Multicenter Trial on Surgical Outcome and Quality of Life in Juxta-medullary Tumors

Introduction

1. Background information Juxta-medullary tumors are mostly benign tumors in the spinal canal that may cause neurological deficits due to spinal cord or nerve root compression. The knowledge about the natural course of the disease, optimal treatment regarding timing of surgery and surgical approach are based on case series from different institutions around the world. Moreover, little is known about the long-term clinical and functional outcome after tumor resection, indicators of quality of treatment and quality of life after surgery.

Main treatment option of juxta-medullary tumors is a neurosurgical resection. The main goal of the surgery is to decompress the neuro structures in order to reveal neurological deficits. However, achieving gross total resection (GTR) is important in order to achieve long progression free survival (PFS).

Therefore, the surgeon should choose the appropriate surgical approach to achieve these goals. Several publications show that GTR, whenever possible, is essential, as subtotal resection is the main reason of tumor regrowth or recurrence. Moreover, revision surgery due to tumor recurrence is one of the main risk factors of unfavorable outcome, probably to intradural adhesions, related to the first procedure. Due to the mostly benign nature of juxtamedullary tumors, it would be very difficult to evaluate overall survival (OS) and progression free survival (PFS) within this progressive registry in the short run. For this reason, data should be kept for late cohort analysis after longer intervals. Probably up to 20 years, as previous publications reported recurrence of spinal meningioma after GTR 10 years or more after surgery.

On the other hand, too large exposure may lead to impaired recovery after surgery, eventual higher blood loss during surgery and thus longer stay in hospital (LOS) and impaired quality of life. Moreover, extensive bone resection may lead to spinal instability requiring instrumentation, during index surgery or during further follow up in case of postoperative deformity).

In addition to the oncological outcome, the neurological outcome is also very important. Depending on the localization of the tumor, its form and compression of intra-spinal structures such as the spinal cord or nerve roots many patients develop neurological deficits. Besides GTR the other goal of resection is the neurological recovery of these patients. Previous reports show that the time point of surgery is important in order to achieve full recovery. However, most of the data is derived from retrospective case series. One of the aims of this registry is to prove this hypothesis. These neurological deficits are, as mentioned above, related to the localization of the tumor within the spine, Tumors in the cervical spine would cause mainly gait ataxia, spasticity, and weakness in the upper extremities while tumors in the lumbar spine would lead to deficits in the lower extremities in combination to disturbances of bladder, bowl, and sexual functions. These functions should be evaluated and monitored, before and after treatment.

Other concerns are safety requirements in order to prevent peri-operative complications. For example, the role of intra-operative neurophysiological monitoring. Some authors recommend the utilization intra operative monitoring, however, the evidence level is very low. Other open questions are for example the utility of microscope, methods for dura closure and thrombosis prevention.

On the other hand, some tumors can be treated with irradiation, some studies showed efficacy of this method mainly in the case of Schwannomas and meningiomas. In case of residual tumor or tumor progression irradiation can be also performed to prevent further growth.

Lastly, in comparison to the methods mentioned above, a wait-and-see approach can be used for asymptomatic patients or those with mild symptoms. In this case, clinical and imaging examinations are performed at regular intervals to check the neurological status and the tumor. This can also be done for longer periods of time because of the benign nature of these tumors with the slow growth. in case of new neurological deficits of or progression surgical treatment should be advocated. Overall, it is not certain at what point therapy is indicated, especially in asymptomatic patients. Because many of these tumors are discovered by coincidence during imaging, which was performed due to other symptoms.

2 Rationale of the study The rationale of the trial is to define benchmarks on quality of life, functionality and neurological outcome after resection of juxtamedullary tumors. Furthermore, to assess and define benchmarks of quality indicators of the treatment. These measurements would be essential for future studies.

Further rationales are to find out the optimal timing, method, and approach to treat juxta-medullary tumors. Because of the low incidence of juxta-medullary tumors, a multi-center trial seems to be essential. This would allow us to analyze a large number of patients, much more than any other published paper. Moreover, the different protocols and standards approaches in each center would allow conducting Comparative Effectiveness Research (CER).

3 Aims The goal of this study is to establish a multicenter cohort of patients operated on juxtamedullary tumors. With especial emphasis on functional outcome, quality indicators (QI) and quality of life after surgery three months after surgery. Causes of unfavorable outcome should be determined.

The main hypothesis is that early and less-invasive surgery with maximal extents of resection would lead to a more favorable outcome. In the future the registry would help assessing further hypothesis can be answered on the base of comparative effectiveness research (CER), examples of these hypothesis are:

1. Functional and neurological outcome in comparison to preoperative status. Comparison between Panties with good preoperative McCormick score (1-2) and those with a high preoperative score (3-5).
2. Risk-factors for non-favorable outcome
3. Non-Inferiority to achieve gross total resection via unilateral approaches
4. Question whether laminectomy as approach may cause mor pain and impact quality of life
5. Risk factors for the development of CFS Leaks
6. Does bed rest prevent CSF leaks
7. Does laminectomy elevate the risk of CSF leaks
8. Does the utility of intraoperative neurophysiological monitoring (IOM) influence surgical outcome: rate of GTR and neurological outcome
9. Rate of postoperative kyphosis and deformity in laminectomy in comparison to non-laminectomy
10. Is facetectomy required for GTR of dumbbell tumors?
11. Risk factors for non-complete resection

Primary outcomes are determined by:

Quality of life based on the questionnaire (EQ-D5) Extent of tumor resection (see CRF): according to surgeon: 1. Meningioma: Simpson grade 1 and 2 2. Schwannoma: complete resection, including nerve root 3. Cauda ependymoma: complete resection, including filum terminale according to postoperative MRI, 3 months after surgery 4. Other: surgeon's decision Neurological status (McCormick Score) (see CRF), 3 months after surgery Secondary Outcome Imaging: preoperative and postoperative MRI Volumetry Spinal canal occupancy ratio in %

Further patient reported outcomes:

Functionality: Neck disability index (NDI) for tumors in the cervical spine, Oswestry disability index (ODI) for tumors in the thoracic and lumbar spine (see CRF) Local and radicular pain (VAS 1-10) (see CFR) Neurological status: motor function of each limb, ataxia and gait (mJOA score) (see CRF) HADS score- based score for anxiety Questionnaire on bladder, bowl, sexual functionality

Quality indicators (QI):

Length of hospital stay 30- and 90-days readmission Nosocomial infections Blood loss Duration of surgery Progression of the disease or recurrence Other adverse events Mortality Assessment of adverse events according to Common Terminology Criteria for Adveres Events (CTCAE) 5.0 and severity according to the Ibañez scale (see CRF) CSF leakage is defined as one, when CSF leakage is identified on imaging of clinicaly and treatment is required: operative or conservative (Lumbar drain for example) Postoperative kyphosis of deformity is defined, when symptomatic (for example pain) or evident on imaging (for example kyphotic fracture on MRI) Methodology All patients treated in one of the study centers are recorded in a databank (Redcap, see below), which includes information about admission, symptoms, other diseases, treatment, quality indicators and questionnaires regarding quality of life and functionality. Data should be recorded in an anonymized in each center (see below).

For the analysis the CRF includes information about admission, surgery, discharge, and 3 months (90 days) after surgery. In addition, patients should fill out questionnaires on quality of life (EQ-D5) and functionality (ODI or NDI). Later, yearly visits can be completed to have long term results in the future regarding progression free survival (PFS) and overall survival (OS). The CRF is attached to this document.

Univariate and multivariate statistics would be applied to prove which variables might lead to a favorable or unfavorable outcome.

A minimum number of one hundred (N=100) inclusions seems to be adequate in order to perform reasonable analysis. In the event of nonsufficient recruitment, results and further recruitment would be discussed two years after initiation of the study, and annually thereafter.