Radiation-induced Myelopathy Research Articles

Long-term changes of prostacyclin secretion in radiation-induced myelopathy

We have previously reported the short-term changes in prostacyclin profile after irradiation of rat cervical cord. Present research investigated the long-term changes of prostacyclin content. Wistar rats in groups of five were irradiated with doses of 2, 4, 6, 15, 25, 30 Gy and a single group of 25 with 35 Gy X-rays. After 26 and 39 weeks, prostacyclin content was quantified by 6-keto-prostaglandin-F1α (prostacyclin stabilized metabolite). Specimens were stained routinely for histological studies. The 50% latent period and effective dose were 14.86±1.16 weeks and 25.66±0.54 Gy (p<0.0001), respectively. Average ratios of 6-keto-PG-F1α for doses of 2–30 Gy were between 78.33–12.93% and 79.48–99.96% for 26 and 39 weeks, respectively. Prostacyclin level after 35 Gy shows approximately a 7:1 ratio in comparison to the control group (p<0.002). Histopathological changes in glial and vascular tissues were diagnosed and scored. Prostacyclin bimodal profile was observed. Radiation can cause complex fluctuations of prostacyclin in association with marked histopathological changes.

Evaluation of image-guided helical tomotherapy for the retreatment of spinal metastasis

Patients with vertebral metastasis that receive radiation therapy are typically treated to the spinal cord tolerance dose. As such, it is difficult to successfully deliver a second course of radiation therapy for patients with overlapping treatment volumes. In this study, an image-guided helical tomotherapy system was evaluated for the retreatment of previously irradiated vertebral metastasis. Helical tomotherapy dose gradients and maximum cord doses were measured in a cylindrical phantom for geometric test cases with separations between the planning target volume (PTV) and the spinal cord organ at risk (OAR) of 2 mm, 4 mm, 6 mm, 8 mm, and 10 mm. Megavoltage computed tomography (CT) images were examined for their ability to localize spinal anatomy for positioning purposes by repeat imaging of the cervical spine in an anthropomorphic phantom. In addition to the phantom studies, 8 patients with cord compressions that had received previous radiation therapy were retreated to a mean dose of 28 Gy using conventional fractionation. Megavoltage CT images were capable of positioning an anthropomorphic phantom to within +/-1.2 mm (2sigma) superior-inferiorly and within +/-0.6 mm (2sigma) anterior-posteriorly and laterally. Dose gradients of 10% per mm were measured in phantom while PTV uniformity indices of less than 11% were maintained. The calculated maximum cord dose was 25% of the prescribed dose for a 10-mm PTV-to-OAR separation and 71% of the prescribed dose for a PTV-to-OAR separation of 2 mm. Eight patients total have been treated without radiation-induced myelopathy or any other adverse effects from treatment. A technique has been evaluated for the retreatment of vertebral metastasis using image-guided helical tomotherapy. Phantom and patient studies indicated that a tomotherapy system is capable of delivering dose gradients of 10% per mm and positioning the patient within 1.2 mm without the use of special stereotactic immobilization.

Re-Irradiation of Brain Metastases and Metastatic Spinal Cord Compression: Clinical Practice Suggestions

The recent improvements of therapeutic approaches in oncology have allowed a certain number of patients with advanced disease to survive much longer than in the past. So, the number of cases with brain metastases and metastatic spinal cord compression has increased, as has the possibility of developing a recurrence in areas of the central nervous system already treated with radiotherapy. Clinicians are reluctant to perform re-irradiation of the brain, because of the risk of severe side effects. The tolerance dose for the brain to a single course of radiotherapy is 50-60 Gy in 2 Gy daily fractions. New metastases appear in 22-73% of the cases after whole brain radiotherapy, but the percentage of reirradiated patients is 3-10%. An accurate selection must be made before giving an indication to re-irradiation. Patients with Karnofsky performance status > 70, age < 65 years, controlled primary and no extracranial metastases are those with the best prognosis. The absence of extracranial disease was the most significant factor in conditioning survival, and maximum tumor diameter was the only variable associated with an increased risk of unacceptable acute and/or chronic neurotoxicity. Re-treatment of brain metastases can be done with whole brain radiotherapy, stereotactic radiosurgery or fractionated stereotactic radiotherapy. Most patients had no relevant radiation-induced toxicity after a second course of whole brain radiotherapy or stereotactic radiosurgery. There are few data on fractionated stereotactic radiotherapy in the re-irradiation of brain metastases. In general, the incidence of an "in-field" recurrence of spinal metastasis varies from 2.5-11% of cases and can occur 2-40 months after the first radiotherapy cycle. Radiation-induced myelopathy can occur months or years (6 months-7 years) after radiotherapy, and the pathogenesis remains obscure. Higher radiotherapy doses, larger doses per fraction, and previous exposure to radiation could be associated with a higher probability of developing radiation-induced myelopathy. Experimental data indicate that also the total dose of the first and second radiotherapy, interval to re-treatment, length of the irradiated spinal cord, and age of the treated animals influence the risk of radiation-induced myelopathy. An alpha/beta ratio of 1.9-3 Gy could be generally the reference value for fractionated radiotherapy. However, when fraction sizes are up to 5 Gy, the linear-quadratic equation become a less valid model. The early diagnosis of relapse is crucial in conditioning response to re-treatment.

Multifractionated image-guided and stereotactic intensity-modulated radiotherapy of paraspinal tumors: A preliminary report

The use of image-guided and stereotactic intensity-modulated radiotherapy (IMRT) techniques have made the delivery of high-dose radiation to lesions within close proximity to the spinal cord feasible. This report presents clinical and physical data regarding the use of IMRT coupled with noninvasive body frames (stereotactic and image-guided) for multifractionated radiotherapy. The Memorial Sloan-Kettering Cancer Center (Memorial) stereotactic body frame (MSBF) and Memorial body cradle (MBC) have been developed as noninvasive immobilizing devices for paraspinal IMRT using stereotactic (MSBF) and image-guided (MBC) techniques. Patients were either previously irradiated or prescribed doses beyond spinal cord tolerance (54 Gy in standard fractionation) and had unresectable gross disease involving the spinal canal. The planning target volume (PTV) was the gross tumor volume with a 1 cm margin. The PTV was not allowed to include the spinal cord contour. All treatment planning was performed using software developed within the institution. Isocenter verification was performed with an in-room computed tomography scan (MSBF) or electronic portal imaging devices, or both. Patients were followed up with serial magnetic resonance imaging every 3-4 months, and no patients were lost to follow-up. Kaplan-Meier statistics were used for analysis of clinical data. Both the MSBF and MBC were able to provide setup accuracy within 2 mm. With a median follow-up of 11 months, 35 patients (14 primary and 21 secondary malignancies) underwent treatment. The median dose previously received was 3000 cGy in 10 fractions. The median dose prescribed for these patients was 2000 cGy/5 fractions (2000-3000 cGy), which provided a median PTV V100 of 88%. In previously unirradiated patients, the median prescribed dose was 7000 cGy (5940-7000 cGy) with a median PTV V100 of 90%. The median Dmax to the cord was 34% and 68% for previously irradiated and never irradiated patients, respectively. More than 90% of patients experienced palliation from pain, weakness, or paresthesia; 75% and 81% of secondary and primary lesions, respectively, exhibited local control at the time of last follow-up. No cases of radiation-induced myelopathy or radiculopathy have thus far been encountered. Precision stereotactic and image-guided paraspinal IMRT allows the delivery of high doses of radiation in multiple fractions to tumors within close proximity to the spinal cord while respecting cord tolerance. Although preliminary, the clinical results are encouraging.

Evaluation of insulin-like growth factor-1 for prevention of radiation-induced spinal cord damage

Aim: To test whether insulin-like growth factor-1 (IGF-1) ameliorates radiation-induced spinal cord myelopathy and to establish the dose-effect relationship for this growth factor which has not been administered in conjunction with spinal cord irradiation to date.Methods: Animal experiments were conducted to test the feasibility of IGF-1 injection in a model of cervical spinal cord irradiation in adult Fisher F-344 rats and to determine the most effective dose level of IGF-1. Irradiation was given in two fractions (16 Gy followed by 18 Gy) and animals were examined for the development of paresis (follow-up 12 months).Results: The dose-finding experiment revealed significant differences in the incidence of radiation myelopathy (RM). The most effective dose of IGF-1 was 50 μg per day.Conclusions: IGF-1 showed promising activity as a radioprotective agent in a model of high-dose spinal cord irradiation. Further studies are needed to examine the results with multiple small doses of radiation as widely applied in clinical protocols.

Management of metastatic spinal cord compression.

Metastatic spinal cord compression, diagnosed in 3-7% of cancer patients, is one of the most dreaded complications of metastatic cancer. It is an oncologic emergency, which must be diagnosed early and treated promptly to achieve the best results and avoid progressive pain, paralysis, sensory loss and sphincter incontinence. Patients who are ambulatory at the time of the diagnosis have a higher probability of obtaining good response to treatment and a longer survival. In clinical practice, back pain accompanies metastatic spinal cord compression in most cases, even in patients with no neurologic deficits. Magnetic resonance imaging is the best tool for diagnosing metastatic spinal cord compression and is able to identify spinal cord compression in 32-35% patients with back pain, bone metastases and normal neurologic examination. Moreover, magnetic resonance imaging gives the extension of the lesion, can diagnose other unsuspected clinical metastatic spinal cord compression sites, and is useful for the radiation oncologist in defining the target volume. Radiotherapy is the treatment of choice in most cases, whereas surgery is advised only in selected patients (ie, if stabilization is necessary, if radiotherapy has already been given in the same area, when vertebral body collapse causes bone impingement on the cord or nerve roots, when there are diagnostic doubts, or when computed tomography-guided percutaneous vertebral biopsy cannot be performed). Laminectomy should be abandoned in favor of more aggressive surgery (ie, posterior, anterior, and/or lateral approach, tumor mass resection, and stabilization of the spine). Generally, radiotherapy must be administered 7-10 days after surgery. The optimal radiation schedule has not been defined. However, as recently suggested by some clinical trials, even the hypofractionated radiotherapy regimens are effective and can be used without increasing radiation-induced myelopathy. Moderate doses of dexamethasone should be used in the early phases of therapy. After radiotherapy, spinal recurrence is generally found in sites different from the first compression area. A close post-treatment follow-up is suggested using clinical parameters (pain, motor and sphincter function), and magnetic resonance imaging should be performed only when a second metastatic spinal cord compression and/or myelopathy are clinically suspected.

27 disc Reduction of radiation-induced myelopathy by platelet-derived growth factor: a dose response study

27 disc Reduction of radiation-induced myelopathy by platelet-derived growth factor: a dose response study

Modification of radiation myelopathy by the transplantation of neural stem cells in the rat.

In a novel approach, neural stem cells were transplanted to ameliorate radiation-induced myelopathy in the spinal cords of rats. A 12-mm section of the cervical spinal cord (T2-C2) of 5-week-old female Sprague-Dawley rats was locally irradiated with a single dose of 22 Gy of (60)Co gamma rays. This dose is known to produce myelopathy in all animals within 6 months of irradiation. After irradiation, the animals were subdivided into three groups, and at 90 days after irradiation, neural stem cells or saline (for controls) were injected into the spinal cord, intramedullary, at two sites positioned 6 mm apart on either side of the center of the irradiated length of spinal cord. The injection volume was 2 microl. Group I received a suspension of MHP36 cells, Group II MHP15 cells, and Group III (controls) two injections of 2 microl saline. All rats received 10 mg/kg cyclosporin (10 mg/ml) daily i.p. to produce immunosuppression. All animals that received saline (Group III) developed paralysis within 167 days of irradiation. The paralysis-free survival rates of rats that received transplanted MHP36 and MHP15 cells (Groups I and II) were 36.4% and 32% at 183 days, respectively. It was concluded that transplantation of neural stem cells 90 days after irradiation significantly (P = 0.03) ameliorated the expression of radiation-induced myelopathy in the spinal cords of rats.

Radiation-induced myelopathy in long-term surviving metastatic spinal cord compression patients after hypofractionated radiotherapy: a clinical and magnetic resonance imaging analysis

Background and purpose: Hypofractionated radiotherapy is often administered in metastatic spinal cord compression (MSCC), but no studies have been published on the incidence of radiation-induced myelopathy (RIM) in long-term surviving patients. Our report addresses this topic. Patients and methods: Of 465 consecutive MSCC patients submitted to radiotherapy between 1988 and 1997, 13 live patients (seven females, six males, median age 69 years, median follow-up 69 months) surviving for 2 years or more were retrospectively reviewed to evaluate RIM. All patients underwent radiotherapy. Eight patients underwent a short-course regimen of 8 Gy, with 7 days rest, and then another 8 Gy. Five patients underwent a split-course regimen of 5 Gy ×3, 4 days rest, and then 3 Gy ×5. Only one patient also underwent laminectomy. Full neurological examination and magnetic resonance imaging (MRI) were performed. Results: Of 12 patients submitted to radiotherapy alone, 11 were ambulant (eight without support and three with support) with good bladder function. In nine of these 11 patients, MRI was negative; in one case MRI evidenced an in-field relapse 30 months after the end of radiotherapy, and in the other, two new MSCC foci outside the irradiated spine. In the remaining patient RIM was suspected at 18 months after radiotherapy when the patient became paraplegic and cystoplegic, and magnetic resonance images evidenced an ischemic injury in the irradiated area. The only patient treated with surgery plus postoperative radiotherapy worsened and remained paraparetic. Magnetic resonance images showed cord atrophy at the surgical level, explained as an ischemic necrosis due to surgery injury. Conclusions: On the grounds of our data regarding RIM in long-term surviving MSCC patients, we believe that a hypofractionated radiotherapy regimen can be used for the majority of patients. For a minority of patients, more protracted radiation regimens could be considered.

Anticoagulation Therapy for Radiation-Induced Myelopathy

Anticoagulation Therapy for Radiation-Induced Myelopathy

Squamous Cell Carcinoma of the Nasopharynx&An Analysis of Treatment Results in 149 Consecuti v e Patients

The purpose of this study was to evaluate the outcome of primary treatment and treatment of recurrences in patients with nasopharyngeal carcinoma. The material included 149 consecutive patients seen at the Aarhus University Hospital from 1963 to 1991 (49 females and 100 males). The stage distribution was: Stage I –9%, II–3%, III–28%, and IV–60%. Primary treatment was delivered with curative intent in 145 patients (97%). Persistent or recurrent disease after primary radical treatment was observed in 82 of the patients; 54% at the T-level, 40% at the N-level, and 33% at the M-level. A curative salvage attempt was carried out in 14 patients only, all with nodal recurrence: surgery in 8 patients (4 controlled) and radiotherapy in 6 patients (2 controlled). The 5-year local tumour control, locoregional tumour control, disease-specific survival rate and the overall survival rate for the patients treated with curative intent were 66%, 53%, 50% and 43%, respectively. Most of the patients (88%) had poorly differentiated tumours and these patients had the best prognosis. A major complication in three patients was radiation-induced myelopathy due to high-dose radiation delivered to the brain stem. Significant positive prognostic factors for treatment outcome in univariate analyses were early T-classification, small clinical stage, poor differentiation and low age. The Cox multivariate analysis showed that early T-categories, low N-categories and poor differentiation were independent, positive prognostic factors. Nasopharyngeal carcinoma is curable with primary radiotherapy; patients with poorly differentiated tumours have the best prognosis. Only a few patients were salvaged after recurrence. The factor most essential for success is primary control of the disease at the T- and N-levels.

MRI in radiation-induced myelopathy and pharyngocutaneous fistula

MRI in radiation-induced myelopathy and pharyngocutaneous fistula

Radiation-induced myelopathy and vertebral necrosis

Radiation-induced myelopathy is often a diagnosis of exclusion. In addition to the classic criteria needed to support the diagnosis, the presence of another radiation-induced lesion, such as aseptic vertebral necrosis, is useful to confirm the cause of the spinal cord lesion.

A new model of radiation-induced myelopathy: A comparison of the response of mature and immature pigs

Purpose : The development of an experimental model of radiation-induced myelopathy in the pig which would facilitate the study of the effects of clinically relevant treatment volumes. Methods and Materials : The effects of local spinal cord irradiation, to a standard 10 × 5 cm field, have been evaluated in mature (37–42.5 weeks) and immature (15.5–23 weeks) pigs. Irradiation was with single doses of 60Co γ-rays at a dose-rate of 0.21–0.65 Gy/min. The incidence of paralysis was used as an endpoint. Results : Irradiation of mature animals resulted in the development of frank paralysis with animals showing combined parenchymal and vascular pathologic changes in their white matter. These lesions, in common with those seen in patients, had a clear evidence of an inflammatory component. The latency for paralysis was short, 7.5–16.5 weeks, but within the wide range reported for patients. However, it was shorter than that reported in other large animal models. The ED 50 value (± SE) for paralysis was 27.02 ± 0.36 Gy, similar to that in rats taking into account doserate factors. The irradiation of immature pigs only resulted in transient neurological changes after doses comparable to those used in the mature animals, ED 50 value (± SE) 26.09 ± 0.37 Gy. The reasons for these transient neurological symptoms are uncertain. Conclusion : A reliable experimental model of radiation-induced myelopathy has been developed for mature pigs. This model is suitable for the study of clinically relevant volume effects.

Permanent radiation myelopathy

Because of the morbidity and mortality associated with radiation myelopathy, radiation injury to the spinal cord has been the subject of more clinical reports than any other normal-tissue injury. The spinal cord is perhaps second only to skin as the organ most frequently studied by radiobiologists. Its response has been investigated in mice, rats, cats, guinea pigs, rabbits, pigs, dogs, and rhesus monkeys—virtually every laboratory animal species. Given this level of attention, it is surprising what is not known about the radiation response of the spinal cord. Relatively few animal studies have been performed on the effect of cytotoxic drugs on the radiation response of the spinal cord, the age effects, the effects of blood pressure or other physiological conditions that are controllable in the laboratory, or the relative response of various anatomical levels of the spinal cord. In addition to these unresolved factors, the dose response in the human is still poorly defined. However, as a result of the attention this injury has received, substantial information is available on the diagnosis, pathogenesis and dose fractionation dependence. This review seeks to establish the facts, expose the myths and define the issues still in dispute regarding radiation-induced myelopathy.

Alteration in myelin-associated proteins following spinal cord irradiation in guinea pigs

The aim of this study was to investigate the pathological and cellular basis for radiation-induced myelopathy in guinea pigs by monitoring biochemical alterations in levels of myelin basic protein and 2′,3′-cyclic nucleotide phosphohydrolase. Guinea pigs were irradiated to the lumbar region with various doses of neutrons or cobalt y irradiation. The ED 50s for paralysis were 17.2 Gy and 67.5 Gy for neutron and cobalt irradiation, respectively, and was histologically associated with demyelination. In spinal cords taken from animals at the onset of paralysis myelin basic protein levels were decreased in direct relationship to the radiation dose. The lowest doses to cause paralysis led to a 25% decrease in MBP levels. In a separate experiment, alterations in MBP were measured in the spinal cords over the time period leading up to paralysis. Surprisingly, decreases in MBP were found immediately after the end of the 4 week irradiation period. These early changes in MBP were not markedly dose dependent and occurred with nonparalyzing doses. Dose-dependent decreases were found only just before the onset of paralysis. CNPase activity measured in the same specimens showed changes that were essentially similar to those for MBP. In the CSF, MBP levels were essentially constant until onset of paralysis. This study showed that demyelination, as assessed by the levels of the myelin-associated proteins MBP and CNPase, can occur soon after spinal cord irradiation but that profound dose-dependant changes are seen only immediately preceding the onset of paralysis. Although increases in MBP in the CSF were associated with the onset of radiation-induced myelopathy, its assay is unlikely to predict this complication of irradiation.

Myelin basic protein and magnetic resonance imaging for diagnosing radiation myelopathy

The identification of radiation myelopathy using biochemical assays and imaging techniques has not previously been accomplished but has clear clinical application. Measurement of myelin basic protein (MBP) in the cerebrospinal fluid (CSF) and visualization of the spinal cord using magnetic resonance imaging (MRI) gives a potentially accurate diagnosis of radiation myelopathy. Female New Zealand white rabbits were irradiated to the thoracic spinal cord with single doses of 15–45 Gy. Animals receiving higher doses (≥22 Gy) generally demonstrated an early paresis (4–8 weeks) that temporarily improved, and then progressed to complete paralysis by 14–18 weeks. MBP levels in the CSF became strikingly elevated to 1001̄000 times the normal value. Subsequent, experiments in which rabbits were serially assessed for MBP levels demonstrated a transient elevation, which corresponded to the transient paresis, followed by dramatic elevations concurrent with the onset of paralysis. Magnetic resonance imaging (MRI) of the irradiated spinal cord showed a geographically distinct region of abnormality that corresponded to the radiation field. Histopathology demonstrated demyelination, focal astrocytosis, erythrodiapedesis, and perineuronal edema in the irradiated sections. It appears that MBP levels in the CSF reflect not only radiation-induced myelopathy but also transient demyelination, and that MRI may have the potential to indicate the region of damage.

Maximum likelihood estimation of dose-response parameters for therapeutic operating characteristic (TOC) analysis of carcinoma of the nasopharynx

A Therapeutic Operating Characteristic (TOC) curve for radiation therapy plots, for all possible treatment doses, the probability of tumor ablation as a function of the probability of radiation-induced complication. Application of this analysis to actual therapeutic situations requires that dose-response curves for ablation and for complication be estimated from clinical data. We describe an approach in which “maximum likelihood estimates” of these dose-response curves are made, and we apply this approach to data collected on responses to radiotherapy for carcinoma of the nasopharynx. TOC curves constructed from the estimated dose-response curves are subject to moderately large uncertainties because of the limitations of available data. These TOC curves suggest, however, that treatment doses greater than 1800 ret may substantially increase the probability of tumor ablation with little increase in the risk of radiation-induced cervical myelopathy, especially for T1 and T2 tumors.

A Case of Lymphosarcoma Complicated with Radiation-Induced Myelopathy &amp; Pericarditis, Who Died of Leukoencephalopathy

A Case of Lymphosarcoma Complicated with Radiation-Induced Myelopathy &amp; Pericarditis, Who Died of Leukoencephalopathy

The effects of single and multifraction radiation courses on the mouse spinal cord.

Thoraco-lumbar spinal cord segments of C3H mice were irradiated with 250 kVp x rays and the acute and late effects of several variables were compared: single and multifraction radiation courses; changes in the length of irradiated spinal cord; and multifraction studies in which three-week and three-month splits were compared to a continuous radiation course. A scoring system for assessing the degree of radiation-induced myelopathy was devised, using a scale ranging from 1.0 (loss of rear limb reflex extension) to 4.0 (paraplegia). A significant increase in severity of spinal cord radiation injury was noted when single doses were compared to equal doses given in 10 consecutive fractions. Increasing the irradiated segment from 6 to 12 mm was also associated with more severe and earlier radiation cord injury.