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Optimizing strategies in gastrointestinal surgery

Vlug, M.S.

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Citation for published version (APA):Vlug, M. S. (2010). Optimizing strategies in gastrointestinal surgery.

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Download date: 04 Dec 2020

LAparoscopy in combination with FAst track multimodal management is the best perioperative strategy in patients undergoing colonic surgery: A Randomized Clinical Trial (LAFA-study)

Malaika S. VlugJan Wind

Markus W. HollmannDirk T. UbbinkHuib A. Cense

Alexander F. EngelMichael F. Gerhards

Bart A. van WagensveldEdwin S. van der Zaag

Anna A.W. van GelovenMirjam A.G. Sprangers

Miguel A. CuestaWillem A. Bemelman

on behalf of the collaborative LAFA study group

Accepted for publication in Ann Surg

Abstract

ObjectiveTo investigate which perioperative treatment, i.e. laparo-scopicoropen surgerycombinedwith fast track (FT)orstandardcare,istheoptimalapproachforpatientsunder-goingsegmentalresectionforcoloncancer.Summary background dataImportantdevelopments inelectivecolorectal surgeryaretheintroductionoflaparoscopyandimplementationofFTcare,bothfocusingonfasterrecovery.MethodsInanine-centretrial,patientseligibleforsegmentalcolec-tomywererandomizedtolaparoscopicoropencolectomy,and to FT or standard care, resulting in four treatmentgroups.Primaryoutcomewastotalpostoperativehospitalstay.Secondaryoutcomeswerepostoperativehospitalstay,morbidity, reoperation rate, readmission rate, in-hospitalmortality,qualityoflifeattwoandfourweeks,patientsat-isfactionandin-hospitalcosts.Fourhundredpatientswererequiredtofindaminimumdifferenceofonedayinhos-pitalstay.Results Median total hospital stay in the laparoscopic/fast trackgroupwas5(inter-quartilerange:4-8)days;open/fasttrack7(5-11)days;laparoscopic/standard6(4.5-9.5)days,andopen/standard7(6-13)days(P<0.001).Medianpostopera-tivehospitalstayinthelaparoscopic/fasttrackgroupwas5(4-7)days;open/fast track6 (4.5-10)days; laparoscopic/standard6(4-8.5)daysandopen/standard7(6-10.5)days(P<0.001).Secondaryoutcomesdidnotdiffersignificantlyamongthegroups.Regressionanalysisshowedthatlaparos-copywastheonlyindependentpredictivefactortoreducehospitalstayandmorbidity.Conclusions Optimalperioperativetreatmentforpatientsrequiringseg-mentalcolectomyforcoloncancerislaparoscopicresectionembeddedinaFTprogram.Ifopensurgeryisapplied,itispreferentiallydoneinFTcare.

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IntroductionWorldwide,coloncanceristhesecondmostcommoncancer.Itsincidenceisexpectedtorisewiththe increasing longevityof theWesternpopulation.Surgical resection is thefirst linestrategy to treat coloniccancerand the implementationof screeningprograms is likely tofurtherincreasethenumberofpatientsrequiringcolonicsurgery. Overthepasttwentyyearstherehavebeentwoimportantdevelopmentsinelectivemajorabdominalsurgery;theintroductionoflaparoscopicsurgeryandtheimplementationofanenhancedrecoveryaftersurgery(ERAS)program,alsoreferredtoas‘fasttrack’(FT)periop-erativecare,bothfocusingonacceleratedrecoveryresultinginshorterhospitalstay.1;2Laparo-scopicresectionofbowelcancerwasfirstdescribedin1991.1Randomizedclinicaltrialshaveshownthatthistechniqueissafeandeffectiveformalignantdisease,andresultsinahospitalstayshorterbyabout1-4days,andlessmorbidityandpostoperativepainthanopencolorectalsurgery.3-5

During themid-ninetiesFTperioperative carewaspioneeredbyHenrikKehlet.2;6-8FTprogramsconsistofamultidisciplinaryapproach,involvingdieticians,nurses,surgeonsandanesthesiologistsandareaimedatreducingsurgicalstressresponse,organdysfunctionandmorbidity, therebypromotinga faster recoveryafter surgery.7;9FTperioperativecarecom-prisesextensivepreoperativecounseling,nobowelpreparation,nosedativepremedication,carbohydrate-loadedliquidsuptotwohoursbeforesurgery,effectivemultimodalpainman-agement,shortactinganaesthetics,adequateperioperativefluidmanagement,smallincisions,andnoroutineuseofdrainsandnasogastrictubes.Postoperativecareincludesearlyoralfeed-ing,enforcedmobilization,earlyremovalofurinarycatheter,andstandardlaxatives. Similar or even faster rates of recovery have been reported for FT open colectomy oncomparisonwith laparoscopiccolectomyina standardperioperativecare setting.10-12Sincetheleadingtrials3-5comparinglaparoscopicwithopensurgeryhavebeendoneinatraditionalperioperativecaresetting,thiscomparisonneedstobere-evaluatedwithinanenhancedre-coveryprogram. TherearenotrialstobefoundinliteratureaddressingthefourcombinationsofstandardorFTcarewithlaparoscopicoropensurgery.Thelongstandingquestionofwhichofthefourperioperativetreatmentoptionsistheoptimaloneforthepatientwithrespecttopostopera-

Chapter7

109

tiverecoveryremainsunanswered.13;14TwosystematicreviewslookedatallavailablestudiescomparingopensurgerywithlaparoscopicsurgerywithinaFTprogram,butnofirmconclu-sioncouldbemadeduetolackofdata.15;16

Hypothetically,combiningthetwonewdevelopments,i.e.FTcareandlaparoscopy,willresultinthefastestpostoperativerecovery.Atthesametime,itisquestionableifbothofthemareasimportantwithrespecttopostoperativerecovery. Hence,ouraimsweretodeterminewhichformofperioperativetreatment,laparoscopicoropensurgerycombinedwithFTorstandardcare,istheoptimalapproachforpatientsunder-goingsegmentalresectionforcoloncancer,andtoinvestigateifeitherlaparoscopy,FTcare,orthecombinationofbothisthemainpredictivefactorforafasterpostoperativerecovery.

MethodsPatientstreatedinnineDutchhospitals(threeUniversityhospitalsandsixteachinghospi-tals)wereeligibleiftheywerebetween40and80yearsofage,hadanAmericanSocietyofAnesthesiologists(ASA)gradeofI,IIorIII,weretoundergoelectivesegmentalcolectomyforhistologicallyconfirmedadenocarcinomaoradenoma,andwithoutevidenceofmetastaticdisease.Exclusioncriteriawerepriormidlinelaparotomy,unavailabilityofalaparoscopicsur-geon,emergencysurgery,oraplannedstoma.ThestudywasconductedinaccordancewiththeprinciplesoftheDeclarationofHelsinkiandaccordingtotheCONSORTstatement.17

The independentmedical ethics reviewboardsof theparticipatinghospitals approved thestudyprotocol.ThestudywasregisteredunderNTR222.18

DesignArandomizedtrialofa2x2balancedfactorialdesignwasperformed.Afterwritteninformedconsenthadbeenobtained,patientswererandomizedbymeansofaninternetrandomizationmodule.Block-randomizationwasusedandrandomizationwasstratifiedfortherandomizingcenters.Patientswererandomizedtolaparoscopicoropencolectomy,andtotheFTprogramorstandardcare.Thisresultedinfourtreatmentgroups:(a)laparoscopiccolectomywithFTcare(Lap/FT)(b)opencolectomywithFTcare(Open/FT)(c)laparoscopiccolectomywithstandardcare(Lap/Standard),and(d)opencolectomywithstandardcare(Open/Standard).Patientsandnursingstaffwereroutinelyinformedabouttheperioperativecareprogram,i.e.FTcareorstandardcare,butwereblindedtothetypeofintervention,i.e.laparoscopicoropensurgery.OutcomesPrimaryoutcomewastotalpostoperativehospitalstay(THS),measuredindays.THSwasdefinedaspostoperativehospitalstayplustheadditionalhospitalizationperiodincasepa-tientswerereadmittedwithin30daysofsurgery.Allpatientsweredischargediftheycompliedwiththefollowingpredefineddischargecriteria:(1)adequatepaincontrolwithparacetamoland/ornon-steroidalanti-inflammatorydrugs(2)abilitytotoleratesolidfood(3)absenceofnausea(4)passageoffirstflatusand/orfirststool(5)mobilizationaspreoperative,and(6)acceptanceofdischargebythepatient.

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110

Secondaryoutcomeswerepostoperativehospital stay(PHS),overallmorbidity,reopera-tionrate,readmissionrate,in-hospitalmortality,qualityoflifeattwoandfourweeks,patientsatisfactionfourweekspostoperativelyandin-hospitalcosts. Generalqualityoflifewasassessedwiththevalidatedandwidely-usedShortForm-36(SF-36).19Bowel-relatedqualityoflifewasassessedwiththevalidatedGastro-IntestinalQualityofLifeIndex(GIQLI).20Physicalfunctioning,bodilypainandsocialfunctioningscales(SF-36),andsocialfunctioningscale(GIQLI)weresecondaryoutcomes. Additionally,aself-reportedpatientsatisfactionquestionnaire,routinelyusedatourcenter,wassenttoallpatients.Itcomprises16items,addressingissuesincludingsatisfactionwithpersonalattentionfromthesurgeonandnursesandmedicalinformation.Totalpatientsatis-factionscoresrangedfrom16(lowestpatientsatisfaction)to80(highestpatientsatisfaction). Themarginaldirectmedicalin-hospitalcostswerecalculatedperpatientforthefourtreat-mentstrategies.Thesecosts includedoutpatientcare,operatingtime,patient-days,thead-ditional costs of laparoscopy and of fast track care, as well as the costs of complications,reoperationsandreadmissionswithin30daysaftertheindexoperation.FT care versus standard careInordertoavoidcross-overtreatmentbythenursingstaff,patientswereadmittedeithertoawardprovidingFTcareorawardprovidingstandardcare,dependingonrandomization.Thesetreatmentprotocolsaredescribedindetailelsewhere.18Nursingandmedicalstaffwork-ingontheFTcarewardwerealreadyfamiliarwithFTcarepriortothisstudy.Surgical techniqueThetechniqueoftheopenorlaparoscopicprocedurewasatthediscretionofthelocalsur-geon.Participatinglaparoscopicsurgeonswererequiredtohaveperformedaminimumof20laparoscopiccolectomiesforbenigndiseaseasstatedintheproclamationoftheAmericanSo-cietyoftheColonandRectumSurgeonsin2004,beforetheywereallowedtoperformlaparo-scopiccolectomyforcancer.Alaparoscopicprocedurewasconsideredconvertediftherewasanunplannedenlargementoftheincision.Noqualityrequirementsweresetforopensurgeryasthiswasstandardcareinallcenters.Arightcolectomywastypicallydoneviamidlinelapa-rotomy.Attheendofsurgerytheabdomenwascoveredwithalargedressingtohidethetypeofapproachinordertoblindthepatient,doctorsandnursesontheward.Data collection Datawerecollectedviaasecureddedicatedwebsite.Uptodischarge,nursingstaffreporteddailyonthepatient’sprogress,i.e.intake,passageofflatus,andpredefineddischargecriteriawerechecked.After30daysoffollow-up,theanestheticandclinicaldossiers(nursingandmedical)werecheckedformissingdata.Outpatientmedicaldossierswerecheckedforanycomplicationthathadoccurredafterdischargewithin30daysoftheoperation.TheSF-36andGIQLIweremailedto thepatientsprior toandat twoandfourweeks followingtheoperation.Thepatientsatisfactionquestionnairewasmailedfourweekspostoperatively.Allqualityoflifedatafrompatientswhohadreturnedbaselinequestionnaireswereincorporatedintotheanalysis,evenifoneortwofollow-upmeasurementsweremissing.

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111

Sample size calculationSincebothFTcareandlaparoscopyaimatfasterrecoveryresultinginareductionofhospitalstay,hospitalstaywasusedastheprimaryefficacyparameter.Usinga5%significancelevel,atotalsamplesizeof400hadapowerof>95%todetectaminimumreductioninTHSofonedaybetweenlaparoscopicandopensurgery,onedayreductioninTHSbetweenFTandstandardcare,andapowerof80%todetectthesamedifferencebetweenthecombinationofFTwithlaparoscopicsurgeryandopensurgerywithstandardcare.18

Statistical analysisStatisticalanalysesofanydifferencesbetweenthe fourgroupswereperformedusingSPSSforWindowsversion16(SPSSInc.Chicago,III.,USA).Datawereanalyzedinaccordingtothe intentiontotreatprinciple.Datawerepresentedasmeans±standarddeviationsorasmediansandinter-quartilerangeswhereappropriate.Fordichotomousoutcomes,treat-mentgroupswere comparedbymeansof theChi-square test.TheMann-WhitneyU testandKruskalWallistestswereusedforcontinuous,notnormallydistributedoutcomes.Forcontinuousnormallydistributeddata,theANOVAtestwasused.Univariateandmultiplelinearorlogisticregressionanalyseswereperformedtoanalyzetheeffectoflaparoscopy,FTcareandthecombinationofbothontheprimaryandsecondaryendpoints.Asthelengthofhospital staywasnotnormallydistributed, thesedatawere log-transformed.Qualityoflifewasinvestigatedthroughmultilevelmodeling,withfixedmeasurementoccasions(levelone)nestedwithinpatients(leveltwo).Theappropriatecovariancestructureforthedatawasunstructuredandallmodelsincludedtimeandtreatmentinteractions.In-hospitalcostswereseparatelyanalyzedfortheuniversityandteachinghospitals.Atwo-sidedP-value<0.05wasconsideredtobestatisticallysignificant.

ResultsBetweenJuly2005andAugust2009,427patientswererandomlyassignedtooneofthefourtreatmentgroups(Figure1).Baselinecharacteristicsbetweenthefourtreatmentgroupsdidnotdiffersignificantly(Table1).

Chapter7

112

Chapter7

113

Chapter7

Table 1 Baseline characteristics and surgical aspects of the included patients per group

Laparoscopy

&

Fast Track

(n = 100)

Open

&

Fast Track

(n = 93)

Laparoscopy

&

Standard care

(n = 109)

Open

&

Standard care

(n = 98)

P

Age – yr* 66±8.6 66±10.3 68±8.8 66±7.1 0.548≠

Male sex – % 53 58 62 60 0.562∂

BMI – kg/m2* 26.8±4.0 26.3±4.2 25.5±3.9 26.5 ±5.0 0.177

≠

ASA – %

- Grade I or II

82

81

80

77

0.436∂

Co-morbidity – % 71 59 68 68 0.331∂

Type of colectomy – %

- Right-sided

- Left-sided

45

55

35

65

44

56

55

45

0.055∂

T stage – %

- T0

- T1

- T2

- T3

- T4

13

10

24

48

5

16

7

19

55

3

15

5

27

50

3

16

5

21

53

5

0.879∂

N stage – %

- N0

- N1

- N2

64

29

7

61

31

8

68

25

7

70

24

6

0.893∂

M stage – %

- M0

- M1

98

2

96

4

94

6

94

6

0.509∂

Conversion – n (%) 12 (12) 12 (11)

Duration of surgery

Median [IQR]

171

139 – 198

129

101 – 175

165

135 – 204

129

110 – 151

<0.001±

Blood loss

Median [IQR]

50

0 – 150

200

100 – 306

100

0 – 200

200

100 – 350

<0.001±

*Values are mean ± standard deviation / BMI = Body Mass Index / ASA = American Society of Anesthesiologists / IQR =

inter-quartile range / ≠ANOVA test /

∂Chi-square test /

±Kruskal-Wallis test

114

Protocol complianceFifteenFTelementswereevaluatedperpatient.Thefollowingelementswerescoredifsuccess-fullyapplied;preoperativecounseling,omissionofbowelpreparation,intakeofcarbohydrate-loadeddrinksatthedaybeforesurgery,intakeofcarbohydrate-loadeddrinksatthemorningbeforesurgery,nopreoperativefastingsincemidnight,omissionofpremedication,thoracicepiduralanalgesia,preventionofhypothermia,adequateperioperativefluidloading,removalof nasogastric tube before extubation, omission of abdominal drains, suprapubic catheterornocatheter,morethan500mlofintakeatpostoperativeday(POD)0including200mlcarbohydrate-loadeddrink,morethan15minutesmobilizationatPOD0,andstartingwithlaxativeatPOD1.IntheLap/FTgroup11.2±2.2outofthe15elementsandintheOpen/FTgroup11.1±2.2elementsweresuccessfullyappliedperpatient(Table2). AsillustratedinTable2someFTelementshavealsobeenimplementedinthestandardcaregroup;intheLap/Standard6.0±1.5elementsandintheOpen/Standard5.8±1.4ele-mentsperpatient.Otherappliedelementswere;preventionofhypothermiain97%ofthepatients,removalofthenasogastrictubebeforeextubationin82%,andomissionofabdomi-naldrainsin93%.Althoughthoracicepiduralanalgesiawasappliedatanequalrateinallgroups,theepiduralcatheterremainedsignificantlylongerinsituinthestandardcaregroups(amedian(IQR)i.e.3(2-4)dayscomparedwith2(2-3)daysintheFTgroups(P<0·001)).Primary outcomeTHSandPHSinpatientsrandomizedtotheLap/FTgroupwassignificantly(median1day)shorterthanintheotherthreetreatmentgroups(P<0.001).Therewasnosignificantdiffer-enceinTHSorPHSbetweenpatientstreatedwithOpen/FTandpatientstreatedwithLap/Standard.PatientswhounderwentOpen/StandardtreatmenthadasignificantlylongerPHSthanLap/FT,Open/FT,andLap/Standard.THSafterOpen/Standardtreatmentwassignifi-cantlylongerthanLap/FTandLap/Standard(Table3). Linearregressionanalysisidentifiedlaparoscopyastheonlyindependentfactortoinflu-enceTHS(B=0.79,confidenceinterval(CI):0.69-0.91,P=0.001),i.e.laparoscopicsurgerywouldleadtoareductioninTHSof21%(CI:9-31%).FTcareshowedatrendtowardashorterTHS (B=0.88,CI: 0.77-1.01,P=0.070), but the combinationofboth showednoadditionalbenefit.PHSwassignificantlyinfluencedbybothlaparoscopy(B=0.80,CI:0.70-0.91,P=0.001),i.e.leadingtoareductioninPHSof20%(CI:9-30%),andFTcare(B=0.86,CI:0.76-0.98,P=0.025),i.e.areductionof14%(CI:10-20%).Thecombinationofbothdidnotaddanybenefit.

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115

Chapter7

Table 2 Protocol compliance

Laparoscopy

&

Fast Track

(n = 100)

Open

&

Fast Track

(n = 93)

Laparoscopy

&

Standard care

(n = 109)

Open

&

Standard care

(n = 98)

Cross-over1 – n (%) 3

a (3) 3

b (3) 3

c (2) 2

d (2)

Preoperative phase – Yes, n (%)

Preoperative counseling*

Omission of bowel preparation

Intake of CHL – day before surgery

Median [IQR] – liter

96 (96)

96 (96)

0.8 (0.3-0.8)

92 (99)

90 (97)

0.8 (0-0.8)

6 (6)

85 (78)

0.0 (0-0)

1 (1)

83 (85)

0.0 (0-0)

Day of surgery – Yes, n (%)

Intake of CHL – 2 hours before surgery

Median [IQR] – liter

No preoperative fasting since midnight

Omission of premedication

Thoracic epidural analgesia

Intraoperative fluid loading

Median [IQR] – liter

Suprapubic catheter or no catheter

Intake of CHL – after surgery

Median [IQR] – liter

Total oral intake – after surgery

Median [IQR] – liter

Mobilization – after surgery

Median [IQR] – minutes

0.4 (0.2-0.4)

87 (87)

69 (69)

87 (87)

2.2 (1.6 – 3)

47 (47)

0.0 (0-0.2)

0.5 (0.1-0.8)

0.0 (0-19)

0.4 (0-0.4)

77 (83)

61 (66)

84 (90)

2.5 (2 – 3)

54 (58)

0.0 (0-0.2)

0.3 (0-0.8)

0.0 (0-20)

0.0 (0-0)

29 (27)

23 (21)

72 (66)

2.5 (2 – 3.1)

42 (39)

0.0 (0-0)

0.05(0-0.2)

0.0 (0-0)

0.0 (0-0)

28 (29)

20 (20)

74 (76)

2.6 (2 – 3.5)

30 (31)

0.0 (0-0)

0.0 (0-0.2)

0.0 (0-0)

Start laxative POD 1 – Yes, n (%) 85 (85) 77 (83) 9 (8) 7 (7)

Intake of CHL – liter (median [IQR])

- POD 1

- POD 2

- POD 3

0.2 (0-0.4)

0.2 (0-0.4)

0.0 (0-0.4)

0.2 (0-0.4)

0.2 (0-0.4)

0.0 (0-0.4)

0.0 (0-0)

0.0 (0-0)

0.0 (0-0)

0.0 (0-0)

0.0 (0-0)

0.0 (0-0)

Total oral intake – liter (median [IQR])

- POD 1

- POD 2

- POD 3

1.5 (0.9-1.9)

1.7 (1.0-2.0)

1.8 (1.2-2.0)

1.1 (0.7-1.6)

1.4 (0.8-2.0)

1.8 (1.0-2.0)

0.9 (0.5-1.5)

1.2 (0.8-1.7)

1.5 (1.0-2.0)

0.7 (0.3-1.0)

1.0 (0.4-1.5)

1.0 (0.7-1.8)

Mobilization – minutes (median [IQR])

- POD 1

- POD 2

- POD 3

120 (50-240)

200 (90-360)

300 (120-400)

120 (60-215)

120 (60-240)

220 (100-360)

30 (15-60)

90 (45-180)

135 (60-240)

20 (0-60)

60 (20-115)

100 (53-195)

a2 pt. received Open FT / 1 pt. received Lap Standard ;

b2 pt. received Lap FT / 1 pt. received Open Standard ;

c1 pt. received Open

Standard / 1 pt. received Lap FT ; d2 pt. received Open FT ;

1Analysis according to intention to treat /

*Preoperative counseling =

separate consultation before admission with a ‘fast track’ trial nurse to discuss the essence of the fast track program / CHL =

carbohydrate-loaded drink / IQR = inter-quartile range / POD = postoperative day  

Chapter7

Tab

le 3 P

osto

perativ

e data

L

ap

aro

scop

y

&

Fast T

rack

(n =

100)

Op

en

&

Fast T

rack

(n =

93)

Lap

aro

scop

y

&

Sta

nd

ard

care

(n =

109)

Op

en

&

Sta

nd

ard

care

(n =

98)

P

Total h

osp

ital stay –

day

s 5

(4 –

8)

7 (5

– 1

1)

6 (4

.5 –

9.5

) 7

(6 –

13

) <

0.0

01

±≠

Posto

perativ

e hosp

ital stay –

day

s 5

(4 –

7)

6 (4

.5 –

10

) 6

(4 –

8.5

) 7

(6 –

10

.5)

<0

.00

1±∂

Day

s to fu

lfill disch

arge criteria

-

Pain

con

trol w

ith o

ral

med

ication

-

To

lerate solid

foo

d

-

Ab

sence o

f nau

sea

-

Passag

e of first flatu

s

-

Passag

e of first sto

ol

-

Mo

bilizatio

n as p

re-op

erative

-

Accep

tance o

f disch

arge

2 (2

-3)

1 (1

-2)

1 (1

-3)

1 (1

-2)

2 (1

-4)

3 (2

-5)

4 (3

-6)

2 (2

-4)

1 (1

-3)

2 (1

-5)

1 (1

-3)

3 (2

-4)

4 (3

-7)

5.5

(4-9

)

3 (2

-4)

2 (1

-3)

1 (1

-3)

2 (1

-3)

3 (2

-4)

5 (4

-7)

5.5

(4-8

)

3 (2

-5)

3 (2

-5)

1 (1

-4)

2 (1

-3)

4 (3

-6)

6 (5

-8)

7 (5

-12

)

In-h

osp

ital costs

- Un

iversity

ho

spitals –

€

Med

ian [IQ

R]

- Teach

ing

ho

spitals –

€

Med

ian [IQ

R]

10

59

4

(5 4

61

– 1

6 7

63

)

57

68

(48

73

– 8

91

7)

12

80

5

(6 8

47

– 2

0 6

58

)

54

97

(45

06

– 6

51

3)

11

96

7

(6 2

22

– 1

7 0

39

)

62

28

(52

80

– 6

60

4)

10

47

9

(6 6

08

– 1

6 8

75

)

56

50

(48

36

– 8

00

3)

0.5

60

±

0.4

11

±

Valu

es med

ian (in

ter-qu

artile rang

e) / ±Kru

skal-W

allis test / ≠S

ign

ificant d

ifference (M

ann

Wh

itney

U) b

etween

Lap

/FT

& O

pen

/FT

(0.0

08

); Lap

/FT

& L

ap/S

tand

ard (0

.02

6); L

ap/F

T &

Op

en/S

tand

ard (0

.00

0); L

ap/S

tand

ard &

Op

en/S

tand

ard (0

.01

0) / ∂

Sig

nifican

t

differen

ce (Man

n W

hitn

ey U

) betw

een L

ap/F

T &

Op

en/F

T (0

.00

5); L

ap/F

T &

Lap

/Stan

dard

(0.0

20

); Lap

/FT

& O

pen

/Stan

dard

(0.0

00

);

Op

en/F

T &

Op

en/S

tand

ard (0

.03

2); L

ap/S

tand

ard &

Op

en/S

tand

ard (0

.00

4)

117

Secondary outcomesTherewerenosignificantdifferencesbetweenthefourtreatmentgroupsregardingoverall-,major-, or minor morbidity, reoperation rate, readmission rate and in-hospital mortality(Table4).Logisticregressionanalysisshowedthatlaparoscopicresectionresultedinasignifi-cantlyloweroverall-andmajormorbidity(OR1.53,CI:1.02-2.29,P=0.041,andOR1.73,CI:1.01-2.95,P=0.045,respectively).NeitherFTcarenorthecombinationofbothreducedoverall-andmajormorbidity.Minormorbidity,reoperationandreadmissionratewerenotsignificantlyinfluencedbythedifferentsurgicalregimens. Therewerenostatisticallysignificantdifferences,adjustedforthetypeofhospital,inin-hospitalcostsamongthetreatmentgroupsastestedwiththeKruskallWallistestandlinearregressionanalysis(Table3). Thedischargecriterion‘absenceofnausea’wasachievedatthesamepostoperativedayinallgroups.Lap/FTpatientshadasignificantlyfasterrecovery,i.e.achievedfivedischargecriteriaearlier,thanpatientsintheLap/StandardorOpen/Standardgroups.Lap/FTpatientsshowedasignificantlyquicker‘passageoffirststool’and‘acceptanceofdischarge’thanthoseintheOpen/FTgroup(Table3). Five discharge criteria were achieved significantly earlier in Open/FT than in Open/Standardtreatment;thecriteria‘toleratesolidfood’and‘mobilizationaspreoperative’wereachievedsignificantlyearlierinOpen/FTthaninLap/Standard. Apartfromthecriteria‘absenceofnausea’,‘toleratesolidfood’and‘passageoffirstflatus’,Lap/Standardpatients achievedallotherdischargecriteria significantlyearlier thanOpen/Standardpatients. Duetomissingdataatbaseline,theoverallanalysisofdatageneratedbytheSF-36andGIQLIwasconductedin352patients(88%).Atfollow-uptherewasanoverallresponserateof80%and84%attwoandfourweekspostoperatively.Qualityoflifeatbaselinewasnotsignificantlydifferentamongthegroupsforthescalesassessed.Overall,physicalfunctioning,bodilypain,andsocialfunctioningmeasuredwiththeSF-36,andsocialfunctioningmea-suredwiththeGIQLI,significantlydeclinedattwoweekspostoperatively.Fourweeksfollow-ingsurgerybodilypainandsocialfunctioningmeasuredwiththeSF-36returnedtobaselinevalues.Theotherfunctioningscalesremainedsignificantlylower.Therewerenostatisticallysignificantdifferencesonanyofthescalesamongthefourtreatmentgroupsatanytimepoint.Patientsatisfactionwassimilaracrossallgroups.

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DiscussionThistrialshowedthatthecombinationoflaparoscopicsurgerywithFTcareresultedinasig-nificantlyfasterrecoveryaftercolonicsurgerythanallothercombinations,i.e.Open/FT,Lap/Standard,orOpen/Standard.PatientstreatedwithOpen/FTorLap/Standardhadasimilarpostoperativerecovery;Open/Standardtreatmentresultedintheworstoutcome.Treatment

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Table 4 Postoperative data Laparoscopy

&

Fast Track

(n = 100)

Open

&

Fast Track

(n = 93)

Laparoscopy

&

Standard care

(n = 109)

Open

&

Standard care

(n = 98)

P

Overall morbidity < 30 days – n

(%)

34 (34.0) 43 (46.2) 37 (33.9) 41 (40.8) 0.203¶

Patients with one or more major

complications – n (%)

15 (15.0) 18 (19.4)

12 (11.0) 21 (21.4) 0.185¶

Total No. of major complications - Intra-operative complication

- Anastomotic leakage

- Mechanical ileus requiring

reoperation

- Iatrogenic bowel perforation

- Abdominal wall dehiscence

- Other surgical complication¥

- Myocardial infarction

- Respiratory

- Infectious

- Cerebral vascular accident

- Acute tubular necrosis

18 2

7

3

0

0

2

0

2 of which 1 †

0

1 which 1 †

1

25 0

8 which 2 †

2

2

6

2

1

2 which 1 †

2 which 1 †

0

0

17 1

6 which 1 †

0

2 which 1 †

1

2

0

2

3

0

0

29 1 which 1 †

7

5

1

3

2

0

4

3

2 which 1 †

1

Patients with one or more minor

complications – n (%)

19 (19.0) 25 (26.8) 25 (23.8) 20 (19.4) 0.575¶

Total No. of minor complications - Prolonged postoperative ileus

*

- Other surgical complication

#

- Wound infection

- Other infectious complication

- Urine retention

- Cardiac

- Central nervous system

- Renal failure

- Other

36 7

2

6

8

4

3

4

2

0

46 5

2

16

11

6

4

2

0

0

43 8

2

8

9

6

3

4

0

3

43 5

2

10

14

1

3

4

1

3

Reoperations – n (%) 10 (10.0) 13 (14.0) 11 (10.1) 18 (18.4) 0.242¶

Readmission < 30 days – n (%) 6 (6.0) 7 (7.5) 7 (6.4) 7 (7.1) 0.974¶

In-hospital mortality – n (%) 2 (2.0) 4 (4.3) 2 (1.8) 2 (2.0) 0.645¶

¶Chi-square test / † = died /

¥Other surgical complication, e.g. postoperative bleeding and abdominal abscess requiring intervention,

bowel necrosis / *Prolonged postoperative ileus = unable to tolerate food with abdominal distension and had no bowel sounds,

flatus and defecation after 5 days / #Other surgical complication, e.g. intraperitoneal haematoma, suprapubic catheter sutured into

laparotomy wound, postoperative bleeding with expectative policy

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groupshadsimilarmorbidity,reoperationandreadmissionrates,equal in-hospitalmortal-ity,comparablelevelsofqualityoflifeandpatientsatisfaction,andsimilarin-hospitalcosts.Laparoscopywasfoundtobetheonlysignificantindependentfactortoreducepostoperativehospitalstayandmorbidity. ThemaingoaloftheFTconceptisnottodischargepatientsearlier,buttoacceleratethepatient’spostoperativerecoveryresultinginashorterhospitalstay.Theprimaryoutcome,to-talpostoperativehospitalstay,wasstandardizedbypredefinedobjectivelyquantifieddischargecriteria,whichisincontrasttootherstudieswheredischargecriteriahavenotbeendefinedproperly.9;13;21-23Inourstudy,dischargecriteriawerescoreddaily. LengthofhospitalstayafteraLap/FTorOpen/FTtreatmentinourstudywasinaccor-dancewiththeliterature,13;22;24;25butlongerthanthatreportedbyKehletetal.9;21;26ItshouldbepointedoutthatKehlet’sresultswereachievedatthecenterwhereFTwasdeveloped,andattheexpenseofahigherreadmissionrate.Ourstudymightthereforereflectdailypracticemoreaccurately. On comparison with the literature overall morbidity in the four treatment groups wasrelativelyhigh.Thiscanbeexplainedbythefactthatallcomplicationsbothintra-andex-tramural,werescoredprospectivelyandbytheinclusionofpatientsagedupto80.Twosys-tematicreviewscomparingFTwithstandardcaresuggestreducedmorbidityandmortalityinFT.10;11Wefoundnosignificantdifferenceinoverallmorbidityandmortalitybetweenthefourgroups.However,lessmorbiditywasassociatedwithlaparoscopicsurgery,whilethiswasnotthecaseforFTcare.Itisremarkableandyetunexplained,thatinthistrialpatientstreatedintheOpen/Standardgroupunderwentreoperationmorefrequently(18%)thanliteraturereports.IntheNetherlandsthemeanfigureis11%. Qualityoflifetwoandfourweekspostoperativelyweresimilaracrossthegroups,whichisinaccordancewitharecentlypublishedsystematicreview.27Thisisprobablyexplainedbythefactthatallpatientswereoperatedforcancerandthereforethemostimportantaimforthemwastogetcured.Anotherexplanationisthatdifferencesinqualityoflifeareexpectedtobethemostprominentinthefirstweekaftersurgery. Moststudies investigatingtheeffectivenessofFTprotocolsdidnotassesshowmanyoftheFTelementswereactuallyimplementedinpractice.Itisimportanttoevaluatethis,par-ticularlyasimplementationofthismultidisciplinaryprotocolinclinicalpracticehasprovendifficult.7;28-30Elevenofthe15predefinedFTelementsweresuccessfullyappliedinourFTgroups.Four systematic reviews10-12;16 reportedmeansofbetween8.5and13FTelementsapplied,wherebyapplieddoesnotnecessarilymeanachieved.Thereductioninhospitalstayofonly1day,asfoundintheLap/FTgroup,isprobablyduetothefactthatstandardcareactuallymeantmoderncare.Intheparticipatingcenters,standardcareincluded6ofthe15predefinedFTitems.Basedonexistingevidencewefeltthatitwouldhavebeenunethicalandunrealtowithholdtheseintrialsetting.31;32

LaparoscopyaswellasFTcare ismoreexpensive thanopensurgeryandstandardcare.Nevertheless,in-hospitalcostsweresimilarbetweenthegroups.Acost-effectivenessanalysis

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wasthereforenotperformed.ThehighercostsoflaparoscopyandFTcareweremostlikelycounterbalancedbyashorterhospitalstayand,althoughnotsignificant,lessoverallmorbid-ity.Moreover,saving1-2dayspertreatedpatient,hospitalbedutilizationwillbereducedby20%. Apartfromthesetofitemsapplied,thediscriminatingfeatureoftheFTprogramisthere-habilitationprocesswhichisalwaysimplementedinthesameway.Forexample,theprotocolprecludedthediscussionof,if,andwhenthepatientcouldeatandmobilizeaftersurgery,orthetimeofremovaloftheepidural.Itislikelytobethefactthatperioperativecareispro-tocolized,ratherthanthecombinationandnumberofappliedFTelements,thatisthetruesourceofthesuccessoftheFTprogram.FurtherstudyisrequiredtodistinguishwhichoftheFTitemsareessentialforenhancedrecovery. The limitationsofour studywere theblindingof the treatment,whichwasdifficult toachieveasthemajorityofthepatientscouldnotresistlookingundertheabdominaldress-ing.Woundinspectionwasnotalimitingfactorasthiswasnotcarriedoutuntilthedayofdischarge,butobviouslyonlyinthosepatientswithoutwoundcomplaintsorcomplications.Nonetheless,thispossiblefailurehasnotinfluencedourprimaryoutcomeasdischargewasclearlydefinedbyapplyingstrictdischargecriteria.Secondly,afterrandomizationmorepa-tientsintheopengroups(n=20)thaninthelaparoscopicgroups(n=7)wereexcluded,nev-erthelesswecanassumethatthisiscoincidental.Thirdly,aspatientshavebeenenrolledforoverfouryears,theremighthavebeenindriftincare,i.e.patientsincludedinalaterphaseofthestudy,allocatedtostandardcare,mighthavereceivedmoreFTelementsthanpatientsincludedatthestartofthestudy.WetriedtoavoidthisthoughbyadmittingpatientstoawardprovidingFTcareorawardprovidingstandardcare. Inconclusion,theoptimaltreatmentcombinationforpatientsrequiringsegmentalcolec-tomyformalignancyisalaparoscopicapproachwithinaFTperioperativecareprogram.Ifopensurgeryhastobeperformed,forexamplebecauseofthelackoflaparoscopicexpertiseorpatient-relatedfactors,thenthisshouldpreferentiallybeembeddedinaFTprotocol.

AcknowledgementsTheauthorswouldliketothankallinvestigatorsoftheLAFAstudygroupandallpatientsthatparticipatedintheLAFA-trial,withoutthemthestudywouldnothavebeenpossible.Furtherwearegratefulforthegovernmentalsubvention(ZonMW)andthefinancialsupportofJohnsonandJohnsonInternationalandNutricia.

Collaborative LAFA study group BenediktPreckel,MD,MA,DEAA,PatrickBossuyt,PhD,DirkGouma,MD,PhD,MarkvanBergeHenegouwen,MD,PhD,JanFuhring,BSc,InekePicard-vanLenthe,BSc,ChrisBakker, BSc, Bellinda King-Kalimanis, MSc, (Academic Medical Center, Amsterdam TheNetherlands),JanHofland,MD,PhD,(ErasmusMedicalCenter,Rotterdam,TheNether-lands),CornelisDejong,MD,PhD,RonaldvanDam,MD,PhD,(AcademicCenterMaas-

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tricht,Maastricht,TheNetherlands),DonaldvanderPeet,MD,PhD,EdithvanZalingen,MD, Astrid Noordhuis, BSc, Dick de Jong, BSc, (VU Medical Center, Amsterdam, TheNetherlands),T.HauwyGoei,MD,EricadeStoppelaar,MD,MarjonvandenDongen,BSc,(ZaansMedicalCenter,Zaandam,TheNetherlands),WillemvanTets,MD,PhD,MaartenvandenElsen,MD,AnnemiekSwart,BSc,(SintLucasAndreasHospital,Amsterdam,TheNetherlands),LaurensdeWit,MD,PhD,MurielSiepel,MD,GlaresaMolly,BSc,(OnzeLieveVrouweGasthuis,Amsterdam,TheNetherlands),JanJuttmann,MD,PhD,WilfredClevers, MD, Andrea Bieleman, BSc, (Tergooi Hospitals, Hilversum, The Netherlands),LudoCoenen,MD,EllyBonekamp,BSc,(GelreHospitals,Apeldoorn,TheNetherlands),JacobusvanAbeelen,MD,DianavanIterson-deJong,MD,andMargrietKrombeen,BSC,(RedCrossHospital,Beverwijk,TheNetherlands).

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