Minimally Invasive versus Open Lumbar Interbody Fusion Trial (MIOLIFT): a randomized controlled trial for surgical treatment of lumbar spondylolisthesis and foraminal stenosis

With the growing global healthcare expenses, economic evaluations are more
important than ever. Due to the aging population, the number of surgical spine
procedures is expected to increase, resulting in higher healthcare-related
costs (1-3). Previous studies, concerning the national US bill for instrumented
spine surgery, have shown a 7.9 fold increase between 1998 and 2008 and a 2.8
fold increase between 2004 and 2015 (4, 5). In the Netherlands, spine
complaints are responsible for 25% of healthcare-related costs for
musculoskeletal disease (6). To limit the increase of the healthcare-related
costs of instrumented spine surgery in an aging population, medical
practitioners should consider the most cost-effective surgical technique,
especially when both techniques have comparable clinical outcomes (3, 7, 8).
Common indications for instrumented lumbar spine surgery are lumbar
spondylolisthesis and degenerative disc disease. Spondylolisthesis is a
slippage of one vertebral body over another, mostly caused by one of the
following three pathophysiological mechanisms; facet joint degeneration, lysis
in the pars articularis, or postoperative changes after decompression surgery
(3, 9). Degenerative disc disease can cause foraminal stenosis by a reduction
in the available space for the exiting nerve root by osseus or ligamentous
hypertrophy, thus leading to nerve root compression. Lumbar spondylolisthesis
and degenerative foramen stenosis can cause back pain, neurogenic claudication,
and lumbar radiculopathy (10). If conservative treatment fails, instrumented
spine surgery can be performed to relieve complaints and restore spinal
stability. A widely used surgical technique is the open transforaminal lumbar
interbody fusion (OTLIF). In OTLIF, a unilateral transforaminal approach with
unilateral facetectomy is used to insert a single cage, combined with posterior
pedicle-screw fixation (11). A newer, minimally invasive variation to this
technique (MITLIF) is gaining popularity. In MITLIF, decompression and cage
insertion are performed through tubular retractors, combined with percutaneous
posterior pedicle-screw fixation. Previous literature generally describes
comparable or improved clinical effectiveness for MITLIF compared to OTLIF.
Furthermore, studies reported significantly less blood loss, less complications
and shorter duration of hospitalization associated with MITLIF compared to
OTLIF. It is hypothesized that these differences are a result from less
iatrogenic damage associated with the minimally invasive approach (3, 12-16).
There are no strict indications for using either technique, nor is literature
in this matter conclusive. As a result, the choice for technique is greatly
based on surgeon*s experience and preference.
Comparable clinical outcome, but less complications, less blood loss, shorter
duration of hospitalization, lower pharmacy and laboratory costs, lower
physical therapy costs could result in MITLIF being more cost-effective
compared to OTLIF. However, prospective randomized studies directly comparing
the cost-effectiveness of OTLIF and MITLIF from both hospital and societal
perspectives are needed to obtain higher levels of evidence (3). In addition,
process evaluation will be performed to improve care.

In summary, the hypothesis of this randomized controlled trial study is that
MITLIF is the preferred technique in patients with neurogenic claudication or
lumbar radiculopathy caused by single level lumbar spondylolisthesis or
degenerative foraminal stenosis for the following reasons: 1) Clinical and
patient*s outcome following MITLIF is not inferior compared to OTLIF; 2) Direct
healthcare-related costs of MITLIF are lower; 3) Indirect costs of MITLIF are
lower; 4) MITLIF is more cost-effective compared to OTLIF.

References
1. Saifi C, Cazzulino A, Laratta J, Save AV, Shillingford JN, Louie PK, et al.
Utilization and Economic Impact of Posterolateral Fusion and
Posterior/Transforaminal Lumbar Interbody Fusion Surgeries in the United
States. Global Spine J. 2019;9(2):185-90.
2. de Kunder SL, Rijkers K, Caelers IJ, de Bie RA, Koehler PJ, van Santbrink H.
Lumbar interbody fusion: a historical overview and a future perspective. Spine.
2018;43(16):1161-8.
3. Droeghaag R, Hermans SM, Caelers IJ, Evers SM, van Hemert WL, van Santbrink
H. Cost-effectiveness of Open Transforaminal Lumbar Interbody Fusion (OTLIF)
versus Minimally Invasive Transforaminal Lumbar Interbody Fusion (MITLIF): A
Systematic Review and Meta-Analysis. The Spine Journal. 2021.
4. Martin BI, Mirza SK, Spina N, Spiker WR, Lawrence B, Brodke DS. Trends in
lumbar fusion procedure rates and associated hospital costs for degenerative
spinal diseases in the United States, 2004 to 2015. Spine. 2019;44(5):369-76.
5. Rajaee SS, Bae HW, Kanim LE, Delamarter RB. Spinal fusion in the United
States: analysis of trends from 1998 to 2008. Spine. 2012;37(1):67-76.
6. RIVM. Volksgezondheid en Zorg in Nederland. 2016.
7. Mishan EJ. Cost-benefit analysis.
8. Hopkins B, Mazmudar A, Kesavabhotla K, Patel AA. Economic Value in Minimally
Invasive Spine Surgery. Current reviews in musculoskeletal medicine.
2019;12(3):300-4.
9. Herkowitz HN, Sidhu KS. Lumbar spine fusion in the treatment of degenerative
conditions: current indications and recommendations. JAAOS-Journal of the
American Academy of Orthopaedic Surgeons. 1995;3(3):123-35.
10. Jenis LG, An HS. Spine update: lumbar foraminal stenosis. Spine.
2000;25(3):389-94.
11. Cole CD, McCall TD, Schmidt MH, Dailey AT. Comparison of low back fusion
techniques: transforaminal lumbar interbody fusion (TLIF) or posterior lumbar
interbody fusion (PLIF) approaches. Current reviews in musculoskeletal
medicine. 2009;2(2):118-26.
12. Karikari IO, Isaacs RE. Minimally invasive transforaminal lumbar interbody
fusion: a review of techniques and outcomes. Spine. 2010;35(26S):S294-S301.
13. Villavicencio AT, Burneikiene S, Roeca CM, Nelson EL, Mason A. Minimally
invasive versus open transforaminal lumbar interbody fusion. Surgical neurology
international. 2010;1.
14. Lu VM, Kerezoudis P, Gilder HE, McCutcheon BA, Phan K, Bydon M. Minimally
invasive surgery versus open surgery spinal fusion for spondylolisthesis: a
systematic review and meta-analysis. Spine. 2017;42(3):E177-E85.
15. Arts MP, Wolfs JF, Kuijlen JM, de Ruiter GC. Minimally invasive surgery
versus open surgery in the treatment of lumbar spondylolisthesis: study
protocol of a multicentre, randomised controlled trial (MISOS trial). BMJ open.
2017;7(11):e017882.
16. Hammad A, Wirries A, Ardeshiri A, Nikiforov O, Geiger F. Open versus
minimally invasive TLIF: literature review and meta-analysis. Journal of
orthopaedic surgery and research. 2019;14(1):229.
17. Asher AL, Kerezoudis P, Mummaneni PV, Bisson EF, Glassman SD, Foley KT, et
al. Defining the minimum clinically important difference for grade I
degenerative lumbar spondylolisthesis: insights from the Quality Outcomes
Database. Neurosurgical focus. 2018;44(1):E2.
18. Parker SL, Mendenhall SK, Shau DN, Zuckerman SL, Godil SS, Cheng JS, et al.
Minimally invasive versus open transforaminal lumbar interbody fusion for
degenerative spondylolisthesis: comparative effectiveness and cost-utility
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Currently, available literature on costs and clinical effectiveness of MITLIF
compared to OTLIF for patients with lumbar spondylolisthesis and degenerative
foraminal stenosis is not sufficient. With a steep increase in the number of
instrumented spinal fusion procedures, the expected further increase in the
future, and the associated costs, there is a need for comparative data to
develop evidence-based treatment recommendations.

Primary objective:
To determine whether the MITLIF procedure is not inferior to the OTLIF
procedure, in increasing quality of life, measured as the amount of change on
the EQ-5D-5L, in patients with degenerative, iatrogenic, or isthmic single
level lumbar spondylolisthesis or degenerative foraminal stenosis.

Secondary objectives:
1. To determine whether the MITLIF procedure is cost-effective (measured with
productivity related costs (iPCQ), informal costs (limited iVICQ), medical
costs (iMCQ), EQ-5D-5L and Short Form (36) Health Survey) compared to the OTLIF
procedure.

2. To determine whether the MITLIF procedure is associated with increased
quality of life (measured with: Oswestry Disability Index (ODI), Short Form
(36) Health Survey, Visual Analogue Scale (VAS) score of back pain and leg
pain, Hospital Anxiety Depression Scale (HADS)) than the OTLIF procedure.

3. To determine whether the MITLIF procedure is associated with less
complications (defined as: dural tear, postoperative infection, deep venous
thrombosis, hematoma, hardware failure, neurological deficits, medical other
complications as pneumonia or urinary tract infection) than the OTLIF procedure.

4. To determine whether the MITLIF procedure is associated with lower/higher
scores postoperatively on Care-related Quality of Life (measured with
CarerQol-7D, SRB) than preoperatively.

5. To evaluate the experiences and opinions of patients, ICG and professionals
regarding MITLIF and OTLIF processes.

Prospective, Randomized Controlled non-inferiority Trial (RCT; blinding for the
statistician, not for the patient, the clinician and the researcher). The study
includes patients with single level symptomatic lumbar degenerative foraminal
stenosis or spondylolisthesis of degenerative, iatrogenic, or isthmic order.
Neurogenic claudication or radicular leg pain are caused by a central spinal
canal stenosis or uni-, or bilateral foraminal stenosis. Preferred surgical
therapy is single level LIF (lumbar interbody fusion) surgery with
decompression of the symptomatic neural structures, combined with pedicle screw
fixation. Patients eligible for inclusion and interested in our study will be
referred to the researchers. The researchers will inform the patient, and when
they are willing to participate and meet the inclusion criteria, include them.
These patients are randomly divided into two parallel groups (1) MITLIF and (2)
OTLIF. The study inclusion period will be approximately two years. Follow-up
period requires two years, which results in a total study duration of four
years.
Treatment is performed by an experienced orthopaedic surgeon and neurosurgeon,
who possesses adequate knowledge of both treatment methods.
To study the quality of life and burden of ICG before and after MITLIF or OTLIF
surgery, ICG of participating patients will be informed and asked for informed
consent.

Investigational treatment

A. MITLIF group. After receiving antibiotic prophylaxis, the patient is brought
under general anaesthesia and positioned in prone position. Tubular retractors
are used to access the posterior elements, allowing decompression. The
retractor is seated against the posterior elements. In case of spinal canal
stenosis, the central part of the spinal canal is decompressed by laminectomy.
Unilateral exposure to the intervertebral disc is assured by total unilateral
facetectomy, decompressing the descending and leaving roots. In case of
bilateral symptomatic leg pain, the side of the unilateral approach is free of
choice for the surgeon. Unilateral facetectomy is performed to gain access to
the intervertebral disc. Endplate cartilage is prepared to provide a host bed
of bleeding subchondral bone for placement of the cage. The TLIF cage size is
determined by a trial cage and fluoroscopy. The definitive cage is filled with
autologous bone or allograft and is tamped into place. Its position is checked
radiological. After placement of the TLIF cage, the remainder of the disc space
is filled with autologous bone, obtained from the decompression. Pedicle-screws
will be placed percutaneously. A titanium rod interconnects the screws on each
side. The retractors are removed and the wounds are thoroughly irrigated and
closed in several layers without suction drainage.

B. OTLIF group. After receiving antibiotic prophylaxis, the patient brought
under general anaesthesia and positioned in prone position. A midline approach
is performed, exposing the posterior lumbar elements including the facet
joints. Pedicle screws are placed bilaterally, using fluoroscopic guidance or
navigation, depending on preference of the surgeon. In case of spinal canal
stenosis, the central part of the spinal canal is decompressed by laminectomy.
Unilateral exposure to the intervertebral disc is assured by total unilateral
facetectomy, decompressing the descending and leaving roots. In the case of
bilateral symptomatic leg pain, the side of the unilateral approach is free of
choice for the surgeon. Unilateral facetectomy is performed to gain access to
the intervertebral disc. Endplate cartilage is prepared to provide a host bed
of bleeding subchondral bone for placement of the cage. The TLIF cage size is
determined by a trial cage and fluoroscopy. The definitive cage is filled with
autologous bone or allograft and is tamped into place. Its position is checked
radiological. After placement of the TLIF cage, the remainder of the disc space
is filled with autologous bone, obtained from the decompression. A titanium rod
interconnects the screws on each side. The spreader is removed and the wound is
thoroughly irrigated and closed in several layers without suction drainage.

Use of co-intervention
Both groups receive the same perioperative protocol. This includes:
- pre-operative Cefazolin (two grams intravenous, 30 minutes before incision,
or adequate alternative whenever a patient is allergic);
- post-operative pain management based on local hospital protocol;
- standard physical therapy during hospitalization for mobilization
instructions;
- no mandatory physical therapy at home for the first six to eight weeks
postoperatively;
- deep venous thrombosis prophylaxis according to local hospital protocol;
- the position of the implants will be checked by the means of lumbar spine
X-ray (AP and lateral);
- Partially (web based) follow-up at 3, 6, 12 and 24 months postoperatively.

MITLIF and OTLIF are currently standard care for patients with symptomatic
single level lumbar degenerative, iatrogenic, or isthmic spondylolisthesis or
degenerative foraminal stenosis. The choice of technique is mainly based on
surgeon*s experience and preference. For patients who are eligible for TLIF
surgery through a posterior approach, participating in this study does not pose
any extra risks.
The burden for patients and ICG participating in this trial is low. Patients
are asked to fill out paper or online questionnaires concerning Patient Related
Outcome Measurements (PROMS) (HADS, ODI, EQ-5D-5L, SF-36, VAS) at five fixed
time-points (pre-operatively, and 3, 6, 12 and 24 months postoperatively). To
determine cost-effectiveness, productivity related costs (iPCQ) and medical
costs (iMCQ)) are recorded additionally at the five time-points. There are no
extra visits to the outpatient clinic. There are no benefits in participating
in this study compared to care as usual. ICG are asked to fill out the paper or
online questionnaire concerning the CarerQol-7D, SRB, the intensity of
caregiving and informal care costs (limited-iVICQ) at 3 fixed time-points
(preoperatively, and 3 and 6 months postoperatively).