Liver Regeneration: a Single-centre, Prospective, Randomised Controlled Trial Comparing Radiofrequency Assisted Liver Partition With Portal Vein Ligation (RALPP) With Portal Vein Embolization (PVE) for Preoperative Induction of Liver Hypertrophy in Patients With Insufficient Future Liver Remnant Volume for Major Liver Resection.
Phase: NA
Conditions: Liver Resection, Cancer
Sponsor: Imperial College London

Protocol – v2.5 – 01 Oct 2014 
 
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R E B I R T H 
 
IRAS SHORT TITLE:  
RALPP versus PVE for induction of liver hypertrophy 
 
SHORT TITLE: 
 
REGENERATION OF LIVER: PORTAL VEIN EMBOLIZATION VERSUS 
RADIOFREQUENCY ASSISTED LIGATION FOR LIVER HYPERTROPHY 
 
 
FULL TITLE: 
 
Liver Regeneration: a single-centre, prospective, randomised controlled 
trial comparing radiofrequency assisted liver partition with portal vein 
ligation (RALPP) with portal vein embolization (PVE) for preoperative 
induction of liver hypertrophy in patients with insufficient future liver 
remnant volume for major liver resection.  
 
 
 
Hammersmith Hospital Campus 
Dept of Surgery and Cancer 
Imperial College London 
 
 
NCT:  
 
 
NCT02216773 
 
Principal Investigator:    
Prof Long R Jiao 
 
Co-investigators:    
Mr Mikael Sodergren, Dr Myura Nagendran 
                               
Collaborators:   
 
Dr Paul Tait  
 
 
Version 2.5 – 01 October 2014 
 

Protocol – v2.5 – 01 Oct 2014 
 
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MAIN SPONSOR: 
 
 
Imperial College London 
FUNDERS:  
 
 
 
Unfunded 
STUDY COORDINATION CENTRE: 
Imperial College London 
NRES reference: 
 
 
14/LO/1123 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
 
 
 
 
 

Protocol – v2.5 – 01 Oct 2014 
 
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Study Management Group 
 
Chief Investigator:  
 
Mr Long R Jiao 
 
Co-investigators:  
 
Mr Mikael Sodergren   
 
Study Management:   
Mr Mikael Sodergren 
 
 
Study Coordination Centre  
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Study Coordinator:  
Mr Mikael Sodergren 
 
Address: 
 
HPB Surgical Unit 
Dept. of Surgery & Cancer, Imperial College 
Hammersmith Hospital Campus, Du Cane Road 
London 
W12 0HS 
 
 
 
 
 
Tel:  
 
 
02033133937  
 
E-mail:   
 
m.sodergren@imperial.ac.uk  
 
 
Clinical Queries 
 
Clinical queries should be directed to Mr Mikael Sodergren who will direct the query to the 
appropriate person. 
 
 
Sponsor 
 
Imperial College London is the main research Sponsor for this study.  For further information 
regarding the sponsorship conditions, please contact the Head of Regulatory Compliance at: 
 
 
 
Joint Research Compliance Office 
Imperial College London 
5th Floor Lab Block 
Charing Cross Hospital 
Fulham Palace Road 
London W6 8RF 
Tel: 0203 311 0204 
Fax: 0203 311 0203 
 
 
Funder 
 
This study is unfunded.  
 
 

Protocol – v2.5 – 01 Oct 2014 
 
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This protocol describes the study and provides information about procedures for entering participants.  
Every care was taken in its drafting, but corrections or amendments may be necessary. These will be 
circulated to investigators in the study.  Problems relating to this study should be referred, in the first 
instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the NHS Research Governance Framework for 
Health and Social Care (2nd edition). It will be conducted in compliance with the protocol, the Data 
Protection Act and other regulatory requirements as appropriate.  
 
 
Table of Contents 
 
1. 
INTRODUCTION 
07 
2.   
STUDY OBJECTIVES 
10 
3.   
STUDY DESIGN 
11 
4. 
PARTICIPANT ENTRY 
14 
5. 
ADVERSE EVENTS 
14 
6. 
ASSESSMENT AND FOLLOW-UP 
16 
7. 
STATISTICS AND DATA ANALYSIS 
16 
8. 
REGULATORY ISSUES 
17 
9. 
STUDY MANAGEMENT 
18 
10. 
PUBLICATION POLICY 
18 
11. 
REFERENCES 
19 
 
 
 
 

Protocol – v2.5 – 01 Oct 2014 
 
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GLOSSARY OF ABBREVIATIONS 
 
 
ALPPS 
Associating liver partition and portal vein ligation with in 
situ liver splitting 
CT 
Computed tomography scan 
FLRV 
Functional liver remnant volume 
PVE 
Portal vein embolization 
PI 
Principal investigator 
RALPP 
Radiofrequency assisted liver partition with portal vein 
ligation 
TLV 
Total liver volume 
WHO 
World Health Organisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
KEYWORDS 
 
Liver hypertrophy; liver resection; portal vein ligation; portal vein embolization; 
radiofrequency splitting 
 

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STUDY SUMMARY 
 
 
 
 TITLE 
Liver Regeneration: a single-centre, prospective, randomised 
controlled trial comparing radiofrequency assisted liver 
partition with portal vein ligation (RALPP) with portal vein 
embolization (PVE) for preoperative induction of liver 
hypertrophy in patients with insufficient future liver remnant 
volume for major liver resection. 
 
DESIGN 
Single centre randomised controlled trial 
 
AIMS 
To ascertain whether radiofrequency in situ splitting with 
portal vein ligation is superior to the traditional portal vein 
embolization for liver hypertrophy. 
 
OUTCOME 
MEASURES 
 
Future liver remnant volume (primary) 
Postoperative liver function tests (secondary) 
Postoperative complication rate (secondary) 
 
POPULATION 
Hospital patients satisfying inclusion criteria 
 
ELIGIBILITY 
Adult patients requiring right or extended right hepatectomy 
and with insufficient future liver remnant volume on pre-
operative scan 
 
DURATION 
18 months from randomisation; 2.5 years for total study 
 
 
 

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1. 
INTRODUCTION  
 
1.1 
BACKGROUND 
 
Liver resection remains the gold standard treatment for patients with liver tumours providing 
them the only chance for long-term survival. In up to 45% of resectable cases, an extended 
hepatectomy is usually necessary to achieve a clear resection margin, a major determinant 
factor for long-term survival.1-2 However, liver failure is usually common with this type of 
major resection due to insufficient remnant liver volume to support postoperative liver 
function, which itself is still the principal cause of postoperative death following a major liver 
resection. This leaves less than 20% patients with liver tumours suitable for this curative 
operation.3 Furthermore, with increased use of neoadjuvant chemotherapy to downstage a 
tumour, liver function is inevitably affected by chemoagents which can induce cholestatic 
changes in liver making patients more prone to postoperative liver failure.   
 
The liver consists of two major lobes: right and left which are made up from 8 segments 
based on the of Caunauid classification liver: segments I-IV of the left lobe and V-VIII of the 
right lobe (Figure 1). A major liver resection is defined as a removal of more than 3 
segments of liver such as a right or left hepatectomy. An empirical estimate for a minimum 
volume of remnant liver required to maintain liver function following a major liver resection is 
around 25% in a healthy patient without any pre-existing liver disease. However, in patients 
with chronic liver disease or cholestasis following chemotherapy, it is impossible to estimate 
this. Volumetric analysis has been described as a tool to predict postoperative liver failure 
and death in patients with liver tumours.3 
 
In order to decrease the complications and improve the safety of extensive liver surgery in 
patients with insufficient future liver remnant volume (FLRV), preoperative portal vein 
embolization (PVE) has been used in patients with or without chronic liver disease prior to 
liver resection to stimulate liver regeneration on the opposite side of the PVE. A meta—
analysis of published human studies on PVE has recently demonstrated that preoperative 
PVE results in an increase in liver volume independent of techniques used for PVE by 12% 
on average.4 In 2012, Schnitzbauer et al. proposed an alternative method known as 
associating liver partition and portal vein ligation (ALPPS).5 They compared this technique to 
PVE in 25 patients requiring a right hepatectomy. During the first procedure, the right portal 
vein was identified, divided and oversewn. In situ splitting (ISS) was subsequently 
undertaken whereby total or nearly total parenchymal dissection was performed. The second 

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stage to complete the extended right hepatectomy was performed after a median interval of 
9 days. The mean hypertrophy rate of the FLRV was 74% with a median volume for the left 
lateral liver lobe of 310mls and 536mls prior to and after the ALPPS procedure respectively.  
Using uptake of 99mTcHIDA, De Santibanes et al. found that the diseased liver lobe, with a 
ligated portal vein, remained functional following ALPPS and represented up to 60% of total 
liver function.6 Thus, the risk of liver failure is far less likely in these patients in the first week 
after ALPPS. Furthermore, the rapid regeneration response also ensures that tumour 
progression is unlikely within 9 days of the second definitive operation prior to the onset of 
adhesions.  Although the reported volume increase of FLRV after ALPPS was far greater 
than that achieved with PVE (74% vs. 12%), there would seem to be a high postoperative 
morbidity rate associated with it ranging from 33% to 58%.7-9       
 
In our centre, a novel technique has been described to achieve a rapid increase in FLRV 
within a short period of time as seen in ALPPS without the increased morbidity rates 
attributed to ALPPS. This technique uses in-line radiofrequency to create a virtual liver 
partition with portal vein ligation - Radiofrequency Assisted Liver Partition with Portal Vein 
Ligation (RALPP).10 It has been shown that it is a feasible and safe alternative to ALPPS to 
achieve a rapid liver regeneration in the contralateral lobe of the liver without increased 
morbidity and mortality related to ALPPS.10   
 
 
1.2 
RATIONALE FOR CURRENT STUDY 
 
CLINICAL ISSUES: 
 
Hepatobiliary surgeons are seeing an increased number of referrals for liver resection of 
patients with primary and secondary liver cancer. A sizeable proportion of these referrals 
would traditionally have been deemed inoperable due to insufficient remnant liver volume 
following hepatectomy. While the technique of portal vein embolization (PVE) has enabled 
liver hypertrophy and subsequent hepatectomy for many previously inoperable patients, 
there is still significant scope for improvement. Specifically, both the final volume of liver 
hypertrophy induced and the time taken to develop such hypertrophy are important factors. 
The more recent technique of associating liver partition and portal vein ligation (ALPPS) 
developed by Schnitzbauer et al. has demonstrated faster and greater volume hypertrophy. 
Unfortunately this technique has a high morbidity rate. 
 

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There is therefore a clinically important need to assess whether the technique of 
radiofrequency assisted liver partition with portal vein ligation (RALPP) can demonstrate the 
superior efficacy of ALPPS as compared to PVE without the increased morbidity profile. This 
method uses the same principle as ALPPS but achieves the in situ liver splitting with 
radiofrequency energy thus reducing the risk of potential visceral damage and bleeding. 
 
 
RADIOFREQUENCY ASSISTED LIVER PARTITION WITH PORTAL VEIN LIGATION  
(RALPP): 
 
RALPP is performed laparoscopically when possible. A five port (2 x 10mm working ports  
on each side of abdomen) technique is used. Following resection of tumour from the left 
lobe for those requiring staged liver resection with bilobar disease, as previously described 
by our group,11 attention is paid to hilar dissection for identification and ligation of the right 
portal vein. The portal vein is carefully separated from the common hepatic duct behind the 
right hepatic artery. Whenever possible, the right hepatic artery is isolated and slung with a 
non-absorbable suture (2/0 Prolene) to aid identification and ligation of this at the second 
stage liver resection. The right portal vein is isolated using blunt dissection and ligated using 
two Hem-o-loks (Teleflex, NC, USA).   
 
Following ligation of the right portal vein, the demarcation between the left and right lobe of 
the liver is clearly visible. Then, radiofrequency ablation with either cool tip RFA (Covidien, 
Hampshire, UK) or laparoscopic Habib Sealer (LH4X, Rita, USA) is performed for completion 
of RALPP along the line of the demarcation to segment VIII of the liver above the right 
hepatic vein superiorly and to segment V above the hilus on the left side of the gallbladder. 
For the open approach, the procedure is performed in a similar manner. To aid the 
identification of the right hepatic artery and portal vein, cholecystectomy is often performed 
first and the cystic duct stump ligated and divided. This can then be retracted medially to 
expose the hilus for dissection of the right hepatic artery and portal vein. The portal vein is 
then ligated with a 2/0 Vicryl tie and clipped with 2 ligaclips (10mm, Ethicon, Berkshire, UK). 
All patients have a restaging CT scan with contrast to assess the liver volume 2 weeks after 
RALPP prior to right hepatectomy.  
 
Five patients requiring extended liver resection were operated on using the new 
radiofrequency ALPPS technique (RALPP). Their outcomes were compared to 5 historical 
patients who were matched for age, sex, initial liver function and pathology. RALPP 
demonstrated superior efficacy to PVE. There was no difference in liver function between the 

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two groups on day 15 post hepatectomy. No patients developed a postoperative bile leak (a 
common source of morbidity post ALPPS) in either group and there was no mortality at 90 
days.10  
 
 
PORTAL VEIN EMBOLISATIOM (PVE): 
 
PVE was first demonstrated in the 1920s in a rabbit model.  Rous and Larimore showed  
compensatory hypertrophy in the contralateral hepatic lobe following portal vein occlusion.12  
The first preoperative PVE in patients was undertaken in 1986 following which there have 
been numerous reports.13  Large case series of PVE have demonstrated an increase in the 
FLRV from 8.0%-49.9%.14, 15 
 
A meta-analysis from our group, including 1,088 patients who underwent PVE prior to 
hepatic resection, showed a mean hypertrophy rate of the FLRV after PVE of only 11.9% 
after an average of 29 days.4 Transient liver failure following resection was seen in 2.5% and 
0.8% of patients developed acute renal failure and died. Major morbidity from PVE was seen 
in 2.2% with no mortality.  After liver resection the morbidity rate was 16.0% with a 1.7% 
mortality rate.   
 
 
ETHICAL ISSUES: 
 
Although RALPP has been demonstrated as superior to PVE, the full comparative efficacy 
profile in the medium and long term between RALPP and PVE remains unknown. A 
randomised controlled trial is required to assess this aspect in a more controlled and 
unbiased manner. Clinical equipoise between RALPP and PVE remains. 
 
 
2.  STUDY OBJECTIVES 
 
Primary endpoint: 
- 
Future liver remnant volume (FLRV) 
 
Secondary endpoints:  
- 
Postoperative liver function tests 

Protocol – v2.5 – 01 Oct 2014 
 
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- 
Postoperative complication rate 
 
 
3.  STUDY DESIGN 
 
This study is a two arm, prospective, single centre randomised control trial of RALPP 
compared with PVE in patients with inadequate FLRV (<25%) prior to elective right or 
extended right hepatectomy. 
 
There will be two groups in this study with 13 subjects in each group, for a total of 26 
subjects.  Each patient will give informed consent. Below are descriptions of operative 
technique, recruitment, and outcome measures.  
 
MEASUREMENT OF LIVER VOLUME 
 
Total liver volume (TLV), FLRV and tumour volume are measured by a single trial 
coordinator (MS).  These volumes are assessed from the CTs carried out before and after 
RALPP, PVE and liver resection.  Liver volumes are calculated using ImageJ (Image 
Processing and Analysis in Java, National Institute of Health) as previously described.16 The 
FLRV is measured as the left lobe of the liver, to the left of Cantlie’s line.  
 
RECRUITMENT 
 
Patients will be approached in the hepatobiliary clinic at Hammersmith Hospital. An 
experienced member of the clinical team will discuss the details of the trial and explain the 
possible risks and benefits of participation. The patient will then be given up to two weeks to 
decide if they wish to participate. During this time, they will have the phone number for a 
senior member of the clinical team should they wish to discuss any points in further detail. 
 
 
RANDOMISATION 
 
Those patients fulfilling the inclusion criteria and providing informed consent will be 
randomised. The randomisation sequence will be generated independently by 
http://www.sealedenvelope.com. This service handles both sequence generation and 
allocation concealment and will employ minimisation techniques to ensure that both 

Protocol – v2.5 – 01 Oct 2014 
 
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treatment groups are well balanced on baseline characteristics. These methods of sequence 
generation and allocation concealment ensure that the two groups are truly random and thus 
minimises selection bias and confounding. In other words, it increases the reliability of the 
final results. 
 
 
PRE-INTERVENTION INVESTIGATIONS 
 
Both groups will then receive pre-intervention blood tests and a contrast enhanced CT scan 
of the abdomen (this is routine clinical practice). 
 
GROUP 1 - PVE GROUP  
 
Patients allocated to the PVE group will have their portal vein embolized radiologically once 
their pre-intervention investigations have been completed and reviewed by the clinical team. 
The patient will be admitted to the ward before and after the procedure for routine monitoring 
post-procedure. Discharge will be at the discretion of a senior member of the clinical team 
once the patient is mobilising, passing urine and pain free with no evidence of procedural 
complication.   
 
They will then receive a further post-intervention set of investigations (again consisting of 
blood tests and CT scan as described above) 4 weeks after the completion of the PVE. At 
this point, they will be listed to receive their definitive surgical hepatectomy. 
 
 
GROUP 2 - RALPP GROUP 
 
Patients allocated to the RALPP group will have their right portal vein surgically ligated 
followed by radiofrequency ablation in situ splitting of the liver. Certain patients may 
additionally have a tumourectomy or wedge resection of the left liver lobe if clinically 
indicated. For analysis purposes, all patients within the RALPP group will be considered 
together and no formal a priori subgroup analysis is planned. 
 
The RALPP procedure will occur once the patient's pre-intervention investigations have 
been completed and reviewed by the clinical team. The patient will be admitted to the ward 
before and after the procedure for routine monitoring post-procedure. Discharge will be at 

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the discretion of a senior member of the clinical team once the patient is mobilising, passing 
urine and pain free with no evidence of procedural complication. 
 
They will then receive a further post-intervention set of investigations (again consisting of 
blood tests and CT scan as described above) 2 weeks after the completion of the RALPP. At 
this point, they will be listed to receive their definitive surgical hepatectomy. 
 
 
DEFINITIVE SURGERY 
 
At the time points described above, patients from both groups will be admitted to the ward 
for right or extended right hepatectomy as per their clinical indication. From the time of 
surgery onwards, both groups will be treated identically. In other words, the intervention 
period of the study lasts from admission for PVE or RALPP procedure to admission for 
definitive surgery. All interactions before and after this intervention period will be identical 
between groups. 
 
Discharge will be at the discretion of a senior member of the clinical team once the patient is 
mobilising, passing urine and pain free with no evidence of procedural complication. 
 
 
FOLLOW-UP CARE 
 
See section 6 of this protocol. 
 
 
3.1 
STUDY OUTCOME MEASURES 
 
Primary endpoint: 
- 
Future liver remnant volume – as measured by volumetric analysis of CT scan 
 
Secondary endpoints:  
- 
Postoperative liver function tests – as measured by blood tests 
- 
Postoperative complication rate – as defined by Dindo Clavien classification of 
surgical complications 
 
 

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4. 
PARTICIPANT ENTRY  
 
4.1 
PRE-REGISTRATION EVALUATIONS  
After informed consent, participants will have routine blood tests taken (full blood count, 
renal profile, bone profile, liver function tests, C-reactive protein, clotting) and a CT scan with 
contrast of the abdomen and pelvis.  
 
4.2 
INCLUSION CRITERIA 
- 
Age ≥ 18 years. 
- 
Any patient requiring right or extended right hepatectomy with FLRV less than 25% 
on preoperative volumetric study. 
- 
WHO performance status 0, 1 or 2. 
- 
Patient able to comply with protocol requirements and deemed fit for surgical 
resection. 
- 
Written informed consent. 
 
4.3 
EXCLUSION CRITERIA 
- 
Inability to give informed consent 
- 
Pregnancy. 
- 
WHO status 3 or 4. 
- 
New York Heart Association Classification Grade III or IV. 
 
4.4 
WITHDRAWAL CRITERIA 
An interim analysis will be conducted after 16 patients have been recruited. The trial may be 
stopped at this point for futility or for overwhelming effect. All participants are free to 
withdraw at any time. Safety monitoring will be conducted by the clinical team with 
withdrawal of the patient from the trial under clinical grounds resting with the PI. 
 
 
5. 
ADVERSE  EVENTS 
 
5.1 
DEFINITIONS   
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that: 
• 
Results in death 

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• 
Is life-threatening – refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe 
 
• 
Requires 
hospitalisation, 
or 
prolongation 
of 
existing 
inpatients’ 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations.  Important AEs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent one 
of the other outcomes listed in the definition above, should also be considered serious. 
 
5.2 
REPORTING PROCEDURES 
All adverse events should be reported.  Depending on the nature of the event the reporting 
procedures below should be followed.  Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.   
 
5.3.1  
NON SERIOUS AEs 
All such events, whether expected or not, should be recorded.   
 
5.3.2  
SERIOUS AEs 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  
However, relapse and death due to underlying cancer, and hospitalisations for elective 
treatment of a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the Bloomsbury (London) REC where in the opinion of the 
Chief Investigator, the event was: 
• 
‘related’, i.e. resulted from the administration of any of the research procedures; 
and 
• 
‘unexpected’, i.e. an event that is not listed in the protocol as an expected 
occurrence 
 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event, using the NRES SAE form for non-IMP studies.  
The Chief Investigator must also notify the Sponsor of all SAEs. 

Protocol – v2.5 – 01 Oct 2014 
 
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Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
 
Contact details for reporting SAEs 
Fax: +44 (0) 20 8383 3179, attention of Mr Mikael Sodergren 
Please send SAE forms to: Mr Mikael Sodergren 
Tel: +44 (0) 20 83833937  
  (Mon to Fri 09.00 – 17.00) 
 
 
6. 
ASSESSMENT AND FOLLOW-UP  
 
Patients from both groups will be reviewed in the HPB Clinic between 2 and 4 weeks post 
discharge. At all times after discharge, patients will have the contact details of a senior 
member of the clinical team should any problems or questions arise. A regular out-patient 
clinic appointment as per current standard of care will take place (so no change from normal 
clinical practice). Patients will remain under follow-up with the HPB clinic for a minimum of 
18 months from the time of definitive surgery. This will involve only outpatient clinic 
appointments as clinically indicated. 
 
The trial is deemed to have ended upon completion of 18 month follow-up of final recruited 
participant. 
 
 
 
7. 
STATISTICS AND DATA ANALYSIS 
 
Sample size was calculated based on the pilot data from our institution published in Annals 
of Surgery.10 This is based on the mean rates of increase in FLRV on the assumption that a 
RCT should be able to detect a clinically meaningful increase in FLRV. The null hypothesis 
was that there was no difference between the intervention and standard treatment in the 
primary endpoint. The sample size calculation assumed two-sided testing. 
 

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The sample size of each arm was calculated using the equation designed for two 
proportions; α was set at 0.05 to control for type I error (false-positive result) and β at 0.10 to 
control for type II error (false-negative result). Based on these data a power calculation 
estimated a total sample size of 16 patients, however due to the relatively small sample size 
of the pilot data it was decided to aim to recruit 26 patients to the trial. 
 
Following recruitment of 16 patients, an interim analysis comparing primary end-point 
outcomes in the two groups will be conducted. The trial will be halted at this point of a 
significant difference of p<0.05 is determined. 
 
Data and all appropriate documentation will be stored for a minimum of 10 years after the 
completion of the study, including the follow-up period.   
 
 
8. 
REGULATORY ISSUES 
 
8.1 
ETHICS APPROVAL 
 
The Chief Investigator has obtained approval from the Imperial College Research Ethics 
Committee.  The study must be submitted for Site Specific Assessment (SSA) at each 
participating NHS Trust.  The Chief Investigator will require a copy of the Trust R&D 
approval letter before accepting participants into the study.  The study will be conducted in 
accordance with the recommendations for physicians involved in research on human 
subjects adopted by the 18th World Medical Assembly, Helsinki 1964 and later revisions. 
 
8.2 
CONSENT  
 
Consent to enter the study must be sought from each participant only after a full explanation 
has been given, an information leaflet offered and time allowed for consideration.  Signed 
participant consent should be obtained.  The right of the participant to refuse to participate 
without giving reasons must be respected.  After the participant has entered the study the 
clinician remains free to give alternative treatment to that specified in the protocol at any 
stage if he/she feels it is in the participant’s best interest, but the reasons for doing so should 
be recorded.  In these cases the participants remain within the study for the purposes of 
follow-up and data analysis.  All participants are free to withdraw at any time from the 
protocol treatment without giving reasons and without prejudicing further treatment. 
 

Protocol – v2.5 – 01 Oct 2014 
 
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8.3 
CONFIDENTIALITY 
 
The Chief Investigator will preserve the confidentiality of participants taking part in the study 
and is registered under the Data Protection Act. 
 
8.4 
INDEMNITY 
 
Imperial College London holds negligent harm and non-negligent harm insurance policies 
which apply to this study. 
 
8.5 
SPONSOR 
 
Imperial College London will act as the main Sponsor for this study.  Delegated 
responsibilities will be assigned to the NHS trusts taking part in this study.   
 
8.6 
FUNDING 
 
This study is unfunded. No payments will be made to participants, investigators or any other 
personnel associated with the study. 
 
8.7 
AUDITS  
The study may be subject to inspection and audit by Imperial College London under their 
remit as sponsor and other regulatory bodies to ensure adherence to GCP and the NHS 
Research Governance Framework for Health and Social Care (2nd edition).  
 
 
9. 
STUDY MANAGEMENT 
 
The day-to-day management of the study will be co-ordinated through Imperial College 
London by Mr Mikael Sodergren.   
 
 
10. PUBLICATION POLICY 
 

Protocol – v2.5 – 01 Oct 2014 
 
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We intend to report and disseminate our findings via conference presentations and peer-
reviewed scientific journal articles. All data used in analysis and public reporting will be non-
identifiable. 
 
Patients will be asked if they wish to receive in writing the anonymised results of the 
research following publication in peer-review journals. If this is the case this will be sent to 
them by post at the appropriate time. 
 

Protocol – v2.5 – 01 Oct 2014 
 
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11. REFERENCES 
 
1. 
Adam R, Avisar E Ariche A et al. Five-year survival following hepatic resection after 
neoadjuvant therapy for nonresectable colorectal (liver) metastases. Ann Surg Oncol. 2001; 
8: 347-53.  
2. 
Yamamoto J, Kosuge T, Takayama T, Shimada K, Yamasaki S, Ozaki H, Yamaguchi 
N, and Makuuchi M. Recurrence of hepatocellular carcinoma after surgery. Br J Surg. 1996; 
83: 1219-1223. 
3. 
Scheele J, Stangl R, and Altendorf-Hofmann A. Hepatic metastases from colo-rectal 
carcinoma: Impact of surgical resection on the natural history. Br J Surg. 1990; 77: 1241-
1246. 
4. 
Abulkhir A, Limongelli P, Healey AJ, Damrah O, Tait P, Jackson J, Habib NA,  Jiao 
LR. Reoperative portal vein embolisation for major liver resection – a meta-analysis. Ann 
Surg. 2008; 247: 49-57. 
5. 
Schnitzbauer AA, Lang SA, Goessmann H et al.: Right portal vein ligation combined 
with in situ splitting induces rapid left lateral liver lobe hypertrophy enabling 2-staged 
extended right hepatic resection in small-for-size settings. Ann Surg. 2012; 255: 405-414. 
6. 
De Santibanes E, Alvarez FA, Ardiles V: How to avoid postoperative liver failure: a 
novel method. World J Surg. 2012; 361: 125-128.. 
7. 
De Santibanes E, Clavien PA: Playing Play-Doh to prevent postoperative liver failure: 
the "ALPPS" approach. Ann Surg. 2012; 255: 415-417..  
8. 
Alvarez FA, Ardiles V, Sanchez Claria R, Pekolj J, De Santibanes E: Associating 
Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS): Tips and Tricks. J 
Gastrointest Surg. 2013; 17: 814-821. 
9. 
Li J, Girotti P, Konigsrainer I, Ladurner R, Konigsrainer A, Nadalin S: ALPPS in Right 
Trisectionectomy: a Safe Procedure to Avoid Postoperative Liver Failure? J Gastrointest 
Surg. 2013; 17: 956-961. 
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Figure 1. Caunauid classification liver