胃癌术后输血与预后

ORIGINAL ARTICLE –GASTROINTESTINAL ONCOLOGYDo Perioperative Blood Transfusions Influence Prognosis of Gastric Cancer Patients?Analysis of 927Patients and Interactions with SplenectomyFabio Pacelli,MD 1,Fausto Rosa,MD 1,Daniele Marrelli,MD 2,Corrado Pedrazzani,MD 2,Maurizio Bossola,MD 1,Marco Zoccali,MD 3,Alberto Marchet,MD 4,Mariantonietta Di Cosmo,MD 5,Claudia Roata,MD 6,Luigina Graziosi,MD 7,Emanuel Cavazzoni,MD 7,Marcello Covino,MD 8,Domenico D’Ugo,MD 3,Franco Roviello,MD 2,Donato Nitti,MD 4,and Giovanni Battista Doglietto,MD 11Department of Digestive Surgery,Catholic University of Rome,Rome,Italy;2Institute of Surgical Sciences,University of Siena,Seina,Italy;31st General Surgery,Catholic University of Rome,Rome,Italy;4Clinica Chirurgica Generale 2,University of Padova,Padova,Italy;51st Division of Surgery,University of Verona,Verona,Italy;6Servizio Trasfusionale,Borgo Trento Hospital,Verona,Italy;7Section of General and Emergency Surgery,University of Perugia,Perugia,Italy;8Department of Emergency Medicine,Catholic University of Rome,Rome,ItalyABSTRACTBackground.This study was to assess the influence of perioperative blood transfusions on the prognosis of patients undergoing a potentially curative resection for gastric cancer and to investigate the interaction between transfusions and splenectomy.Materials and Methods.Between January 1990and December 2005,927patients from 6Italian tertiary referral centers underwent curative resections for gastric cancer.Clinical and pathologic variables were prospectively col-lected.The influence of perioperative blood transfusions on survival were evaluated by univariate and multivariate analysis.Moreover,the influence of splenectomy both in transfused and nontransfused patients undergoing total gastrectomy was also evaluated.Results.The overall 5-year survival was 54.6%.The 5-year survival rate in transfused patients (n =327)was 50.6%compared with 56.6%in nontransfused patients (n =600)(P =.094).In the subgroup of patients who underwent total gastrectomy with spleen preservation(n =209),5-year survival rate was 46%and 51.4%in transfused and nontransfused patients,respectively (P =.418);those who underwent total gastrectomy with splenectomy (n =199)presented a 5-year survival rate of 45%in transfused group compared with 39.1%in non-transfused patients (P =.571).Conclusions.Our study indicates a slightly,but not sig-nificantly,negative effect of allogeneic blood transfusion on prognosis of gastric cancer patients.In the subgroup of patients who underwent total gastrectomy,splenectomy seems to invert this mild effect,with a positive influence on overall survival.The negative effects of transfusion-induced immuno-suppression on cancer recurrence have been debated in the literature for more than a decade,with contradictory results,although most recent issues on gastric cancer conclude that transfused patients experience more tumor recurrences and less overall survival.1–6Interactions between splenectomy and blood transfusion were also hypothesized,and evidence that the immuno-suppressive effects of transfusion could be abrogated by splenectomy was first shown in organ-transplantation experiments.7–9The issue takes particular importance in gastric cancer surgery as splenectomy may or may not be added to gastric resection;in actual fact,although most authors recommend splenic preservation in the surgical treatment of gastric cancer,splenectomy is still considered for proximal gastric and gastroesophageal junction (GEJ)This study is conducted on behalf of the Italian Research Group for Gastric Cancer—IRGGC.ÓSociety of Surgical Oncology 2011First Received:26June 2010;Published Online:15January 2011F.Pacelli,MDe-mail:fpacelli@rm.unicatt.itAnn Surg Oncol (2011)18:1615–1623DOI10.1245/s10434-010-1543-9cancers(type II and III),because the incidence of lymph node metastases in the splenic hilum is thought to be higher in these tumors.10–12The aim of this study was to assess,in a large multi-centric national series,the prognostic effect of perioperative blood transfusion in patients undergoing a potentially curative resection for gastric cancer and to investigate the interaction between transfusions and splenectomy in patients undergoing total gastrectomy.PATIENTS AND METHODSPatients and TreatmentIn this retrospective multicentric study,data were col-lected from the medical records of986patients who underwent radical resection(R0)for histologically con-firmed gastric carcinoma from January1990through December2005.Patients were operated on at6Italian centers experienced in gastric cancer treatment:Digestive Surgery,Catholic University of Rome(n=393);Institute of Surgical Sciences,University of Siena(n=255);1st General Surgery,Catholic University of Rome(n=112); 1st Division of General Surgery,University of Verona (n=101);Clinica Chirurgica Generale2,University of Padova(n=99);Section of General and Emergency Surgery,University of Perugia(n=26).Eligibility criteria included histologically confirmed R0 gastric resection(i.e.,negative resection margins,en bloc resection of adherent organs,and en bloc resection of greater and lesser omentum)and pathologic evaluation of the total number of resected lymph nodes(at least15). Patients with distant metastases(e.g.,hepatic,lung,peri-toneal dissemination,or extraregional lymph nodes—superior mesenteric artery,middle colic artery,and para-aortic lymph nodes),those with fewer than15lymph nodes dissected,previous neoplastic diseases,and hematological pathologies were excluded from the study.In addition,patients dead in the perioperative period (n=34)and lost at follow-up(n=25)were excluded from the analysis.As a result,927patients who had undergone curative resections for gastric cancer were enrolled for analysis.Patients who underwent curative surgery with patho-logicfindings of serosal involvement or nodal metastases were potentially eligible for adjuvant chemotherapy.The total number of patients who received adjuvant chemo-therapy was460(49.6%).The most used regimens were epirubicin hydrochloride,cisplatin,andfluorouracil(ECF) for a mean of3cycles after surgery,depending on clinical response or the occurrence of adverse effects.The following operative procedures were performed: total gastrectomies and distal subtotal gastrectomies.D2or more extended lymph node dissection was performed on all patients,according to the rules of the Japanese Research Society for Gastric Cancer.13The definitions as to the extent of the lymphadenectomy are as follows.The regional lymph nodes of the stomach were classified into4 partment1consisted of the perigastric lymph partment2consisted of lymph nodes along the left gastric artery,along the common hepatic artery,around the celiac axis,and along the splenic artery. Compartment3consisted of lymph nodes in the hepa-toduodenal ligament,at the posterior aspect of the head of the pancreas,and at the root of the mesenterium.When the cancer was located in the lower third of the stomach,lymph nodes along the splenic artery were classified as compart-ment3.The anatomical level of D2lymphadenectomy included complete dissection of compartments1and2;D3 lymphadenectomy included that of compartments1,2,and 3.Extensive surgery was defined as combined resection of adjacent organs(gallbladder,left pancreas,liver,or colon).Splenectomy was performed for the purpose of lymph node dissection or because of suspicion of direct tumor invasion to the spleen or because of intraoperative iatro-genic reasons.Perioperative blood transfusion was defined as either whole blood or packed red blood cells administered within 14days before surgery,during surgery,or14days after surgery at the discretion of the surgeon and anesthesiolo-gist.Amount and timing of transfusion were also recorded. Usually,a hemoglobin level of8–10g/dL or hemody-namically significant intraoperative blood loss was used as thresholds for transfusion.The mean amount of blood transfusion in the transfused patients was4.1±2.7units (range,1–25units).Hospital morbidity and mortality were recorded.Post-operative septic complications were classified according to:(1)major septic complications:pneumonia,requires radiographic evidence and documentation of a pathologic organism in sputum or pleuralfluid;abdominal abscess, requires clinical or instrumental(ultrasound or computed tomographic scan)evidence of an abdominal purulent collection and spontaneous or operative drainage;and septicemia,requires a temperature of38.5°C or higher and at least1blood culture yielding a pathogenic organism; and(2)minor septic complications:wound infection, requires purulent exudate in the wound with or without culture growth;and urinary tract infection,requires bac-teriologic confirmation of more than100.000organisms per1mL of urine.1616 F.Pacelli et al.Tumor stage was classified according to the6th edition of the International Union Against Cancer/American Joint Committee on Cancer guidelines.14Patients were fol-lowed-up until death or until December31,2008.Patient demographics,clinicopathological features,type of surgery,and survival were evaluated in all population and in patients undergoing total gastrectomy.Statistical AnalysisAll statistical analyses were conducted by using SPSS 10.0for Windows(SPSS,Chicago,IL).Intergroup com-parisons were made by using a2-tailed chi-square test and the t test.Risk factors associated with tumor recurrence were determined by using logistic regression analysis. Survival curves were conducted according to the Kaplan–Meier method and compared by means of the log-rank test. Multivariate analysis to identify the independent prognos-tic factors was performed by using the Cox regression model with backward stepwise procedure.Differences were considered significant at the P\.05level. RESULTSThe characteristics of the927patients included in this study,according to transfusion and nontransfusion group, are shown in Table1.Of the927patients,327patients (35.3%)had received perioperative blood transfusion and 600patients(64.7%)had not.The majority of transfused patients(211patients,64.5%)received2U of blood or less,whereas50patients(15.3%)received more than4U. Most patients(81.1%)were transfused intraoperatively, postoperatively,or both(Table2).Among927patients,246patients(26.5%)had under-gone splenectomy and681patients(73.5%)had not. Indications for splenectomy in246patients(26.5%) included:lymph node dissection and/or extent of tumor in 207patients,bleeding in20patients,and ischemia of the spleen in5patients.The basis for splenectomy could not be determined in14patients.In the207patients who underwent splenectomy with the purpose of lymph node dissection and/or extent of tumor, the recurrence rate from lymph nodes in the splenic hilum was8.7%.The median follow-up was97months(range1–193).At last follow-up,423patients had died.For all patients of the study group,overall5-year sur-vival was54.6%.According to cancer stage was89.2%for stage IA disease,74.1%for stage IB disease,66.5%for stage II disease,41.4%for stage IIIA disease,19.0% for stage IIIB disease,and10.7%for stage IV disease (P\.0001)(Fig.1a).The5-year survival was50.6%in TABLE1Characteristics of all patients(927)according to transfu-sion and nontransfusion groupPatient variable Nontransfusiongroup(600)Transfusiongroup(327)P valueAge(years).0014 \65293124C65307203Sex.231 Male352205Female248122Tumor location.058 Lower third312134Middle third193129Upper third9564Tumor size(cm)\.0001 \6341133C6254199Lauren classification.138 Diffuse526228Intestinal6340Undetermined1951Type of operation.125 Total gastrectomy a253155Subtotal distal-gastrectomy347172Extended operation\.0001 No510245Yes9082Type of lymphadenectomy.032 D15134D2321191D3228102 Splenectomy.066 No429252Yes17175Cancer stage.155 IA3453IB9764II10661IIIA10358IIIB4836IV11255Preoperative hemoglobin(Hb)value(g/dL,mean±SD)12.0±2.111.8±7.0.566Major postoperativecomplications.0089 No493245Yes10782a Includes20total resections of gastric stump and9upper polar resectionsPrognostic Factors in Gastric Cancer1617patients who had received perioperative blood transfusion and56.6%in those who had not(P=.094)(Fig.1b).Results of the univariate and multivariate analysis of prognostic factors for all population are shown in detail in Table3.Considering all patients,the5-year survival rate was significantly affected by age,tumor location,tumor size,type of operation,need for extensive operation, splenectomy,cancer stage,and major postoperative com-plications;cancer stage and age were independent predictors of lower survival rate according to multivariate analysis.Among927patients,408patients(44%)had undergone total gastrectomy,among them155patients(38%)had received perioperative blood transfusion and253patients (62%)had not;199patients(48.8%)had undergone sple-nectomy and209patients(51.2%)had not.For75patients who both had received perioperative blood transfusion and had undergone splenectomy,the mean amount of blood transfusion was3.8±2.1units (range1–13units).For81patients who had received per-ioperative blood transfusion,without splenectomy,the mean amount of blood transfusion was4.3±2.9units (range1–25units).A total of110patients did not receive either transfusion or splenectomy.Results of the univariate and multivariate analysis of prognostic factors for patients undergoing total gastrec-tomy are shown in detail in Table4.Considering all patients,the5-year survival rate was significantly affected by age,tumor location,need for extensive operation,type of lymphadenectomy,splenectomy,and cancer stage;cancer stage,age,tumor location,and type of lymphade-nectomy were independent predictors of lower survival rate according to multivariate analysis.The interaction between perioperative blood transfu-sions and splenectomy on cumulative survival was analyzed in patients undergoing total gastrectomy,where splenectomy was mostly performed to achieve an R0 resection and is shown in Fig.2.In patients(n=209)who underwent splenic preservation(Fig.2a),5-year survival rate was46%and51.4%in transfused and nontransfused patients,respectively(P=.418);those who underwent total gastrectomy with splenectomy(n=199)presented a 5-year survival rate of45%in transfused group compared with39.1%in nontransfused patients(P=.571)(Fig.2b).TABLE2Incidence,timing,and amount of transfusionVariable No.%Incidence of transfusionsNontransfused60035.3 Transfused32764.7 Amount of transfusions(U)1–221164.5 3–46620.2 [45015.3 Mean±SD 4.1±2.7 Median2Range1–25TimingPreoperative transfusions only3410.4 Intraoperative transfusions only13942.5 Postoperative transfusions only9529.1 Preoperative and intraoperative transfusions18 5.5 Intraoperative and postoperative transfusions319.5Preoperative,intraoperative,and postoperative transfusions 1031618 F.Pacelli et al.Among the460patients(49.6%)who received adjuvant chemotherapy,207patients(45%)had been transfused and 253patients(55%)had not;292patients(63.5%)had undergone splenectomy and168(36.5%)had not.No heavy,statistically significant influence on prognosis of gastric cancer patients resulted by adjuvant chemotherapy.TABLE3Factors affecting5-year overall survival according to univariate and multivariate analysis in all927 patientsNS not statistically significant, OR odd ratioa Includes29total resections of gastric stump Patient variable No.5-yearsurvival(%)Univariateanalysis P valueMultivariateanalysisP value OR Age(years)\6541763.7\.0001\.0001 1.617 C6551047.1SexMale37051.9Female55758.7.0534NSTumor locationLower third and middle third76858.2Upper third15937.2\.0001NSTumor size(cm)\647460.4C645349.2.0061NSLauren classificationDiffuse40855.4Intestinal44964.8Undetermined7054.4.122NSType of operationTotal gastrectomy a40845.6Subtotal distal-gastrectomy51961.3\.0001NSExtended operationNo75557.0.00026NSYes17243.1Type of lymphadenectomyD18749.4D250056.6.232NSD334053.0SplenectomyNo68159.4\.0001NSYes24640.1Cancer stageIA18789.2IB16174.1II16766.5\.0001IIIA16141.4\.0001 1.753 IIIB8419.0IV16710.7Perioperative transfusionNo60056.6.094NSYes32750.6Major postoperative complicationsNo73857.4.00034NSYes18943.3Prognostic Factors in Gastric Cancer1619DISCUSSIONBlood transfusion therapy may result in immunologic changes that may be harmful in neoplastic patients.As far as gastric cancer in particular is considered,although both in retrospective and prospective randomized studies many attempts have been made to determine the effects of perioperative transfusion on survival,theirfindings resulted to be contradictory and even confusing.3,15–21 Some reports have demonstrated the adverse effect of transfusion on the prognosis of patients with gastric can-cer.3,15–18,21Decreased helper/suppressor T-cell ratios, decreased natural-killer cell activity,decreased macro-phage antigen presentation,suppression of lymphocyteTABLE4Factors affecting5-year overall survival according to univariate and multivariate analysis in408 patients undergoing total gastrectomy(includes20total resections of gastric stump and 9upper polar resections)NS not statistically significant, OR odd ratio Patient variable No.5-yearsurvival(%)Univariateanalysis P v alueMultivariateanalysisP value OR Age(years)\6521552.4.032\.05 1.478 C6519338.0.032SexMale27645.7.451NSFemale13242.8Tumor locationLower third?middle third24950.1.00124\.05 1.39 Upper third15935.7Tumor size(cm)\621753.0.055NSC619038.7Lauren classificationDiffuse21441.7Intestinal15744.2.235NS Undetermined3749.4Extended operationNo28648.2.0051NSYes12236.4Type of lymphadenectomyD15638.6D230471.8.0012\.05.807 D34852.8SplenectomyNo20949.3\.0081NSYes19940.4Cancer stageIA6189.1IB5366.6II6561.9\.0001\.0001 1.717 IIIA8334.7IIIB5319.7IV9311.2Perioperative transfusionNo25344.1.0982NSYes15545.8Major postoperative complicationsNo30747.2.108NSYes10137.51620 F.Pacelli et al.blastogenesis,and decreased delayed-type hypersensitivity have been observed after transfusion,demonstrating a relative immunosuppression.22The mechanism of this transfusion effect is not well defined.Different hypothe-ses,such as overload of the reticuloendothelial system, alterations in interleukin-2and prostaglandin metabolism, and immunosuppression by clonal deletion or generation of active suppressor factors have been proposed.Active suppressor factors include anti-idiotypic antibodies or suppressor T lymphocytes that are generated after trans-fusion.22The latter effect is strictly related to the results of this study,as splenectomy precludes the development of suppressor T-lymphocytes,explaining a possible interaction between the effects of splenectomy and blood transfusion on the immune system.23By contrast,other studies have shown that allogeneic blood transfusions do not seem to have deleterious effects on the5-year survival rates of patients who undergo curative surgery for gastric carcinoma.19,20Hyung et al.retrospectively reported that among the treatment factors in gastric cancer,total gastrectomy, splenectomy,D3or more extended lymphadenectomy,and postoperative adjuvant chemotherapy were associated with transfusion.6In their study,they showed a significantly poor survival rate in the transfused group,and a dose–response relationship between the amount of transfused blood and prognosis was evident.Heiss et al.have reported that the prognostic effect of transfusion is mediated through its effect on minimal residual disease in resected-cancer patients.24They have observed that transfusion-associated immune modulation affects minimal residual disease after curative tumor resection.They have also witnessed that quantitative assessment of tumor cells in bone marrow during follow-up demonstrated a significant quantitative increase of tumor cells in transfused patients only.24The further the stage advances,the greater the possibility of minimal residual disease,even when curative surgery is performed.In advanced stages,immunosuppression may cause progres-sion of metastatic foci and failure to remove circulating cancer cells and cells in bone marrow.Sa´nchez-Bueno et al.analyzed the influence of packet red blood cell transfusions on the prognosis of163 patients with gastric adenocarcinoma undergoing subtotal gastrectomy with a curative intention,and they con-cluded that blood transfusion per se does not influence the long-term survival of resected patients,although it does have an influence when associated with other prognostic factors and has a statistically significant influence on prognosis only in patients with tumor stage III(P=.0051).19These contradictory results,however,may arise through inadequate study design,inadequate eligibility criteria, small sample sizes,or inadequate statistical analysis.The present study,which is one of the largest conducted on a population of western patients assessing this specific issue,aims to overcome some of these methodological problems.Thefirstfinding is that the need for transfusion in our population of gastric cancer patients was related to some demographic,pathologic,and surgical variables (patient’s age,tumor location,need for extensive surgery, number of major postoperative complications)but not to preoperative hemoglobin values.Secondly,univariate and multivariate survival analysis clearly show that transfu-sions have no significant influence on prognosis of gastricPrognostic Factors in Gastric Cancer1621cancer patients.The only variables independently associ-ated with survival are patient’s age and cancer stage.The additional aim of our study was to assess the prognostic interaction between spelenectomy and transfu-sion.It is well known that splenectomy might facilitate a more complete lymphadenectomy by thorough clearance of the lymph nodes in the splenic hilum;however,numerous retrospective as well as prospective randomized trials have not demonstrated a prognostic benefit for splenectomy or extended lymphadenectomy.25Moreover,in gastric cancer patients,some retrospective studies even demonstrated a worse survival with splenectomy.26–32Evidence for an interaction between splenectomy and blood transfusion was first demonstrated in animal organ transplantation experi-ments.Immunosuppressive effects of transfusion were abrogated by splenectomy in these experiments;animals that underwent splenectomy and blood transfusion showed an increased rate of rejection of the transplanted organs compared with animals that only received blood transfu-sions before transplantation.7–9,33Weitz et al.were thefirst to clinically investigate the interaction between perioperative allogeneic blood trans-fusions and splenectomy on the prognosis of patients undergoing resection of proximal gastric or GEJ cancer.34 The most strikingfinding of their study was that periop-erative allogeneic blood transfusion and splenectomy showed an interaction in their effect on survival.Patients who received a perioperative blood transfusion showed a shorter relapse-free survival only if the spleen was pre-served.They concluded that the adverse effect of allogeneic blood transfusion on prognosis in patients with gastric cancer seemed to be associated with the presence of an intact spleen and is abrogated by its absence.By contrast,Shen et al.,in patients undergoing total gastrectomy,showed that splenectomy was associated with a higher rate of tumor recurrence among transfused patients with stage III gastric cancer but not among nontransfused patients.35In addition,splenectomy was not associated with survival among either transfused or nontransfused patients. Theyfinally concluded that splenectomy did not appear to abrogate the adverse effect of perioperative transfusion on prognosis in gastric cancer patients.Moreover,it may increase postoperative recurrence in transfused patients.Results of the present study show that splenectomy, aiming at a superior lymphadenectomy,negatively influ-ences survival both in all patients,and in those undergoing total gastrectomy,although this variable turned out to be not statistically significant at multivariate survival analysis.Moreover,in the subgroup of patients who underwent total gastrectomy among those who received splenic pres-ervation,perioperative blood transfusion had a slightly negative effect,even if not significant,whereas,in patients who underwent splenectomy,this effect on survival turned out to be inverted.Our data do not statistically support the notion of a routine splenectomy in patients who had undergone total gastrectomy,for this reason we cannot recommend a rou-tine‘‘prophylactic’’splenectomy in patients undergoing perioperative blood transfusion.Although the immunological understanding of the trans-fusion effect in gastric cancer patients was beyond the aim of the present study,these results suggest an evident role of the spleen in this context.Immune regulation is the mechanism responsible for outcomes in patients undergoing both trans-fusion and splenectomy.34,35However,no retrospective study could adequately address these mechanism issues. Further investigation after splenectomy in patients receiving perioperative blood transfusion are needed.In conclusion,the mainfindings of this study are that allogeneic blood transfusions have a slightly,but not sig-nificantly,negative effect on prognosis of gastric cancer patients,and splenectomy counteracts this effect,with a positive influence on overall survival. ACKNOWLEDGMENT Prof.Fabio Pacelli had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.REFERENCES1.Vamvakas EC,More SB.Blood transfusion and postoperativeseptic complications.Transfusion.1994;34:714–27.2.Blumberg N,Heal J,Chuang C,Murphy P,Agarwal M.Furtherevidence supporting a cause and effect relationship between blood transfusion and earlier cancer recurrence.Ann Surg.1988;207:410–5.3.Maeta M,Shimizu N,Oka A,Kondo A,Yamashiro H,TsujitaniS,et al.Perioperative blood transfusion exacerbates surgical stress-induced postoperative immunosuppression and has a neg-ative effect on prognosis in patients with gastric carcinoma.J Surg Oncol.1994;55:149–53.4.Bellantone R,Sitges-Serra A,Bossola M,Doglietto GB,MalerbaM,Franch G,et al.Transfusion timing and postoperative septic complications after gastric cancer surgery.A retrospective study of179consecutive patients.Arch Surg.1998;133:988–92.5.Yamashita K,Sakuramoto S,Kikuchi S,Katada N,Kobayashi N,Watanabe M.Transfusion alert for patients with curable cancer.World J Surg.2007;31:2315–22.6.Hyung WJ,Noh SH,Shin DW,Huh J,Huh BJ,Choi SH,et al.Adverse effects of perioperative transfusion on patients with stage III and IV gastric cancer.Ann Surg Oncol.2002;9:5–12.7.Marquet RL,Heineman E,Tank B,Obertop H,Niessen GJ,Bijnen AB,et al.Abrogation of the beneficial blood transfusion effect in dogs by splenectomy.World J Surg.1984;8:408–13.8.Shelby J,Wakely E,Corry RJ.Suppressor cell induction in donorspecific transfused mouse heart recipients.Surgery.1984;96: 296–301.9.Shelby J,Wakley E,Corry RJ.Splenectomy abrogates theimproved graft survival achieved by donor-specific transfusion.Transplant Proc.1985;17:1083–6.1622 F.Pacelli et al.。