ORANGE SEGMENTS: Open Versus Laparoscopic Parenchymal Preserving Postero-Superior Liver Segment Resection

The ORANGE SEGMENTS - Trial: an International Multicentre Randomized Controlled Trial of Open Versus Laparoscopic Parenchymal Preserving Postero-superior Liver Segment Resection

The international and multicentre ORANGE SEGMENTS - Trial is a prospective, double blinded, randomized controlled study comparing patients undergoing parenchymal preserving resection of postero-superior liver segments (involving one or two of segments 4a, 7, 8). All patients will be participating in an enhanced recovery programme.

Primary outcome is time to functional recovery. Secondary study parameters include hospital length of stay, intraoperative blood loss, operation time, liver specific morbidity, readmission percentage, resection margin, quality of life, body image and cosmesis , reasons for delay of discharge after functional recovery, long term incidence of incisional hernias, hospital and societal costs during one year, time to adjuvant chemotherapy initiation, overall five-year survival.

Study Overview

• Status: Active, not recruiting
• Conditions: Liver Surgery
• Intervention / Treatment: Procedure: Parenchymal preserving postero-superior liver segment resection

Detailed Description

Liver resection for colorectal metastasis is a potential curative therapy and has become the standard of care in appropriately staged patients, offering five-year survival rates ranging from 38 up to 61% in selected cases, with approximately 30% of patients surviving ten years or more, compared to five-year survival rates of less than 5% for patients not amenable to resection. Liver surgery is also a widely accepted treatment for symptomatic benign lesions and those of uncertain nature or large size. Whilst the figures are a vast improvement on the past, there is still a need to refine the treatment of these patients, including surgical technique.

Open hepatectomy is the current standard of care for the management of primary and secondary tumours. The open postero-superior liver segment resection requires a large incision to achieve adequate access and proper control during resection. This has a significant impact on patient's recovery and, in cases of small resections, this access may represent the major component of surgical trauma. Advances in surgical technique and expertise now permit these operations to be performed with minor incisions by using the laparoscopic approach. Although the feasibility of laparoscopic hepatectomy has been established, only select centres use this technique as their primary modality.

Laparoscopic liver resection was first reported in 1991. Over the past decades, the method has gained wide acceptance for various liver resection procedures. Multiple retrospective case series, patient cohorts, systematic reviews and meta-analyses have compared open with laparoscopic liver surgery and indicate the laparoscopic approach to be safely applicable for the resection of 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 and earlier recovery. Despite this, concerns remain over operative times, the ability to control haemorrhage laparascopically and long-term oncological outcomes.

Initially, the left lateral segments of the liver were chosen for anatomic laparoscopic resection, with good results. Many liver centres worldwide currently use laparoscopy for resection of the anterior liver segments. Whilst case control studies would now seem sufficient to allay such concerns in the context of minor liver resections and left lateral sectionectomies, the adoption and dissemination of laparoscopy by hepatobiliary oncologic surgeons for major hepatectomies and resections of postero-superior segments has been restricted. Besides the relatively low volume of patients, major laparoscopic liver resections are technically demanding, have a significant learning curve, are time consuming, are thought to hold an increased morbidity risk and lack in evidence.

Nevertheless, a new impulse for the laparoscopic management of major liver lesions came after the first reports of laparoscopic hemihepatectomies, which demonstrated that in expert hands major anatomical laparoscopic liver resections are feasible with good efficacy and safety. When comparing surgical procedures, one of the easiest to measure and often used outcomes is the length of hospital stay; the time it takes for a patient to be discharged from the hospital after an operation. On the whole, a median hospital length of stay of 6.0 to 13.1 days and 3.5 to 10.0 days have been observed after open and laparoscopic hepatic resections in European centres respectively. For major surgery in expert centres, median duration of hospital admission varied between 6 to 12.5 days for open surgery and 4 to 8.2 days for laparoscopic resections. Concentrating on postero-superior liver segment resections, the median hospital stay is 6 days (3-44 days) for those undergoing open compared with 4 days (1-11 days) for those having laparoscopic resections.

Besides the immediate benefits to the patient, such as decreased intraoperative blood loss, diminished postoperative pain, earlier recovery and reduced hospital length of stay, laparoscopic liver surgery may also have the potential to improve outcomes in the longer term by reducing complications, enhancing quality of life, improving cosmesis, ensuring early commencement and completion of adjuvant therapies. However, level-1 evidence on all outcomes is still to be presented.

Within the framework of optimized perioperative care, broader indications for hepatic surgery and further adoption of laparoscopic liver resections, there is a clear need for a randomized trial. Therefore, the multicentre and international ORANGE SEGMENTS - Trial has been designed to provide evidence on the merits of laparoscopic versus open parenchymal preserving postero-superior liver segment resection within an enhanced recovery programme 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.

• Study Type: Interventional
• Enrollment (Actual): 250
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Kortrijk, Belgium
    • General Hospital Groeninge
• Italy
  • Brescia, Italy
    • Poliambulanza Hospital
  • Milan, Italy
    • San Raffaele Hospital
  • Rome, Italy
    • San Camillo-Forlanini Hospital
• Netherlands
  • Amsterdam, Netherlands
    • Academic Medical Center
  • Maastricht, Netherlands
    • Maastricht University Medical Center+
• Norway
  • Oslo, Norway
    • University Hospital Oslo
• Russian Federation
  • Moscow, Russian Federation
    • Moscow Clinical Scientific Center
• United Kingdom
  • Aintree, United Kingdom
    • Aintree University Hospital
  • Birmingham, United Kingdom
    • Queen Elizabeth Hospital
  • London, United Kingdom
    • King's College Hospital
  • Manchester, United Kingdom
    • Manchester Royal Infirmary
  • Newcastle, United Kingdom
    • Freeman Hospital
  • Oxford, United Kingdom
    • Oxford University Hospitals
  • Plymouth, United Kingdom
    • Derriford Hospital
  • Southampton, United Kingdom
    • University Hospital Southampton

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients requiring a parenchymal sparing liver resection (including wedge resections and full segmentectomies) involving one or two of segments 4a/7/8 for accepted indications . A segment 6/7 resection would also be eligible.
• Able to understand the nature of the study and what will be required of them.
• Men and non-pregnant, non-lactating women, aged 18 years and older.
• BMI between and including 18-35 kg/m2
• Patients with ASA physical status I-II-III.

Exclusion Criteria:

• Inability to give (written) informed consent.
• Patients requiring other liver surgery than a parenchymal sparing resection involving one or two of segments 4a, 7, 8.
• Patients requiring parenchymal sparing liver resection involving segment 1. This is due to the high level of technical difficulty.
• Patients with hepatic lesion(s), that are located with insufficient margin from vascular or biliary structures to be operated laparoscopically.
• Patients with ASA physical status IV-V.
• Repeat hepatectomy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Open; Open liver surgery	Procedure: Parenchymal preserving postero-superior liver segment resection; Parenchymal preserving liver segment resection of one or two of the postero-superior liver segments (4A, 7 or 8).
Other: Laparoscopy; Laparoscopic liver surgery	Procedure: Parenchymal preserving postero-superior liver segment resection; Parenchymal preserving liver segment resection of one or two of the postero-superior liver segments (4A, 7 or 8).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to functional recovery	Time until a patient is functionally recovered	expected average of 4-10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital length of stay	Total length of hospital stay	30 days
Intraoperative blood loss	Net intraoperative blood loss	during procedure
Operating time		surgical time from incision until closure
(Liver specific) morbidity	Composite endpoint of liver specific morbidity (intra-abdominal bleeding, intra-abdominal abcess, ascites, postresectional liver failure, intra-operative mortality, bile leakage)	1 year
Readmission percentage	Total percentage of patients being readmitted	1 year
Resection margin	Residual tumor cells in resection border	1 year
Quality of life	The physical, social and emotional well-being of the patient	1 year
Body image and cosmesis	The aesthetic appearance of the scars associated with the operation and its influence on the patient self-view	1 year
Reasons for delay of discharge after functional recovery	All reasons that may cause delay in discharge after the patient has recovered functionally, such as administrative reasons, patient confidence, logistics problems, etc.	1 year
Incisional herniation	Cicatricial hernia	1 year
Hospital and societal costs	All costs that are associated with the operation, including in-hospital costs and out of hospital costs, such as home care, work absence, etc.	1 year
Time to adjuvant chemotherapy initiation	The time it takes to start adjuvant chemotherapy after the patient has been operated	1 year
Overall five-year survival	Five-year survival	5 years

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: King's College Hospital NHS Trust; Oslo University Hospital; Federico II University; Liverpool University Hospitals NHS Foundation Trust; General Hospital Groeninge; Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); Manchester University NHS Foundation Trust; University Hospital Southampton NHS Foundation Trust; Newcastle-upon-Tyne Hospitals NHS Trust; Oxford University Hospitals NHS Trust; Fondazione Poliambulanza Istituto Ospedaliero; The Queen Elizabeth Hospital; San Raffaele University Hospital, Italy; Derriford Hospital; Moscow Clinical Scientific Center; San Camillo Hospital, Rome
• Investigators: Study Chair: Mohammed Abu Hilal, Prof., University Hospital Southampton NHS Foundation Trust; Study Chair: John Primrose, Prof., University Hospital Southampton NHS Foundation Trust

Publications and helpful links

General Publications

• Coles SR, Besselink MG, Serin KR, Alsaati H, Di Gioia P, Samim M, Pearce NW, Abu Hilal M. Total laparoscopic management of lesions involving liver segment 7. Surg Endosc. 2015 Nov;29(11):3190-5. doi: 10.1007/s00464-014-4052-2. Epub 2015 Jan 13.
• Cipriani F, Shelat VG, Rawashdeh M, Francone E, Aldrighetti L, Takhar A, Armstrong T, Pearce NW, Abu Hilal M. Laparoscopic Parenchymal-Sparing Resections for Nonperipheral Liver Lesions, the Diamond Technique: Technical Aspects, Clinical Outcomes, and Oncologic Efficiency. J Am Coll Surg. 2015 Aug;221(2):265-72. doi: 10.1016/j.jamcollsurg.2015.03.029. Epub 2015 Mar 27.
• Scuderi V, Barkhatov L, Montalti R, Ratti F, Cipriani F, Pardo F, Tranchart H, Dagher I, Rotellar F, Abu Hilal M, Edwin B, Vivarelli M, Aldrighetti L, Troisi RI. Outcome after laparoscopic and open resections of posterosuperior segments of the liver. Br J Surg. 2017 May;104(6):751-759. doi: 10.1002/bjs.10489. Epub 2017 Feb 13.
• Zheng B, Zhao R, Li X, Li B. Comparison of laparoscopic liver resection for lesions located in anterolateral and posterosuperior segments: a meta-analysis. Surg Endosc. 2017 Nov;31(11):4641-4648. doi: 10.1007/s00464-017-5527-8. Epub 2017 Apr 7.
• Kuemmerli C, Fichtinger RS, Moekotte A, Aldrighetti LA, Aroori S, Besselink MGH, D'Hondt M, Díaz-Nieto R, Edwin B, Efanov M, Ettorre GM, Menon KV, Sheen AJ, Soonawalla Z, Sutcliffe R, Troisi RI, White SA, Brandts L, van Breukelen GJP, Sijberden J, Pugh SA, Eminton Z, Primrose JN, van Dam R, Hilal MA; ORANGE trials collaborative. Laparoscopic versus open resections in the posterosuperior liver segments within an enhanced recovery programme (ORANGE Segments): study protocol for a multicentre randomised controlled trial. Trials. 2022 Mar 9;23(1):206. doi: 10.1186/s13063-022-06112-3.

Helpful Links

• The ORANGE - Trials consortium webpage

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Anticipated): January 1, 2022
• Study Completion (Anticipated): December 1, 2026

Study Registration Dates

• First Submitted: August 28, 2017
• First Submitted That Met QC Criteria: August 31, 2017
• First Posted (Actual): September 1, 2017

Study Record Updates

• Last Update Posted (Actual): December 30, 2021
• Last Update Submitted That Met QC Criteria: December 10, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Hepatectomy; Laparoscopy; Parenchymal preserving; Postero-superior
• Other Study ID Numbers: NL36215.068.11*

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No