disclosuresGrant/research support fromAbbvieHonoraria fromCelgene, BMS - PDF document

disclosuresGrant/research support fromAb
disclosuresGrant/research support fromAbbvieHonoraria fromCelgene, BMS, Abbvie, Agios, DaichiSankyoImaging neurooncologyToday: justsomeelementsRealisingpitfallsRANO essentialsHow toassessa tumor withinclinicaltrial usingRANO criteriaFluctuating deficits in an anaplastic oligodendroglioma patientyearoldfemale, treatedyrsforAOD withRT/PCVNovember 2010: stableMRI scanFebru

ary2011: admissionbecauseof fluctuatingp
ary2011: admissionbecauseof fluctuatingparesisright arm, aphasiafordaysMRI: new enhancement, rCBVperfusionimage) increase(ratio 2.24)baselinebaselineadmissionFluctutatingdeficits 13 yearsRT/PCV forAnaplasticOligodendrogliomaWhattreatment wouldTemozolomideirradiationBevacizumabNew anticonvulsantFluctuating deficits in an anaplastic oligodendroglioma patientOurchoiceClu

efluctuatingdeficitsEEG: continuousepile
efluctuatingdeficitsEEG: continuousepilepticdischargesMRI threemonthslater: normalizationDiagnosis: periictalenhancementbaselineadmissionmonthslaterPeriictalenhancementtheSMART syndromestrokelike migraine attacks after radiation therapy)Multiple case reportsirradiatedbraintumor patientsPresenting withor without seizuresheadachefocaldeficits Or nonconvulsivestatus epil

epticusTreatseizuresproactivelyIncreasin
epticusTreatseizuresproactivelyIncreasingenhancement, & increasedrCBVet al, J Neurol2012, Kerklaan et al, J Neurol2011;258:1098Rheimset al, Neuro Oncol 2011;13:775Take home messageincreasein enhancementprogressionEndpointsEndpointOverall SurvivalImaging Related EndpointsPFS according to RANO criteria and assessed by central review and local investigators Objective respo

nse rate (ORR)Quality of Life/Survival e
nse rate (ORR)Quality of Life/Survival endpointsHRQoLCognitionetcTemozolomide in recurrent anaplastic astrocytomamale, 44 yrs of age, first surgery and RT in 1996, recurrence in 8/01 & start temozolomide, TTP 8 moT1 contrast enhancedMR in braintumors: limitationsBasicallyusesarea of enhancementas theprimarytargetEnhancement impliesleakyvessels= endothelialproliferation

bloodbrainbarrierdisruptionEnhancement d
bloodbrainbarrierdisruptionEnhancement does tumor but reflectshigh gradetumor activityEnhancement is aspecificOthercauses: infarction, inflammation, necrosisBrain tumors are frequently difficult to measureRANO criteria: no magic Current standard for assessing treatment response for highgrade gliomas11Surgeryforlow grade1p/19q codeletedSept 2014 1st seizureNovember re

section, waitseeMarch2015: new enhanceme
section, waitseeMarch2015: new enhancement: PD?T1CADCyearoldmale, treatedforglioblastomaRecurrencein Julyross totalresectionAugust 2, 2012Start chemotherapyweeks aftersurgeryNew baseline MRI scan 4 weeks later: increaseWithout a new baseline scan: SD wouldhave been diagnosedas PDPost surgicalassessment: needtoobtaina furtherscan at baseline…1/8/123/8/1230/8/12Ps

eudoprogressionTreatment effects may mim
eudoprogressionTreatment effects may mimic progression within 12 weeks of True progression can be called within the 12 weeks if there is new enhancement outside of the radiation field (beyond the highdose region or 80% isodoselineIf there is no new enhancement outside of the radiation field, progression must be confirmed by imaging •12 weeks from radiation therapyI

f disease burden is no longer increasing
f disease burden is no longer increasing, true progression is not confirmed and the timepointwith the largest SPPD within the 12 weeks from radiation therapy should be considered the ‘new baseline’ for % change purposes14••BeforesurgeryftersurgeryAfterRT/TMZ + 1 adjTMZAfteradjTMZAfteradjTMZGlioblastoma patienttreatedwithradiotherapytemozolomide

Non1p/19q codeleted oligodendrogliomaFe
Non1p/19q codeleted oligodendrogliomaFemale, 30 yearsAsymptomatic right frontal lesionComplete resection, oligodendrogliomaNo 1p/19q lossRT 59,4 post RT: new enhancement2 years later: disappearance of all enhancement32904484 months post RT2 years post RTrCBV: no increase (but small lesion)Incidence of pseudoprogressionin lowgrade gliomas treated with radiotherapy63 c

ases of low gradegliomatreatedwithRT, me
ases of low gradegliomatreatedwithRT, medianup 5 yrs(range yrs): PsPDobserved in 13 patients (20.6%), Occurred after median of 12 months (range 378 months); median duration 6 months (range 226 months) Always occurred within the RT high dose fields (• 45 Gy). rea of the enhancement of psPDsmaller compared to "true" median size 54mm2 [range 12340mm2] vs 270mm2 [range

303420mm2= .009an est et al, NeuroOnco
303420mm2= .009an est et al, NeuroOncol2017;19:71925Imaging protocol: standardizationEORTC/International standardizedMR protocolBasicAdvanced Imaging2014: internationalwishtodevelopstandardizedimaging protocolNBTSJumpstarting Brain Tumor Drug Development CoalitionAll current MR imaging within consortia, big pharma needs to be performed according to the imaging recommen

dations by the NBTSYou can do this at ho
dations by the NBTSYou can do this at home…••17••Ellingsonet al. Neuro Oncol. 2015 Sep;17(9):118898. doi: 10.1093/neuonc/nov095The EORTC Imaging Protocol••180.1 mmol/kg BW of a based contrast agent3D T1w precontrastMPRAGE, 3D IR FSPGR T1w2D FLAIR Transverse3D FLAIR (optionalminimum TETI, TR flip angleaccordingmanufacturer

specific/ field strengthspecificrecommen
specific/ field strengthspecificrecommendationsforoptimum image qualitySENSE / SMASH / GRAPPA / ASSET allowedSlice/3D slab orientationsagittalor transverseFOV: 256 mm x 256 mmMatrix: 256x256Slice thickness1.5 mmFull braincoverageminimum TE•TR > 3000 Spectralfat suppression•b: 0 1000 s/mm2 (3 directions•SENSE / SMASH / GRAPPA / ASSET: optionalfor1.5 T,

obligatoryfor3 T.•Slice orientat
obligatoryfor3 T.•Slice orientationtransverse•Slice thickness5mm•Slice gap: 0Numberof slices: Full braincoverage• FOV: 240 mm x 240 mm•Matrix: 128 x 128 or higher•Postprocessing: Calculationof ADC mapsdiffusiontracemapsTE: 90140ms• TR: 600010000 • TI: 20002500 useTI accordingoptimizedprotocol forspecificinversionpul

sesfield strength• SENSE / SMASH
sesfield strength• SENSE / SMASH / GRAPPA / ASSET allowed• Slice orientationtransverse• Slice thickness: 5mm• Slice gap: 0Numberof slices: sameas sequence• FOV: 240 mm x 240 • Matrix: 256 x 256 or higher• Slice positioning as in sequenceTE: 90140msTR: 600010000 TI: 20002500 useTI accordingoptimizedprotocol forspecificinvers

ionpulsesfield strengthSENSE / SMASH / G
ionpulsesfield strengthSENSE / SMASH / GRAPPA / ASSET / ARC allowedSlice orientationsagittalor transverseSlice thickness1.5 mmNumberof slices: Full braincoverageFOV: 250 mm x 250 mmMatrix: 224 x 224 or higherSlice positioning as in sequenceessentialsComplete Response (CR)100% decrease in SPPD* from BaselinePartial Response (PR)≥ 50% decrease in SPPD from BaselineS

table Disease (SD) 50% decrease in SPPD
table Disease (SD) 50% decrease in SPPD from Baseline and 25% increase from nadirProgressive disease• 25% increase from nadir••19••*SPPD: Sumof PerpendicularDiametersessentialsSteroidsNo response possiblein case of increaseIn case of taper: tumor area mayincreaseSteroidsincreasealonedoes progressionClinicalstatusIn case of deteriorat

ion: equalsprogressionNew LesionEqualspr
ion: equalsprogressionNew LesionEqualsprogressionT2/FLAIR toassessed••20T2 and FLAIR in RANOIntroductionof T2/FLAIR in RANO criteria was drivenantiVEGF treatment associatedpseudoresponsesT2/FLAIR abnormalitiesconsideredmeasurableSignificantincreaseis consideredLimited relevancein evaluationof otherantiVEGF treatmentsBELOB case 144: Well definedlocalrecurre

nce: afteronecycledecreasein enhancement
nce: afteronecycledecreasein enhancement, but increasein T2 abnormalitiesandmasseffectMeasuringMeasure the sum of products of perpendicular diameters of all measurable enhancing lesionsMeasureat leasttwomore thanlesionis presentUp toa maximum of 5 lesionsAdditionallesionsare nontargetMeasureon the plane& slice wherethe lesionis largestadjust the perpendicular measurement

to the longest short axisMeasurabledis
to the longest short axisMeasurablediseaseMeasurable (RANO): Enhancing diseaseinimal bidirectional diameter of ≥ 10 mm and visible on at least two axial slices that are preferably, at most, 5 mm apart with skipRationale: too small lesions cannot be measured reliablyFor progression: ideally, the change should be significant (5mm increase in maximal diameter or 25% in

crease in sum of the products of perpend
crease in sum of the products of perpendicular diameters of enhancing lesionsToo small lesionscannotmeasuredreliablySpecial Considerations for classification of lesions: Lesions with cysts or surgical cavitiesLesions around a cyst or surgical cavity are to be considered nonmeasureable unless there is an enhancing component meeting the measurable disease criteriaThe cysti

c or surgical cavity should not be measu
c or surgical cavity should not be measured in determining responseLesions with a necrotic componentLesions with a necrotic component can be selected as target if they are the only lesion(s) present, otherwise they should be selected as nontarget.The necroticcysticpart is unlikelyshrinkeven in respondingtumorsDefining Lesions at Baseline••25LesionsMeasur

ableNonmeasurableTarget Measurableles
ableNonmeasurableTarget Measurablelesions not selected as targetNontargetTarget NontargetMR measurementsforstudyevaluationPreferablythe sameDocument the MRI series slice(s)Review previousmeasurementsat the time of new measerementsforconsistencyA different planemaycomparedthe baseline scanDo alsodocument measurementsin the patientfile (source document)% Change of S

um of PerPendicularDiameter (SPPD)The %
um of PerPendicularDiameter (SPPD)The % change in SPPD is determines responseor progressionof the target lesions••27From Baseline (for response):••(Current SPPDBaseline SPPD) x 100 = % change from BaselineBaseline SPPD From Nadir (for progression):••(Current SPPDNadir SPPD) x 100 % change from Nadir••Nadir S

PPD Sum of the Product of the Perpendic
PPD Sum of the Product of the Perpendicular Diameters (SPPD)SPPD is calculated at every evaluation for all target lesionsThe change in SPPD determines response or progression of the target lesionsIn case of multiple lesions: select at least twomphasistoplaced on lesions that are likely to allow reproducible repeated measurements.28••Lesion 1Lesion 215 x

10 = 150x 10 = Overall AssessmentCompl
10 = 150x 10 = Overall AssessmentComplete Response all the following must be trueComplete disappearance of all enhancing measurable and measurable disease sustained for at least 4 weeks No new lesions Stable or improved nonenhancing nonmeasureable (T2/FLAIR) lesions Patients must be off corticosteroids (or on physiologic replacement doses only)Stable or improved clinica

lly. Note: Patients with nonmeasurable d
lly. Note: Patients with nonmeasurable disease only cannot have a CR; the best response possible is SD.••29Overall AssessmentPartial Response all the following must be true50% decrease compared with baseline in SPPD of all measurable enhancing lesions sustained for at least 4 weeks Enhancing nonmeasureable disappeared or is stableNo new lesionsStable or imp

roved nonenhancing nonmeasureable (T2/FL
roved nonenhancing nonmeasureable (T2/FLAIR) lesionsCorticosteroids dose at the time of the scan evaluation should be no greater than the dose at time of baseline scanStable or improved clinicallyNote: Patients with nonmeasurable disease only cannot have a PR; the best response possible is SD.30Overall AssessmentStable Disease all the following must be trueDoes not q

ualify for CR, PR, or PDStable nonenhanc
ualify for CR, PR, or PDStable nonenhancing nonmeasureable (T2/FLAIR) lesionsCorticosteroids dose at the time of the scan evaluation should be no greater than the dose at time of baseline scanNote: If the corticosteroid dose was increased for new symptoms and signs (no radiographic confirmation of PD) and followimaging shows PD, the last scan considered SD will be the sca

n that coincides with corticosteroid dos
n that coincides with corticosteroid dose equivalent to the baseline31Dexamethasonefactor in response evaluationyearoldmale glioblastoma patientMarch20 2014 progressivedisease: 52 x 34 mmApril 3 admission: headache, right sidedweakness; start dexamethason 16 mg daily, with taper to12 mg dailyApril 11 new baseline MRI scan at start new treatment: decreasein size, 50 x

27 mm (76%)Works in bothdirections: Decr
27 mm (76%)Works in bothdirections: DecreaseSPPD afterstart or increasesteroidsIncreaseSPPD at decreaseor discontinuationof steroidsAlways: register steroidat time MR evaluationApril 3April 11Overall AssessmentProgressive Disease if any of the following are true25% increase in SPPD of enhancing lesions compared with the nadir, on stable or increasing doses of corticoster

oidsClear progression of nonmeasurable d
oidsClear progression of nonmeasurable diseaseSignificant increase in nonenhancing nonmeasureable (T2/FLAIR) lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapyIncrease should not be caused by comorbid eventsAny new lesionClear clinical deterioration not attributable to other causes apart from t

he tumor or changes in corticosteroid do
he tumor or changes in corticosteroid dose*Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent clinical deterioration.••33PD is diagnosedwhentumor increases25% fromnadir, necessarilybaselinebaselinecycle 1cycle 2cycle 3cyclce 4tumor areatumor area25%PDNadir = the lowest SPPD value fr

om any timepointSummary of the RANO Res
om any timepointSummary of the RANO Response CriteriaT1 gadolinium enhancing disease≥50% ↓<50% ↓ but <25% ↑≥25% ↑T2/FLAIRstableor ↓stableor ↓stableor ↓New lesionsNoneNonepresentCorticosteroidsstable or ↓stable or ↓Clinical statusstable or ↑stable or ↑stable or ↑Requirement for responseAllAllProgressionoccurswhenthiscriterionis present. Increa

sein corticosteroidsalonewilltaken intoa
sein corticosteroidsalonewilltaken intoaccount in determiningprogressionin absence of persistent clinicaldeteriorationWen et al, J Clin Oncol 2010;28:1963Overall Assessment PostBaseline••36••BL&#x/MCI; 14; 00;&#x/MCI; 14; 00;TP2TP3TP4TP5magingSteroid doseMRI assessmentClinical assessmentBL: Baseline; TP: TimepointOnlyin conj

unctionwithclearneurological signs and s
unctionwithclearneurological signs and symptoms deterioration PDPDbaselineCycleCycleCycle3CycleOverall Assessment PostBaseline••37••BL&#x/MCI; 14; 00;&#x/MCI; 14; 00;TP2TP3TP4TP5magingSteroid doseMRI assessmentClinical assessmentBL: Baseline; TP: TimepointPDbaselineCycleCycleCycle3CycleSomedetailsFailure to return for e

valuation as a result of death or deteri
valuation as a result of death or deteriorating condition is to be considered progression.For progression: ideally, the change should be significant (5mm increase in maximal diameter or 25% increase in sum of the products of perpendicular diameters of enhancing lesions)Ifin PD (‘equivocalPD’) , RANO allowscontinuationof treatmentIfthenext scan confirmsPD thenth

edate of PD is backdatedtothedate of the
edate of PD is backdatedtothedate of thescan withequivocaloperatedpatientsin studies withOS, PFS endpointsPatient may have been operated for recurrence. If operated protocol may stipulate that:Residual and measurable disease after surgery is not required but surgery must have confirmed the recurrenceIf so: required:a postsurgery MRI must be available within 48 hours foll

owing surgery: defines target (if presen
owing surgery: defines target (if present)MRI scan has to be done within 2 weeks prior to randomizationsurgery completed at least 2 weeks before randomization and patients should have fully recovered as assessed by investigators. ••39RANO is communicationObjectiveof outcomescoring is tounderstandcommmunicatetheimaging findingsBruegheltheelderBabel’sTo