Laparoscopic Versus Open Ablation of Liver Malignancies: a Randomized, Controlled Multicenter Trial
Phase: NA
Conditions: Hepatocellular Carcinoma, Cholangiocarcinoma, Liver Metastases
Sponsor: Rigshospitalet, Denmark

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1. Title 
 
Laparoscopic versus open ablation of liver malignancies: 
a randomized, controlled multicenter trial 
2. Aims 
 
We will conduct a randomized study to compare laparoscopic ablation for liver tumors with the 
standard care (open ablation) with the hypothesis to reduce complications and maintain similar 
treatment success rate. We will 
 
• Investigate differences in complications (primary outcome), length of hospital stay 
and mortality between laparoscopic and open ablation.  
• Investigate differences in success rate (complete ablation response) between 
laparoscopic and open ablation. 
• Investigate differences in quality of life between laparoscopic ablation and open 
ablation and explore how patients with liver tumors experience ablation of a liver 
tumor. 
 
Background 
Surgically treated malignancies in the liver include primary liver cancers and liver metastases. 
Hepatocellular carcinoma (HCC) accounts for almost 90% of primary liver cancers, which is the sixth 
most common cancer worldwide and the fourth leading cause of cancer-related death globally.1, 2 
Furthermore, hematogenous spread of other cancers to the liver is very common due to the dual 
vascular supply, arising from both systemic arterial and portal venous systems.3 The most common 
primary site is colorectal cancer, however, depending on age and sex a wide range of primary cancers 
spread to the liver including breast, pancreatic, and neuroendocrine cancers.4-9 Patients with liver 
metastases have significantly reduced survival compared to those without liver metastases.4, 5, 10  
 

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Many patients suffering from liver malignancies are not candidates for surgical interventions such as 
transplantation or hepatic resection due to extensive tumor burden, underlying liver disease, age, or 
other comorbidities. For some of these patients, ablation has proven to be a valuable alternative that 
is less invasive with fewer complication and with a shorter postprocedural hospital stay compared to 
resection.11 In addition, it preserves more of the liver parenchyma than resection which is especially 
important in patients with impaired liver function.  
 
Ablation therapy is often guided by real-time ultrasound and can be performed either percutaneously, 
by laparoscopy or by laparotomy (open). Percutaneous ablation is the least invasive approach and is 
gold standard for the treatment of HCC and liver metastases when possible.12, 13 However, some 
tumors may not be accessible percutaneously due to risk of injury to adjacent organs or due to 
insufficient visualization of the tumor. Ablation during open surgery allows treatment of tumors in 
locations difficult to reach percutaneously. At present, patients who cannot be treated percutaneously 
are offered open ablation in most centers. However, open surgery may be associated with a higher 
risk of complications which may be devastating for frail patients and patients with impaired liver 
function.14 More than 80% of patients diagnosed with HCC have preexisting cirrhosis15, 16, and these 
patients are at a higher risk of complications and have a higher postprocedural mortality due to the 
impaired liver function and portal hypertension.13, 17-19 Therefore, a minimally invasive approach is 
considered especially relevant in these high-risk patients.  Laparoscopic ablation is less invasive with 
a presumed lower complication rate than the open approach, however, offers some of the same 
advantages needed for tumors in locations not favorable for percutaneous ablation.  
 
Success of the procedure is demonstrated by a complete ablation of the macroscopic tumor assessed 
by contrast-enhanced ultrasound or CT one month after procedure.20 Previous studies reported a 
complete ablation achieved in 94-100% of patients treated with ablation with no significant difference 
between percutaneous, laparoscopic, or open approach.8, 21-27 However, no comparative study has 
been performed.  
 
A study from our department found complications in 45% of open ablations based on the Clavien 
Dindo Classification which was comparable to that of patients undergoing liver resection.28 An 
external study found comparable results of 39.5%.29 In contrast, the complication rate after 

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percutaneous ablation is as low as 5%30 and the literature suggests that laparoscopic approach have 
similar low complication rates.31, 32  
 
Previous studies 
No previous randomized studies or even comparative studies have been carried out investigating 
this subject. The literature consists of few smaller reports of case series 31, 32. These reports support 
that laparoscopic ablation is both safe and efficient.  
 
3. Method 
The study is a randomized, controlled, multicenter study in patients with liver malignancies treated 
at the four Danish liver surgery centers (Rigshospitalet, Odense, Århus and Aalborg). Patients with 
one or more liver tumor suitable for ablation as primary treatment, but not amenable for 
percutaneous ablation will be randomized between laparoscopic and open ablation. Opaque 
envelopes with patient numbers containing the randomization sequence will be opened after 
informed consent has been obtained. We plan to include 80 patients with 40 patients per arm. 
Patients will be randomized 1:1 (see below). Randomization will be stratified on center level to 
ensure comparable populations between the groups within each center.  
 
Due to perioperative findings, the treatment to which the patient is randomized to may be 
considered not feasible or inappropriate, e.g. due to insufficient visualisation of tumor or findings 
that warrant a different treatment strategy. In these cases, the treatment strategy is based on the 
surgeons preferences. In laparoscopic cases, a minimally invasive approach should be maintained if 
possible, e.g. by combining laparoscopy with percutanous ablation needle placement.  
 
Ninety days after the procedure, the patient chart will be evaluated to register patient characteristics 
and outcomes. Moreover, at one month all patients will receive a CT-scan to evaluate success rate 
(complete ablation response). The CT-scan is part of  standard of care, it is assessed by an 
experienced radiologist, and it is not part of this study. Before surgery and one month after, health 
related quality of life (HRQoL), the psychological burden and level of recovery will be assessed. 
Open ablation is standard of care. Thus, the intervention group will receive a treatment with 
assumed fewer compliations and similar success rate.  

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Treatment and follow-up 
Patients will be randomized 1:1 between ablation during open surgery and laparoscopic ablation 
 
Ablation procedure 
The procedure will be performed in general anesthesia and with the patient in supine position on the 
operating table. The laparotomy or laparoscopy will be performed by a surgeon specialized in liver 
surgery. A perioperative ultrasound is performed to visualize and to guide the electrode into the 
tumor. Using a heat-based ablation modality which generates high temperatures, the tumor cells are 
destroyed leaving an ablation zone. Included center may used either radiofrequenly ablation and 
micwowave ablation as modality. However, the modality should be the same in both groups in each 
center.  
 
Endpoints and outcome measurement 
Primary outcome 
• Treatment-related complications that develop within 30 days following ablation will be 
reported according to the Clavien-Dindo Classification, which is considered the best validated 
classification to rate surgical complications.33 The primary outcome is defined as any 
complication (Grade 2 or above) in the Clavien-Dindo Classification.  
Secondary outcomes 
• Success rate of the procedure is described as rate of complete ablations one month after 
procedure. A complete ablation response is defined as complete absence of enhancing tissue 
at the tumor site after one month on CT-scan.20  
• Complications reported as Comprehensive Complication Index (CCI). CCI is a scoring system 
for overall morbidity and is reflected on a scale from 0 (no complication) to 100 (death). It is 
based on Clavien-Dindo classification and takes all complications after a procedure into 
account.34  
• Highest complication grade according to the Clavien-Dindo Classification 
• Wound infections within 30 days is defined as wound dehiscence requiring secondary suturing 
or treated conservatively. Fascial dehiscence will be recorded separately. 

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• Postoperative liver failure is defined by the “50-50 criteria” (prothrombin time <50% and 
serum bilirubin >50 μml/L on postoperative day five).35  
• Postoperative pain will be assessed by Visual Analogue Scale for acute and chronic pain, pre-
operatively and on each post-operative day until discharge, after seven days, 14 days and one 
month.36 
• Overall and disease-free survival. 
• Procedure related mortality within 90 days.  
• HRQoL before and one month after the procedure will be assessed using  the Danish version 
of The European Organization for Research and Treatment of Cancer Quality of Life (EORTC 
QLQ C30)37 and a disease specific form for patients with HCC (QLQ HCC18),38 cholangio 
carcinoma (QLQ BIL21)39 or colorectal liver metastases (QLQ LM21).40 Depression and 
anxiety will be assessed before and one month after procedure using PHQ-9 and GAD-7, 
respectively.41, 42 Recovery will be assessed with the Quality of recovery (QoR-15) before and 
seven days after the procedure.43  
• Length of hospital stay defined as time in days from operation to discharge.  
• Blood loss during surgery  
• Need for perioperative blood transfusion 
• Conversion rate in the laparoscopic group 
• Duration of procedure 
• Model for Endstage Liver Disease (MELD) and Child-Pugh score before operation and on 
postoperative day five.  
• Patients experiences of undergoing ablation will be explored by individual interviews one 
months after the procedure.  
 
Feasibility and timeline 
The project will be carried out at the four Danish liver surgery centers (Rigshospitalet, Odense, 
Århus and Aalborg). Office space and facilities will be provided. The project group includes 
experienced researchers and surgeons specialized in liver surgery.  
 
In 2019 and 2020, approximately 45-50 patients each year with liver malignancies were treated solely 
with ablation during open surgery in Rigshospitalet. The majority of these patients may be included 
in the present study. Approximately half of the procedure in Denmark are performed at Rigshospitalet 

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with the remaining distributed between the others centers in Odense, Århus and Aalborg. Thus, we 
expect that all patients for this study can be recruited in approximately 1.5 years (see sample-size 
calculation). The procedures will be performed by experienced liver surgeons to maintain the 
technical skills required.  
 
The project will form the basis of a PhD project and results will be published in international peer-
reviewed scientific journals. The PhD-student will handle inclusion at Rigshospitalet, follow-up, data 
collection, statistical analyses, and writing of three papers. A PhD-student will be hired through the 
job portal of Copenhagen University and sundhedsjobs.dk. Based on interviews, we will hire the best 
qualified candidate. The study group members in Odense, Århus and Aalborg will handle inclusion 
of patients and perform the procedures in their own center. The study has been funded from The 
Danish Cancer Society “Knæk Cancer”, which covers three year salary for a PhD-student and a 20% 
research position designated to the primary investigator.  
 
Study group 
Department of Surgery and Transplantation, Rigshospitalet:  
• Hans-Christian Pommergaard (primary investigator), Lucas Knøfler (PhD-student), Peter 
Nørgaard Larsen, Christoph Tschuor, Daisuke Fukumori, Christian Ross Pedersen, Nicolai 
Schultz, Jens Hillingsø, Allan Rasmussen, Paul Krohn, Stefan Burgdorf, Jan Storkholm, 
Carsten Palnæs, Martin Sillesen, Susanne Dam Poulsen, Kristine Dengsø and Jeanett 
Klubien (PhD-student)  
 
Department of Surgery, Århus Universtiy Hospital 
• Anders Riegels Knudsen  
 
Department of Surgery, Odense University Hospital 
• Claus Wilki Fristrup 
 
Department of Surgery, Aalborg University Hospital 
• Mogens Stender  
 
 

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4. Statistical considerations 
We will use descriptive statistics and the dataset will be described with frequencies and percentages 
for categorical variables and means or medians for continuous variables. Primary outcome and rates 
of secondary dichotomous outcomes will be compared between the groups using Fischer’s exact 
test. Mean VAS score will be compared using Mann-Whitney U-test. To determine risk factors 
affecting ablation response, logistic regressions will be used in both univariable and multivariable 
analyses. The EORTC Quality of Life questionnaire is designed to measure cancer patients' social, 
physical, and psychological functions. Quality of life will be reported using the summary score with 
the intention of comparing patients treated with either laparoscopic or open ablation. Mann-
Whitney  U-test will be used to assess differences in the summary scores. Analyses will be 
performed both on intention-to-treat and per protocol levels. The level of statistical significance will 
be set to p<0.05. All statistical analyses will be performed using R, version 4.0.3. 
 
Sample size 
Based on a previous study from our center28, the primary outcome (any complication Grade 2 or 
above, Clavien-Dindo Classification) occurred in 45% of patients undergoing open ablation. The 
similar complication rate from another external study was 39.5%.29 The hypothesis is that with a 
laparoscopic approach, the complication rate can be reduced to 10%. With an alpha of 5% and power 
of 80%, we will need 60 patients (30 in each arm).  
 
The rate of complete ablation in one month is approximately 95% for open ablations.44-46 Using a 
non-inferior approach and assuming a similar rate of complete ablation in the laparoscopic group, we 
will need 54 patients (non-inferiority limit 15%, alpha 5% and power 80%).  
 
By including 80 patients, both above sample-size calculations will be covered, and we will have 
sufficient material compensate for possible excluded patients. Before randomization, we will perform 
training of laparoscopic ablation using a training fantom developed for the purpose. Accuracy of 
laparoscopic needle placement with ultrasonography will be assessed using a gel with artificial 
tumors and an artificial abdominal wall. In addition, we will perform 20 cases with laparoscopic 
ablation to ensure that technique and learning curve is sufficient compatred with our standard of care 
(open ablation). At this point, sufficient safety and efficacy (comparable to the litterature) will be 

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ensured prior to randomization and additional cases and additional training may be performed is 
nescessary.  
 
After randomization of the first 15 laparoscopic cases, we will perform an interim analysis looking 
only at conversion rates in the laparoscopic group due to lack of feasibility. In case of a conversion 
rate above 20%, sample size will be increased according to the conversion rate, e.g. 20% more 
patients in each group with a conversion rate of 20%. This is done to ensure suffcient power in our 
comparison between the open and laparoscopic technique.  
 
5. Patients 
Inclusion criteria: one or more tumors not amenable to percutaneous ablation, age > 18 years, signed 
informed consent, diagnosis of primary liver cancer or liver metastases from any primary tumor, and 
tumor suitable for ablation as primary treatment  
Exclusion criteria: ablation performed in conjunction with resection, patients who cannot cooperate 
with the study, and patients who do not understand or speak Danish 
 
6. Risks, side effects or disadvantage for the patients 
All procedures will be done in general anestesia with specialized post-operative pain management. 
Patients are randomized between the standard care (open ablation) and laparoscopic ablation. 
Laparoscopic ablation is less invasive including small incision with assumed less pain and risk of 
postoperative ablation. All side effects should be less severe compared with standard of care. The 
main possible disadvantage for the patients would be if laparoscopic ablation had less treatment 
success rate compared with open due to limitation in tumor visualization with ultra-sound or 
placement of ablation needle in the tumour. In laparoscopic ablation, the needle is placed 
transabdominally compared with open ablation, where the needle is placed directly in the liver. If 
the success rate was lower, this would entail a risk of subsequent open procedure to ensure 
sufficeint ablation of the tumor. However, previous reports suggest a similar success rate for 
laparoscopic ablation compared with open 31, 32. Thus, we consider this risk to me minimal.  
 

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7. Biological material from research subjects 
We will not collect biological material from the patients for the study.  
 
8. Information from patient records 
Patient information will be retrieved from patient electronic charts. Patient characteristics include 
cancer diagnosis and stage, age, gender, primary liver disease, co-morbidities, MELD-score 
(patients with HCC), Child Pugh-score (patients with HCC), previous surgery, viral infections and 
medical comorbidities. Thirty days after the procedure, information regarding success rate of 
ablation, complications and lengths of stay will be collected from the electronic records. Ninety 
days after the procedure, procedure related mortality will be recorded. At the end of the study, 
complete follow-up regarding overall and disease-free survival will be recorded. The collected 
information will be used to assess primary and secondary outcomes and to assess whether patient 
characteristics are equally distributed between the two treatment groups.  
 
The primary investigator and sub-investigators have direct access to obtain information in the 
patient's medical record which is necessary to carry out the research project and for control 
purposes, including self-control, quality control and monitoring, which they are obliged to carry 
out.   
 
The information to be used in the project before consent is given from the subjects is passed on to 
the primary investigator. 
 
9. Processing of personal data in the project 
The General Data Protection Regulation (GDPR), the Danish Data Protection Act, and the Helsinki 
II declaration are observed and will be complied with unconditionally.  
 
Throughout the project all patient information will be labeled with non-personal identifiers (pseudo-
anonymized). Information to identify individual patients will only be available to the study 

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coordinator Hans-Christian Pommergaard and will only be used if it becomes necessary to collect 
new clinical information from the patient files.  
 
Collected data will be registered in a Case Report Form (CRF), this and the patient record will be 
made available to third parties in accordance with Danish legislation, e.g. in connection with 
inspection by authorized representatives from relevant authorities. Patients will be informed about 
the possibility of an audit by public authorities. 
 
No data or patient information are transferred outside this country.  
 
10. Economy 
This is a researcher-initiated study. The initiative to establish the study was taken by the primary 
investigator, Hans-Christian Pommergaard. The study has been funded from The Danish Cancer 
Society “Knæk Cancer 2022” with 2,231,250 DKK. The funding covers salary for a PhD-student in 
three years and a 20% research position in three years for Hans-Christian Pommergaard. Funding 
for additional ultra-sound equipment for laparoscopic ablation has been sought from The 
Independent Research Fund Denmark (DFF). However, this equipment is not mandatory to initiate 
the project. These are no additional expenses for the involved departments associated with the 
project. The partners in this project have no financial interests in the project. 
 
11. Remuneration to participants 
The patients do not receive remuneration in connection with this study. 
 
12. Recruitment of subjects and informed consent 
The participants are among the patients who are already referred for treatment of a liver tumor at 
the included centers. These patients are identified by a clinician, and informed about the possibility 
of being informed about the project. 
 

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After a joint decision between a specialist and the patient about ablation of a liver tumor not 
amenable for percutaneous ablation, typically at the first visit to the surgical outpatient clinic, and 
after it has been ensured that the inclusion and exclusion criteria are met, the patient will be 
oriented about the project and offered written and oral information. 
 
Interested patients are informed orally and given written participant information. The patient will be 
offered an in-depth interview during the day. During the interview, the patient will receive verbally 
sufficient information about the purpose and structure of the study, as well as potential risks and 
disadvantages. The patients will be informed that participation is voluntary and that they can 
withdraw from the study at any time, without this having an impact on their further progress in the 
department. They will also be informed that they may be withdrawn from the study at the discretion 
of the investigator responsible for the study. 
 
The patients will also be informed about the treatment they will be offered if they choose to say no 
to participating, and they will also be informed that all data will be treated confidentially. 
 
A copy of the information and signed declaration of consent will be given to the patient and a copy 
will be kept in the medical record. Current regulations from the Scientific Ethics Committee 
regarding informed consent will be followed.  
 
It is the responsibility of the primary investigator that all patients receive oral information, so that it 
is ensured that the patient is completely aware of all aspects of participation in the study. The 
patient can withdraw his consent to participate in the study at any time. If the patient decides to do 
this, it will not impair his or her relationship with investigators or other staff, and the patient will 
continue to receive the best treatment the department can offer. 
 
The conversation with the patient will be handled by the investigator, or a person with delegated 
responsibility for this, when the patient accepts ablation as treatment in the outpatient clinic, and 
will take place in a calm environment and with the possibility for the patient and any relatives can 
ask questions. By written summons, the patient is invited to have a relative with him/her on the day 
of the outpatient interview. 
 

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The patient can give informed consent immediately at the outpatient interview, where the decision 
on ablation as treatment and project information have taken place. Alternatively, the patient can be 
offered a new interview after a few days of reflection. Longer reflection time will not be appropriate 
for the patient's treatment, as this could delay the time to surgery. If the patient so wishes, he/she 
will be offered time to think before giving consent until the morning of the operation day. 
 
When it is ensured that the patient has understood the information given, had the desired time to 
think, and has received answers to any questions, informed consent is sought. 
 
 
13. Publication 
Positive, negative and non-conclusive results are published in international peer-reviewed journals. 
Authorship will be offered based on fulfilment of the ICMJE criteria.  
 
14. Ethical considerations 
Currently, ablation during open surgery is the standard of care for tumors not amenable for 
percutaneous ablation. Compared with laparoscopic technique, open surgery is associated with 
higher risk of complications and post-operative pain. However, currently there is insufficient 
evidence to use laparoscopic ablation of liver tumors as the standard of care. The current study has 
the potential to provide this evidence.  
 
Laparoscopic ablation is less invasive including small incisions with assumed less pain and risk of 
postoperative ablation. All side effects should be less severe compared with standard of care. The 
main possible disadvantage for the patients would be if laparoscopic ablation had less treatment 
success rate compared with open due to limitation in tumor visualization with ultra-sound or 
placement of ablation needle in the tumour. If the success rate was lower, this may entail a 
subsequent procedure to ensure sufficeint ablation of the tumor. However, previous reports suggest 
a similar success rate for laparoscopic ablation compared with open.31, 32 Thus, we consider this risk 
to me minimal. Even so, we consider that lower complication would outweight the risk of a 
subsequent treatment. Moreover, if success rate was initially lower in the laparoscopic group, this 

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would likely improve with more experience with the technique among the surgeons. Thus, included 
patients as well as future patients will likely receive terapeutical benefit with the study.  
 
The study will be conducted in accordance with the principles of the Helsinki Declaration. 
Approval will be obtained from the local Scientific Ethics Committees and the Data Protection 
Authority before the start of the study. The investigator responsible for the study will also inform 
the Scientific Ethics Committee of significant or major changes in the protocol, and the study will 
be conducted in accordance with current regulations for clinical studies on humans. All patients 
participating in the study must provide oral and written informed consent before being included in 
the study. The patients are informed that the consent includes obtaining relevant medical record 
information related to their current admission, as well as that this information will be submitted 
upon inspection by relevant authorities. 
 
Patients are evaluated regarding depressive symptoms using the PHQ-9 questionaire42. The score 
from PHQ-9 correlates with risk of major depressive disorder.47 Patient scoring 20-27 (severe), 15-
19 (moderately severe), 10-15 (moderate), 5-9 (mild) and 0-4 (minimal) will have major depressive 
disorder in 34.1%, 34.1%, 19.5%, 9.8% and 2.4% of cases, respectively. If a patient in the study 
scores 15 or above or if the patient is deemed at risk for suicide, a psychiatrist will be consulted 
immediately. Patients scoring between 5 and 15 will be advised to seek medical counseling 
regarding evaluation of depression.  
 
15. Patient compensation scheme (patient erstatningen) 
 
The study is covered by the patient compensation scheme. For any injury caused directly or 
indirectly by the intervention in this clinical study, the hospital in question assumes the legal 
responsibility on behalf of the investigator responsible for the study and his staff. This is provided 
that the investigator responsible for the study and his employees have followed the instructions 
given in this protocol and any supplements thereto, and that these persons have carried out the study 
scientifically and in accordance with current rules and accepted techniques. In the event of injury or 
death unrelated to the completion of the study, the patient is insured by each individual hospital's 
insurance. 

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