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Liver Lesions Requiring HemihepatectomyNCT01441856

The ORANGE II PLUS - Trial: Open Versus Laparoscopic Hemihepatectomy

A study testing Open or Laparoscopic left hemihepatectomy and Open or Laparoscopic right hemihepatectomy in people with Liver Lesions Requiring Hemihepatectomy, run by Maastricht University Medical Center at 16 sites in 6 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The added value of the laparoscopic hemihepatectomy compared to the open hemihepatectomy has never been studied in a randomized controlled setting. Therefore, the multicenter international ORANGE II PLUS - trial has been constructed and will provide evidence on the merits of laparoscopic versus open hemihepatectomy in… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Liver Lesions Requiring Hemihepatectomy
What is being tested?
Open or Laparoscopic left hemihepatectomy and Open or Laparoscopic right hemihepatectomy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
350 participants
Where
16 sitesin 6 countries
Study dates
1 Oct 2013to 4 Dec 2023
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients requiring open or laparoscopic left / right hemihepatectomy, with or without the need for one additional hepatic wedge resection or metastasectomy, for accepted indications.
  • Able to understand the nature of the study and what will be required of them.
  • Men and non-pregnant, non-lactating women age 18 years and older.
  • BMI between 18-35.
  • Patients with ASA I-II-III.

Who cannot join

  • Inability to give written informed consent.
  • Patients undergoing liver resection other than left or right hemihepatectomy, with or without the need for one additional hepatic wedge resection or metastasectomy.
  • Patients with hepatic lesion(s), that are located with insufficient margin from vascular or biliary structures to be operated laparoscopically.
  • Patients with ASA IV-V.
  • Repeat hepatectomy.

Trial locations and contacts

16 sites in 6 countries.

16 sites in 6 countries

United Kingdom7 sites
  • Aintree University Hospital

    Aintree

  • Queen Elizabeth Hospital

    Birmingham

  • King's College Hospital

    London

  • Freeman Hospital

    Newcastle

  • Oxford University Hospitals

    Oxford

  • Derriford Hospital

    Plymouth

  • University Hospital Southampton

    Southampton

Other trials in United Kingdom

Belgium4 sites
  • Erasmus Hospital

    Brussels

  • Ghent University Hospital

    Ghent

  • Jessa Hospital

    Hasselt

  • General Hospital Groeninge

    Kortrijk

Other trials in Belgium

Netherlands2 sites
  • Academic Medical Center

    Amsterdam

  • Maastricht University Medical Center+

    Maastricht

Other trials in Netherlands

Germany1 site
  • University Hospital Aachen

    Aachen

Other trials in Germany

Italy1 site
  • San Raffaele Hospital

    Milan

Other trials in Italy

Norway1 site
  • University Hospital Oslo

    Oslo

Other trials in Norway

About this study

Official title: The ORANGE II PLUS - Trial: an International Multicenter Randomized Controlled Trial of Open Versus Laparoscopic Hemihepatectomies.

The added value of the laparoscopic hemihepatectomy compared to the open hemihepatectomy has never been studied in a randomized controlled setting. Therefore, the multicenter international ORANGE II PLUS - trial has been constructed and will provide evidence on the merits of laparoscopic versus open hemihepatectomy in terms of time to functional recovery, hospital length of stay, intraoperative blood loss, operation time, resection margin, time to adjuvant chemotherapy initiation, readmission percentage, (liver-specific) morbidity, quality of life, body image, reasons for delay of discharge after functional recovery, long term incidence of incisional hernias, hospital and societal costs during one year and overall five-year survival.

Read the detailed description

Liver resection for colorectal metastasis is the only potentially curative therapy and has become the standard of care in appropriately staged patients, offering 5-year survival rates of approximately 35-40%. Also for symptomatic benign lesions and those of uncertain nature or large size, liver resection is a widely accepted treatment. Open hepatectomy (OH) is the current standard of care for the management of primary and secondary malignancies. Although the feasibility of laparoscopic hepatectomy (LH) has been established, only select centres have used this technique as their primary modality.

Laparoscopic liver resection was first reported in 1991. Over the last decade the method has gained wide acceptance for various liver resection procedures. Multiple retrospective case series and reviews comparing open with laparoscopic liver resection indicate that laparoscopic liver resection can be applied safely for both malignant and benign liver lesions. Laparoscopic liver resection has been associated with shorter hospital length of stay, reduced intraoperative blood loss, less postoperative pain, earlier recovery and better quality of life. Initially the left lateral segments of the liver were chosen for anatomic laparoscopic resection with good results. Many liver centres worldwide are currently adopting laparoscopic surgery for resection of anterior segments, but relatively low volumes to operate on, a significant learning curve and lack of evidence restrict the majority of liver surgeons to further adopt and disseminate this technique.

Recently, indications for resectability have been broadened by new (neo)adjuvant chemotherapies and (radio)embolisation techniques. A new impulse for the laparoscopic management of liver lesions came after the first reports of laparoscopic hemihepatectomies. Major hepatic resections can be technically demanding and hold an increased risk for morbidity. It was demonstrated that in expert hands major anatomical laparoscopic liver resections were feasible with good efficacy and safety. Expert liver centers are already performing laparoscopic (extended) hemihepatectomies. Currently, in European centers, a median hospital length of stay of 6.0 to 13.1 and 3.5 to 10.0 days is observed after respectively open and laparoscopic hepatic resection. In expert hands median duration of admission after major hepatic resection varies between 6 - 12.5 for open and 4 - 8.2 for laparoscopic surgery. However, reports are scarce and level 1 evidence on this matter is still to be presented.

Within the framework of optimising postoperative recovery, broader indications for resection and further adoption of laparoscopic liver surgery there is a need for a randomized trial.Regarding postoperative care, enthusiasm has arisen for the Enhanced Recovery After Surgery (ERAS®) program. This multimodal program, derived from Kehlet's 1990's pioneer work in the multimodal surgical care field, involves optimization of several aspects of the perioperative management of patients undergoing major abdominal surgery. In patients undergoing segmental colectomy, the ERAS® -program enabled earlier recovery and consequently shorter hospital length of stay. Furthermore, a reduction of postoperative morbidity in patients undergoing intestinal resection was reported. These results stimulated liver surgeons of the ERAS® group (Maastricht, Edinburgh and Tromsö) to adapt the ERAS®-program to patients undergoing open liver resection. Van Dam et al. found a significantly reduced hospital length of stay after open liver resection when patients were managed within a multimodal ERAS®-program. Besides a reduction of median total hospital length of stay from 8 to 6 days (25%), the data also suggested that a further reduction of stay could be possible as there was a delay between recovery and actual discharge of the patients. Moreover, Stoot et al. showed - retrospectively - a further reduction in length of stay from 7 days to 5 days when patients were operated laparoscopically and managed within an ERAS®-program. In this study there was also a delay between recovery and actual discharge of the patients. Earlier, Maessen et al. reported a median delay to discharge of 2 days after patients had functionally recovered from colonic surgery managed within an ERAS®-program. This delay is often linked to social problems, problems in homecare support or logistic problems.

The added value of the laparoscopic hemihepatectomy compared to the open hemihepatectomy has never been studied in a randomized controlled setting. Therefore, the multicenter international ORANGE II PLUS - trial has been constructed and will provide evidence on the merits of laparoscopic versus open hemihepatectomy.

Being tested
Open or Laparoscopic left hemihepatectomy, Open or Laparoscopic right hemihepatectomy
Keywords
Open, Laparoscopic, Hemihepatectomy, Hepatectomy, Enhanced Recovery After Surgery, Functional recovery

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Open or Laparoscopic left hemihepatectomyProcedure or surgery

    Patients in this arm will undergo a left hemihepatectomy within an Enhanced Recovery After Surgery Program.

  • Open or Laparoscopic right hemihepatectomyProcedure or surgery

    Patients in this arm will undergo a right hemihepatectomy within an Enhanced Recovery After Surgery Program.

Study groups in NCT01441856
Study groupRoleWhat they receive
Open or Laparocopic LeftActive comparatorOpen or Laparoscopic left hemihepatectomy
Receives: Procedure: Open or Laparoscopic left hemihepatectomy
Open or Laparoscopic RightActive comparatorOpen or Laparoscopic right hemihepatectomy
Receives: Procedure: Open or Laparoscopic right hemihepatectomy
Prospective registryActive comparatorProspective registry of patients that cannot be randomized (both open and laparoscopic left + right hemihepatectomy)
Receives: Procedure: Open or Laparoscopic left hemihepatectomy; Procedure: Open or Laparoscopic right hemihepatectomy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Time to functional recovery

    Time until a patient is functionally recovered

    Measured: expected average of 4-10 days

Secondary outcomes (15)
  1. Length of hospital stay

    Total length of hospital stay

    Measured: 30 days

  2. Readmission percentage

    Total percentage of patients being readmitted

    Measured: 1 year

  3. Total morbidity

    Total morbidity during one year

    Measured: 1 year

  4. Composite endpoint of liver specific morbidity

    Composite endpoint of liver specific morbidity(intra-abdominal bleeding, intra-abdominal abcess, ascites, postresectional liver failure, intra-operative mortality, bile leakage)

    Measured: 1 year

  5. Long term incidence of incisional hernia

    Incidence of incisional hernia after 1 year

    Measured: 1 year

  6. Quality of life: QLQ-C30 + LM 21

    Quality of life assessment (QLQ-C30 + LM 21) during one year

    Measured: 1 year

  7. Body image and cosmesis

    Influence of intervention on body image and cosmesis during one year

    Measured: 1 year

  8. Reasons for delay in discharge after functional recovery

    Measured: 1 year

  9. Intraoperative blood loss

    Measured: During procedure

  10. Intraoperative time

    Measured: Surgical time from incision to closure

  11. Resection margin

    Measured: During pathology assessment

  12. Time to adjuvant chemotherapy initiation

    Measured: 1 year

  13. Disease-free survival

    Measured: 1 year

  14. Hospital and societal costs

    Measured: 1 year

  15. Overall survival

    Measured: 1 year and 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Sep 2011 (estimated)
  2. Study start1 Oct 2013
  3. Primary completion4 Dec 2019
  4. Study completion4 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Care provider
Enrolment
350 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01441856
Sponsor's protocol ID
NL36215.068.11
Status last verified
May 2025
First submitted
27 Apr 2011
Last updated
18 May 2025
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Olij B, Pilz da Cunha G, Ratti F, Abu Hilal M, Troisi RI, Sutcliffe RP, Besselink MG, Aroori S, Menon KV, Edwin B, D'Hondt M, Lucidi V, Ulmer TF, Diaz-Nieto R, Soonawalla Z, White S, Sergeant G, Kuemmerli C, Korenblik R, Scuderi V, Berrevoet F, Vanlander A, Marudanayagam R, Tanis PJ, Coolsen MME, Fichtinger RS, Eminton ZB, Neumann UP, Brandts L, Pugh SA, Fretland AA, Primrose JN, van Dam RM; ORANGE II PLUS Collaborative. Laparoscopic versus open hemihepatectomy: does side matter? A post-hoc analysis of the ORANGE II PLUS randomized controlled trial. Surg Endosc. 2026 May;40(5):4195-4205. doi: 10.1007/s00464-026-12588-w. Epub 2026 Mar 9.

    PubMed 41803352
  • Olij B, Pilz da Cunha G, Kimman M, Ratti F, Abu Hilal M, Troisi RI, Sutcliffe RP, Besselink MG, Aroori S, Menon KV, Edwin B, D'Hondt M, Lucidi V, Ulmer TF, Diaz-Nieto R, Soonawalla Z, White S, Sergeant G, Coolsen MME, Kuemmerli C, Scuderi V, Berrevoet F, Vanlander A, Marudanayagam R, Tanis PJ, Dewulf MJL, Fichtinger RS, Eminton ZB, Neumann UP, Brandts L, Pugh SA, Fretland AA, Primrose JN, van Dam RM; ORANGE II PLUS Collaborative. Healthcare Utilization, Costs, and Cost-Effectiveness of Patients Undergoing Laparoscopic and Open Hemihepatectomy: A Secondary Analysis of the ORANGE II PLUS Randomized Controlled, Phase 3, Superiority Trial. Ann Surg Oncol. 2026 Apr;33(4):2882-2898. doi: 10.1245/s10434-025-18779-4. Epub 2025 Dec 12.

    PubMed 41385067
  • Olij B, Fichtinger RS, Aldrighetti LA, Abu Hilal M, Troisi RI, Sutcliffe RP, Besselink MG, Aroori S, Menon KV, Edwin B, D'Hondt M, Lucidi V, Ulmer TF, Diaz-Nieto R, Soonawalla Z, White S, Sergeant G, Ratti F, Kuemmerli C, Scuderi V, Berrevoet F, Vanlander A, Marudanayagam R, Tanis PJ, Dewulf MJL, Eminton ZB, Neumann UP, Brandts L, Pugh SA, Fretland AA, Kimman ML, Primrose JN, van Dam RM; ORANGE II PLUS Collaborative. Health-related quality of life in patients undergoing laparoscopic versus open hemihepatectomy: a secondary analysis of the ORANGE II PLUS randomised controlled, phase 3, superiority trial. Lancet Reg Health Eur. 2025 May 19;54:101311. doi: 10.1016/j.lanepe.2025.101311. eCollection 2025 Jul.

    PubMed 40491830
  • Fichtinger RS, Aldrighetti LA, Abu Hilal M, Troisi RI, Sutcliffe RP, Besselink MG, Aroori S, Menon KV, Edwin B, D'Hondt M, Lucidi V, Ulmer TF, Diaz-Nieto R, Soonawalla Z, White S, Sergeant G, Olij B, Ratti F, Kuemmerli C, Scuderi V, Berrevoet F, Vanlander A, Marudanayagam R, Tanis P, Dewulf MJL, Dejong CHC, Eminton Z, Kimman ML, Brandts L, Neumann UP, Fretland AA, Pugh SA, van Breukelen GJP, Primrose JN, van Dam RM; ORANGE II PLUS Collaborative. Laparoscopic Versus Open Hemihepatectomy: The ORANGE II PLUS Multicenter Randomized Controlled Trial. J Clin Oncol. 2024 May 20;42(15):1799-1809. doi: 10.1200/JCO.23.01019. Epub 2024 Apr 19.

    PubMed 38640453

Questions about this trial

What is this clinical trial studying?

A study testing Open or Laparoscopic left hemihepatectomy and Open or Laparoscopic right hemihepatectomy in people with Liver Lesions Requiring Hemihepatectomy, run by Maastricht University Medical Center at 16 sites in 6 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 16 sites in United Kingdom, Belgium, Netherlands, Germany, Italy and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Time to functional recovery (time frame: expected average of 4-10 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01441856, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 May 2025.

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