Low-Dose Radiation to Prevent Complications of Back Surgery

[Wise Young]

http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00018876?order=19&JServSession Idzone_ct=zhn5b9gan1 (http://clinicaltrials.gov/ct/gui/c/a1b/show/NCT00018876?order=19&JServSessionIdzone_ct=zhn5b9gan1)

Low-Dose Radiation to Prevent Complications of Back Surgery

This study is currently recruiting patients.

Sponsored by

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Purpose

More than 10,000 people each year in the United States have "failed back surgery syndrome" caused by scars that form around the outer surface of the spinal cord. Such scarring, known as peridural fibrosis, is common after back surgery known as either lumbar discectomy or laminectomy. Peridural fibrosis may cause recurring low back pain or leg pain after surgery. Operating again to remove the scar tissue often leads to more scarring.

Researchers have not previously studied radiation as a way to prevent peridural fibrosis. We will test whether low-dose radiation given 24 hours before surgery will decrease the amount of peridural fibrosis and if this reduction will lead to improved results of surgery. Half of the participants will receive radiation before surgery and the other half will not. We will evaluate patients at followup visits 1, 3, 6, and 12 months after surgery with a physical exam and questionnaire. At 12 months, we will obtain magnetic resonance imaging (MRI) of the lower spine.


Condition Treatment or Intervention Phase Failed back surgery syndrome
Postlaminectomy syndrome
Postdiscectomy epidural fibrosis

Procedure:Lumbar nerve root decompression Procedure:Preoperative low-dose external beam radiation

Phase I

MEDLINEplusrelated topics:BoneDiseases; Osteoporosis

Study Type:Interventional
Study Design:Treatment,Randomized,Double-Blind Method,Placebo Control,Single Group Assignment,Safety/Efficacy Study

Official Title:Radiotherapy to Prevent Fibrosis After Lumbar Laminectomy

Further Study Details:


Researchers have long known that low-dose radiation inhibits fibroblast and osteoblast activity. Studies in humans have shown that perioperative radiation therapy is a useful way to prevent both keloid and heterotopic bone formation. However, researchers have not previously studied radiation as a means to inhibit peridural fibrosis. Our previous studies of both rat and dog models showed a significant reduction in peridural fibrosis after laminectomy using low-dose external beam radiation (700 cGy) given 24 hours prior to surgery. Based on our results from these animal studies, we will test whether (1) low-dose radiation given 24 hours before surgery will decrease the amount of peridural fibrosis in people and (2) this reduction in peridural fibrosis will lead to improved results of surgery.

For this study, we will enroll 46 patients with failed back surgery syndrome believed to be secondary to perineural fibrosis in a randomized, double-blinded, controlled clinical trial. We will assign patients to one of two groups before surgery: preoperative radiation (treatment group) or no preoperative radiation (control group). We will treat half of the patients with external beam radiation before re-exploration and decompression of their peridural fibrosis (treatment group) and perform re-exploration and decompression in the other half without preoperative radiation (control group).

All patients will undergo simulation radiation treatment planning and will not know if they received radiation or not. For patients randomized to receive preoperative radiation, we will administer a single dose of 700 cGy to a 6.0-cm-wide field centered on the spinal cord at the affected level, using a 6 MV Varian 600C linear accelerator. We will administer treatment with two fields angled 45 degrees from the vertical plane so that the skin surface for the proposed incision will not be irritated. This should prevent any wound healing problems. Only the radiation oncologist and research assistant will know whether radiation was administered. The patient and the surgeon will be masked as to the treatment.

The neurosurgeon co-investigators will perform the same surgical procedure on all patients 24 hours after their radiation (or sham) treatment. We will give all patients preoperative antibiotics. The surgeon will reopen the previous midline posterior lumbar skin incision and dissect the subcutaneous tissue away from the spinous process and laminae. Once the surgeon has adequately exposed the previous surgical site, he or she will place a self-retaining retractor. The surgeon will decompress the nerve by removing the scar tissue from around the nerve root and thecal sac. The surgeon will also remove any intravertebral disc material thought to be causing nerve root compression. On completion of the operation, the surgeon will stop bleeding with electrocautery, irrigate the wound with antibiotic, and close the wound in layers. In general, the hospital stay after surgery is one night. The patient begins gradual ambulation on the evening of surgery.

We will administer the North American Spine Society (NASS) Lumbar Spine Outcome Assessment to patients before treatment and at followup visits to assess their physical functioning. We will also use the NASS questionnaire to collect demographic and lifestyle information at baseline and to assess patient expectations regarding treatment and level of satisfaction with the treatment during the followup period. We will do a physical examination and administer the patient-reported questionnaire prior to surgery and at 1, 3, 6, and 12 months after surgery. We will obtain magnetic resonance (MR) imaging of the lumbar spine 12 months after treatment.


Eligibility

Ages Eligible for Study: 18 Years - 80 Years, Genders Eligible for Study: Both

Participants: Patients

Criteria

Inclusion Criteria:
* Patients with a clinical diagnosis of failed back surgery syndrome.
* Previous surgery at either the L4-5 or L5-S1 levels.
* Patients with peridural fibrosis around the symptomatic nerve root (either L5 or S1) on contrast-enhanced MR imaging.
* Willing and able to be treated and followed at the University of Pittsburgh Medical Center. * Cooperative individuals with no language barrier, and who sign an informed consent form.

Exclusion Criteria:
* Patients less than 18 years of age. * Patients with prior radiotherapy to the same region of the back.
* Female patients with a functioning, intact reproductive system are ineligible until a pregnancy test performed within 48 hours of radiotherapy rules out pregnancy.
* Patients with organic brain syndrome or dementia.
* Severe vascular, pulmonary or coronary artery disease which would place them at an unacceptably high risk to undergo general anesthesia.
* Myocardial infarction within the last 6 months.
* Metastatic cancer.
* Excessive alcohol consumption or evidence of drug use.
* Spondylolisthesis requiring surgical fusion (greater than 5 mm of vertebral slippage.)
* Unable to undergo MR imaging.

Expected Total Enrollment: 46

Location and Contact Information

Pennsylvania
University of Pittsburgh Medical Center,Pittsburgh, Pennsylvania, 15213, United States;Recruiting

Peter C. Gerszten, M.D. 412-647-0994 gerszten@neuronet.pitt.edu

Study chairs or principal investigators

Peter C. Gerszten, M.D., Principal Investigator University of Pittsburgh

More Information

Publications

Abitbol JJ, Lincoln TL, Lind BI, Amiel D, Akeson WH, Garfin SR. Preventing postlaminectomy adhesion. A new experimental model. Spine. 1994 Aug 15;19(16):1809-14. PMID: 7973979 [PubMed - indexed for MEDLINE]

Brotchi J, Pirotte B, De Witte O, Levivier M. Prevention of epidural fibrosis in a prospective series of 100 primary lumbo-sacral discectomy patients: follow-up and assessment at re-operation. Neurol Res. 1999;21 Suppl 1:S47-50. PMID: 10214572 [PubMed - indexed for MEDLINE]

Daltroy LH, Cats-Baril WL, Katz JN, Fossel AH, Liang MH. The North American spine society lumbar spine outcome assessment Instrument: reliability and validity tests. Spine. 1996 Mar 15;21(6):741-9. PMID: 8882698 [PubMed - indexed for MEDLINE]

Dullerud R, Graver V, Haakonsen M, Haaland AK, Loeb M, Magnaes B. Influence of fibrinolytic factors on scar formation after lumbar discectomy. A magnetic resonance imaging follow-up study with clinical correlation performed 7 years after surgery. Spine. 1998 Jul 1;23(13):1464-9. PMID: 9670398 [PubMed - indexed for MEDLINE]

Fandino J, Botana C, Viladrich A, Gomez-Bueno J. Reoperation after lumbar disc surgery: results in 130 cases. Acta Neurochir (Wien). 1993;122(1-2):102-4. PMID: 8333299 [PubMed - indexed for MEDLINE]

Geisler FH. Prevention of peridural fibrosis: current methodologies. Neurol Res. 1999;21 Suppl 1:S9-22. Review. PMID: 10214566 [PubMed - indexed for MEDLINE]

Gerszten PC, Moossy JJ, Bahri S, Kalend A, Martinez AJ. Inhibition of peridural fibrosis after laminectomy using low-dose external beam radiation in a rat model. Neurosurgery. 1999 Mar;44(3):597-602; discussion 602-3. PMID: 10069597 [PubMed - indexed for MEDLINE]

Grane P, Tullberg T, Rydberg J, Lindgren L. Postoperative lumbar MR imaging with contrast enhancement. Comparison between symptomatic and asymptomatic patients. Acta Radiol. 1996 May;37(3 Pt 1):366-72. PMID: 8845271 [PubMed - indexed for MEDLINE]

Hinton JL Jr, Warejcka DJ, Mei Y, McLendon RE, Laurencin C, Lucas PA, Robinson JS Jr. Inhibition of epidural scar formation after lumbar laminectomy in the rat. Spine. 1995 Mar 1;20(5):564-70; discussion 579-80. PMID: 7604326 [PubMed - indexed for MEDLINE]

Jonsson B, Stromqvist B. Repeat decompression of lumbar nerve roots. A prospective two-year evaluation. J Bone Joint Surg Br. 1993 Nov;75(6):894-7. PMID: 8245078 [PubMed - indexed for MEDLINE]

Lo TC, Seckel BR, Salzman FA, Wright KA. Single-dose electron beam irradiation in treatment and prevention of keloids and hypertrophic scars. Radiother Oncol. 1990 Nov;19(3):267-72. PMID: 2126387 [PubMed - indexed for MEDLINE]

Long DM. Failed back surgery syndrome. Neurosurg Clin N Am. 1991 Oct;2(4):899-919. Review. PMID: 1840393 [PubMed - indexed for MEDLINE]

Maroon JC, Abla A, Bost J. Association between peridural scar and persistent low back pain after lumbar discectomy. Neurol Res. 1999;21 Suppl 1:S43-6. PMID: 10214571 [PubMed - indexed for MEDLINE]

Nguyen CM, Haughton VM, Ho KC, An HS. MR contrast enhancement: an experimental study in postlaminectomy epidural fibrosis. AJNR Am J Neuroradiol. 1993 Jul-Aug;14(4):997-1002. PMID: 8352176 [PubMed - indexed for MEDLINE]

North RB, Campbell JN, James CS, Conover-Walker MK, Wang H, Piantadosi S, Rybock JD, Long DM. Failed back surgery syndrome: 5-year follow-up in 102 patients undergoing repeated operation. Neurosurgery. 1991 May;28(5):685-90; discussion 690-1. PMID: 1831546 [PubMed - indexed for MEDLINE]

Porchet F, Lombardi D, de Preux J, Pople IK. Inhibition of epidural fibrosis with ADCON-L: effect on clinical outcome one year following re-operation for recurrent lumbar radiculopathy. Neurol Res. 1999;21 Suppl 1:S51-60. PMID: 10214573 [PubMed - indexed for MEDLINE]

Ross JS, Robertson JT, Frederickson RC, Petrie JL, Obuchowski N, Modic MT, deTribolet N. Association between peridural scar and recurrent radicular pain after lumbar discectomy: magnetic resonance evaluation. ADCON-L European Study Group. Neurosurgery. 1996 Apr;38(4):855-61; discussion 861-3. PMID: 8692415 [PubMed - indexed for MEDLINE]

Yukawa Y, Kato F, Kajino G, Nakamura S. Serial gadolinium-enhanced MR imaging after lumbar disc resection: observation of the affected root. J Spinal Disord. 1997 Oct;10(5):404-9. PMID: 9355057 [PubMed - indexed for MEDLINE]

Study ID Numbers NIAMS-057; R21 AR47121
NLM Identifier NCT00018876

Date study startedOctober 2000; Date Study Completed October 2002 Record last reviewed March 2001

[This message was edited by Wise Young on August 06, 2001 at 12:20 PM.]

[Wise Young]

Please note that several studies suggest that low-dose radiation given to rats at 1-2 weeks after injury improves function recovery in rats.

1. Kalderon N, Xu S, Koutcher JA and Fuks Z (2001). Fractionated radiation facilitates repair and functional motor recovery after spinal cord transection in rat. Brain Res. 904 (2): 199-207. Summary: Previous studies suggest that motor recovery does not occur after spinal cord injury because reactive glia abort the natural repair processes. A permanent wound gap is left in the cord and the brain-cord circuitry consequently remains broken. Single-dose x-irradiation destroys reactive glia at the damage site in transected adult rat spinal cord. The wound then heals naturally, and a partially functional brain-cord circuitry is reconstructed. Timing is crucial; cell ablation is beneficial only within the third week after injury. Data presented here point to the possibility of translating these observations into a clinical therapy for preventing the paralysis following spinal cord injury in the human. The lesion site (at low thoracic level) in severed adult rat spinal cord was treated daily, over the third week postinjury, with protocols of fractionated radiation similar to those for treating human spinal cord tumors. This resulted, as with the single-dose protocol, in wound healing and restoration of some hindquarter motor function; in addition, the beneficial outcome was augmented. Of the restored hindlimb motor functions, weight-support and posture in stance was the only obvious one. Recovery of this motor function was partial to substantial and its incidence was 100% instead of about 50% obtained with the single-dose treatment. None of the hindlimbs, however, regained frequent stepping or any weight-bearing locomotion. These data indicate that the therapeutic outcome may be further augmented by tuning the radiation parameters within the critical time-window after injury. These data also indicate that dose- fractionation is an effective strategy and better than the single-dose treatment for targeting of reactive cells that abort the natural repair, suggesting that radiation therapy could be developed into a therapeutic procedure for repairing injured spinal cord. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=11406117> Sloan-Kettering Institute for Cancer Research, 10021, New York, NY, USA

2. Ridet JL, Pencalet P, Belcram M, Giraudeau B, Chastang C, Philippon J, Mallet J, Privat A and Schwartz L (2000). Effects of spinal cord X-irradiation on the recovery of paraplegic rats. Exp Neurol. 161 (1): 1-14. Summary: Axonal regrowth is limited in the adult CNS, especially in the spinal cord, one of the major sites of traumatic lesions. Pathophysiological changes occurring after spinal cord injury include complex acute, subacute, and late processes. In this study, we assessed whether X- irradiation interferes with the acute/subacute phases, thereby improving the functional recovery of paraplegic animals. Two days after acute compression of adult rat spinal cords, various doses (0, 2, 5, 10, 20 Gy) of X-rays were administered as one single dose to the compression site. The animals were functionally evaluated over the course of 1 month after injury, using the Tarlov scale and the Rivlin and Tator scale. We also designed a "physiological" scale, including an assessment of urinary function and infection, appropriate for the evaluation of spinal-cord-lesioned animals. Behavioral analysis suggested that the high doses, 20 Gy and, to a lesser extent, 5 and 10 Gy, were toxic, as shown by morbidity rate and "physiological" score. The 2-Gy group showed better motor performances than the lesioned nonirradiated (LNI) animals and the 5- and 20-Gy groups. Motor performance in the 5-, 10-, and 20-Gy groups was poorer than that seen in the LNI group. Gliosis was reduced in the 2-Gy group compared to LNI animals, and there was high levels of gliosis in the highly (>/=5 Gy) irradiated animals. There was a 23% less lesion-induced syringomyelia in the 2-Gy group than in the other groups (LNI and 5-20 Gy). Thus, low doses of X-rays may interfere with the formation of syringomyelia and glial scar, thereby facilitating the recovery of paraplegic animals. These findings suggest that low-dose irradiation of the lesion site, in association with other therapies, is a potentially promising treatment for improving recovery after spinal cord injury. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=10683269> CNRS UMR 9923, Hopital Pitie-Salpetriere, Paris. luc.ridet@chuv.hospvd.ch

3. Kalderon N and Fuks Z (1996). Severed corticospinal axons recover electrophysiologic control of muscle activity after x-ray therapy in lesioned adult spinal cord. Proc Natl Acad Sci U S A. 93 (20): 11185-90. Summary: Mechanical injury to the adult mammalian spinal cord results in permanent loss of structural integrity at the lesion site and of the brain-controlled function distal to the lesion. Some of these consequences were permanently averted by altering the cellular constituents at the lesion site with x-irradiation delivered within a critical time window after injury. We have reported in a separate article that x-irradiation of sectioned adult rat spinal cord resulted in restitution of structural continuity and regrowth of severed corticospinal axons across and deep into the distal stump. Here, we report that after x-ray therapy of the lesion site severed corticospinal axons of transected adult rat spinal cord recover electrophysiologic control of activity of hindlimb muscles innervated by motoneurons distal to the lesion. The degree of recovery of control of muscle activity was directly related to the degree of restitution of structural integrity. This restitution of electrophysiologic function implies that the regenerating corticospinal axons reestablish connectivity with neurons within the target field in the distal stump. Our data suggest that recovery of structural continuity is a sufficient condition for the axotomized corticospinal neurons to regain some of their disrupted function in cord regions distal to the lesion site. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=8855330> Rockefeller University, New York, NY 10021, USA. kalderon@mskcc.org

4. Kalderon N and Fuks Z (1996). Structural recovery in lesioned adult mammalian spinal cord by x- irradiation of the lesion site. Proc Natl Acad Sci U S A. 93 (20): 11179-84. Summary: Mechanical injury to the adult mammalian spinal cord results in permanent morphological disintegration including severance/laceration of brain-cord axons at the lesion site. We report here that some of the structural consequences of injury can be averted by altering the cellular components of the lesion site with x-irradiation. We observed that localized irradiation of the unilaterally transected adult rat spinal cord when delivered during a defined time-window (third week) postinjury prevented cavitation, enabled establishment of structural integrity, and resulted in regrowth of severed corticospinal axons through the lesion site and into the distal stump. In addition, we examined the natural course of degeneration and cavitation at the site of lesion with time after injury, noting that through the third week postinjury recovery processes are in progress and only at the fourth week do the destructive processes take over. Our data suggest that the adult mammalian spinal cord has innate mechanisms required for recovery from injury and that timed intervention in certain cellular events by x- irradiation prevents the onset of degeneration and thus enables structural regenerative processes to proceed unhindered. We postulate that a radiation-sensitive subgroup of cells triggers the delayed degenerative processes. The identity of these intrusive cells and the mechanisms for triggering tissue degeneration are still unknown. <http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=8855329> Rockefeller University, New York, NY 10021, USA. kalderon@mskcc.org