No effective treatment for delayed radiation-induced neurotoxicity has been established. Its natural course is highly variable, but spontaneous recovery has been well documented. Here we report our experience with therapeutic anticoagulation in patients with cerebral lesions (n=3), cranial nerve lesions (n=1) or myelopathy (n=4) attributed to irradiation. Two of three patients with cerebral lesions and the patient with cranial nerve lesions showed a minor improvement of clinical symptoms. In contrast, none of the patients with radiation myelopathy improved. No patient suffered hemorrhage or other adverse effects of anticoagulation. Overall, anticoagulation therapy demonstrates only modest activity for delayed radiation-induced neurotoxicity in this small case serie

Ernemann, Ulrike

Happold, Caroline

Roth, Patrick

Schmidt, Friederike

Weller, Michael

Wick, Wolfgang

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CLINICAL STUDY - PATIENT STUDYAnticoagulation for radiation-induced neurotoxicity revisitedCaroline Happold Æ Ulrike Ernemann Æ Patrick Roth ÆWolfgang Wick Æ Michael Weller Æ Friederike SchmidtReceived: 5 May 2008 / Accepted: 4 August 2008 / Published online: 22 August 2008 Springer Science+Business Media, LLC. 2008Abstract No effective treatment for delayed radiation-induced neurotoxicity has been established. Its naturalcourse is highly variable, but spontaneous recovery hasbeen well documented. Here we report our experience withtherapeutic anticoagulation in patients with cerebral lesions(n = 3), cranial nerve lesions (n = 1) or myelopathy(n = 4) attributed to irradiation. Two of three patients withcerebral lesions and the patient with cranial nerve lesionsshowed a minor improvement of clinical symptoms. Incontrast, none of the patients with radiation myelopathyimproved. No patient suffered hemorrhage or other adverseeffects of anticoagulation. Overall, anticoagulation therapydemonstrates only modest activity for delayed radiation-induced neurotoxicity in this small case series.Keywords Radiation  Neurotoxicity  Anticoagulation MyelopathyAbbreviationsCHOP Cyclophosphamide, doxorubicin, oncovin(vincristine), prednisoloneFEC 5-Fluorouracil, epirubicin, cyclophosphamideFLAIR Fluid attenuated inversion recoveryLMWH Low molecular weight heparinMRI Magnetic resonance imagingMTX MethotrexateNHL Non-Hodgkin lymphomaPCNSL Primary CNS lymphomaPCV Procabazine, CCNU (lomustine), vincristineRT RadiotherapyT1w T1 weightedUH Unfractionated heparinVAD Vincristine, adriablastin, dexamethasoneWBRT Whole brain radiotherapyIntroductionPotentially irreversible treatment-induced damage to thenervous system has become a relevant management prob-lem as more cancer patients experience prolonged survival.Long-term radiation-induced neurotoxicity includes cere-bral radionecrosis, diffuse cerebral white matter changes,radiation myelopathy, and plexus lesions [1–3]. There maybe spontaneous recovery, but most clinical symptomsassociated with radiation-induced neurotoxicity are slowlyprogressive. Treatment with steroids is often insufficientlyeffective and associated with significant side effects whenadministered for months. Since a vascular pathogenesis hasbeen proposed to mediate some of these symptoms, anti-coagulation using heparin and warfarin has been exploredfor possible efficacy [4, 5]. The largest series [5] reportedsome recovery of function in 5 of 8 patients with cerebralC. Happold  P. Roth  W. Wick  M. Weller  F. SchmidtDepartment of General Neurology, Hertie Institute for BrainResearch, Tubingen, GermanyC. Happold (&)  P. Roth  M. WellerDepartment of Neurology, University Hospital Zurich,Frauenklinikstrasse 26, 8091 Zurich, Switzerlande-mail: Caroline.Happold@usz.chU. ErnemannDepartment of Neuroradiology, University of Tu¨bingen MedicalSchool, Tubingen, GermanyW. WickDepartment of Neurooncology, University of Heidelberg,Heidelberg, GermanyF. SchmidtDepartment of Neurology, Technische Universita¨t Mu¨nchen,Munich, Germany123J Neurooncol (2008) 90:357–362DOI 10.1007/s11060-008-9674-6radionecrosis and all of 3 patients with myelopathy orplexopathy (1 myelopathy, 2 plexopathies). A furthertreatment option is hyperbaric oxygen therapy, based onthe assumption that oxygen therapy induces neovasculari-zation [6–8]. Finally, some patients with radiation-inducedneurotoxicity may benefit from oral treatment with bo-swellic acid-containing medicines such as H15 [9]. Herewe report our experience with anticoagulation using hep-arin or warfarin or both sequentially as an experimentaltreatment for delayed radiation-induced neurotoxicity.Patients and methodsWe searched the charts of the Department of Neurologyfrom 1998 to 2007 for patients who received heparin orwarfarin or both for the treatment of suspected radiation-induced injury to the nervous system. The diagnosis ofradiation injury was based on clinical symptoms and signsthat could not be attributed to progressive or recurrenttumor as defined by neuroimaging or to any other neuro-logical disease. Moreover, a history of irradiation of thenervous system region affected was required. Eight patientswere identified. Clinical histories, neuroimaging studiesand the evolution of symptoms were reviewed.ResultsIn 1998, it became practice at our institution to offeranticoagulation to patients with a tentative diagnosis ofradiation-induced injury to the nervous system who had notresponded to steroids and who had no contraindications forthis treatment. Patient characteristics are summarized in theTable 1. There were 3 patients with cerebral lesions, onepatient with cranial nerve lesions, and 4 patients withradiation-induced myelopathy. None of the patients had abiopsy of the lesion before anticoagulation was started, butthe neuroradiological features were not suggestive ofrecurrent tumor in any patient (Fig. 1a). Neuroimagingfindings were consistent with radiation injury (Fig. 2).Spectroscopy performed in one patient supported thediagnosis of radiation-induced leukencephalopathy(Fig. 1b). An unusual treatment predicted to induce radia-tion injury to the nervous system was only given to patient2 who received two courses of WBRT for PCNSL. Sixpatients had also received chemotherapy before, during orafter radiotherapy, which may have contributed to radiationinjury of the nervous system. This is particularly true forpatient 6 who had received multiple courses of intrathecalchemotherapy, too.Patients 3, 4, 5, and 6 had had a prior course of steroidsand had not responded. No patient was on steroids whenanticoagulation was started. No patient was newly startedon steroids when anticoagulation was instituted, excludingconfounding effects of steroid comedication.Two out of three patients with cerebral lesions (patients 2and 3) and the patient with cranial nerve lesions (patient 4)showed a minor improvement of their clinical symptoms.These patients were switched from heparin to warfarin after afew days because the minor clinical response were seenearly. Patient 1 refused to continue warfarin beyond day 2. Incontrast, none of the patients with radiation myelopathyimproved clinically, although patient 7 showed a distinctregression on MR imaging (Fig. 3). Although this might beattributed to the anticoagulation therapy, it possibly occurredas a result of subsequent hyperbaric oxygen therapy orspontaneous recovery. Since the patient cohort reportedearlier [5] included only one patient suffering radiation-induced myelopathy, the evaluation on the effects of anti-coagulation on radionecrosis of the myelon is onlypreliminary.Our patients 2 and 3 improved with regard to level ofconsciousness and hemiparesis within 3 days of the insti-tution of anticoagulation, raising the possibility thatanticoagulation was the cause for improvement. Partialremission of cranial nerve palsies took days in patient 4,rendering a causal relationship to anticoagulation moredoubtful. The neurological deficits in the 4 patients withradiation myelopathy remained stable throughout thetherapeutic trial of anticoagulation. No patient sufferedhemorrhage or other adverse effects of anticoagulationtherapy.DiscussionThe increasing use of more efficacious multimodalitytreatments for various types of cancer results in significantsurvival benefits for many patients, but has also raisedawareness for therapy-related injury to the nervous system.Such lesions may often be multifactorial in origin and notonly caused by irradiation, but also to chemotherapy, pre-existing comorbidities, notably diabetes and cerebrovas-cular disease, as well as the underlying cancer itself.Although it is often difficult to distinguish radiation injuryfrom recurrent tumor, such patients rarely undergo a biopsyfor a histological verification of radiation injury to thenervous system.Steroids, anticoagulation [5], hyperbaric oxygen [6–8]and boswellic acids [9] have been proposed to alleviateneurological deficits associated with delayed radiation-induced neurotoxicity. Given the relative rarity of thiscondition and the heterogeneity of patient characteristics, itis unlikely that prospective randomized trials may everbeen performed to standardize management. Moreover,358 J Neurooncol (2008) 90:357–362123Table1ClinicalhistoryandcourseofdiseasePatientAgePrimarytumorRadiotherapyChemotherapySymptomsandsignsNeuroimaging(MRI)AnticoagulationSteroidsOxygenImprovementFollow-upwithoutevidenceofrecurrenttumor163B-NHL6/0136Gy1/02WBRTCHOP798–12/01PCV292–5/02Disturbanceofmemorypseudoparkinsonism[13]11/0211/02Leukencephalopathy2daysofwarfarin-––Progression-free6/04(2yearslater)240PCNSL11/8640.5Gy86WBRT25Gy2/92stereotacticRT45.5Gy10/92WBRT–Cognitiveimpairmentglobalaphasiaright-sidedhemiparesis5/985/98 LeukencephalopathyHeparin(UF)for5days,thenwarfarin5–12/98-–ImprovementoflevelofconsciousnessandhemiparesisProgressin-free2/99339Glioblastoma11/9954Gy11–12/9936Gy8/00stereotacticRTBCNU6910/00–3/01Progressiveseizuresleft-sidedhemiparesis1–4/014/01 Contrast-enhancingcerebrallesionHeparin(UF)for6days,thenwarfarin4–6/01for8weeks?–Mild improvementofhemiparesisLosttofollowup453Clivuschordoma11/0062.5Gy11–12/01stereotacticRT–Oculomotorandlateralrectuspalsy9/079/07 Contrast-enhancingnervesHeparin(UF)for8days,thenwarfarin9–11/07for8weeks?–ImprovementofdiplopiaProgression-free6/08552Multiplemyeloma11/999Gy3/00wholebodyRT21.6Gy5/00TH8–10Idarubicin?dexamethasone4911/99–1/00Busulfan?cyclophosphamide3–4/02Stemcelltransplantation4/02Paresisoftheleftleg8/028/02 MyelopathyTH8Heparin(UF)5–6/02for4weeks?––Progression-free9/02659Breastcancer5/991–2/0038Gysupraclavicularregion38Gylocalbreast38Gylefthemithorax30Gy2/00TH9–12FEC695–12/99UrinaryincontinenceparaplegiaTH113/023/02 MyelopathyTH9–12Heparin(UF)6/02for1weekTinzaparin(LMWH)6/02for2weeks?––Progression-free6/02753Multiplemyeloma4/9632Gy5/96TH5–732Gy5/96L1–S19Gy8/96wholebodyRTVAD294/96Cyclophosphamide194/96Co-interferon4–11/01Bendamustine5912/01–3/02Paresisoftherightleghypesthesia11/014/02 MyelopathyTH5–6Heparin(UF)4/02for10daysFraxiparine(LMWH)4–5/02for6weeks-4095–7/02–Distantprogression4/04(2yearslater)835Tcelllymphoma11/0024Gy1–2/01mediastinum24Gy12/00–1/01WBRTMTX,Ara-C,thioguanine,adriamycin,etoposide,vindesine,PEG-asparaginase,cyclophosphamide,4–11/01intrathecalMTX,Ara-C,dexamethasone8–11/01Paresthesiaataxia11/011/02 NolesionHeparin(UF)1/02for6days-––LosttofollowupJ Neurooncol (2008) 90:357–362 359123there may be distinct differences in the pathogenesis ofvarious syndromes of radiation injury. Accordingly, spe-cific syndromes may respond differentially to treatmentssuch as steroids, anticoagulation or hyperbaric oxygen.Steroids are considered to be effective mainly for acute andsubacute radiation-induced injury to the nervous system.No further studies on the possible beneficial role ofanticoagulation have been published since 1994 [5]. Therationale of anticoagulation is based on histologicalobservations of endothelial damage and lesions induced byirradiation [10]. The case series reported here is only thesecond in the literature to assess this treatment. Patientswho responded clinically to i.v. heparin did so early andwere then switched to warfarin. The only patient whoexperienced no benefit from warfarin discontinued warfarinanticoagulation after 2 days. Thus we feel that our obser-vations justify a short trial of up to a week ofanticoagulation with i.v. heparin in patients with pre-sumptive radiation-induced cerebral lesions whereas thelack of any change in the symptoms and signs of all 4Fig. 1 (a) Sixty three year oldwoman presenting withdisturbance of memory afterWBRT with 36 Gy (patient 1).Upper row (A, axial FLAIR andpost contrast T1w images)shows several lesions (blackarrows) with homogenouscontrast enhancement andpronounced perifocal edemarepresenting an intracerebrallymphoma. Lower row (B, axialFLAIR and post contrast T1wimages) represents a follow upexamination 10 months afterradiation therapy showing apathologic signal in FLAIRimages (arrow heads) in theperiventricular white matterwith no evidence of tumorrecurrence in post contrast T1wimages. (b) Patient 1: singlevoxel spectroscopy shows anelevated lactate peak in theperiventricular white matter(white arrow), consistent withactive inflammation, andstrongly suggestive of radiationinjury. MRI ruled out tumorrecurrenceFig. 2 Thirty nine year old manafter irradiation of aglioblastoma in the right parietallobe (patient 3). Axial T1w,contrast-enhanced T1w, andFLAIR images are presentedfrom left to right. A star-shaped,hemorrhagic, contrast-enhancing lesion (arrow) and alarge edema (asterisk),consistent with a radiationinjury, can be appreciated in theright parietal lobe360 J Neurooncol (2008) 90:357–362123patients with radiation-related myelopathy is not encour-aging. Moreover, all reports on the apparent beneficialeffects of therapeutic interventions for radiation-associatedneurotoxicity must be considered with caution in view ofthe variable course of such lesions which includes spon-taneous recovery. For instance, it is impossible to saywhether the improvement seen in patient 7 (Fig. 3) wasrelated to heparin or hyperbaric oxygen or reflected thenatural course of the lesion.More importantly, there is an increasing awareness ofpseudoprogression of tumors within the CNS as an earlymisleading MRI feature after focal radiotherapy. This maylead to the erroneous assumption of treatment failure andtrigger false therapeutic decisions [11, 12]. In summary, thepresent case series demonstrates that anticoagulation therapyis safe but has probably only modest activity in patients withdelayed radiation-induced neurotoxicity. Prospective stud-ies using stringent diagnostic criteria for therapy-inducedFig. 3 Fifty three year old man(patient 7) with multiplemyeloma after spinal irradiationof Th 5–7 with 32 Gy. Sagittal,contrast-enhanced T1w (upperrow), sagittal T2w (middlerow), and axial T2w images(lower row) are shown. The firstMRI showed a pronouncededema of the myelon at the levelTh 5–9 and a significant contrastuptake (A, white arrows). Threemonths later, MRI showedregression with residual edemaand reduced contrast uptake ofthe myelon at the level Th 5–6(B, white arrows); 10 days ofi.v. heparin therapy and 6 weeksof fraxiparine therapy as well as40 administrations of hyperbaricoxygen had preceded the MRI.Follow-up 7 months after initialexamination showed furtherimprovement with only minimalresidual findings (C, whitearrows). Another 40applications of hyperbaricoxygen had been administeredJ Neurooncol (2008) 90:357–362 361123injury to the nervous system are required to explore in moredepth the therapeutic potential of both anticoagulants andhyperbaric oxygen therapy.References1. Crossen JR, Garwood D, Glatstein E, Neuwelt EA (1994) Neu-robehavioral sequelae of cranial irradiation in adults: a review ofradiation-induced encephalopathy. J Clin Oncol 12:627–6422. 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Anticoagulation for radiation-induced neurotoxicity revisited

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Anticoagulation for radiation-induced neurotoxicity revisited

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