Scandinavian Journal of Urology and Nephrology, 2011; 45: 102–112

ORIGINAL ARTICLE

LAPPRO: A prospective multicentre comparative study ofrobot-assisted laparoscopic and retropubic radical prostatectomy forprostate cancer

THORDIS THORSTEINSDOTTIR1,2, JOHAN STRANNE3,4, STEFAN CARLSSON5,6,BO ANDERBERG6, INGELA BJÖRHOLT7, JAN-ERIK DAMBER3,8, JONAS HUGOSSON3,8,ULRICA WILDERÄNG1, PETER WIKLUND5,6, GUNNAR STEINECK1,4 & EVA HAGLIND2

1Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy,Gothenburg, Sweden, 2Scandinavian Surgical Outcomes Research Group (SSORG/Göteborg), Department of Surgery,Institution of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden, 3Department of Urology, SahlgrenskaUniversity Hospital, Gothenburg, Sweden, 4Division of Clinical Cancer Epidemiology, Department ofOncology–Pathology, Karolinska Institute, Stockholm, Sweden, 5Department of Urology, Division of Surgery, KarolinskaHospital, Stockholm, Sweden, 6Division of Urology, Department of Molecular Medicine and Surgery, KarolinskaInstitute, Stockholm, Sweden, 7Nordic Health Economic Research, Sahlgrenska Science Park, Gothenburg, Sweden, and8Department of Urology, Institution of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden

AbstractObjective. This study describes the study design and procedures for a prospective, non-randomized trial comparing openretropubic and robot-assisted laparoscopic radical prostatectomy regarding functional and oncological outcomes.Material andmethods. The aim was to achieve a detailed prospective registration of symptoms experienced by patients using validatedquestionnaires in addition to documentation of surgical details, clinical examinations, medical facts and resource use. Fourpatient questionnaires and six case-report forms were especially designed to collect data before, during and after surgery with afollow-up time of 2 years. The primary endpoint is urinary leakage 1 year after surgery. Secondary endpoints include erectiledysfunction, oncological outcome, quality of life and cost-effectiveness at 3, 12 and 24 months after surgery. Results. The studystarted in September 2008 with accrual continuing to October 2011. Twelve urological departments in Sweden wellestablished in performing radical prostatectomy are participating. Personal contact with the participating departments andpatients was established to ascertain a high response rate. To reach 80% statistical power to detect a difference of 5 absolute percent in incidence of urinary leakage, 700 men in the retropubic group and 1400 in the robotic group are needed. Conclusions.The Swedish healthcare context is well suited to performing multicentre long-term prospective clinical trials. The similar careprotocols and congruent specialist training are particularly favourable. The LAPPRO trial aims to compare the two surgicaltechniques in aspects of short- and long-term functional and oncological outcome, cost effectiveness and quality of life,supplying new knowledge to support future decisions in treatment strategies for prostate cancer.

Key Words: Clinical trial, retropubic radical prostatectomy, robot-assisted laparoscopic radical prostatectomy, prostateneoplasm, study design, urological surgical procedures

Introduction

Robot-assisted laparoscopic radical prostatectomy(RALP) has spread rapidly in clinical practice,

although its superiority to open retropubic radicalprostatectomy (RRP) concerning long-term outcomehas not been documented in either randomized orprospective comparative observational studies [1,2].

Correspondence: T. Thorsteinsdottir, Department of Surgery, University of Gothenburg/Sahlgrenska University Hospital östra, SE-41685 Göteborg, Sweden.E-mail: thordis.thorsteinsdottir@oc.gu.se

(Received 29 June 2010; accepted 6 October 2010)

ISSN 0036-5599 print/ISSN 1651-2065 online � 2011 Informa HealthcareDOI: 10.3109/00365599.2010.532506

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Single institutional series indicate that compared toRRP, RALP gives a lower mean amount of bloodloss during the procedure, and a lower prevalence ofpostoperative wound infections, bladder neck con-tractures and shorter hospitalization [3,4]. However,no available results reveal significant advantages interms of functional or oncological outcomes [4].Advocates of RALP argue that the three-dimensionalvisual field with magnification, the decreased bleedingdue to increased abdominal pressure and the intuitiverobotic movement with six degrees of freedom offeradvantages not available with open surgery. Scepticssay lacking the tissues’ haptic feedback and thedemanding anatomical orientation compromisesurgical precision to such a degree that it might provedetrimental. A recent registry-based comparisonreported that contrary to results from earlier caseseries, the frequency of postoperative urinary leakagewas higher after minimal invasive techniques, includ-ing both conventional and robot-assisted laparo-scopy, than after RRP [5]. An analysis of availableevidence asks for high-quality studies to resolve thisissue [4].In Sweden,where 2247 radical prostatectomieswere

performed in 2008 [6], the authorities in the 18 countycouncils and two regions are responsible for healthcare,which is financed by taxes. Residency in some partmimics allocation to treatmentmodality since residentsof a certain area belong to a hospital offering careaccording to local protocols, including the determina-tion of surgical technique. In this setting, a prospective,non-randomized comparative trial, LAParoscopicProstatectomy Robot Open (LAPPRO), was started.The trial utilizes the favourable conditions for long-term treatment evaluation in Sweden. In addition, asmany features as possible from the design of random-ized clinical trials, as well as from etiological epidemi-ology, are included, striving for a high validity of theeffectmeasure.The design andprocedures of the studyare described here.

Material and methods

LAPPRO is a detailed, prospective registration ofsymptoms experienced by patients, and informationon examinations, surgical details, medical facts andresource use from hospital charts. The aim is toenable comparison of outcomes from RRP andRALP, hypothesizing that RALP leads to a lowerincidence of long-term functional complicationsthan RRP without affecting oncological outcome.All means for collecting data were standardized,

bearing in mind the idea of blinding assessors ofoutcome, to make sensitivity and specificity of

assessments similar in the compared groups. Refer-ring to a clinical trial paradigm, one primary endpointand several secondary endpoints were decided upon.The primary endpoint is urinary leakage, defined asthe incidence of men changing pads (Table I). Someof the secondary endpoints are listed in Tables Iand II, while the variable sources are shownin Tables III and IV. Making the primary and sec-ondary endpoints comparable, the same measureswere used at all follow-up points, taking into accountthe potential confounders each time, independent ofsurgical technique. An independent pathologist willperform a re-examination of a random sample of thesurgical specimens.When planning and designing the study, epidemi-

ological methods were used, as adapted to this field bythe hierarchical step model for study design and datainterpretation described earlier [7–9] and applied inover 70 empirical articles from the Division of ClinicalCancer Epidemiology [10–14]. This interactive pro-cess combined earlier research, clinical practice andqualitative methods in aspects of the primary andsecondary endpoints, possible confounders and effectmodifiers. During this process, concepts protruded,leading to new hypothesis on associations and, con-sequently, either modifying existing questions or inte-grating new questions into the questionnaires. Thefollow-up points were chosen according to ongoingclinical practice to achieve efficiency and uppermostrelevant documentation of the outcomes.

Participants

Well-established urology departments, defined assuch by a yearly volume of around 50 proceduresor by having a very experienced urologist specializedin prostate surgery, were contacted for participation.Twelve decided to participate, accounting for approx-imately half of the yearly incidence of prostatectomiesin Sweden [6]. At the participating departmentsevery patient scheduled for prostatectomy would beeligible for the study if meeting the following inclusioncriteria: category T1–T3 prostate cancer (accordingto the TNM Classification of Malignant Tumours[15]), with no clinical signs of distant metastases(bone scan not mandatory), prostate-specific antigen(PSA) £20 (according to the respective depart-ment’s PSA assay routine), any Gleason grade, age75 years or younger, fit for prostatectomy, no previousmalignancy, giving informed consent, and able toread and write Swedish (if participants did notunderstand Swedish well enough to answer the ques-tionnaires, only medical data were collected bycase-report forms).

LAPPRO: robot versus open prostatectomy 103

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Analysis for the primary endpoint only includepatients operated on by a urologist with a previousexperience of more than 100 procedures using thetechnique in question. Urologists in training wereallowed to perform parts of the procedure if an accre-dited urologist, with experience of more than 100 pro-cedures, was the senior surgeon during the procedure.Procedures performed by urologists in trainingwere included to perform a secondary analysis ofthe learning curve for radical prostatectomy by bothtechniques.

Case-report forms

The surgical case report form (CRF) was partly basedon quality control forms from two of the participatingdepartments. The protocol committee revised theseCRFs as well as designing the other study forms(Table III), aiming at including relevant questionsand having them applicable in daily practice.One question was developed for each concept to bestudied, striving for a combination of recent evidence

and clinical experience with pragmatic answeringscales. All CRFs were tested in a clinical setting byface-to-face validity: an investigator accompaniedthe healthcare personnel while answering, makingsure that they understood the questions. This resultedin modifications to the questions’ order and answer-ing scales until gradually the final version wasreached.

Questionnaires

Participants were supposed to answer the first ques-tionnaire before surgery, establishing baseline data.Further questionnaires should be distributed at 3,12 and 24 months after surgery. The questionsaddressed primary and secondary endpoints, the pos-sible confounders and effect modifiers as summarizedin Table IV.Figure 1 shows schematically the preparatory phase

of the study. The preoperation and 3 month ques-tionnaires were influenced by earlier questionnairesfor similar populations [10,14]. Interviews with

Table I. Primary endpoint and some of the secondary endpoints with the respective questions stated in the patient questionnaires and theiranswering categories.

Endpoint Variable Question Answering categories

Primary Urinary leakage How often do you change pad, diaperor sanitary aid during a typical day (24 h)?

Irrelevant, I don’t use pads, diapers orany sanitary aids

Less often than once every 24 h

About once every 24 h

About two to three times every 24 h

About four to five times every 24 h

About six times or more often every 24 h

Secondary Erectile dysfunction How hard was your penis duringsexual activity during the last month?

Irrelevant, I haven’t had any sexual activity

My penis was never hard enough forintercourse

My penis was hard enough for intercourseless than half of the time

My penis was hard enough for intercoursemore than half of the time

My penis was always hard enough forintercourse

Quality of life How would you describe your qualityof life during the last month?

Answering scale with endpoints marked:

0 = No quality of life

6 = Best possible quality of life

Intrusive thoughts aboutprostate cancer

How often in the last month have youhad negative respective positive thoughtsabout your prostate cancer, suddenlyand involuntary?

Never

More seldom than once a week

At least once a week

At least three times a week

At least once every day

At least three times every day

At least seven times every day

104 T. Thorsteinsdottir et al.

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prostate cancer survivors at different time-points aftersurgery revealed common themes in their narrativeswhich gave rise to new questions, some of them notraised before in similar study groups. While designingthe questionnaires special considerations were madeabout stating questions in an understandable way,applicability to the current situation and the orderof sections in the questionnaire. For example, aninformal, everyday phrase for urinating was chosento normalize the concept and the questions on peri-operative care were applied in the 3 month question-naire only. The section about sexual function, whichwas considered very private, came last, assuming thatif the participant was acquainted with the question-naire he would rather not skip them. In the 12 and24 month questionnaires, new questions were addedto the earlier questionnaires and questions not suit-able for these follow-up points removed. All ques-tionnaires were tested and validated by experts andprostate cancer survivors (Figure 1).

Health economics

A standardized instrument of health status developedfor clinical and economical studies, the EuroQol5 Dimensions (EQ-5D) [16], will be used to calculatequality-adjusted life years (QALYs), the measureapplied in the cost-effectiveness analysis. The instru-ment comprises five dimensions of health at three levelsof severity, as well as a vertical 20 cm visual analoguescale, with 0 representing “worst imaginable healthstate” and 100 “best imaginable health state” [16].Calculationofhealthcareandsocietal costswill bebasedon data listed in Table II. The length of hospitalizationmay be influenced by factors other than the patients’recovery from the surgery, such as the departments’routines and incentives to discharge patients early orlate. Therefore, a surrogate variable, “ready to be dis-charged”, will be defined as patients being acceptablymobile, able to take care of their catheter, able to feedand having no troublesome pain [17].

Table II. Some of the secondary endpoints with some of the respective sections from the case report forms (CRFs) including information frommedical charts and clinical resources, or the patient questionnaires.

Section examplesSourceSecondary endpoint

6–12weekCRFOncological outcomes

Bleeding, infections and pain (analgesics)ReoperationIntensive careHospitalization

Short-term surgical complications Surgical CRFPostoperative care CRF6–12 week CRF

6–12 week CRF12 month CRF24 month CRF3 months after surgery12 months after surgery24 months after surgery

Long-term morbidity

Cost effectiveness QALYsLength of hospitalizationSurgical timeSurgical equipmentLength of stay at recovery unitNeed for intensive careTransfusionsUse of analgesicsReadmissionsReoperationsAdjuvant treatmentsUsage of aidsDuration of sick leavea

Overall and stage-spefic positivie surgical margin ratesRelapse of measurable serum level of PSA

Readmittance to hospitalSurgeryDiseasesCancer recurrenceAdjuvant treatmentsMortality

Surgical CRFPostoperative care CRF6–12 week CRF12 month CRF24 month CRFPre-operation3 months after surgery12 months after surgery24 months after surgery

aInformation extracted from the Swedish Social Insurance Agency.PSA = prostate-specific antigen; QALYs = quality-adjusted life-years.

LAPPRO: robot versus open prostatectomy 105

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Tab

leIII.

Case-repo

rtform

s(C

RFs)

intheLAPPRO

stud

y:follo

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ints

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andtherespective

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rge

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12weekfollo

w-up

5.12

mon

thfollo

w-up

6.2year

follo

w-up

Preop

.CRF(29)

SurgicalCRF(94)

Postop.

care

CRF(60)

6–12

weekCRF(55)

12mon

thCRF(56)

24mon

thCRF(56)

PSAa(3)

Blood

coun

t(4)

Blood

coun

t(2)

PSAa(2)

PSAa(2)

PSAa(2)

Blood

coun

t(2)

Urologistsexpe

rien

ce(2)

Len

gthof

hospitalization(2)

Dayswithcatheter

(1)

Adjuv

anttreatm

ent(5)

Adjuv

anttreatm

ent(5)

ASA

classb

(1)

Duration(7)

Needforintensivecare

(3)

pTcatego

ryc(1)

Can

cerrelapse(1)

Can

cerrelapse(1)

Tcatego

ryc(3)

Gleason

grad

e(biopsies)

(1)

Positivebiop

sies

(2)

mm

canc

erin

diagno

stic

biop

sies

(1)

Diagn

osticproc

edure(7)

Ambition

for

nerve-sparing(2)

Surgicalproc

edure:

lymph

-nod

eresection(3),

diathe

rmyusage(1),

clips(2),

sutures(5),

dissection

s(5),

nerve-sparing(15),drain(1)

Lossof

bloo

d(2)

Transfusion

(3)

Ana

lgesics(1)

Usage

ofloup

esspectacles

(2)

Urologist’s

percep

tion

oftheproc

edure(13)

Transfusion

(2)

Needforintraven

ous

opiates(5)

Com

plications

e(19)

Reo

peration

e(17)

Mortality(4)

Ncatego

ryc(1)

Final

Gleason

grad

e(1)

Tum

oursize

(1)

Surgicalmargins

d(3)

Metastasis(8)

Adjuv

anttreatm

ent(1)

Lym

phoe

dema(2)

Lateco

mplications

e(9)

Reo

peration

e(17)

Mortality(4)

Metastasis(8)

Lym

phoe

dema(2)

Lateco

mplicatione

(9)

Reo

peration

e(17)

Mortality(4)

Metastasis(8)

Lym

phoe

dema(2)

Hospitalad

mission

se(9)

Reo

peration

e(17)

Mortality(4)

a Prostate-specifican

tigenacco

rdingto

therespective

depa

rtmen

t’sPSAassayroutine;

bAmerican

Soc

iety

ofAna

esthesiologistsPhy

sicalS

tatusClassification

System

[23];cTNM

Classification

ofM

aligna

ntTum

ours

[15];dPatho

logicalan

atom

ical

diagno

ses(P

AD);

e Interna

tion

alClassification

ofDisease

(ICD)co

ding

.

106 T. Thorsteinsdottir et al.

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Tab

leIV

.Patient

question

naires

intheLAPPRO

stud

y,indicating

thefollo

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nan

swered

andthequ

estion

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Beforesurgery

3mon

thsaftersurgery

12mon

thsaftersurgery

24mon

thsaftersurgery

Age

Sickleavean

dreha

bilitation

Employ

men

tan

dworksituation

Employ

men

tan

dworksituation

Marital

status,ed

ucationan

dem

ploy

men

tEmploy

men

tPartner’s

employ

men

tPartner’s

employ

men

t

BMI

Healthc

areco

ntacts

Adjuv

anttreatm

ent

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anttreatm

ent

Hered

ity

Exp

erienc

eof

healthcare

Pha

rmaceu

ticals

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rmaceu

ticals

Co-morbidity,he

rnia

State

aftersurgery:

complications,he

rnia

Healthc

areco

ntacts

andexpe

nses

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areco

ntacts

andexpe

nses

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rmaceu

ticals

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ing:

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moo

d,an

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pressivene

ssHealthstate:

complaints,

hernia

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complaints,

hernia

Well-be

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d,an

xiety,

self-esteem

,de

pressivene

ssQua

lityof

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psycho

logicalan

dph

ysical

health,EQ-5D

bWell-be

ing:

sleep,

moo

d,an

xiety,

self-esteem

,de

pressivene

ssWell-be

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self-esteem

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lityof

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bTho

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Tho

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Writing

,talkingan

dsocial

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Writing

,talking,

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Tob

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,tran

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and

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,tran

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analgesics

andalco

holha

bits

Tob

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,tran

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analgesics

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Activitiesof

daily

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Urina

ryvaluation:

continen

ce,

voiding,

freq

uenc

y,bo

ther,IPSSc

Activitiesof

daily

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daily

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Urina

ryvaluation:

continen

ce,vo

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ther,IPSSc

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ther,IP

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ryvaluation:

continen

ce,

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ther,IPSSc

Sexua

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tion

:po

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ality,

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Sexua

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].

LAPPRO: robot versus open prostatectomy 107

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At discharge participants receive standardized sickleave for 14 days, i.e. a few days after the catheterhas normally been removed. After that they call alocal answering service at each department and

request additional sick leave for 1 week at a timeuntil 6 weeks after surgery. If in need of longersick leave, a urologist evaluates the patient’s situa-tion. The documented sick leave will be extracted

Interviews with menabout the experience

of prostate cancerdiagnosis andprostatectomy

Expert validityUrology nurses

UrologistsPsychologists

EpidemiologistsStatisticians

Health economist

Face-to-face validity12 men before surgery

5 men 3 months after surgery4 men 12 months after

surgery2 men 24 months after

surgery

Prestudy100 men from 4

urology departments.Questionnaires tested.

Data collection procedure tried out

Expert valdity

Main studyMen planned for

prostatectomy at 12 urology departments in Sweden screened for

eligibility

3 months after sugeryPatient questionnaire

284 variables

12 months after surgeryPatient questionnaire

305 variables

PreoperationPatient questionnaire

207 variables

Refinement

Refinement

Refinement

7 men interviewed 3 months after surgery

3 men interviewed 12 months after surgery

Theme analysisQuestion

development

Questionnaire

24 months after surgery Patient questionnaire

332 variables

Figure 1. The process of developing the patient questionnaires for the LAPPRO study. In the preparatory phase, interviews with prostatecancer survivors were performed. Common themes in the men’s narratives were clustered and analysed. The next step was testing thequestionnaires with experts as well as by face-to-face validation with prostate cancer patients: an investigator accompanied them whileanswering, making sure they understood the questions, otherwise modifications were made. Then the questionnaires were further tested in aprestudy, gradually resulting in the final version.

108 T. Thorsteinsdottir et al.

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from the database of the Swedish Social InsuranceAgency.

Data collection procedure

Figure 2 depicts the ongoing data collection proce-dure. By means of a telephone call to the studysecretariat, personal data (name, personal identitynumber, address, telephone number, urologicaldepartment, surgical technique, date of surgery)are entered into a registry database that gives backthe individual study number all questionnaires aremarked with. This information is transformed intothe patient contact database, specially designed inFileMakerPro 9. Reminders on contacting the parti-cipants appear automatically at fixed time-points inthe database, enabling the researchers to keep track of

each patient through the trial pathway shown inFigure 2. As the inclusion consists of more than100 patients each month, this database is the back-bone of and vital for the trial procedures.

Power calculation and statistical analysis

The incidence of urinary leakage was estimated apriori to be 10% in the patient group undergoingRRP. To be able to detect a difference of morethan 30 relative per cent, the desired number ofpatients in each arm was calculated to be 600 (signif-icance level 0.05, power 80%). Fifteen months afterthe inclusion started the power calculation wasupdated by an interim analysis committee, consistingof three independent scientists. Data regarding theprimary endpoint were analysed with and without age

Decision onprostatectomy(RALP or RRP)

Invited toLAPPRO

Surgery3 monthfollow-up

24 monthfollow-up

Checklist forinclusion

Inclusion phonecall. Study number

Patient contactdatabase

Informed consent

Preoperative patient

questionnaire

3 monthpatient

questionnaire

12 monthpatient

questionnaire

24 monthpatient

questionnaire

PreoperativeCRF

SurgicalCRF

6–12 weekCRF

12 monthCRF

24 monthCRF

Post-operative

CRF

Contactphone call

Questionnaire sent out

Thankyou card

Reminderphone call

Contactletter

12 monthfollow-up

Forms filled in at urology department

Questionnaires filled in by patients

Study procedure

Secretariat procedures

CRF = case report formRALP = robot – assisted laparoscopic radical prostatectomyRRP = retropubic radical prostatectomy

Figure 2. Flowchart of the LAPPRO study revealing the procedure for patient inclusion, contact with participants and the follow-up points forquestionnaires and case-report forms (CRFs). The admitting doctor gave information and filled in a checklist for eligibility for inclusion whilepatients accepting participation signed an informed consent form. The first questionnaire (preoperative patient questionnaire) was given to thepatient at admission and either collected there or sent back by the patient in a prestamped envelope. The doctors filled out the preoperativeCRF and the surgical CRF while nurses could fill out the postoperative CRF at discharge, the follow-up CRFs at 6–12 week, 12 month and24 month follow-up. An elaborate contact schedule included a letter to the participant 2 weeks before each follow-up point. Some days later anassistant called by telephone and asked for permission to send the questionnaire, applying to the 3, 12 and 24 month patient questionnaires.Two weeks later a “thank you and reminder” card was sent to the participant. Participants not answering a questionnaire were asked if theywanted to be excluded or if further CRFs could be collected.

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adjustment. No one from the trial’s steering commit-tee or secretariat had access to the interim results.The interim analysis suggested using unequal groupsizes for the main analysis, i.e. 700 in the retropubicgroup and 1400 in the robotic, to be able to detecta difference of five absolute per cent assuming thefrequency of urinary leakage after RRP would bebetween 10% and 18%. Accrual is therefore predictedto be fulfilled by October 2011.Data from the questionnaires and CRFs are entered

verbatim into EpiData 3.1. If a question is markedwith two answers the procedure is to enter the firstchoice every other time and the second choice theother time, i.e. only one answer is allowed. All dataentering procedures, exceptions and comments aredocumented. Data will be exported to SAS 9.2 (SASInstitute, Cary, NC, USA) for statistical analysis.Variables will be dichotomized according to previousroutines at the Division of Clinical Cancer Epidemi-ology [10,12,14], manually reassuring that these cut-offs are reasonable according to the nature of thequestion and the prevalence. The effect measure forthe association between surgical technique and end-points will be calculated as relative risks. Confidenceintervals and statistical significance will be calculatedassuming a binomial distribution of prevalence.Open-ended answers and comments are transcribedverbatim into Microsoft Word, making content anal-ysis of the text possible. Non-completed questionsfrom the CRFs are sent back for completion, andmissed pages from questionnaires sent back to parti-cipants with return envelopes.

Ethics

The trial was approved by the regional ethics reviewboard in Gothenburg (277-07) and use of personalidentification data reported to the privacy officer ofthe Sahlgrenska University Hospital (no. 29280). Thetrial is registered in the Current Controlled Trialsdatabase as study number ISRCTN06393679 [18].

Results

Study population

A group from the trial secretariat visited the parti-cipating departments to present the study, to startup and to make the essential personal contact withlocal investigators. All men scheduled for a radicalprostatectomy at the participating urological depart-ments from 1 September 2008 were screenedfor eligibility and participation (n = 2186 at 31 May2010).

Participating centres

Twelve urological departments are taking part in thetrial: seven practise RRP and five practise RALP.A research nurse visits the departments once a yearfor support and monitoring, ascertaining that theCRFs are answered according to hospital charts.The local investigators and research nurses participatein meetings with the steering committee twice a year.The departments were recruited within 6 months andstarted inclusion within the first 12 months of the trialstart.

Prestudy

A prestudy of 100 men from four of the participatingdepartments was performed to test the questionnairesas well as the data collection procedure and response,leading to defined procedures and modifications ofthe questionnaires and CRFs. These cases will not beincluded in the final analysis.

Discussion

The Swedish healthcare system is well suited to per-forming multicentre long-term prospective clinicaltrials since the patient’s residence to some partmimics randomization and tracking subjects by theirpersonal identity number is easy. The structure andfinancing of the healthcare system also motivateresearch. The regulations stipulate that the healthcareprovider has a responsibility not only for qualitycontrol but also for research into and developmentof new methods and treatment modalities. It is pos-sible to perform multicentre trials in Sweden, sincethe national care programmes for specific patientgroups make the drawbacks less pronounced inSweden than in many other countries. Single-centre comparative studies can have several disadvan-tages, such as the potential institutional bias: while anew technique is introduced all resources tend tofocus in that direction as well as chancing patientselection bias in favour of the new technique.LAPPRO’s study design is compact, aiming at

documenting possible factors that can affect patients’experience after prostatectomy, with respect to pri-mary endpoints, secondary endpoints and confound-ing factors. The inclusion rate has been high.However, the influx of robots to virgin departmentshas meant that the number of “learning curve” pro-cedures for the robot-assisted operation has beenhigher than expected. An interim analysis was under-taken to ensure that inclusion continues until a suf-ficient population size is reached, as the initial power

110 T. Thorsteinsdottir et al.

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calculation was based on results emanating fromsingle-centre experiences. The trial steering commit-tee accepted the interim analysis recommendation,subsequently prolonging the inclusion period. Asincoming data are entered directly, secondary analysison variables not related to the main study hypothesisor divided after surgical technique can be donecontinuously.The medical world considers the randomized clin-

ical trial the fundamental ideal for acquiring newknowledge concerning wanted and unwanted effectsof a medical intervention. Applying these methods,which function well when comparing a pharmaceuti-cal substance with placebo, to compare RALP to RRPpresents challenges. A surgical technique differs con-ceptually from a pharmaceutical substance. Surgeonscannot be unaware of the technique with which theyoperate, and keeping a patient unaware of the tech-nique may be cumbersome and even unethical. More-over, a surgeon’s yearly and accumulated experience,skills, individual technique and previous traininginfluence outcome [19–21]. The centre’s volumeand the qualifications of all healthcare personnelassisting the surgeon and caring for the patient mayinfluence the long-term outcome [21,22]. All thesemodifying factors may be specific for one or bothof the techniques. To move forward, data must becollected within realistic study designs instead ofletting the restriction of efforts to perform randomizedtrials result in no trials and, thus, no new knowledge.The design of the LAPPRO trial, its promising

accrual and high response rates will presumably resultin valuable and detailed information on radical pros-tatectomy. Such information has not, to the authors’knowledge, been addressed in any other multicentreprospective observational study to date. The trial willbe able to compare the two surgical techniques inaspects of short- and long-term functional and onco-logical outcome, cost effectiveness and quality oflife, thereby supplying new and much sought afterknowledge.

Acknowledgements

The authors are grateful to the members of the LAP-PRO steering committee and local investigators at theparticipating urology departments: Anders Bjartell,Malmö University Hospital; Ola Bratt, HelsingborgHospital; Hans Boman, Alingsås Hospital; ChristerEdlund, Kungsbacka Hospital; Sven Grundtman,Uddevalla Hospital; Ove Gustafsson, KarolinskaUniversity Hospital/Huddinge; Thomas Jiborn,Malmö University Hospital; Ingrid HöglundKarlsson, Sahlgrenska University Hospital; Ali

Khatami, Sahlgrenska University Hospital; MikaelLagerkvist, UroClinic Stockholm; Eric Pileblad,Capio Lundby Hospital; Mikael Sylme, VarbergHospital; and Ulrika Westlund, Södersjukhuset.The authors are also grateful to the personnel atthe LAPPRO trial secretariat and the regional tumourregistry and oncologic centre, Sahlgrenska UniversityHospital, for their essential input into the study pro-cedure. Torgny Anderson at Interezza developedand supported technically the management of thepatient-contact database. The trial is supported bygrants from the Swedish Cancer Foundation, theWest Gothia Region, Sahlgrenska University Hospi-tal, Sanofi-Aventis and Mary von Sydow Foundation.

Declaration of interest: The authors report noconflicts of interest. The authors alone are responsiblefor the content and writing of the paper.

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