Radiation myelopathy following stereotactic body radiation therapy for spine metastases.

PURPOSE: Stereotactic body radiation therapy (SBRT) is now considered a standard of care treatment option in the management of spine metastases. One of the most feared complications of spine SBRT is radiation myelopathy (RM). METHODS: We provided a narrative review of RM following spine SBRT based on review of the published literature, including data on spinal cord dose constraints associated with the risk of RM, strategies to mitigate the risk, and management options for RM. RESULTS: There are limited published data of cases of RM following spine SBRT with detailed spinal cord dosimetry. The HyTEC report provided recommendations for the point maximal dose (Dmax) for the spinal cord that is associated with a < 5% risk of RM for 1-5 fractions spine SBRT. In the setting of spine SBRT reirradiation after previous conventional external beam radiation therapy (cEBRT), factors associated with RM are: SBRT spinal cord Dmax, cumulative spinal cord Dmax, and the time interval between previous RT and SBRT reirradiation. There are various strategies to mitigate the risk of RM, including accurate delineation of the spinal cord (or thecal sac), strict adherence to the recommended spinal cord dose constraints, and robust treatment immobilisation set-up and delivery. Limited effective treatment options are available for patients who develop RM, and these include corticosteroids, hyperbaric oxygen, and bevacizumab; however, none have been supported by high quality evidence. CONCLUSION: RM is a rare but devastating complication following SBRT for spine metastases. There are strategies to minimise the risk of RM to ensure safe delivery of spine SBRT.

New clinical data on human spinal cord re-irradiation tolerance.

PURPOSE: To provide additional clinical data about the re-irradiation tolerance of the spinal cord. METHODS: This was a retrospective bi-institutional study of patients re-irradiated to the cervical or thoracic spinal cord with minimum follow-up of 6 months. The maximum dose (Dmax) and dose to 0.1cc (D0.1cc) were determined (magnetic resonance imaging [MRI]-defined cord) and expressed as equivalent dose in 2­Gy fractions (EQD2) with an α/ß value of 2 Gy. RESULTS: All 32 patients remained free from radiation myelopathy after a median follow-up of 12 months. Re-irradiation was performed after 6-97 months (median 15). In 22 cases (69%) the re-irradiation spinal cord EQD2 Dmax was higher than that of the first treatment course. Forty-eight of 64 treatment courses employed fraction sizes of 2.5 to 4 Gy to the target volume. The median cumulative spinal cord EQD2 Dmax was 80.7 Gy, minimum 61.12 Gy, maximum 114.79 Gy. The median cumulative spinal cord D0.1cc EQD2 was 76.1 Gy, minimum 61.12 Gy, maximum 95.62 Gy. Besides cumulative dose, other risk factors for myelopathy were present (single-course Dmax EQD2 ≥51 Gy in 9 patients, single-course D0.1cc EQD2 ≥51 Gy in 5 patients). CONCLUSION: Even patients treated to higher cumulative doses than previously recommended, or at a considerable risk of myelopathy according to a published risk score, remained free from this complication, although one must acknowledge the potential for manifestation of damage in patients currently alive, i.e., still at risk. Individualized decisions to re-irradiate after appropriate informed consent are an acceptable strategy, including scenarios where low re-irradiation doses to the spinal cord would compromise target coverage and tumor control probability to an unacceptable degree.

Repeat reirradiation of the spinal cord: multi-national expert treatment recommendations.

BACKGROUND: Improved survival of patients with spinal bone metastases has resulted in an increased number of referrals for retreatment and repeat reirradiation. METHODS: A consortium of expert radiation oncologists (RO) has been established with the aim of providing treatment recommendations for challenging clinical scenarios for which there are no established guidelines. In this case, a patient developed local progression of a T5 vertebral lesion after two prior courses of palliative radiotherapy (time interval >12 months, assumed cumulative biologically equivalent dose in 2­Gy fractions [EQD2] for spinal cord [alpha/beta 2 Gy] 75 Gy). Expert recommendations were tabulated with the aim of providing guidance. RESULTS: Five of seven RO would offer a third course of radiotherapy, preferably with advanced techniques such as stereotactic radiotherapy. However, the dose-fractionation concepts were heterogeneous (3-20 fractions) and sometimes adjusted to different options for systemic treatment. All five RO would compromise target volume coverage to reduce the dose to the spinal cord. Definition of the spinal cord planning-organ-at-risk volume was heterogeneous. All five RO limited the EQD2 for spinal cord. Two were willing to accept more than 12.5 Gy and the highest EQD2 was 19 Gy. CONCLUSIONS: The increasing body of literature about bone metastases and spinal cord reirradiation has encouraged some expert RO to offer palliative reirradiation with cumulative cord doses above 75 Gy EQD2; however, no consensus was achieved. Strategies for harmonization of clinical practice and development of evidence-based dose constraints are discussed.

Demyelination Occurred as the Secondary Damage Following Diffuse Axonal Loss in a Rat Model of Radiation Myelopathy.

The main purpose of the present study was to examine the time and dose-dependent course of demyelination in the rat radiation myelopathy model in the first 180 days after irradiation of the spinal cord. An irradiated cervical spinal cord rat model (C2-T2 segment) was generated using a 60Co irradiator to deliver 50 Gy and 100 Gy, respectively. The behavioral dysfunction was observed by the forelimb paralysis scoring system. The histological damage in the irradiated spinal cord was examined by hematoxylin/eosin staining, luxol fast blue staining, immunohistochemical analysis, methylene blue/Azure II staining, and uranyl/lead salts staining. The gene expression of oligodendrocyte-related markers were also determined by quantitative real-time PCR. The complete loss of forelimb motor function in all animals was observed at 180 days 50 Gy post-irradiation and at 120 days 100 Gy post-irradiation. We demonstrated that a 50 and 100-Gy single-dose irradiation of the C2-T2 spinal cord segment resulted in diffuse axonal loss and elicited secondary demyelination damage in the spinal cord. We further observed that 100-Gy irradiation reduced the gene expression of myelin oligodendrocyte glycoprotein in irradiated spinal cord. Taken together, our data not only define diffuse axonal loss as the main histological damage but also provide the first evidence that demyelination occurred as the secondary damage in irradiated spinal cord.

Radiation Myelopathy: A Case Report and Literature Review.

Proton beam therapy is a common type of radiation treatment that delivers a beam of proton particles to treat cancer and minimize damage to nearby healthy tissue. In this paper, we describe a case of a 20-year-old male patient with osteosarcoma of the distal right femur that eventually metastasized to his thoracic cavity. The patient underwent radiation beam therapy treatment that was directed at his left thorax and nine months later presented with clinical and radiographic findings of delayed radiation myelopathy (RM).

Radiation Myelopathy Caused by Palliative Radiotherapy and Intrathecal Methotrexate.

Radiation myelopathy is a rare, late-stage adverse event that develops following irradiation at or above 50 Gy. Here, we report a case of irreversible paraplegia caused by palliative radiation (20 Gy in 5 fractions) to the spinal cord combined with intrathecal methotrexate (IT-MTX). A 69-year-old man presented with back pain, prompting a diagnosis of acute myeloid leukemia. At the first visit, he complained of muscle weakness and hypoesthesia in both legs; spinal magnetic resonance imaging (MRI) revealed an epidural mass compressing the spinal cord at the fifth to seventh level of the thoracic vertebrae. This was considered to be an extramedullary lesion of leukemia, and he received remission induction therapy including IT-MTX; palliative radiation (20 Gy in 5 fractions) of the epidural mass was initiated the following day. Then, during the course of consolidation therapy, a second IT-MTX was performed after 1 month and a third after 3 months. While the consolidation therapy was complete, yielding remission, he developed sudden paraplegia, as well as bladder and bowel dysfunction (BBD), 10 months later. Spinal MRI showed extensive intramedullary high signal intensity on T2-weighted image, including the irradiation field. It was thought myelopathy was due to irradiation of the spinal cord combined with IT-MTX. He immediately received steroid pulse therapy; however, the paraplegia and BBD did not improve. It is extremely rare for irreversible radiation myelopathy to occur with IT-MTX and palliative radiation to the spinal cord. We believe that even with low-dose palliative radiation, caution is required for combined use with IT-MTX.

Low risk of radiation myelopathy with relaxed spinal cord dose constraints in de novo, single fraction spine stereotactic radiosurgery.

BACKGROUND AND PURPOSE: Spine stereotactic radiosurgery (SSRS) offers high rates of local control in a critical anatomic area by delivering precise, ablative doses of radiation for treatment of spine metastases. However, the dose tolerance of the spinal cord (SC) after SSRS with relation to radiation myelopathy (RM) is not well-described. MATERIALS AND METHODS: We reviewed patients who underwent single fraction, de novo SSRS from 2012-2017 and received >12 Gy Dmax to the SC, defined using MRI-CT fusion without PRV expansion. The standard SC constraint was D0.01cc ≤ 12 Gy. Local control was estimated with the Kaplan-Meier method. Bayesian analysis was used to compute posterior probabilities for RM. RESULTS: A total of 146 SSRS treatments among 132 patients were included. The median SC Dmax was 12.6 Gy (range, 12.1-17.1 Gy). The SC Dmax was >12 and <13 Gy for 109 (75%) treatments, ≥13 and <14 Gy for 28 (19%) treatments, and ≥14 Gy for 9 (6%) treatments. The 1-year local control rate was 94%. With a median follow-up time of 42 months, there were zero (0) RM events observed. Assuming a prior 4.3% risk of RM, the true rate of RM for SC Dmax of ≤14 Gy was computed as <1% with 98% probability. CONCLUSION: In one of the largest series of patients treated with single fraction, de novo SSRS, there were no cases of RM observed with a median follow-up of 42 months. These data support safe relaxation of MRI-defined SC dose up to D0.01cc ≤ 12 Gy, which corresponds to <1% risk of RM.

A Case of Delayed Radiation Myelopathy of the Thoracic Vertebrae Following Low Dose Radiation Therapy for Metastatic Renal Cell Carcinoma.

Delayed radiation myelopathy (DRM) is a rare disorder that rapidly leads to disabilities, and the median incubation period was reported to be about 2 years (from 6 months to a few years). In this report, we describe a 61-year-old woman who presented with rapid progressive numbness and weakness in both legs 22 months after palliative radiation therapy with 39 Gy in 3 Gy fractions. She was diagnosed with DRM of the thoracic vertebrae and was treated sequentially with corticosteroids, heparin, and hyperbaric oxygen therapy. However, they were not effective, and complete paralysis of the legs occurred in 3 months.

An analysis of the structure of the compound biological effectiveness factor.

This report is an analysis of the structure of the compound biological effectiveness (CBE) factor. The value of the CBE factor previously reported was revalued for the central nervous system, skin and lung. To describe the structure, the following terms are introduced: the vascular CBE (v-CBE), intraluminal CBE (il-CBE), extraluminal CBE (el-CBE) and non-vascular CBE (nv-CBE) factors and the geometric biological factor (GBF), i.e. the contributions that are derived from the total dose to the vasculature, each dose to vasculature from the intraluminal side and the extraluminal side, the dose to the non-vascular tissue and the factor to calculate el-CBE from il-CBE, respectively. The el-CBE factor element was also introduced to relate il-CBE to el-CBE factors. A CBE factor of 0.36 for disodium mercaptoundecahydrododecaborate (BSH) for the CNS was independent of the (10)B level in the blood; however, that for p-Boron-L-phenylalanine (BPA) increased with the (10)B level ratio of the normal tissue to the blood (N/B). The CBE factor was expressed as follows: factor = 0.32 + N/B × 1.65. The factor of 0.32 at 0 of N/B was close to the CBE factor for BSH. GBFs had similar values, between BSH and BPA, 1.39 and 1.52, respectively. The structure of the CBE factor for BPA to the lung was also elucidated based on this idea. The factor is described as follows: CBE factor = 0.32 + N/B × 1.80. By this elucidation of the structure of the CBE factor, it is expected that basic and clinical research into boron neutron capture therapy will progress.

Diffusion Tensor Imaging in Radiation-Induced Myelopathy.

Radiation myelopathy (RM) is a rare complication of spinal cord irradiation. Diagnosis is based on the history of radiotherapy, laboratory tests, and magnetic resonance imaging of the spinal cord. The MRI findings may nevertheless be quite unspecific. In this paper, we describe the findings of diffusion tensor imaging in a case of the delayed form of RM. We observed areas of restricted diffusion within the spinal cord which probably corresponded to the ischemic changes. This would concur with the currently accepted pathogenetic theory concerning RM.

Alternative models for estimating the radiotherapy retreatment dose for the spinal cord.

PURPOSE: To review the available experimental animal and patient data on response of the spinal cord to re-irradiation in order to identify appropriate data sets to investigate the clinical potential of models that would allow evaluation of the increase in the retreatment dose with elapsed time from the initial exposure. MATERIALS/METHODS: Analysis of published data on irradiated rat and primate spinal cord identified results for the rat cervical spinal cord that could be compared, where the development of myelopathy was caused by selective white matter necrosis. This data, although limited, provide some important insights. Two models, derived from simple differential equations, provide a time- and dose-dependency for recovery and could be fitted to these data. These models predict the remaining tolerance, in a phase space above the line that connects the 100% biological effectiveness (BEDTOL) tolerance dose of the first and second treatment courses when these are plotted together. A third, much simpler, linear model, assumed that recovery was time but not initial dose dependent. RESULTS: The experimental results showed a non-linear time dependency for the change in biological effectiveness (BED) of the re-irradiation dose. Comparison of the three different models paid particular attention to changes in the re-irradiation dose, when the initial radiation dose was either low or high. For each model, cautious data interpretations were also introduced to reduce the effects of the near completeness of recovery with time derived from the important experiments with primates, which include few data points. Model 1 predicts the least recovery following low initial doses, but with greater recovery following larger initial doses. Model 2 allowed no further irradiation after an initial full tolerance dose, but also greater than expected recovery following the use of smaller priming doses. Model 3 gives unrealistically high doses when used after an initial full tolerance irradiation dose. CONCLUSIONS: These results show that it is possible to model these time-dependent relationships for the spinal cord and that Model 1 is probably the most realistic, especially when it is used conservatively. To give greater confidence as to which of the three presented methods is best, further experiments and/or more analysis of human data are necessary. In the meantime clinicians will need to exert caution and judgement as to the choice of the re-irradiation BED, bearing in mind the other clinical factors that influence radio-tolerance. Further research is necessary to provide the safest recommendations and best clinical outcomes. Some suggestions as to what needs to be done are given.

Delayed radiation myelopathy: Differential diagnosis with positron emission tomography/computed tomography examination.

Myelopathy is a rare but serious complication of radiation therapy (RT). Radiation myelopathy is white matter damage to the spinal cord developed after a certain period of application of ionizing radiation. Factors such as radiation dose and time between applications affect the occurrence as well as the severity of myelopathy. In those patients, positron emission tomography/computed tomography examination has a very important role both in the diagnosis and in the differential diagnosis of lesions. In this case report, the case of progressive paraparesis, developed in a 52-year-old female patient operated with pulmonary mucinous cystadenocarcinoma diagnosis and who received chemotherapy and RT following surgery, has been reported.

Reporte de 2 casos de mielopatía progresiva tardía posradiación / Report of two cases of late progressive myelopathy postradiation

Las complicaciones de la radioterapia se pueden presentar de manera aguda, subaguda o retardada y son diferentes en sus manifestaciones, según afecten al cerebro, la médula espinal o los nervios periféricos. Se presentaron 2 pacientes que recibieron tratamiento con radioterapia y después de un año del proceder terapéutico desarrollaron manifestaciones clínicas e imaginológicas compatibles con una mielopatía posradiación. Ninguno ha tenido progresión de la enfermedad con el uso de los esteroides aplicados...

Complications of radiation therapy can occur in acute, subacute or delayed manner and they are different in manifestations, as they affect the brain, spinal cord or peripheral nerves. Two patients who were treated with radiotherapy were presented and after a year of therapeutic procedure, they developed clinical manifestations and imaging features consistent with a post-radiation myelopathy. None had disease progression with the use of steroids...

Reporte de 2 casos de mielopatía progresiva tardía posradiación / Report of two cases of late progressive myelopathy postradiation

Las complicaciones de la radioterapia se pueden presentar de manera aguda, subaguda o retardada y son diferentes en sus manifestaciones, según afecten al cerebro, la médula espinal o los nervios periféricos. Se presentaron 2 pacientes que recibieron tratamiento con radioterapia y después de un año del proceder terapéutico desarrollaron manifestaciones clínicas e imaginológicas compatibles con una mielopatía posradiación. Ninguno ha tenido progresión de la enfermedad con el uso de los esteroides aplicados(AU)

Complications of radiation therapy can occur in acute, subacute or delayed manner and they are different in manifestations, as they affect the brain, spinal cord or peripheral nerves. Two patients who were treated with radiotherapy were presented and after a year of therapeutic procedure, they developed clinical manifestations and imaging features consistent with a post-radiation myelopathy. None had disease progression with the use of steroids(AU)

The effect of pentoxifylline on radiobiological parameters in the rat radiation myelopathy.

PURPOSE: There is great recent interest in the potential value of using pentoxifylline (3,7-dimethyl-1(5-oxyhexyl)-xanthine, PTX) as an inhibitor of radiation-induced late normal tissue damage. The effects of PTX on the radiobiological parameters (alpha/beta ratio, repair half time T(1/2)) of radiation myelopathy were studied in a rat model. MATERIALS AND METHODS: Anesthetized Sprague-Dawley rats received irradiation to 2 cm of their cervical spines with using a 6MV LINAC (dose rate: 3 Gy/min). Radiation was administered in single, two, four and eight fractions with a fraction interval of 24 h with or without PTX. PTX was added to the rats' distilled drinking water at a concentration of 2 g/L; the water was consumed ad libitum. After tabulation of the ED(50) (the estimated dose needed to produce 50% paralysis in a group of irradiated animals), alpha/beta could be estimated from the ratio of the slope to the intercept of the reciprocal-dose plot. Subsequently, the repair half time T(1/2) was obtained from the data of the experimental group that received a pair of 7 Gy fractions on each day, separated by intervals of 4 and 8 h. RESULTS: The alpha values calculated for RT alone and RT+ PTX were almost the same. We noticed that the beta value for the RT+PTX was lower than that for RT alone. So, the alpha/beta ratio for the RT+PTX was higher. The T(1/2) obtained from monoexponential model was 3.27 and 2.58 h for RT alone and RT+PTX, respectively. CONCLUSION: PTX increased the alpha/beta ratio and it decreased the T(1/2) of radiation myelopathy, suggesting that a decreasing fractionation sensitivity occurred. This implies that PTX, which distinctly acts upon the bending region of the high dose, may be expected to protect the spinal cord with a larger fraction size.

The Effect of Pentoxifylline on Radiobiological Parameters in the Rat Radiation Myelopathy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: There is great recent interest in the potential value of using pentoxifylline (3,7-dimethyl-1(5-oxyhexyl)- xanthine, PTX) as an inhibitor of radiation-induced late normal tissue damage. The effects of PTX on the radiobiological parameters (alpha/beta ratio, repair half time T1/2) of radiation myelopathy were studied in a rat model. MATERIALS AND METHODS: Anesthetized Sprague-Dawley rats received irradiation to 2 cm of their cervical spines with using a 6MV LINAC (dose rate: 3 Gy/min). Radiation was administered in single, two, four and eight fractions with a fraction interval of 24 h with or without PTX. PTX was added to the rats' distilled drinking water at a concentration of 2 g/L; the water was consumed ad libitum. After tabulation of the ED(50) (the estimated dose needed to produce 50% paralysis in a group of irradiated animals), alpha/beta could be estimated from the ratio of the slope to the intercept of the reciprocal-dose plot. Subsequently, the repair half time T(1/2) was obtained from the data of the experimental group that received a pair of 7 Gy fractions on each day, separated by intervals of 4 and 8 h. RESULTS: The alpha values calculated for RT alone and RT+PTX were almost the same. We noticed that the beta value for the RT+PTX was lower than that for RT alone. So, the alpha/beta ratio for the RT+PTX was higher. The T(1/2) obtained from monoexponential model was 3.27 and 2.58 h for RT alone and RT+PTX, respectively. CONCLUSION: PTX increased the alpha/beta ratio and it decreased the T(1/2) of radiation myelopathy, suggesting that a decreasing fractionation sensitivity occurred. This implies that PTX, which distinctly acts upon the bending region of the high dose, may be expected to protect the spinal cord with a larger fraction size.

Chronic Progressive Radiation Myelopathy Associated with Radiation Therapy: A case report

Chronic progressive radiation myelopathy(CPRM) is a rare but serious complication of radiation therapy. It's exact cause is unknown and the diagnosis is usually made based on the exclusion of other causes of myelopathy. Magnetic resonance imaging(MRI) with gadolinium- diethylenetriamine pentaacetic acid(DTPA) enhancement seems to be useful for the diagnosis of CPRM. There is no known effective treatment and the complication is irreversible. We report a case of CPRM after radiation therapy for subglottic cancer which was not respond to high-dose steroid therapy with review of literature.