Patient Management Problem—Preferred Bellvitge. … · Which of the following is the most...

Patient ManagementProblem—PreferredResponses

Jordi Bruna, MD, PhD; Patrick Y. Wen, MD, FAAN

Learning ObjectivesUpon completion of this activity, the participant will be able to:

& Discuss the optimal medical and neurologic management of patients withhigh-grade gliomas

& Recognize the most frequent adverse events related to treatments inpatients with high-grade gliomas

& Choose the best treatment for patients with high-grade gliomas& Recognize the pitfalls and advantages of neuroimaging studies in

high-grade gliomas

Address correspondence toDr Jordi Bruna, Feixa LlargaStreet s/n 08907,Hospital Universitari deBellvitge. Hospitalet delLlobregat, Barcelona, Spain,[email protected].

Relationship Disclosure:

Dr Bruna reports no disclosure.Dr Wen has served as aconsultant for AbbVie, Inc;Celldex Therapeutics; CubistPharmaceuticals, Inc; FoundationMedicine, Inc; Genentech, Inc;Midatech Ltd, MomentaPharmaceuticals; Novartis AG;Sigma-Tau Pharmaceuticals,Inc; and Vascular Biogenics Ltd;and serves as section editor,Neuro-oncology, for UpToDate,Inc, and as editor-in-chief forNeuro-oncology. Dr Wen hasreceived personal compensationfor speaking engagements fromMerck & Co, Inc.

Unlabeled Use of

Products/InvestigationalUse Disclosure:Drs Bruna and Wen report nodisclosure.

* 2015, American Academyof Neurology.

CaseA 62-year-old right-handed man with a history of hypertension and type2 diabetes mellitus presents to the emergency department after 3 days ofprogressive right arm weakness accompanied by speech problems and mildheadaches. Hiswife reports he has also hadproblemswith attention andmemoryover the previous 8 weeks. On examination, he has 4/5 weakness involving theright arm and 2/5 weakness of the right hand, as well as a mild motor aphasia.No sensory deficits are detected. The patient has no fever, cough, weightloss, hemoptysis, or gastrointestinal bleeding. There is no history of foreigntravel, alcohol or drug addiction, or high-risk sexual behavior. Completeblood count, routine blood chemistry, and chest x-ray are normal. However,a CT scan of the head shows a single contrast-enhancing left frontoparietallesion surrounded by low-density signal compatible with vasogenic edema.

Following are the preferred responses for the Patient Management Problemin this issue. The case, questions, and answer options arerepeated, and the preferred response is given, followed by an explanation anda reference with which you may seek more specific information. You areencouraged to review the responses and explanations carefully to evaluateyour general understanding of the material. The comment and referencesincluded with each question are intended to encourage independent study.

In order to obtain CME credits for this activity, subscribers must completethis Patient Management Problem online at www.aan.com/continuum/cme.Upon completion of the Patient Management Problem, participants may earnup to 2 hours of AMA PRA Category 1 Creditsi. Participants have up to 3 yearsfrom the date of publication to earn CME credits. No CME will be awarded forthis issue after April 30, 2018.

541Continuum (Minneap Minn) 2015;21(2):541–556 www.ContinuumJournal.com

Self-Assessment and CME

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

http://www.aan.com/continuum/cme

b 1. Which of the following is the most appropriate and efficient approach toachieve a diagnosis with minimum delay?A. assess results of blood cultures, sputum cytology and CSF analysis if the

patient does not have significant midline shiftB. obtain a brain MRI with and without contrast, complemented with other

sequences (spectroscopy, diffusion-weighted sequences, apparent diffusioncoefficientmaps, and perfusion parameters such as relative cerebral blood volume)

C. obtain a chest, abdomen, and pelvis CT scan and upper and lowergastrointestinal endoscopy

D. obtain a repeat CT of the brain with contrast in 4 weeks to assess forchange in the size of the lesion

E. obtain brain and whole-body positron emission tomography (PET) scans

The preferred response is B (obtain a brain MRI with and without contrast,complemented with other sequences [spectroscopy, diffusion-weighted sequences,apparent diffusion coefficient maps, and perfusion parameters such as relativecerebral blood volume]). Patients with progressive mass lesions have a widedifferential diagnosis. These range from pyogenic abscess and other CNS infections(eg, toxoplasmosis, tuberculosis, cysticercosis, syphilis, fungal infection),autoimmune disorders (eg, acute demyelinating lesions, sarcoidosis, Beh0etdisease), and subacute ischemic strokes to neoplastic lesions (brain metastasesor primary brain tumors including gliomas and primary CNS lymphoma).1

However, a prompt diagnosis is required to avoid neurologic deterioration. Thisis especially relevant when brain tumors are suspected because the patient’sclinical status is a strong prognostic factor for survival, and it also influencestreatment options.2 A thorough history, physical examination, and minimalworkup can provide important clues on the nature of the lesion, especially whenthe diagnosis of brain tumor is being considered. Although MRIs do not have100% specificity and sensitivity, they demonstrate the full extent of the lesionand may provide information suggesting a neoplastic lesion. Such informationincludes increased relative cerebral blood volume (rCBV) on perfusion imagingand characteristic increased choline-to-creatine ratios (suggestive of increasedmembrane turnover) and decreased N-acetyl aspartate (NAA), a marker ofneuronal tissue, on magnetic resonance spectroscopy. These radiologic findings,used in conjunction with clinical judgment, usually provide sufficient diagnosticaccuracy in cases of malignant brain tumors and allow surgery to proceed,avoiding delays in the diagnosis.1,3,4 Only when MRI results are not clearregarding the likely neoplastic nature of the lesion are other complementaryexaminations necessary.

1. Omuro AM, Leite CC, Mokhtari K, Delattre JY. Pitfalls in the diagnosis of brain tumours. LancetNeurol 2006;5(11):937Y948. doi:10.1016/S1474-4422(06)70597-X.

2. Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors inthree Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst1993;85(9):704Y710. doi:10.1093/jnci/85.9.704.

3. Kao HW, Chiang SW, Chung HW, et al. Advanced MR imaging of gliomas: an update. BiomedRes Int 2013;2013:970586. doi:10.1155/2013/970586.

4. Essig M, Nguyen TB, Shiroishi MS, et al. Perfusion MRI: the five most frequently asked clinicalquestions. AJR Am J Roentgenol 2013;201(3):W495YW510. doi:10.2214/AJR.12.9544.

542 www.ContinuumJournal.com April 2015

PMP—Preferred Responses


b 2. Which is the best initial medical treatment for this patient at this time?A. 4 mg to 8 mg dexamethasone daily, given in one or two daily dosesB. 4 mg to 8 mg dexamethasone daily, given in three to four daily dosesC. 12 mg to 16 mg dexamethasone daily, given in one or two daily dosesD. 12 mg to 16 mg dexamethasone daily, given in three to four daily dosesE. 500 mg acetaminophen every 8 hours, avoiding steroids

The preferred response is A (4 mg to 8 mg dexamethasone daily, given inone or two daily doses). Glucocorticoids, by only partially understoodmechanisms, decrease tumor-associated edema and reduce the vascular permeabilityof tumors. This effect commonly results in an improvement in thepatient’s condition within 24 to 72 hours after the initiation of therapy. Thebenefits are usually transient and tend to benefit recent deficits more than thelonger-established ones. Surgery in patients with extensive brain edema isassociated with increased morbidity as a result of intraoperative increases inintracranial pressure and postoperative edema. Dexamethasone, which wasinitially investigated by Galicich and colleagues in 1961 for peritumoral edema,1

remains the most commonly used corticosteroid because of its lowermineralocorticoid effects compared with other corticosteroids. The generalrecommended starting dose (although based on few trials with small samplesizes) is 4 mg to 8 mg per day in patients with mild symptoms (as in this patient)and higher doses, such as 12 mg to 16 mg per day, in patients reporting moresevere symptoms related to mass effect. Asymptomatic patients do not needto be started on corticosteroids. In general, because of its long half-life of 36 to54 hours, dexamethasone can be administered as once-daily dosing in themorning, although it is commonly given at least twice daily.2,3,4 When primaryCNS lymphoma cannot be ruled out byMRI, unless significant or life-threateningmass effect is present, corticosteroids should be avoided until a biopsy isperformed to obtain a histologic diagnosis, as corticosteroids have a cytolyticeffect that may prevent a diagnostic biopsy from being obtained.

1. Galicich JH, French LA, Melby JC. Use of dexamethasone in treatment of cerebral edemaassociated with brain tumors. J Lancet 1961;81:46Y53.

2. Roth P, Wick W, Weller M. Steroids in neurooncology: actions, indications, side-effects. CurrOpin Neurol 2010;23(6):597Y602. doi:10.1097/WCO.0b013e32833e5a5d.

3. Vecht CJ, Hovestadt A, Verbiest HB, et al. Dose-effect relationship of dexamethasone onKarnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and16 mg per day. Neurology 1994;44(4):675Y680. doi:10.1212/WNL.44.4.675.

4. Sarin R, Murthy V. Medical decompressive therapy for primary and metastatic intracranialtumors. Lancet Neurol 2003;2(6):357Y365. doi:10.1016/S1474-4422(03)00410-1.

Brain MRI shows an isolated ring-enhancing lesion in the left frontoparietal lobe,surroundedby increased fluid-attenuated inversion recovery (FLAIR) signal, sparingthe cortex, and involving the pyramidal pathways and opercular area. There isno midline shift; moreover, the enhancing and nonenhancing lesion shows anincreased rCBV and hypointense signal in diffusion-weighted imaging (DWI)sequences with increased apparent diffusion coefficient (ADC) maps, togetherwith detection of lactate and lipid peaks and an increased choline-to-creatineratio and decreased NAA on magnetic resonance spectroscopy, suggestingthat a high-grade glioma is the most likely diagnosis.



b 3. Which of the following represents the next appropriate diagnostic andtreatment step?A. administer chemotherapy or radiation therapy without histologic confirmationB. maintain the steroid schedule and refer the patient to the palliative care

service because of the poor prognosis of his diseaseC. perform gross total resection despite the possibility of producing

neurologic deficits following a radical removalD. performmaximal safe surgical resection assisted by preoperative functional MRI

(fMRI) and, if necessary, intraoperative language andmotor mapping techniquesE. perform stereotactic biopsy because the tumor probably infiltrates eloquent areas

The preferred response isD (perform maximal safe surgical resection assistedby preoperative functional MRI [fMRI] and, if necessary, intraoperativelanguage and motor mapping techniques). Although the prognosis inglioblastoma patients remains poor, treatments may increase overall survival andmaintain the quality of life of patients, especially in those belonging to RadiationTherapy Oncology Group (RTOG) recursive partitioning analysis classes III to V.This prognostic classification is based on age, performance status, mental status,and extent of surgery.1 Although glioblastomas are characterized by theirinfiltrative nature, making curative resection impossible, these variables havebeen found to be important independent prognostic factors in most clinicalseries.2 It is also crucial at surgery to obtain enough tissue for an accuratedefinitive diagnosis and, increasingly, to provide material for molecular testingand eligibility for clinical trials. However, no class I evidence indicates that greaterextent of resection leads to better overall survival, and randomized trials addressingthis question may never occur. One phase 3 trial assessed the value of resectionguided by 5-aminolevulinic acid, a precursor in the hemoglobin synthesis pathwaythat elicits the synthesis and accumulation of fluorescent protoporphyrin IX withinglioma cells and, under blue-violet light, permits direct visualization of tumor tissueduring the operative session. The study demonstrated that patients with gross totalresection had significant improvement in 6-month progression-free survival.3

Retrospective studies suggest that the benefit of surgery is greatest when morethan 95% of the tumor can be removed, but some survival benefit may exist withresections as low as 78%.4 To date, general consensus favors maximal safe resection.Although the resection must be balanced by the risk of neurologic compromise,advances in fMRI and intraoperative motor and language mapping enable resectionof tumors located in eloquent brain areas with minimal morbidity, as demonstratedin a meta-analysis that included 8091 patients with supratentorial gliomas.5

1. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newlydiagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3phase III randomized trial. J Clin Oncol 2006;24(16):2563Y2569. doi:10.1200/JCO.2005.04.5963.

2. Sanai N. Emerging operative strategies in neurosurgical oncology. Curr Opin Neurol2012;25(6):756Y766. doi:10.1097/WCO.0b013e32835a2574.

The patient shows marked clinical improvement after 3 days of corticosteroidtreatment at a total dose of 8mgdaily in twodivided doses. His headaches haveresolved, and there is partial recovery of speech and strength in his arm,althoughhe still has some cognitive complaints and3/5weakness ofhis right hand.




3. Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinicacid for resection of malignant glioma: a randomised controlled multicentre phase III trial.Lancet Oncol 2006;7(5):392Y401. doi:10.1016/S1470-2045(06)70665-9.

4. Sanai N, Polley MY, McDermott MW, et al. An extent of resection threshold for newlydiagnosed glioblastomas. J Neurosurg 2011;115(1):3Y8. doi:10.3171/2011.2.JNS10998.

5. De Witt Hamer PC, Robles SG, Zwinderman AH, et al. Impact of intraoperative stimulationbrain mapping on glioma surgery outcome: a meta-analysis. J Clin Oncol2012;30(20):2559Y2565. doi:10.1200/JCO.2011.38.4818.

b 4. Which of the following is the most appropriate next step in medicalmanagement of this patient?A. progressive tapering of corticosteroids until the patient is off them

completely if no worsening of neurologic symptoms occursB. prophylactic use of lacosamide to reduce the risk of seizures and

progressive tapering of corticosteroids until the patient is off themcompletely if no worsening of neurologic symptoms occurs

C. prophylactic use of levetiracetam to reduce the risk of seizures andprogressive tapering of corticosteroids until the patient is off themcompletely if no worsening of neurologic symptoms occurs

D. prophylactic use of phenytoin to reduce the risk of seizures andprogressive tapering of corticosteroids until the patient is off themcompletely if no worsening of neurologic symptoms occurs

E. prophylactic use of valproic acid to reduce the risk of seizures andprogressive tapering of corticosteroids until the patient is off themcompletely if no worsening of neurologic symptoms occurs

The preferred response is A (progressive tapering of corticosteroids until thepatient is off them completely if no worsening of neurologic symptomsoccurs). Corticosteroids should be tapered off as soon as possible to avoidcomplications. In addition to the known complications of long-term corticosteroiduse, evidence also exists that these medications reduce the effectiveness ofsubsequent antitumor therapy.1 Prophylactic antiepileptic drugs (AEDs) are notneeded in patients with brain tumors who have not had seizures.2 Approximately30% of patients with high-grade gliomas present with seizures, and another20% to 30% will develop seizures sometime during the course of their illness.2

The risk of seizures is lower in patients with brain metastases. Approximately20% of metastatic patients present with seizures and another 10% to 20% willdevelop seizures during the course of their illness.2 The pathogenesis oftumor-related seizures is not completely understood and is likely to bemultifactorial, involving genetic alterations of proteins, ion channels, andreceptors, and dependent upon specific tumor cell type and localization.3

The patient undergoes fMRI, which shows that the tumor is adjacent to thelanguagearea, leadingtosurgerywith intraoperativeneurophysiologicmonitoringwith language andmotormapping. The immediate postsurgicalMRI shows a 95%tumor removal from its initial volume, and he has no new neurologic symptomspostoperatively. After the postoperative recovery, the patient has a KarnofskyPerformanceStatusScale scoreof70.Thepathologyreport indicates that thetumoris a glioblastoma (World Health Organization [WHO] grade IV). Following surgery,the patient’s corticosteroid dose is tapered to 4 mg dexamethasone daily. He isreferred to the neuro-oncology clinic for additional treatment options.



Emerging evidence shows that the increased risk of seizures in tumors isrelated to downregulation of the excitatory amino acid transporter 2 (EAAT-2)and upregulation of the cysteine exo- (or anti-) transporter (Xc[-] transporter),resulting in increased concentrations of extracellular glutamate.4 Theincreased risk of seizures can be reduced in preclinical models using the Xc(-)transporterYblocking agent sulfasalazine.4 Currently, no evidence shows thatprophylactic AEDs are useful; if they are given perioperatively, they should betapered and discontinued after the first postoperative week. Theserecommendations were proposed in a practice parameter from the AmericanAcademy of Neurology in 2000.2 This practice parameter, which also includeda meta-analysis of the available prophylactic studies of AEDs in patients withbrain tumors, concluded that seizure prophylaxis was not effective in preventingfirst seizures in patients with brain tumors who had no history of epilepsy andthat the incidence and severity of adverse events related to AEDs wereappreciably higher in patients with brain tumors than in the general populationof patients receiving anticonvulsants.2 Two additional meta-analyses havesubsequently been performed over the past 10 years showing similar findings,5,6

although one considers the evidence as inconclusive at best.6 Moreover, thelatter study noted that the increased risk of adverse events reported in patientswith brain tumors receiving AED therapy were obtained from retrospective studies,making it possible that this was overestimated.6 However, only older AEDs, suchas valproic acid, phenytoin, and phenobarbital, were used in the studies includedin the meta-analyses; the value of newer AEDs with better side effect profilesremains to be tested. Meta-analyses of the studies evaluating AEDs for prophylaxisfollowing craniotomies for any reason, and for brain tumors, found no benefit ofprophylaxis after the first postoperative week.7

1. Roth P, Wick W, Weller M. Steroids in neurooncology: actions, indications, side-effects. CurrOpin Neurol 2010;23(6):597Y602. doi:10.1097/WCO.0b013e32833e5a5d.

2. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients withnewly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the AmericanAcademy of Neurology. Neurology 2000;54(10):1886Y1893. doi:10.1212/WNL.54.10.1886.

3. Ruegg S, Roelcke U. Brain tumor-associated seizures: glutamate, transporters, and an old drug.Neurology. 2012;79(9):844Y845. doi:10.1212/WNL.0b013e318266fd11.

4. Yuen TI, Morokoff AP, Bjorksten A, et al. Glutamate is associated with a higher risk of seizuresin patients with gliomas. Neurology 2012;79(9):883Y889. doi:10.1212/WNL.0b013e318266fa89.

5. Sirven JI, Wingerchuk DM, Drazkowski JF, et al. Seizure prophylaxis in patients with braintumors: a meta-analysis. Mayo Clin Proc 2004;79(12):1489Y1494. doi:10.4065/79.12.1489.

6. Tremont-Lukats IW, Ratilal BO, Armstrong T, Gilbert MR. Antiepileptic drugs for preventingseizures in people with brain tumors. Cochrane Database Syst Rev 2008;(2):CD004424.doi:10.1002/14651858.CD004424.pub2.

7. Kuijlen JM, Teernstra OP, Kessels AG, et al. Effectiveness of antiepileptic prophylaxis usedwith supratentorial craniotomies: a meta-analysis. Seizure 1996;5(4):291Y298. doi:10.1016/S1059-1311(96)80023-9.

The patient is decreased to 4 mg of dexamethasone after the first postoperativeweek. On his postoperative evaluation, the patient is doing well with the sameKarnofskyPerformanceStatusScale scoreandneurologic functionas the immediatepresurgical evaluation. In addition to a histologic diagnosis of glioblastoma, additionalmolecular analysis of the tumor shows thepromoter of theO-6-methylguanine-DNAmethyltransferase (MGMT ) gene is methylated, the isocitrate dehydrogenase1 (IDH1) gene is not mutated, the epidermal growth factor receptor (EGFR)is amplified, and Ki-67 index (a cellular proliferation marker) is 38%.




b 5. What is the most appropriate oncologic treatment for this patient?A. a clinical trial that includes radiation therapy plus concurrent and adjuvant

temozolomide as well as assessment of an investigational drugB. radiation therapyC. radiation therapy with concurrent temozolomide, followed by temozolomideD. radiation therapy with concurrent temozolomide plus bevacizumab,

followed by temozolomide and bevacizumabE. surgery only

The preferred response is A (a clinical trial that includes radiation therapyplus concurrent and adjuvant temozolomide as well as assessment ofan investigational drug). Surgery alone only increases survival by a fewmonths in most patients with glioblastoma (median 3.2 months). Thestandard management for these patients includes maximal safe resection,followed by fractionated radiation therapy (total dose of 60 Gy in dailyfractions of 1.8 Gy or 2 Gy) with concurrent temozolomide (an oral alkylatingagent) chemotherapy, followed by an additional 6 months of adjuvanttemozolomide.1 The addition of temozolomide results in a significant survivalbenefit with modest additional toxicity compared to radiation therapyalone.1 However, even with meticulous surgery and strict chemotherapycompliance, recurrence is inevitable. The overall prognosis remains poor,with a median overall survival rate of 14.6 months and 5-year survival rate of9.8% in patients treated with radiation therapy and temozolomide.2 Forthis reason, the National Comprehensive Cancer Network recommendsparticipation in a clinical trial to improve the results obtained with thecurrent standard treatment (radiation therapy plus concomitant and adjuvanttemozolomide) as the best management of patients with glioblastoma.3

Unfortunately, two recent phase 3 trials using bevacizumab (a monoclonalantibody against vascular endothelial growth factor [VEGF]) in addition tostandard combined chemotherapy and radiation in newly diagnosed glioblastomapatients failed to show a benefit over standard treatment.4,5

1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvanttemozolomide for glioblastoma. N Engl J Med 2005;352(10):987Y996. doi:10.1056/NEJMoa043330.

2. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvanttemozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase IIIstudy: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10(5):459Y66. doi:10.1016/S1470-2045(09)70025-7.

3. NCCN Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network website.www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed January 30, 2015.

4. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newlydiagnosed glioblastoma. N Engl J Med 2014;370(8):709Y722. doi:10.1056/NEJMoa1308345.

5. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newlydiagnosed glioblastoma. N Engl J Med 2014;370(8):699Y708. doi:10.1056/NEJMoa1308573.

Thepatient receives 6weeks of radiation therapy and concurrent temozolomide(no clinical trials of first-line treatment with investigational drugs are available forthis patient at this time). During the last days of radiation therapy and the 4-weekbreak between radiation therapy and the beginning of adjuvant chemotherapywithtemozolomide, thepatientbecomesmorefatiguedandexperiencesaslightworseningof cognitive function. The neurologic examination does not show other changes.



http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site

b 6. What is the most appropriate next step in this patient’s management?A. obtain brain MRI before starting adjuvant treatment, then go on with the

planned treatment irrespective of the status of the irradiated lesionB. obtain brain MRI before starting adjuvant treatment, then go on with the

planned treatment unless a new lesion is clearly visible outside theradiation field

C. obtain brain MRI to assess the response, and if the residual tumor is largerthan on the postsurgical MRI, assume that it is due to early progression ofthe disease and change the treatment

D. obtain brain MRI to assess the response, and if the residual tumor is largerthan on the postsurgical MRI, obtain a new biopsy

E. proceed with the adjuvant temozolomide, and obtain brain MRI to assessthe response after two or three temozolomide cycles

The preferred response is B (obtain brain MRI before starting adjuvanttreatment, then go on with the planned treatment unless a new lesion isclearly visible outside the radiation field). MRI of high-grade gliomasduring and after radiation therapy, especially if the patient has also beentreated with temozolomide, can show increased contrast enhancement dueto transiently increased permeability of the tumor vasculature or to aninflammatory process from radiation or combined chemotherapy andradiation.1 This phenomenon, termed ‘‘pseudoprogression,’’ can be observedin 10% to 30% of patients and may be more frequent in patients with amethylated MGMT gene promoter.2 Therefore, it is difficult to reliably assessresponse using MRI performed during this time frame. To address thisproblem, the Response Assessment in Neuro-Oncology (RANO) WorkingGroup proposed new neuroimaging response criteria.3 Given the difficultyof differentiating pseudoprogression from true progression in the first12 weeks after radiation, the first scan performed about 4 weeks after radiationshould be considered as the new baseline for all further follow-ups, unlessthe enhanced lesion appears clearly outside the radiation field.3 Therefore,although an MRI is usually performed before starting adjuvant temozolomidetreatment, the patient can continue with therapy even if the scan showsmore enhancement as long as no new lesions are found outside of the mainradiation field. If the patient is very symptomatic, surgical resection isoccasionally recommended to reduce mass effect and obtain a more definitivediagnosis of recurrent tumor or pseudoprogression. However, even withsurgery, the diagnosis is not always conclusive.

1. Brandsma D, Stalpers L, Taal W, et al. Clinical features, mechanisms, and management ofpseudoprogression in malignant gliomas. Lancet Oncol 2008;9(5):453Y461.doi:10.1016/S1470-2045(08)70125-6.

2. BrandesAA, Franceschi E, TosoniA, et al.MGMTpromotermethylation status canpredict the incidenceand outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosedglioblastoma patients. J Clin Oncol 2008;26(13):2192Y2197. doi:10.1200/JCO.2007.14.8163.

3. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria forhigh-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol2010;28(11):1963Y1972. doi:10.1200/JCO.2009.26.3541.




b 7. In addition to repeating the brain MRI, which of the following drugs is mostappropriate for the initial management of this patient’s seizure?A. lacosamideB. lamotrigineC. levetiracetamD. oxcarbazepineE. phenytoin

The preferred response is C (levetiracetam). The efficacy of older and newerAEDs on tumor-related seizures have not been compared. Therefore, todate, no firm evidence-based guidelines exist regarding the optimal AEDs formanagement of seizures in these patients. However, some practicalconsiderations can be taken into account when selecting a first-line AED1:

1. A drug that has an IV preparation can be useful, especially in the perioperativeperiod or when the patient cannot take medications by mouth.

2. The AED selected must achieve therapeutic concentrations relatively quickly.3. Second- and third-generation AEDs have not proven to be more effective

than older AEDs, although they are generally better tolerated.4. Among AEDs, levetiracetam and valproate have been the most widely used

in treating glioma-related seizures. They are both effective and generallywell tolerated, alone or in combination.

5. Levetiracetam and valproic acid have no significant effects on the metabolismof the commonly used antineoplastic agents, such as temozolomide andbevacizumab. Valproic acid is associated with increased hematologic toxicitywhen used with temozolomide, but this toxicity usually does not result ina significant reduction in the number of cycles or the total dose ofchemotherapy administered to the patients.

6. Some retrospective data and a meta-analysis study show that treating patientswith glioblastomas with some first-generation AEDs, such as valproic acid,is associated with improved survival.2,3,4 Although this has not been

A brain MRI obtained 4 weeks after completion of radiation therapy andbefore starting adjuvant chemotherapy shows mildly increasedfluid-attenuated inversion recovery (FLAIR) signal intensity and contrastenhancement but nonew lesions outsideof the radiation field. These changesare felt to be consistent with pseudoprogression related to radiation effects.The patient proceeds with his planned chemotherapy treatment withtemozolomide at 150 mg/m2/d for 5 days for the first 28-day cycle,maintaining the same steroid dose. The worsening of symptoms thatappeared during radiation therapy resolves over the next month. A repeatbrain MRI after the first cycle of adjuvant temozolomide shows a milddecrease in enhancement compared to his postradiation therapy MRI,suggesting that the changes on the first MRI were due topseudoprogression. The patient tolerates the chemotherapy withouthematologic toxicity. His temozolomide is increased in the second cycleto the full dose of 200 mg/m2/d for 5 days. However, during the thirdcycle of temozolomide, he develops a partial motor seizure withsecondary generalization.



confirmed by prospective trials and the underlying mechanism remainsuncertain, valproic acid is often recommended as first-line AED therapy inEurope.1,3 In the United States, levetiracetam is generally recommended asfirst-line therapy because of its ease of use and rapid onset of action.Second-line AEDs may include lacosamide, valproic acid, lamotrigine, andpregabalin, among others. In patients with new seizures, an MRI is usuallyadvisable to rule out spontaneous intratumoral bleeding or tumorprogression, which present with seizures in 19% of patients.1

1. Bruna J, Miro J, Velasco R. Epilepsy in glioblastoma patients: basic mechanisms and currentproblems in treatment. Expert Rev Clin Pharmacol 2013;6(3):333Y344. doi:10.1586/ecp.13.12.

2. Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77(12):1156Y1164. doi:10.1212/WNL.0b013e31822f02e1.

3. Kerkhof M, Dielemans JC, van Breemen MS, et al. Effect of valproic acid on seizure control andon survival in patients with glioblastoma multiforme. Neuro Oncol 2013;15(7):961Y967.doi:10.1093/neuonc/not057.

4. Yuan Y, Xiang W, Qing M, et al. Survival analysis for valproic acid use in adult glioblastomamultiforme: a meta-analysis of individual patient data and a systematic review. Seizure 2014;23(10):830Y835. doi:10.1016/j.seizure.2014.06.015.

b 8. How should this patient’s new neurologic problems be managed?A. give benzodiazepinesB. increase dexamethasone dose to 8 mg dailyC. obtain nerve conduction studiesD. obtain spinal cordMRI to excludedropmetastases or leptomeningeal disseminationE. withdraw dexamethasone progressively and completely

The preferred response is E (withdraw dexamethasone progressively andcompletely). Treatment with corticosteroids is commonly associated withconsiderable undesirable effects. These complications can be observed aftertaking the medications for weeks or months. Their severity corresponds to thedose, duration of therapy, low serum albumin levels (high risk with albuminlevels less than 2.5 g/dL), and the potency of the medication chosen. Proximalmyopathy (especially with the fluorinated steroids), behavioral changes,visual blurring, tremor, insomnia, and reduced taste and smell are the mostcommon neurologic side effects of corticosteroids. In addition, patients mayexperience well-known complications, such as cushingoid features, diabetesmellitus, and osteoporosis. Fortunately, most of these complications resolveafter steroid withdrawal, although the recovery from some complications, suchas myopathy, can take several months.1,2 Therefore, it is important to alwaystry to taper patients off corticosteroids; maintaining them on a constant dose

Levetiracetam is started. A repeat brain MRI does not show tumor-relatedcomplications or tumor progression. The patient continues with his chemotherapytreatment as planned. At the end of the sixth adjuvant temozolomide cycle, anew MRI shows significant reduction of the T1 gadolinium-enhancing lesion.However, clinically the patient has deteriorated. While hand strength andlanguage are slightly improved, he has serious difficulties getting up from achair, walking, and climbing stairs, as well as new-onset bilateral tremor in bothhands. He is irritable and has insomnia and blurred vision.




indefinitely will inevitably lead to complications. However, no evidence-basedguidelines exist for the tapering of dexamethasone in patients with brain tumors.In most studies, the steroid dose is reduced by 25% to 50% every 4 to 5 days forpatients showing improvement of neurologic symptoms. In patients withprogressive or persistent tumors who worsen with dose reduction, prolongedsteroid use may be warranted, and careful monitoring for adverse events has tobe implemented. Occasionally, bevacizumab may be used for its steroid-sparingeffects. It is also important to encourage patients to exercise to attempt to avoida steroid myopathy.3 In patients with neurologic deficits that do not respond tocorticosteroids,maintaining themedication is unhelpful and should be avoided.2,4

It is important to check that other medications taken by the patient are notcontributing to potential side effects. For example, valproic acid can causetremors, and levetiracetam can occasionally cause depression and irritability.

1. Dietrich J, Rao K, Pastorino S, Kesari S. Corticosteroids in brain cancer patients: benefits andpitfalls. Expert Rev Clin Pharmacol 2011;4(2):233Y242. doi:10.1586/ecp.11.1.

2. Wen PY, Schiff D, Kesari S, et al. Medical management of patients with brain tumors. JNeurooncol 2006;80(3):313Y332. doi:10.1007/s11060-006-9193-2.

3. Seene T. Turnover of skeletal muscle contractile proteins in glucocorticoid myopathy. J SteroidBiochem Mol Biol 1994;50(1Y2):1Y4.

4. Sarin R, Murthy V. Medical decompressive therapy for primary and metastatic intracranialtumors. Lancet Neurol 2003;2(6):357Y365. doi:10.1016/S1474-4422(03)00410-1.

b 9. Which of the following next steps in management or diagnosis is mostappropriate at this time?A. administration of an antidepressantB. administration of donepezil 10 mg/dC. administration of memantine 20 mg/dD. administration of methylphenidate 20 mg/dE. neuropsychological testing, including assessment for depression, and

cognitive rehabilitation

The preferred response is E (neuropsychological testing, including assessmentfor depression, and cognitive rehabilitation). Cognitive impairment is one ofthe most prevalent symptoms in patients with brain tumors. It can be caused bymultiple factors, including the direct effects of the tumor or as a result of treatment.Moreover, mood disorders or concurrent infections can precipitate or aggravate thesedeficits. Among all of these factors, radiation therapy is the main treatment-relatedfactor causing cognitive impairment and even dementia. Several medical interventionshave been evaluated to reduce orminimize the impact of radiation-induced cognitiveimpairment. Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist,was evaluated in a placebo-controlled trial in patients with brain metastaseswho received whole-brain radiation therapy.1 The medication, which wasadministered during radiation therapy and for the first 24 weeks afterward, waswell-tolerated and delayed time to cognitive decline, with improvementsin memory and executive functions. However, the trial failed to improve the

The patient receives physical therapy, and after the steroids are tapered off hegradually regains strength in his legs and his gait becomes steadier. However,during the next month, his cognitive complaints remain. His wife noticesincreasing problems with his short-term memory, decreased concentration,and lack of initiative, despite the fact that his MRI shows stable disease.



primary end point (verbal memory), and the results of several cognitive testswere not maintained during follow-up, although the large number of patientswho dropped out of the study as a result of death undoubtedly contributedto these negative results.1 Moreover, since the drug was administered atthe initiation of radiation therapy, its use after cognitive impairment hasdeveloped remains uncertain. Methylphenidate has been widely studied inchildhood cancer survivors and has shown efficacy in improving attention andexecutive function with a good safety profile.2 However, its use in patientswith brain tumors has not been evaluated in large controlled randomizedstudies. On the other hand, cognitive rehabilitation in a controlled randomizedtrial on patients with low-grade and high-grade brain tumors showed improvementin attention, verbal memory, and mental fatigue.3 In addition, a recentlyreported placebo-controlled phase 3 trial with the acetylcholinesteraseinhibitor donepezil at doses of 5 mg to 10 mg showed possible benefit inimproving verbal and working memory, visual and psychomotor performance,and executive function in patients with severe baseline cognitive impairment.4

However, when patients with less-severe cognitive impairment wereincluded, the primary end point (cognitive composite score) did not showsignificant differences compared to placebo.4 AEDs can have a negativeimpact on cognition, especially the ,-aminobutyric acidYmediated (GABA-ergic)AEDs, and should be administered as monotherapy and in the lowesteffective doses whenever possible. However, a recent study suggested thatthe use of levetiracetam and valproate in patients with high-grade gliomas didnot result in cognitive impairment and may even have had a beneficial resulton verbal memory compared to patients not receiving AEDs.5

1. Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction inpatients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlledtrial. Neuro Oncol 2013;15(10):1429Y1437. doi:10.1093/neuonc/not114.

2. Conklin HM, Reddick WE, Ashford J, et al. Long-term efficacy of methylphenidate in enhancingattention regulation, social skills, and academic abilities of childhood cancer survivors. J ClinOncol 2010;28(29):4465Y4472. doi:10.1200/JCO.2010.28.4026.

3. Gehring K, Sitskoorn MM, Gundy CM, et al. Cognitive rehabilitation in patients with gliomas:a randomized, controlled trial. J Clin Oncol 2009;27(22):3712Y3722. doi:10.1200/JCO.2008.20.5765.

4. Rapp SR, Case D, Peiffer A, et al. Phase III randomized, double-blind, placebo-controlled trial ofdonepezil in irradiated brain tumor survivors. J Clin Oncol 2013;31(15 suppl):A2006.

5. de Groot M, Douw L, Sizoo EM, et al. Levetiracetam improves verbal memory in high-gradeglioma patients. Neuro Oncol 2013;15(2):216Y223. doi:10.1093/neuonc/nos288.

Formal neuropsychological testing shows no evidence of depression. Cognitiverehabilitation is started.Over thefollowingmonths, thepatient’sMRIs showstabledisease. However, he remains tired throughout the day and has no energy formany of his daily activities.




b 10. Which of the following is the most appropriate intervention to improvethis patient’s fatigue?A. administration of erythropoietin 30,000 units weeklyB . administration of low doses of steroidsC. administration of methylphenidate 10 mg/d or modafinil 200 mg/dD. administration of paroxetine 20 mg/dE . switch from levetiracetam to gabapentin

Thepreferred response isC (administration of methylphenidate 10mg/d or modafinil200 mg/d). Cancer-related fatigue is one of the most common symptoms reported bypatients with cancer, especially patients with brain tumors. The prevalenceexceeds 60% and may be present at diagnosis, during treatment, or even wellafter active therapy has been completed.1 This fatigue negatively impacts thepatient’s quality of life.1 Before starting any medications for fatigue, it isimportant to exclude conditions that may contribute to fatigue, such asanemia, depression, metabolic disorders, and endocrine dysfunction, especiallyhypothyroidism or adrenal insufficiency. Therefore, blood tests, includingcomplete blood count, thyroid function tests, and possibly morning cortisol andtestosterone levels, should be performed. It is also important to considertreatment-related factors, such as chemotherapy, radiation therapy, and AEDs,as potential causes of the fatigue. In addition to a direct effect of radiationtherapy in producing fatigue, radiation therapy can also cause progressivehypothalamic-pituitary axis insufficiency. At 5 years with total doses of 40 Gyof radiation, 50% of patients will have thyrotropin deficiency.2 It is importantnot to miss this cause of fatigue as these patients will greatly benefit fromthyroid replacement therapy. A recent meta-analysis about the efficacy ofdrug therapy for cancer-related fatigue management showed thatmethylphenidate at 10 mg or 20 mg is a safe and useful intervention.3

Modafinil 200 mg/d also appeared useful in a phase 3 trial.4 Antidepressants andhemopoietic growth factors have not been shown to be beneficial for fatigueand can even be unsafe, as in the case of erythropoietin.3 Because manypatients are on long-term corticosteroids, occasionally fatigue may be caused byadrenal insufficiency as the corticosteroids are tapered. In these patients,resumption of a low dose of corticosteroids followed by a slow taper may bebeneficial. Because dexamethasone has low mineralocorticoid activity,hydrocortisone or prednisone may be preferable in treating adrenal insufficiency.Other potential interventions include switching or reducing the AED dose.Drugs acting on the GABA-ergic system have the highest incidence of fatigue,followed by gabapentin and levetiracetam, which mainly inhibit sodiumchannels.5 Aerobic exercise has been shown to be beneficial for fatigue inother cancers and may potentially be effective for patients with brain tumors.6

1. Iop A, Manfredi AM, Bonura S. Fatigue in cancer patients receiving chemotherapy: an analysisof published studies. Ann Oncol 2004;15(5):712Y720. doi:10.1093/annonc/mdh102.

2. Littley MD, Shalet SM, Beardwell CG, et al. Radiation-induced hypopituitarism is dose-dependent.Clin Endocrinol (Oxf) 1989;31(3):363Y373. doi:10.1111/j.1365-2265.1989.tb01260.x.

3. Minton O, Richardson A, Sharpe M, et al. Drug therapy for the management of cancer-relatedfatigue. Cochrane Database Syst Rev 2010;(7):CD006704. doi:10.1002/14651858.CD006704.pub3.

4. Jean-Pierre P, Morrow GR, Roscoe JA, et al. A phase 3 randomized, placebo-controlled,double-blind, clinical trial of the effect ofmodafinil on cancer-related fatigue among 631 patients



receiving chemotherapy: a University of Rochester Cancer Center Community Clinical OncologyProgram Research base study. Cancer 2010;116(14):3513Y3520. doi:10.1002/cncr.25083.

5. Siniscalchi A, Gallelli L, Russo E, De Sarro G. A review on antiepileptic drugs-dependent fatigue:pathophysiological mechanisms and incidence. Eur J Pharmacol 2013;718(1Y3):10Y16.doi:10.1016/j.ejphar.2013.09.013.

6. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults.Cochrane Database Syst Rev 2012;11:CD006145. doi:10.1002/14651858.CD006145.pub3.

b 11. Which of the following tumor treatments is the best option for this patient?A. bevacizumab plus irinotecanB. CCNU (lomustine) plus bevacizumabC. dose-dense temozolomide schedule (75mg/m2 to 100 mg/m2 for 21 consecutive

days of a 28-day cycle)D. enrollment in a clinical trialE. temozolomide rechallenge

The preferred response is D (enrollment in a clinical trial). No standardtreatment exists for recurrent glioblastoma. Surgery may occasionally have arole in relieving symptoms from mass effect and provide time for additionaltherapies to work, but it is unlikely to prolong survival significantly unless agross total resection can be achieved.1 The value of repeat radiation is unclear.Treatment with chemotherapeutic agents such as CCNU and temozolomidehave produced modest prolongation of 6-month progression-free survival butquestionable improvement in overall survival.2 No evidence has shown thatcombination therapies are better than single agents. Rechallenge withtemozolomide can be helpful in patients who did well initially with prioradjuvant temozolomide and a subsequent treatment-free period (6-monthprogression-free survival of approximately 35%) but tends to have minimalbenefit in patients who progress while on standard-dose temozolomide.2,3

Dose-dense regimens do not appear to be more effective than standard doseregimens.2,4 The prognostic and predictive role of tumor MGMT methylationstatus in recurrent disease is controversial.2,5

Another option is bevacizumab, a humanized monoclonal antibody againstvascular endothelial growth factor (VEGF). This drug received acceleratedapproval by the US Food and Drug Administration (FDA) in 2009 for treatmentof recurrent glioblastoma based on improvement in response rate andresponse duration relative to historical controls in two phase 2 trials(progression-free survival ranging from 4.2 to 5.6 months).2,6,7 However, it isunclear whether bevacizumab alone improves overall survival, and it iscurrently not approved in Europe for use in patients with glioblastomas.Recently, a randomized phase 2 trial showed that the combination ofbevacizumab and CCNU in patients with recurrent glioblastoma appeared tohave improved progression-free and 9-month survival compared to eitheragent alone.8 This led the European Organisation for Research and Treatment

Blood tests, including assessment of endocrine function, are unrevealing. Thepatient’s fatigue improves slightly with administration of modafinil, and heremains clinically stable for thenext7months.However, thepatient thendevelopsincreased right arm weakness. An MRI shows a new enhancing lesion adjacentto the surgical cavity, which is not felt to be amendable to gross total resection.




of Cancer (EORTC) to conduct a phase 3 trial evaluating the combination.Given the limited available options, the best choice for these patients is to considerenrollment in a trial evaluating a new treatment approach. Important progresshas been made in targeted molecular therapies and immunotherapies that will,with hope, translate into improved patient outcomes as a result of clinical trials.9

1. Bloch O, Han SJ, Cha S, et al. Impact of extent of resection for recurrent glioblastoma on overallsurvival: clinical article. J Neurosurg 2012;117(6):1032Y1038. doi:10.3171/2012.9.JNS12504.

2. Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrentglioblastomaVare we there yet? Neuro Oncol 2013;15(1):4Y27. doi:10.1093/neuonc/nos273.

3. Perry JR, Belanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomidein recurrent malignant glioma: RESCUE study. J Clin Oncol 2010;28(12):2051Y2057. doi:10.1200/JCO.2009.26.5520.

4. Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosedglioblastoma: a randomized phase III clinical trial. J Clin Oncol 2013;31(32):4085Y4091.doi:10.1200/JCO.2013.49.6968.

5. Norden AD, Lesser GJ, Drappatz J, et al. Phase 2 study of dose-intense temozolomide inrecurrent glioblastoma. Neuro Oncol 2013;15(7):930Y935. doi:10.1093/neuonc/not040.

6. Friedman HS, PradosMD,Wen PY, et al. Bevacizumab alone and in combination with irinotecan inrecurrent glioblastoma. J Clin Oncol 2009;27(28):4733Y4740. doi:10.1200/JCO.2008.19.8721.

7. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed bybevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol2009;27(5):740Y745. doi:10.1200/JCO.2008.16.3055.

8. Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or lomustine versusa combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOBtrial): a randomised controlled phase 2 trial. Lancet Oncol 2014;15(9):943Y953. doi:10.1016/S1470-2045(14)70314-6.

9. Alexander BM, Lee EQ, Reardon DA, Wen PY. Current and future directions for phase II trials inhigh-grade glioma. Expert Rev Neurother 2013;13(4):369Y387. doi:10.1586/ern.12.158.

b 12. What is the most accurate assessment, given this MRI result?A. the patient had a partial response because the T1-weighted

contrast-enhancing lesion has decreased in sizeB. the patient has progressive disease because the FLAIR signal has increasedC. the patient has stable disease because he has not changed clinicallyD. the patient has stable disease because the T1-enhancing lesion has

decreased in size but the FLAIR signal has increasedE. this is a pseudoprogression phenomenon due to the nitrosourea treatment

The preferred response is B (the patient has progressive disease because theFLAIR signal has increased). Antiangiogenic therapies, such as bevacizumab,can reduce vascular permeability and decrease contrast enhancement within 1 to2 days after initiation of therapy. These apparent responses, calledpseudoresponses, may be partially the result of normalization of abnormallypermeable vessels and are not necessarily indicative of a true antiglioma effect.1Y4

As a result, radiologic responses in studies with antiangiogenic agents shouldbe interpreted with caution.2,3 Moreover, it is known that some patients who

The patient does not have access to a clinical trial near his home, so heproceeds with treatment with CCNU and bevacizumab. He is stableneurologically, but his fatigue worsens. The third cycle of CCNU is delayedbecause ofhematologic toxicity.MRI performedprior to initiationof the thirdcycle shows a significant reduction of the T1-weighted contrast-enhancingareas with increase in the extent of FLAIR signal.



initially experience reduction in tumor contrast enhancement subsequentlydevelop progressive increase characterized by an increase in nonenhancingT2/FLAIR signal suggestive of infiltrative tumor.3 For this reason, the RANOWorking Group proposed an updated response criteria, in which a significantincrease in T2/FLAIR sequences compared with the baseline MRI or thebest response achieved after initiation of therapy, in absence of alternativeexplanations such as radiation injury, ischemic or demyelinating events,infections, seizures, or postoperative changes, should be interpretedas progressive disease.4 On the other hand, pseudoprogression occurringmore than 1 year after radiation therapy during second-line treatment withnitrosoureas is very uncommon.

1. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinaseinhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. CancerCell 2007;11(1):83Y95. doi:10.1016/j.ccr.2006.11.021.

2. Brandsma D, van den Bent MJ. Pseudoprogression and pseudoresponse in the treatment ofgliomas. Curr Opin Neurol 2009;22(6):633Y638. doi:10.1097/WCO.0b013e328332363e.

3. Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas:efficacy, toxicity, and patterns of recurrence. Neurology 2008;70(10):779Y787. doi:10.1212/01.wnl.0000304121.57857.38.

4. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria forhigh-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol2010;28(11):1963Y1972. doi:10.1200/JCO.2009.26.3541.

Soon afterward, the patient’s clinical condition begins to decline. After anextensive discussion of the goals of care, he decides to stop active therapy andfocus on comfort measures.




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