The ORANGE II PLUS - Trial: An international multicentre randomized controlled trial of open versus laparoscopic liver surgery (hemihepatectomy and postero-superior liver segment resection).

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. Both open hemihepatectomy and open postero-superior liver segment
resection require 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.

At the international consensus conference on laparoscopic liver surgery in
Morioka in 2014, it was concluded that laparoscopic resections of
postero-superior liver segments should be considered *major* liver surgery;
while parenchymal sparing resection of lesions in the postero-superior segments
of the liver are often minor in terms of the resected liver volume, they are
technically major due to the anatomical location of these segments. At that
same conference, it was stated that major laparoscopic liver surgery (including
hemihepatectomies and postero-superior liver segment resections amongst others)
is to be regarded as an innovative procedure, still in its exploration or
learning phase (IDEAL 2b) and ought to be introduced with great caution.
Furthermore, as the quality of the available studies comparing open with
laparoscopic major liver resections was generally designated to be low, there
was a strong recommendation to organise higher quality studies.

Besides improvements in surgical procedures, enthusiasm has also arisen for
standardization of the postoperative care in the form of fast-track recovery
protocols over the past decades, such as the Enhanced Recovery After Surgery
(ERAS®) programme. This fast-track recovery programme, 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 liver surgery, it was demonstrated that
functional recovery and hospital length of stay after open and laparoscopic
liver resection could be reduced when patients were managed within the
multimodal ERAS® programme. Functional recovery can be regarded as the moment
in time when it is medically justified to discharge a patient from hospital
care. It is important to emphasize the discrepancy between hospital length of
stay (LOS) and the time to functional recovery, which is influenced by tertiary
(out-of-hospital) problems such as patient insecurity, problems in homecare
support or logistic problems. Scoring functional recovery instead of hospital
length of stay may thus be a more adequate, reliable and comparable outcome
measure.

An evaluation of the benefits of the laparoscopic approach in patients
undergoing major liver surgery, either hemihepatectomy or parenchymal
preserving resection of postero-superior liver segments, is both timely and
necessary and will inform clinical practice. 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 II PLUS -
Trial has been designed to provide evidence on the merits of laparoscopic
versus open hemihepatectomy and 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.

Hypotheses:
- For patients undergoing a laparoscopic left or right hemihepatectomy (with or
without the need for one additional hepatic wedge resection or metastasectomy),
time to functional recovery is reduced by 2 days in comparison with patients
undergoing the open procedure.
- For patients undergoing parenchymal preserving laparoscopic resection of
postero-superior liver segments, time to functional recovery is also reduced by
2 days compared with the open procedure.

Primary objective: to provide evidence on the merits of laparoscopic compared
with open liver surgery, for standard indications and within an enhanced
recovery programme in terms of time to functional recovery in:
- Patients undergoing either left or right hemihepatectomy (with or without the
need for one additional hepatic wedge resection or metastasectomy).
- Patients undergoing parenchymal preserving resection of postero-superior
liver segments.

Secondary objectives: to provide evidence on the benefits of laparoscopic
compared with open surgery, for standard indications and within an enhanced
recovery programme in terms of 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 in:
- Patients undergoing either left or right hemihepatectomy (with or without the
need for one additional hepatic wedge resection or metastasectomy).
- Patients undergoing parenchymal preserving resection of postero-superior
liver segments.

The international and multicentre ORANGE II PLUS - Trial is a prospective,
double blinded, randomized controlled study of two separate and independent
patient populations, each producing two arms (open versus laparoscopy) with a
parallel registry. These populations involve patients undergoing left or right
hemihepatectomy and patients having 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.

Baseline values of the primary and secondary outcomes are established before
surgery. Next, data is gathered during surgery, while the patient is admitted
and when the patient is discharged. Follow-up moments are planned at 10 days,
3, 6, 12 months and 5 years after discharge.

Randomisation for open or laparoscopic surgery for two separate and independent
patient populations:

Either: patients in need for a hemihepatectomy (with or without the need for
one additional hepatic wedge resection or metastasectomy).
Or: patients requiring parenchymal sparing resection involving one or two of
liver segments 4a, 7, 8.

There are no risks or benefits associated with participation.

The main burden is the blinding of the patients.

Another burden may be the completion of questionnaires:
- 3 questionnaires at admission (15 minutes)
- a patient diary during admission (2 minutes per day)
- 3 questionnaires at discharge (15 minutes)
- 3 questionnaires at 10 days, 3, 6 and 12 months after discharge (15 minutes
per follow-up moment)

Furthermore, patients will receive an additional ultrasound to diagnose
incisional hernia. Patients will be followed for the total duration of 5 years
(5-year survival).

Patients do not need to come to the hospital extra and do not receive any
reimbursements for participation.