Clinical trial NCT03270917: ORANGE SEGMENTS: Open Versus Laparoscopic Parenchymal Preserving Postero-Superior Liver Segment Resection
Official title: The ORANGE SEGMENTS - Trial: an International Multicentre Randomized Controlled Trial of Open Versus Laparoscopic Parenchymal Preserving Postero-superior Liver Segment Resection
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Liver Surgery
Keywords: Parenchymal preserving
Postero-superior
Laparoscopy
Hepatectomy
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: The Queen Elizabeth Hospital
name: General Hospital Groeninge
name: Liverpool University Hospitals NHS Foundation Trust
name: King's College Hospital NHS Trust
name: San Raffaele University Hospital, Italy
name: Newcastle-upon-Tyne Hospitals NHS Trust
name: Oslo University Hospital
name: Oxford University Hospitals NHS Trust
name: Derriford Hospital
name: University Hospital Southampton NHS Foundation Trust
name: Manchester University NHS Foundation Trust
name: Moscow Clinical Scientific Center
name: San Camillo Hospital, Rome
name: Fondazione Poliambulanza Istituto Ospedaliero
name: Federico II University
First posted: 2017-09-01
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients will be randomised to either the open or the laparoscopic treatment arm.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to functional recovery
timeFrame: expected average of 4-10 days
Secondary outcomes:
measure: Hospital length of stay
timeFrame: 30 days
measure: Intraoperative blood loss
timeFrame: during procedure
measure: Operating time
timeFrame: surgical time from incision until closure
measure: (Liver specific) morbidity
timeFrame: 1 year
measure: Readmission percentage
timeFrame: 1 year
measure: Resection margin
timeFrame: 1 year
measure: Quality of life
timeFrame: 1 year
measure: Body image and cosmesis
timeFrame: 1 year
measure: Reasons for delay of discharge after functional recovery
timeFrame: 1 year
measure: Incisional herniation
timeFrame: 1 year
measure: Hospital and societal costs
timeFrame: 1 year
measure: Time to adjuvant chemotherapy initiation
timeFrame: 1 year
measure: Overall five-year survival
timeFrame: 5 years
Other outcomes:
Locations:
city: Kortrijk
country: Belgium
facility: General Hospital Groeninge
city: Brescia
country: Italy
facility: Poliambulanza Hospital
city: Milan
country: Italy
facility: San Raffaele Hospital
city: Rome
country: Italy
facility: San Camillo-Forlanini Hospital
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center+
city: Oslo
country: Norway
facility: University Hospital Oslo
city: Moscow
country: Russian Federation
facility: Moscow Clinical Scientific Center
city: Aintree
country: United Kingdom
facility: Aintree University Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
Study officials:
affiliation: University Hospital Southampton NHS Foundation Trust
name: Mohammed Abu Hilal, Prof.
role: STUDY_CHAIR
affiliation: University Hospital Southampton NHS Foundation Trust
name: John Primrose, Prof.
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Kuemmerli C, Fichtinger RS, Moekotte A, Aldrighetti LA, Aroori S, Besselink MGH, D'Hondt M, Diaz-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.