended to be worse for high-pek CRP groups thn for low-pek CRP groups (Fig. S1, b in the ESM). We believe tht it is difficult to completely bolish the impct of inflmmtion, but the results of this study show n improved prognosis compred to the report by Kubot et l. [12]. There re severl limittions of our study. First, this study ws retrospective nlysis conducted t single institution nd thus might be subject to severl bises. The number of cses ws reltively smll, nd the ptient bckground chrcteristics showed nonuniform distributions. Hence, prospective multi-institutionl study is desirble to vlidte the present findings. Second, this study ws subject to the shortcomings generlly ssocited with observtionl studies. The medin follow-up of 33.7 months ws reltively short. However, when it occurs, recurrence of GC usully develops within the first 2 yers fter surgery, so our follow-up time my hve been sufficient considering the recurrence rte [28]. In conclusion, the results we hve presented here re the first to demonstrte the possibility tht NAC bolishes the poor prognosis induced by postopertive complictions fter curtive resection in ptients with GC, suggesting novel effect of NAC s prophylctic therpy for GC. Further bsic nd clinicl studies of the mechnisms of micrometstsis, inflmmtory meditors, nd the microenvironment of the tumor re necessry in the future. These findings my help to improve the prognosis of ptients with GC.

7 Prophylctic effect of neodjuvnt chemotherpy in gstric cncer ptients with postopertive 709 Author contributions Study conception nd design: KE, NH, KK, TS, nd TY; cquisition of the dt: KE, NH, nd KK; nlysis nd interprettion of the dt: KE, NH, nd KK; writing of the mnuscript: KE, NH, KK, TS, nd TY. All uthors pproved the finl mnuscript. Complince with ethicl stndrds Conflict of interest The uthors declre tht they hve no conflict of interest. Ethicl pprovl nd ptient consent The dt collection nd nlysis were pproved by the institutionl review bord of the Cncer Institute Hospitl. Informed consent ws obtined from ll ptients before they were included in this study. References 1. Kmngr F, Dores GM, Anderson WF. Ptterns of cncer incidence, mortlity, nd prevlence cross five continents: defining priorities to reduce cncer disprities in different geogrphic regions of the world. J Clin Oncol. 2006;24: River F, Veg-Villegs ME, Lopez-Bre MF. Chemotherpy of dvnced gstric cncer. 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