|Year : 2016 | Volume
| Issue : 1 | Page : 22-30
Local application of mitomycin C for prevention of epidural fibrosis: study protocol for a prospective randomized controlled double-blinded trial
Tao Sui1, Lei Liu2, Xiao-tao Wu2, Xiao-jian Cao3
1 Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
2 Department of Orthopedics, the Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province, China
3 Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University; Department of Orthopedics, the Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province, China
|Date of Web Publication||16-Mar-2016|
Department of Orthopedics, the First Affiliated Hospital of Nanjing Medical University; Department of Orthopedics, the Affiliated Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province
Source of Support: None, Conflict of Interest: None
Background: Interventions including lumbar discectomy are a primary treatment method for degenerative disc disease. However, after surgery, scar adhesion often forms at the spinal dura mater or adventitial nerves in the defective vertebral plate region and affects recovery. Our previous animal experiments showed that mitomycin C applied topically could safely protect against epidural fibrosis at an optimal dose of 0.5 mg/mL. However, randomized controlled clinical studies have shown that 1 mg/mL mitomycin C does not show obvious therapeutic effects on epidural fibrosis in patients after lumbar discectomy.
Methods/Design: This prospective, randomized, controlled, double-blinded, single-center clinical trial will be performed at the Affiliated Zhongda Hospital of Southeast University in China. Seventy-five patients with single-level lumbar disc protrusion will be included in this study and undergo microendoscopic discectomy. The site of discectomy will be topically treated with cotton wool impregnated with 0.5 mg/mL mitomycin C (treatment group) or 0.9% physiological saline (control group) for 5 minutes. Contrast-enhanced MRI score of the lumbar spine will be the primary outcome measure used to evaluate epidural scar proliferation and adhesion, and Lumbar Spine Outcomes Questionnaire score will be the secondary outcome used to evaluate epidural fibrosis-related clinical symptoms.
Discussion: This study protocol will try to establish an imaging method to precisely grade epidural fibrosis data acquired after microendoscopic discectomy via a prospective, randomized, controlled, double-blinded trial. A safe and effective mitomycin C dose, 0.5 mg/mL, will be topically applied, and the efficacy and safety of mitomycin C for the prevention of epidural fibrosis will be investigated to provide evidence for the clinical use of mitomycin C.
Trial registration: This protocol was registered at Chinese Clinical Trial Registry (identifier: ChiCTR-TRC-10001079) on 6 September 2010.
Ethical approval: The study protocol has acquired written approval from Ethics Committee of the First Affiliated Hospital (Jiangsu Province Hospital), Nanjing Medical University, China (approval No. 2010-SR-088) and will be performed in accordance with the guidelines of the Declaration of Helsinki, formulated by the World Medical Association.
Keywords: clinical trial; epidural firbosis; mitomycin C; topical injection; microendoscopic discectomy; randomized controlled trial
|How to cite this article:|
Sui T, Liu L, Wu Xt, Cao Xj. Local application of mitomycin C for prevention of epidural fibrosis: study protocol for a prospective randomized controlled double-blinded trial. Clin Trials Orthop Disord 2016;1:22-30
|How to cite this URL:|
Sui T, Liu L, Wu Xt, Cao Xj. Local application of mitomycin C for prevention of epidural fibrosis: study protocol for a prospective randomized controlled double-blinded trial. Clin Trials Orthop Disord [serial online] 2016 [cited 2019 Apr 19];1:22-30. Available from: http://www.clinicalto.com/text.asp?2016/1/1/22/178847
| Background|| |
The current methods used for clinical treatment of degenerative disc disease primarily include decompressive laminectomy, intervertebral discectomy, and spine fusion (Häkkinen et al., 2007). However, after surgery, scar fibrosis often forms at the spinal dura mater or adventitial nerves in the defective vertebral plate region. This can lead to nerve root involvement and oppression, resulting in failed back surgery syndrome (FBSS), recurring lumbar and leg pain, and an increase in the risk and difficulty of a secondary surgery. Inhibition of epidural fibrosis after lumbar surgery is an important method of reducing the incidence of FBSS and improving therapeutic effects. Several studies have attempted to prevent the development of epidural fibrosis using multiple materials or methods, improving surgical methods, developing minimally invasive techniques, and reducing hemorrhage (Jou et al., 2007; Cemil et al., 2009; Kasimcan et al., 2011).
Mitomycin C has been shown to exhibit strong inhibitory effects on the proliferation of fibroblasts, and to effectively reduce postoperative tissue fibrosis and epidural fibrosis (Rabb, 2010). It has been widely used to protect against postoperative scar adhesion in the Departments of Ophthalmology and Otorhinolaryngology in our hospital. Furthermore, we have completed a series of animal experiments regarding the use of mitomycin C for prevention of epidural fibrosis from the curative effects, administration method, optimal drug concentration, and safety perspectives (Wang et al., 2005a,b, 2012; Cao et al., 2006; Sun et al., 2007; Zhang et al., 2008; Lu et al., 2011). We found that 0.5 mg/mL mitomycin C applied topically for 5 minutes had strong inhibitory effects on the proliferation of fibroblasts, but did not affect sciatic nerve function (Lu et al., 2011). Our previous studies are summarized in [Table 1].
|Table 1: Animal experiments on the use of mitomycin C for prevention of epidural fibrosis published by the team led by Xiao-jian Cao|
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A prospective, randomized, controlled, clinical trial evaluated the preventive effects of mitomycin C on epidural scar adhesion after lumbar microdiscectomy (Celik et al., 2008). The authors reported that although no obvious adverse events were observed, 1 mg/mL mitomycin C did not improve clinical symptoms or radiographic changes in patients at 6 months after lumbar disc surgery. Discrepancies in outcomes between animal experiments and clinical trials are likely attributable to the different doses of mitomycin C applied locally, indirect versus direct application of mitomycin C, and a lack of methodological differences between studies. Thus, we have designed a prospective, randomized, controlled, double-blinded clinical trial where 0.5 mg/mL mitomycin C, which has been shown to be safe and effective in animal experiments, will be used directly on the site of surgery. Additionally, we will attempt to establish a method to more precisely grade imaging data regarding epidural scar formation after lumbar disc surgery.
| Methods/Design|| |
This prospective, randomized, controlled, double-blinded, single-center clinical trial will be performed at the Affiliated Zhongda Hospital of Southeast University in China. Patients with one-segment lumbar intervertebral disc protrusion eligible for inclusion in this study will be divided into a treatment group and control group. In the treatment group, after intervertebral discectomy, the site of surgery will be treated with 0.5 mg/mL mitomycin C applied topically for 5 minutes. In the control group, similar procedures will be performed with mitomycin C replaced by 0.9% physiological saline. At postoperative 1 week, and 3 and 6 months, Lumbar Spine Outcomes Questionnaire (LSOQ) score will be used to evaluate whether low-dose mitomycin C applied topically can reduce epidural scar-related clinical symptoms after microendoscopic discectomy. At postoperative 3 months, contrast-enhanced MRI of the lumbar spine will be performed to investigate whether low-dose mitomycin C, applied topically, can inhibit epidural scar proliferation and adhesion after microendoscopic discectomy [Figure 1]. This trial was registered at the Chinese Clinical Trial Registry (identifier: ChiCTR-TRC-10001079) on 6 September 2010.
Ethical considerations and informed consent
This trial protocol has acquired written approval from the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), China (approval No. 2010-SR-088). Written informed consent has been acquired from each patient, and the trial protocol will be performed in accordance with the Declaration of Helsinki, formulated by the World Medical Association.
Seventy-five patients with one-segment lumbar intervertebral disc protrusion are scheduled to undergo microendoscopic posterior discectomy at the Affiliated Zhongda Hospital of Southeast University in China. All patients who meet the following inclusion criteria will be eligible for participation in this trial.
- Age < 60 years, of either sex.
- Indications for microendoscopic posterior discectomy (VIIID)
- Informed consent from patients or their relatives or guardians
- Patients who have one of the following: withdrawal of steroids applied at the epidural region less than 4 weeks prior to surgery; withdrawal of steroids taken orally less than 10 days prior to surgery; withdrawal of aspirin less than 7 days prior to surgery
- Patients who have one of the following complications: cauda equina syndrome; lumbar intervertebral disc protrusion presenting with lumbar slippage and lumbar intervertebral instability; need of internal fixation to stabilize the spine after decompression; severe spinal stenosis with clinical symptoms that require disc decompression; nonunion or fracture of the pars interarticularis, vertebral body or intraspinal tumor and adhesive arachnoiditis
- Patients with multiple-segment (n ≥ 2) lumbar intervertebral disc protrusion
- Patients who have a long course of disease and receive several intrathecal administrations prior to surgery, or myelography or acupuncture within 24 hours prior to surgery
- Patients who previously underwent spine surgery, such as recurring lumbar intervertebral disc disease at the same segment after conventional open lumbar discectomy
- Patients with systematic disease, history of hypersensitiveness, local or systemic infection, anemia and hepatic and renal dysfunction
- Patients who have allergic constitutions, or those with bronchial asthma or a history of other diseases.
- Patients with mental disorders.
- Patients participating in other trials.
- Voluntarily withdrawing from the trial
- Requirement to undergo lumbar spine surgery during the follow-up period (admission to postoperative month 6)
- Patients who cannot complete clinical follow-up during the follow-up period because of unalterable reasons
- Patients who have adverse events caused by interventions during the trial period
Randomization and blinding
Seventy-five patients were numbered 1-75 by the order of their recruitment and then randomly assigned to either a treatment group (mitomycin C applied topically) or a control group (physiological saline applied topically) according to randomization schedules generated by the SAS PROC PLAN program (SAS Institute, Cary, NC, USA). One person, not involved in the trial, will hold the randomly assigned sequence numbers in a sealed opaque envelope in a locked place. If the randomly assigned sequence numbers are saved electronically, then this data file will be encrypted. At the end of microendoscopic discectomy, one nurse blinded to grouping will dispense either mitomycin C or physiological saline. Patients, nurses responsible for drug administration, orthopedists administering interventions, and radiological data assessors will all be blinded to group assignment.
The same highly experienced spine surgeon will perform all surgical procedures, and microendoscopic posterior discectomy will be performed. After epidural anesthesia, all patients will be asked to lie in a prone position. The site for entry of a detent pin will be selected at 1 cm lateral to the line between the spinous processes in the intervertebral space of the diseased segments. The detent pin will be inserted at the inferior border of the upper-level vertebral plate in the intervertebral space of the diseased segment, which will be confirmed using a C-arm digital radiography system. A 1.8-2.0-cm longitudinal incision centered at the detent pin will be made to establish a passage for discoscope assembly and accommodation. The soft tissue on the inside surface of the vertebral plate and articular process will be removed using a nucleus pulposus clamp and spatula to expose the intervertebral space, upper-level vertebral plate, and inside of the articular process. Access through the vertebral plate and inside of the inferior articular process will be made. Flavectomy will be performed via a standard longitudinal splitting approach. Part of the vertebral plate and inside of the inferior articular process will be resected if necessary.
A Kerrison punch will be used to expose the dura and traversing nerve root. Nerve roots will be pulled toward the midline with a detacher and a retractor-equipped aspirator to expose the intervertebral discs. A fibrosis ring will be opened and an incision made on the posterior longitudinal ligament. The nucleus pulposus and degenerated intervertebral discs will be removed with a clamp. If nerve root canal stenosis exists, hypertrophic ligamenta flava and hyperplastic sclerotin in the crypt will be removed. The nerve root canal will be expanded and the nerve root completely released. After strict hemostasis, the person holding the random assignment number sequence will prepare treatments according to grouping.
In the treatment group, the anterior fibrosis ring wound, the lateral side of the nerve root, and the posterior vertebral plate-injured region of the exposed surgical site will be covered with cotton wool and impregnated with 0.5 mg/mL mitomycin C (no water drops) for 5 minutes, and then thoroughly washed with a large amount of physiological saline. In the control group, the same intervention will be performed with the exception that 0.5 mg/mL mitomycin C will be replaced with physiological saline. Thereafter, a suction catheter will be inserted into the intervertebral plate and debris in the intervertebral plate will be thoroughly cleaned. The patient's blood pressure will be monitored during the entire surgical period. After wound washes, the wound will be closed layer by layer using absorbable sutures.
The primary outcome is radiological score for diseased lumbar segment at 3 months after surgery.
- The Ross grading system: contrast-enhanced MRI images will be graded according to a grading system proposed by Ross et al. (1999). Five axial T1-weighted MRI images centered around the surgically treated intervertebral disc will be observed, and each image will be divided into four quadrants a, b, c, and d by a vertical line and a horizontal line, both of which cross in the vertebral canal center. The percentage of epidural fibrosis in the vertebral canal space will be graded on a scale of 0-4 for each quadrant for each imaging slice encompassing the operative level: 0 = no/trace scar; 1 = > 0% and ≤ 25% of quadrant filled with scarring; 2 > 25% and ≤ 50% of quadrant filled with scarring; 3 > 50% and ≤ 75% of quadrant filled with scarring; 4 > 75% and ≤ 100% of quadrant filled with scarring.
- Modified grading system: Five slices of axial T1-weighted MRI images of the lumbar spine will be evaluated using a modified grading system [Figure 2]. The percentage of epidural scarring in the vertebral canal space for each slice will be graded on an 11-point scale: 0 indicates no scar; 1 indicates a slice with 1-10% scar filling; 2, 11-20%; 3, 21-30%; 4, 31-40%; 5, 41-50%; 6, 51-60%; 7, 61-70%; 8, 71-80%; 9, 81-90%; and 10, 90-100%. In addition, the cross-sectional area (CSA) of the vertebral canal (CSA vc ), dural sac (CSA ds ), and nerve roots (CSA nr ) will be measured using a standard measurement program for MR images. During measurement, the partitions of the boundary of the vertebral canal will be defined according to cavity. The front of the CSA vc is at the tail of the intervertebral body or disc; the back of the CSA vc is at the front of the ligament flava; the bilateral sides of the CSA vc are located at the wall of the pedicle of the vertebral arch. If the shapes of the two sides on the vertebral canal image are open, the outer margins of the nerve root are used to locate boundaries [Figure 2]. The following formulas will be used to calculate the mean CSA of the epidural space (CSA es ), epidural fibrosis (CSA ef ), and epidural fibrosis index.
|Figure 2: Corresponding magnetic resonance images detailing the location of epidural fibrosis. |
Reprinted with permission from Liu et al. (2013).
Click here to view
Mean CSA es = Σ (CSA es - CSA ds - CSA nr ) × 1/5
Mean CSA ef = Σ [(CSA es - CSA ds - CSA nr )] × the scale of a single slice × 10%] × 1/5
Epidural fibrosis index = mean CSA ef /mean CSA es × 100%
The secondary outcome is LSOQ score (Bendebba et al., 2007) at 3 and 6 months after surgery. The LSOQ scoring system comprises a lumbar back pain severity score, leg pain severity score, physical symptoms and radiculopathy score, and functional disability and activity-related pain score.
Timing of outcome measures is shown in [Table 2].
Lumbar spine MR scans and enhanced MRI examination
MRI examinations will be performed 3 months after surgery. All patients will be asked to lie in a supine psoas-relaxed position. A spinal surface coil (field of view 25 cm) will be used at a field strength of 1.5 T (Siemens), and slice thickness will be 4 mm (matrix will be 256 × 256 for sagittal and axial sections). Sagittal T1-weighted spin echo images (TR/TE 300/225 milliseconds, sagittal T2-weighted images (TR/TE 3900/150 milliseconds), and axial T1-weighted images (TR/TE 300/22 milliseconds) will be obtained within 10 minutes after intravenous administration of 0.1 mmol/kg Gd-DTPA. Axial images spanning across two levels above the central axial slice of the operative intervertebral disc to two levels below will be taken.
LSOQ scores at postoperative 1 week and 3 months, and MRI scans of the lumbar spine at postoperative 3 months, will be evaluated at outpatient clinic follow-up. LSOQ scores at postoperative 6 months will be obtained via telephone follow-up. The researchers responsible for the trial will designate a person to manage and perform the follow-up. If patients are lost to follow-up, they will be excluded from the final analysis. The reasons for loss to follow-up will be recorded in the patient's medical records.
A censor will monitor adverse events. The possible complications may include wound infection, delayed wound healing, leakage of cerebrospinal fluid, nerve root injury, epidural hematoma, and arachnoiditis. If severe adverse events occur, detailed information including medical data, management method, and any associations will be recorded. The management protocol will be reported to the person in charge and the clinical ethics committee within 5 days.
All data will be collected via Case Report Forms and gathered together. The collected information will be inputted to an electronic database using the double-data entry strategy by professional staff. Information accuracy will be checked when all recruited patients are followed up. The database will be locked down by the researcher in charge and will not be altered. All information relating to this trial will be preserved at the Affiliated Zhongda Hospital of Southeast University in China. The electronic database will be fully disclosed to a professional statistician for statistical analysis. According to the statistical analysis report, the researcher in charge will make a report regarding the trial. An independent Data-Monitoring Committee will monitor and administer the trial data throughout the trial to ensure a robust scientific study process, and to ensure the validity and completeness of data.
All continuous data will be expressed as the mean ± SD, and categorical data as a percentage or number. Statistical analysis regarding differences in primary and secondary outcomes between experimental and control groups will be performed using two-sample t-tests or nonparametric Kruskal-Wallis tests. Statistical analysis regarding differences in categorical variables between experimental and control groups will be performed using chi-square tests or Fisher's exact test. Intraclass correlation coefficients (ICC) will be used to assess the consistency between raters. SPSS 13.0 software will be used for all statistical analyses.
| Discussion|| |
In this prospective, randomized, controlled, double-blind trial, radiological scores used to grade epidural fibrosis of diseased vertebral disc segments after topical application of low-dose mitomycin C, post-microendoscopic discectomy, aim to provide precise data and reproducibility. The framework of this trial protocol aims to provide preliminary theoretical evidence for topical application of mitomycin C to prevent epidural fibrosis after microendoscopic discectomy, and encourage other interventions to prevent epidural fibrosis in clinical practice.
This trial had been completed in 2013. The trial outcomes are shown in [Table 3], [Table 4] and [Table 5]. 
Conflicts of interest
XJC conceived and designed the study protocol. LL recruited the participants. XTW performed the operations. TS was responsible for MRI evaluations and statistical process. All authors approved the final version of this paper.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reivewed by international expert reviewers.
Funding: This work was supported by the National Natural Science Foundation of China (No. 81371969, 81371968, 81401791).
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]