High Grade Gliomas: Case Presentation and Discussion of Management

High Grade Gliomas: Case Presentation and Summary of Evidence for Radiation Therapy ManagementJonathan KleinPGY3, Radiation OncologyUniversity of Toronto

Case #1Mr. A64M presents to ER with two weeks of dizziness and things on my left side look funny. Feels he veers to the left side when walking.

WorkupHistoryPhysical

WorkupHistoryCharacterize symptoms: OPQRSTGeneral: headache, seizures, N/V, syncope, cognitive Focal: weakness, sensory loss, aphasia, visual Family historyPMHx/Meds/allergies

PhysicalWorkupHistoryCharacterize symptoms - OPQRSTGeneral: headache, seizures, N/V, syncope, cognitive Focal: weakness, sensory loss, aphasia, visual Family historyPMHx/Meds/allergies

PhysicalCNS: GCS, CNII-XII, gait, strength, DTRs, BabinskiScreening CVS, lung, abdomen exam

ImagingMRI with gadolinium is preferred modalityRelevant imaging findings for contouringT1 with gadolinium: enhancing cavityT2/FLAIR: edema and enhancement

Workup

Imaging

Histology4 criteria (AMEN) :nuclear Atypia MitosisEndothelial proliferationNecrosis

# Criteria 01*23-4GradeIIIIIIIV*1 criterion = atypia for Grade II

StagingAJCC TNM Staging System not usedStagingGBM can be primary or secondary (10%)

PrognosisPrognosis by classification

Oligodendroglial component is positive prognostic factor

PrognosisCurran, JNCI, 1993Recursive partitioning analysis to retrospectively analyze 1578 patients with high grade glioma3 RTOG studies testing RT +/- Chemo

Results50yo: KPS most important prognostic factorMental status differentitated poor KPS groupConclusion: Older and poor KPS do worse

Curran et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.

Lamont ED, Christakis NA. Survival estimates in advanced cancer. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2013.

PrognosisBy recursive partitioning analysis (RPA)

Curran et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.

ManagementReferred to NeurosurgeryWhat should they do?SurgeryNO RCTs have studied Surgery vs notTotal vs subtotal resection

Standard: Attempt at gross resectionNot always possibleLocationCritical structuresSurgerySimpson, Int J Radiat Oncol Biol Phys, 1993Review of 3 RTOG trials: 643 patients with GBM

Improved survival with more resection

Surgery:BiopsyPartialTotal% of patients:17%64%19%MS (months):6.610.411.3

Simpson JR et al. Int J Radiat Oncol Biol Phys. 1993 May 20;26(2):239-44.

SurgeryLacroix, J Neurosurg, 2001Retrospective review, 416 patients with GBM

Improved survival with total resection (>98%)

SurgeryPartial (98%)MS (months)8.813

Predictors of survivalAge, KPS, extent of resection, degree of necrosis, pre-op MRI enhancement

Lacroix M, et al. J Neurosurg. 2001 Aug;95(2):190-8.

Back to CasePatient taken to ORResection attempted, but 2.4cm segment of tumour remainsManagementReferred to Radiation OncologyWhat should we do?RadiationWalker, J Neurosurg, 1978Phase III, 303 patients with anaplastic glioma

Surgery then randomized to: RT vs BCNU vs RT+BCNU vs ObsMS (mo) 8.1 4.2 8 3.2

Showed no benefit from chemo RT = 50Gy WBRT + 10 Gy boostBCNU = carmustine 80mg/m2 x days 1-3 every 6-8 weeks

Walker MD et al. J Neurosurg. 1978 Sep;49(3):333-43.

RadiationWalker, Int J Radiat Oncol Biol Phys, 1979Meta-analysis of 3 RCTs621 patients with Gr. III/IV glioma

Surgery then: Obs vs 45Gy vs 50Gy vs 55Gy vs 60GyMS (mo) 4 3 7 9 10

Showed benefit for RT and dose-response relationship

Walker MD, et al.Int J Radiat Oncol Biol Phys. 1979 Oct;5(10):1725-31.

RadiationWalker, NEJM, 1980Phase III, 358 patients with anaplastic gliomaSurgery then randomized toRT vs RT+BCNU vs RT+Semus vs Semus

ResultsNo arm significant difference between arms

Conclusion: RT alone remains standard

Walker MD et al. N Engl J Med. 1980 Dec 4;303(23):1323-9.

RadiationKristiansen, Cancer, 1981Phase III, 118 patients with Gr III/IV astrocytoma

Surgery then randomized to: RT vs RT+Bleomycin vs ObsMS (mo) 10.810.8 5.2

Showed no benefit from chemo RT = 45Gy WBRTBleomycin = carmustine 180mg 3/week, 1hr prior to RT, weeks 1,2,4,5

Kristiansen K et al. Cancer. 1981 Feb 15;47(4):649-52.

RadiationLaperriere, Radiother apy + Oncology, 2002 Systematic review of 6 RCTs

Confirmed benefit from post-op RT

Recommended:Young (< 70 yo)Treat enhancing tumour + margin (e.g. 2 cm)Dose: 50-60 Gy in 1.8-2Gy per fractionOlder with good KPSCan use short course RTOlder with poor KPSCan consider supportive care aloneThis review did not recommend addition of chemo

Laperierre N et al. Radiother Oncol. 2002 Sep;64(3):259-73.

RadiationSo RT is goodWhat dose should we give?RadiationNelson, NCI Monog., 1988 RTOG 74-01626 patients with Gr III/IV astrocytoma

Randomized to:60Gy* vs 60+10 vs 60+B** vs 60+C+D***Median survival: 60Gy: 9.3 months vs 60+10Gy: 8.2 months

Subsets:>60 yo: RT+chemo did not improve survival 40-60 yo: RT+BCNU = 23% 2 year survival vs RT alone = 8%*60 Gy WBRT**60 Gy + carmustine (=BCNU)***60 Gy + semustine + dacarbazineNelson DF et al. NCI Monogr. 1988;(6):279-84.

RadiationBleehen, BJC, 1991474 patients with Gr III/IV astrocytoma

Surgery, no chemo, then randomized to:

45/20* vs 40/20+20/10**MS (mo) 912

60/30 improved survival with similar toxicity

*=45/20 to all known and potential tumour**=40/20 as above, then 20/10 to defined tumour volumetogether with a 1 cm margin around it.Bleehen NM, Stenning SP. Br J Cancer. 1991 Oct;64(4):769-74.

RadiationScott, Int J Radiat Oncol Biol Phys, 1998 RTOG 9006712 patients with Gr III/IV glioma

Randomized to carmustine + : 60/30 vs 72/60 (1.2 Gy/# BID)MS (mo) 13.2 11.2

72/60 not better for any subgroup60/30 was better for all patients < 50 yo

Scott CB et al. Int J Radiat Oncol Biol Phys. 1998 Jan 1;40(1):51-5.

RadiationShould we use SRS??SRS?Early series showed promising survival w/SRSBuatti et al., 1995 Int J Radiat Oncol Biol Phys. 1995 Apr 30;32(1):205-10.Int J Radiat Oncol Biol Phys. 1995 Jul 15;32(4):1161-6.Gannett et al., 1995Int J Radiat Oncol Biol Phys. 1995 Sep 30;33(2):461-8.Masciopinto et al., 1995J Neurosurg. 1995 Apr;82(4):530-5.?SRS?RTOG 9305Souhami, Int J Radiat Oncol Biol Phys, 2004RCT, 203 GBM pts all received 60Gy EBRT +carmustineRandomized to upfront SRS vs no SRS (15-24Gy)Median survival not different: 13.5 v 13.6 monthsSRS not currently standard for GBM

Souhami et al. Int J Radiat Oncol Biol Phys 2004;60:853-860.

ManagementReferred to Medical OncologyShould the patient have chemotherapy?ChemotherapyStewart, Lancet, 2002Metanalysis, 12 RCTs, 3004 patients

Hazard ratio for death = 0.85Chemotherapy group did better

Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8. Review.

Chemotherapy

Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8. Review.

ChemotherapyStupp, JCO, 2002Phase II, 64 patients with primary GBMRT + TemozolomideRT: 60Gy/30TMZ: 75 mg/m2/d x 42d then 200 mg/m2/d for 5d q28d x6 cyclesMedian survival = 16 monthsOS: 1 yr = 58% ; 2 yr = 31%Grade 3 toxicity = 6% Good prognosis subsets: 50 years old patients who had debulking surgeryStupp R et al. Clin Oncol. 2002 Mar 1;20(5):1375-82.

WAKE UP!!!!Important Study AlertEORTC 26981Stupp, NEJM, 2005 (2009 Lancet Oncology update)Phase III, 573 patients 60 yo with GBM/GliosarcomaTest dose-dense TMZ regimenRandomized toEORTC 26981 RT+TMZ protocolvs60Gy/30 + daily TMZ followed by 21d adjuvant chemo

Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

RTOG 0525

Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

RTOG 0525

Gilbert MR et al. Journal of Clinical Oncology, 2011 ASCO Annual Meeting Proceedings (Post-Meeting Edition).Vol 29, No 15_suppl (May 20 Supplement), 2011: 2006

RTOG 0525Improved response for patients with methylated MGMT continuedNo difference in PFS or OS between study arms for either methylated or non-methylated subgroupsOngoing StudiesWhat is being tested now?Biologic agentsOngoing StudiesRTOG 0837Phase IIIRT+TMZ vs RT+TMZ+bevacizumabBevacizumab (Avastin) shown effect in RCC,NSCLC,CRC

RTOG 0825Phase IIIRT+TMZ vs RT+TMZ+cediranib

Back to casePatient receives concurrent 60Gy/30 RT Planned for continuing adjuvant monthly TMZPatient returns to clinic 1 month after treatment with MRIScan shows increased enchancement of treated tumour cavity

Now what?Did treatment fail?PseudoprogressionSanghera, Can J Neurol Sci, 2010Retrospective, 111 patients GBM or Gr.III with GBM-like radiographic featuresUsed Stupp RT+TMZ protocolPseudoprogression (psP) = no further radiographic progression, without salvage therapy, within 6 months after TMZ+RTRepresent transient increase in vessel permeability and damaged peritumoural BBBSanghera P. Can J Neirol Sci. 2010 Jan;37(1):36-42.

PseudoprogressionResultspsP group had stable dexamethasone dose25% had evidence of early progression, with 32% of these representing psPMedian OS : whole cohort = 56.7 weeks psP = 125 weeks true early progression = 36 weeks

Conclusion: Maintenance TMZ should not be stopped on the basis of seemingly discouraging imaging features within first three months after RT/TMZ.Pseudoprogression

Sanghera P. Can J Neirol Sci. 2010 Jan;37(1):36-42.

PseudoprogressionBrandes, JCO, 2008Cohort, 103 patients with MGMT statusTreated with Stupp TMZ+RT protocol

ResultspsP occurs in 91% of methylMGMT +ve GBM vs 41% -ve+ve methylMGMT and psP each improved survivalPatients more sensitive to treatment more likely to get psPBrandes AA. J Clin Oncol. 2008 May 1;26(13):2192-7.

PseudoprogressionSanghera, Clin Oncol, 2012Expert consensus on psP

Poor efficacy 2nd line Tx so need to minimize inappropriate withdrawal of adjuvant TMZpsP unlikely if radiographic progression over 2 mo within 6 mo post-Tx

Sanghera P. Clin Oncol (R Coll Radiol). 2012 Apr;24(3):216-27.Pseudoprogression

Sanghera P. Clin Oncol (R Coll Radiol). 2012 Apr;24(3):216-27.

Sanghera P. Clin Oncol (R Coll Radiol). 2012 Apr;24(3):216-27.Back to casePatient continues on monthly adjuvant TMZReturns for 6 month post-RT appointment and has another MRIScan shows clearly increased size of disease

Now what?Recurrent GBM - RTMedian time to recurrence is ~7 monthsRe-irradiation trialsOver 300 patients reportedCombs 2005; Nieder 2008; Fogh 2010Results6 month PFS: 28-39%1 year median OS: 26% (range 18-46%)Source: RTOG 0125 protocol. May be accessed at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205Recurrent GBM - RTFogh, JCO, 2010147 patients with recurrent GBMTreated with stereotactic RT 35/10

Cox analysis performedSurvival improved with:Younger age Smaller GTVShorter time between diagnosis and recurrence High RT dose (35Gy) showed trend to significance (p = .07).Survival not improved by:Surgical resection ChemotherapySource: RTOG 0125 protocol. May be accessed at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205Fogh SE et al. J Clin Oncol. 2010 Jun 20;28(18):3048-53Recurrent GBM - ChemoPhase II chemo trialsWong ET et al. J Clin Oncol. 1999 Aug;17(8):2572-8. Carson KA et al. J Clin Oncol. 2007 Jun 20;25(18):2601-6.6 month PFS: 15%; Median OS: 6 months

Bevacizumab/other monoclonal Abs studied in ph. II trialsVredenburgh JJ et al. J Clin Oncol. 2007 Oct 20;25(30):4722-9.32 pts given bevacizumab + irinotecan6 month PFS: 38%; MS for GBM patients: 9.2 months

Kreisl TN et al. J Clin Oncol 2009 Feb 10;27(5):740-5.48 recurrent glioblastoma patients received bevacizumab aloneResponse rate: 25%; Median PFS: 16 weeks; 6-month PFS:29

Other trials have added bevacizumab to other chemo agents such as low dose TMZ, etoposide, erlotinib, nitrosureaNo improvement in survival shown, but worse toxicity

Source: RTOG 0125 protocol. May be accessed at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205Recurrent GBM - ChemoFriedman HS et al. J Clin Oncol. 2009 Oct 1;27(28):4733-40.RCT, 167 patients with recurrent GBM in 1st or 2nd relapse Randomized to bevacizumab alone 10 mg/kg q2weeks vs bevacizumab +irinotecan (82 patients)

Results not significant:Beva aloneBeva+irino6-month PFS: 42.6%; 50.3%Median survival: 9.2 months9.7 months

Conclusion: No increase in efficacy with irinotecan, but increase toxicitySource: RTOG 0125 protocol. May be accessed at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205Recurrent GBM - ChemoSalvage chemotherapy post-bevacizumab failure has 6-month PFS of 2% (Quant 2009).

Recurrent GBM patients should be enrolled on trial whenever possibleOngoing trials include RTOG 1205:Randomized Phase II for recurrent GBMBevacizumab + RT vs bevacizumab alone

Source: RTOG 0125 protocol. May be accessed at: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1205Case #2Mr. B.80M2 weeks persistent headache and malaiseRefractory to OTC analgesia

Diagnosed with GBM on imagingReferred to NeuroSxTaken to OR for biopsyPlatelets decreasing so procedure abandonedMr. Z.Referred to Rad Onc for managementWork upHistoryPhysicalImaging

Mr. Z.What to do?No biopsy, so no tissue diagnosis

Treated as presumed GBMManagementCurran, JNCI, 1993Recursive partitioning analysis to retrospectively analyze 1578 patients with high grade glioma3 RTOG studies testing RT +/- Chemo

Results50yo: KPS most important prognostic factorMental status differentitated poor KPS groupConclusion: Older and poor KPS do worse

Curran et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.

ManagementBauman, Int J Radiat Oncol Biol Phys, 1994Prospective, 29 patients with GBMTreated with 30Gy/10 WBRTCompared with historical radical and supportive care controlsResultsOverall median survival 6 monthsMedian survival: RT = 10 mos; Supp. care = 1 moImproved survival for radical dose if KPS>50Conclusion: 30/10 reasonable for older patients with poor KPS

Bauman GS et al. Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):835-9.

ManagementRoa W, J Clin Oncol, 2004RCT, 100 patients with GBM 60 yoRandomized to radical RT 60/30 vs short course RT 40/15No chemo during Tx (some got for recurrence)ResultsMedian survival: Radical= 5.1 mos; Short= 5.6 mos6 months survival: Radical= 44.7%; Short= 41.7%Short course reduced steroid requirementsConclusion: Short course reasonable to older patients

Roa W et al. J Clin Oncol. 2004 May 1;22(9):1583-8.

73Management

Roa W et al. J Clin Oncol. 2004 May 1;22(9):1583-8.

ManagementKeime-Guibert, NEJM, 2007RCT, 81 patients with Gr. III/IV astrocytomaAll got surgeryAge 70 yo and KPS 70Randomized to RT 50 Gy vs supportive care aloneResultsTrial stopped early due to superiorityMedian survival: RT= 29.1 wks; No RT= 16.9 wks Survival benefit independent of extent of surgeryNo effect on HRQoL or cognition from RTConclusion: RT is good for older, good KPS patients

Keime-Guibert et al. N Engl J Med. 2007 Apr 12;356(15):1527-35.

75Management

OSManagementMuni, Tumori, 2010Prospective comparison study 45 patients with GBMAge 70 yo OR Age 50-70 and KPS < 701:1 split of 30Gy/6 TMZ 150-200 mg/m2 x5d q28dRT+TMZNo TMZMedian OS 9.4 mos7.3 mos6 mo OS 95%78%Median PFS5.5 mos4.4 mos6 mo PFS45%22%

Minimal additional toxicity (Gr 3 = 46%)Conclusion: RT+TMZ beneficial for older or poor KPS patients

Muni R et al. Tumori. 2010 Jan-Feb;96(1):60-4.

77NOA-08Wick, Lancet Oncol, 2012RCT, 412 patients with Gr III/IV astrocytomaAge 65 yo AND KPS 70Powered for non-inferiorityRandomized to: RT 60Gy/30 vs TMZ 100mg/m2 x7d 1wk-on/1wk-off

Wick W et al. Lancet Oncol. 2012 Jul;13(7):707-1578NOA-08ResultsMedian survival: RT=9.6 mo; TMZ=8.6 mo P(non-inferiority)=0.033Event-free survival: RT=4.7mo; TMZ=3.3moP(non-inferiority)=0.043

SubgroupsMGMT methylation cohort had improved survivalMedian survival: Methylated=11.9mo; Unmethylated=8.2moPatients with MGMT methylation did better with TMZEFS for +ve methMGMT: RT=4.6 months; TMZ=84 months; RT=46 [42-50]), Patients without MGMT methylation did better with RTEFS for ve methMGMT: RT=4.6 months; TMZ=3.3 months

Conclusion: TMZ alone is not inferior to RT for elderly, good KPS patients. MGMT methylation status can aid decisions.

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Wick W et al. Lancet Oncol. 2012 Jul;13(7):707-15RT +/- TMZMalmstrom, Lancet Oncol, 2012RCT, 291 patients with GBM 60 yoRandomization stratified by centreTMZ 200 mg/m2 x5d q28d for 6 cycles vshypo# RT: 34 Gy/3-4 Gy per fraction vs standard RT: 60Gy/30Malmstrom A et al. Lancet Oncol. 2012 Sep;13(9):916-26. RT +/- TMZResultsOverallTMZ better than standard 60Gy RTmedian OS: TMZ=8.3 months; 60Gy RT=6.0 month

Standard 60 Gy RT not better than hypo# 34Gy RTMedian OS: 34Gy RT=7.5 mos; 60 Gy RT =6.0 mos p=0.24

TMZ not better than hypo# 34Gy RTMedian OS: TMZO=84 mos; 34Gy RT= 74 mos p=012

RT +/- TMZSubset resultsPatients > 70 years oldTMZ better than standard RTHR 0.35 p