Presentation on theme: "Jonathan Klein PGY3, Radiation Oncology University of Toronto"— Presentation transcript:
1Jonathan Klein PGY3, Radiation Oncology University of Toronto High Grade Gliomas: Case Presentation and Summary of Evidence for Radiation Therapy ManagementJonathan KleinPGY3, Radiation OncologyUniversity of Toronto
2Case #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.
12Prognosis Prognosis by classification Oligodendroglial component is positive prognostic factor
13PrognosisCurran, JNCI, 1993Recursive partitioning analysis to retrospectively analyze 1578 patients with high grade glioma3 RTOG studies testing RT +/- ChemoResults<50yo: histology most important prognostic factor>50yo: KPS most important prognostic factorMental status differentitated poor KPS groupConclusion: Older and poor KPS do worseCurran et al. J Natl Cancer Inst May 5;85(9):
15Prognosis By recursive partitioning analysis (RPA) Curran et al. J Natl Cancer Inst May 5;85(9):
16ManagementReferred to NeurosurgeryWhat should they do?
17Surgery NO RCTs have studied Standard: Attempt at gross resection Surgery vs notTotal vs subtotal resectionStandard: Attempt at gross resectionNot always possibleLocationCritical structures
18Surgery Simpson, Int J Radiat Oncol Biol Phys, 1993 Review of 3 RTOG trials: 643 patients with GBMImproved survival with more resectionSurgery: Biopsy Partial Total% of patients: 17% 64% 19%MS (months):Simpson JR et al. Int J Radiat Oncol Biol Phys May 20;26(2):
19Surgery Lacroix, J Neurosurg, 2001 Retrospective review, 416 patients with GBMImproved survival with total resection (>98%)Surgery Partial (<98%) Total (>98%)MS (months)Predictors of survivalAge, KPS, extent of resection, degree of necrosis, pre-op MRI enhancementLacroix M, et al. J Neurosurg Aug;95(2):190-8.
20Back to Case Patient taken to OR Resection attempted, but 2.4cm segment of tumour remains
21ManagementReferred to Radiation OncologyWhat should we do?
22Radiation Walker, J Neurosurg, 1978 Phase III, 303 patients with anaplastic gliomaSurgery then randomized to:RT vs BCNU vs RT+BCNU vs ObsMS (mo)Showed no benefit from chemoRT = 50Gy WBRT + 10 Gy boostBCNU = carmustine 80mg/m2 x days 1-3 every 6-8 weeksWalker MD et al. J Neurosurg Sep;49(3):
23Radiation Walker, Int J Radiat Oncol Biol Phys, 1979 Meta-analysis of 3 RCTs621 patients with Gr. III/IV gliomaSurgery then:Obs vs 45Gy vs 50Gy vs 55Gy vs 60GyMS (mo)Showed benefit for RT and dose-response relationshipWalker MD, et al.Int J Radiat Oncol Biol Phys Oct;5(10):
24RadiationWalker, NEJM, 1980Phase III, 358 patients with anaplastic gliomaSurgery then randomized toRT vs RT+BCNU vs RT+Semus vs SemusResultsNo arm significant difference between armsConclusion: RT alone remains standardWalker MD et al. N Engl J Med Dec 4;303(23):
25Radiation Kristiansen, Cancer, 1981 Phase III, 118 patients with Gr III/IV astrocytomaSurgery then randomized to:RT vs RT+Bleomycin vs ObsMS (mo)Showed no benefit from chemoRT = 45Gy WBRTBleomycin = carmustine 180mg 3/week, 1hr prior to RT, weeks 1,2,4,5Kristiansen K et al. Cancer Feb 15;47(4):
26Radiation Laperriere, Radiother apy + Oncology, 2002 Systematic review of 6 RCTsConfirmed benefit from post-op RTRecommended:Young (< 70 yo)Treat enhancing tumour + margin (e.g. 2 cm)Dose: 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 chemoLaperierre N et al. Radiother Oncol Sep;64(3):
27RadiationSo RT is good…What dose should we give?
28Radiation Randomized to: Median survival: Subsets: Nelson, NCI Monog., 1988 RTOG 74-01626 patients with Gr III/IV astrocytomaRandomized to:60Gy* vs vs 60+B** vs 60+C+D***Median survival:60Gy: 9.3 months vs Gy: 8.2 monthsSubsets:>60 yo: RT+chemo did not improve survival40-60 yo: RT+BCNU = 23% 2 year survival vsRT alone = 8%*60 Gy WBRT**60 Gy + carmustine (=BCNU)***60 Gy + semustine + dacarbazineNelson DF et al. NCI Monogr. 1988;(6):
29Radiation Bleehen, BJC, 1991 474 patients with Gr III/IV astrocytoma Surgery, no chemo, then randomized to:45/20* vs 40/20+20/10**MS (mo)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 Oct;64(4):
30Radiation Scott, Int J Radiat Oncol Biol Phys, 1998 RTOG 9006 712 patients with Gr III/IV gliomaRandomized to carmustine + :60/30 vs 72/60 (1.2 Gy/# BID)MS (mo)72/60 not better for any subgroup60/30 was better for all patients < 50 yoScott CB et al. Int J Radiat Oncol Biol Phys Jan 1;40(1):51-5.
32?SRS? Early series showed promising survival w/SRS Buatti et al., 1995 Int J Radiat Oncol Biol Phys Apr 30;32(1):Int J Radiat Oncol Biol Phys Jul 15;32(4):Gannett et al., 1995Int J Radiat Oncol Biol Phys Sep 30;33(2):461-8.Masciopinto et al., 1995J Neurosurg Apr;82(4):530-5.
33?SRS? RTOG 9305 Souhami, Int J Radiat Oncol Biol Phys, 2004 RCT, 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 GBMSouhami et al. Int J Radiat Oncol Biol Phys 2004;60:
34Management Referred to Medical Oncology Should the patient have chemotherapy?
35Chemotherapy Stewart, Lancet, 2002 Metanalysis, 12 RCTs, 3004 patients Hazard ratio for death = 0.85Chemotherapy group did betterStewart LA. Lancet Mar 23;359(9311): Review.
36ChemotherapyStewart LA. Lancet Mar 23;359(9311): Review.
37Chemotherapy Stupp, JCO, 2002 Phase II, 64 patients with primary GBM RT + 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 oldpatients who had debulking surgeryStupp R et al. Clin Oncol Mar 1;20(5):
39EORTC 26981 Stupp, NEJM, 2005 (2009 Lancet Oncology update) Phase III, 573 patients <70 yo with primary GBMRandomized toRT alone vs Stupp Phase II protocol:RT: 60Gy/30TMZ: 75 mg/m2/d x 42d then 200 mg/m2/d for 5d q28d x6 cyclesStupp R et al. N Engl J Med Mar 10;352(10):
40EORTC 26981 88% of patients received full course ChemoRT 40% of patients completed adjuvant ChemoGrade ≥3 toxicity = 4%
41EORTC 26981 MS (med) 12.1 mo 14.6 mo PFS (med) 5 mo 6.9 mo RT ChemoRTMS (med) mo 14.6 moPFS (med) 5 mo 6.9 moOS: 2 yr 10% 26%4 yr 3% 12%5 yr 2% 10%
42EORTC 26981 Overall survival curve Stupp R et al. N Engl J Med Mar 10;352(10):
43EORTC 26981 Subgroups: Methylated MGMT Unmethylated Stupp R et al. N Engl J Med Mar 10;352(10):
44EORTC 26981 Improved response for patients with methylated MGMT gene Epigenetic silencing of MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents.Hegi ME et al. N Engl J Med Mar 10;352(10):
45MGMT Methylation Hegi, NEJM, 2005 206 patients from EORTC trial assessed for MGMT methylation statusMethylMGMT found in 45%ResultsMethylMGMT was a favorable prognostic factor: HR =0.45For methylMGMT TMZ better than RT: 21.7 vs 15.3 monthsFor unmethylMGMT, no statistically significant differenceConclusionsGBM with methylMGMT benefited from TMZ, but unmethylMGMT promoter did not benefitHegi ME et al. N Engl J Med Mar 10;352(10):
46Hegi ME et al. N Engl J Med. 2005 Mar 10;352(10):997-1003.
47RTOG 0525Gilbert, ASCO, 2011RCT, 833 pts > 60 yo with GBM/GliosarcomaTest dose-dense TMZ regimenRandomized toEORTC RT+TMZ protocol vs60Gy/30 + daily TMZ followed by 21d adjuvant chemoGilbert 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
48RTOG 0525Gilbert 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
49RTOG 0525Gilbert 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
50RTOG 0525Improved response for patients with methylated MGMT continuedNo difference in PFS or OS between study arms for either methylated or non-methylated subgroups
51Ongoing StudiesWhat is being tested now?Biologic agents
52Ongoing Studies RTOG 0837 RTOG 0825 Phase III RT+TMZ vs RT+TMZ+bevacizumabBevacizumab (Avastin) shown effect in RCC,NSCLC,CRCRTOG 0825RT+TMZ vs RT+TMZ+cediranib
53Back to case Patient 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?
54Pseudoprogression Sanghera, Can J Neurol Sci, 2010 Retrospective, 111 patientsGBM 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 Jan;37(1):36-42.
55Pseudoprogression Results psP group had stable dexamethasone dose25% had evidence of early progression, with 32% of these representing psPMedian OS : whole cohort = 56.7 weekspsP = 125 weekstrue early progression = 36 weeksConclusion: Maintenance TMZ should not be stopped on the basis of seemingly discouraging imaging features within first three months after RT/TMZ.
56PseudoprogressionSanghera P. Can J Neirol Sci Jan;37(1):36-42.
57Pseudoprogression Brandes, JCO, 2008 Cohort, 103 patients with MGMT statusTreated with Stupp TMZ+RT protocolResultspsP 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 May 1;26(13):
58Pseudoprogression Sanghera, Clin Oncol, 2012 Expert 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-TxSanghera P. Clin Oncol (R Coll Radiol) Apr;24(3):
59PseudoprogressionSanghera P. Clin Oncol (R Coll Radiol) Apr;24(3):
60Sanghera P. Clin Oncol (R Coll Radiol). 2012 Apr;24(3):216-27.
61Back to case Patient continues on monthly adjuvant TMZ Returns for 6 month post-RT appointment and has another MRIScan shows clearly increased size of disease…Now what?
62Recurrent GBM - RT Median time to recurrence is ~7 months Re-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:
63Recurrent GBM - RT Fogh, JCO, 2010 147 patients with recurrent GBM Treated with stereotactic RT 35/10Cox analysis performedSurvival improved with:Younger ageSmaller GTVShorter time between diagnosis and recurrenceHigh RT dose (≥35Gy) showed trend to significance (p = .07).Survival not improved by:Surgical resectionChemotherapySource: RTOG 0125 protocol. May be accessed at:Fogh SE et al. J Clin Oncol Jun 20;28(18):
64Recurrent GBM - Chemo Phase II chemo trials Wong ET et al. J Clin Oncol Aug;17(8):Carson KA et al. J Clin Oncol Jun 20;25(18):6 month PFS: 15%; Median OS: 6 monthsBevacizumab/other monoclonal Abs studied in ph. II trialsVredenburgh JJ et al. J Clin Oncol Oct 20;25(30):32 pts given bevacizumab + irinotecan6 month PFS: 38%; MS for GBM patients: 9.2 monthsKreisl 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:29Other trials have added bevacizumab to other chemo agents such as low dose TMZ, etoposide, erlotinib, nitrosureaNo improvement in survival shown, but worse toxicitySource: RTOG 0125 protocol.May be accessed at:
65Recurrent GBM - ChemoFriedman HS et al. J Clin Oncol Oct 1;27(28):RCT, 167 patients with recurrent GBM in 1st or 2nd relapseRandomized tobevacizumab alone 10 mg/kg q2weeks vsbevacizumab +irinotecan (82 patients)Results not significant:Beva alone Beva+irino6-month PFS: %; %Median survival: months 9.7 monthsConclusion: No increase in efficacy with irinotecan, but increase toxicitySource: RTOG 0125 protocol.May be accessed at:
66Recurrent 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 aloneSource: RTOG 0125 protocol.May be accessed at:
67Case #2 Mr. B. 80M 2 weeks persistent headache and malaise Refractory to OTC analgesiaDiagnosed with GBM on imagingReferred to NeuroSxTaken to OR for biopsyPlatelets decreasing so procedure abandoned
68Mr. Z. Referred to Rad Onc for management Work up History Physical Imaging
70Mr. Z. What to do? No biopsy, so no tissue diagnosis Treated as presumed GBM
71Management Curran, JNCI, 1993 Recursive partitioning analysis to retrospectively analyze 1578 patients with high grade glioma3 RTOG studies testing RT +/- ChemoResults<50yo: histology most important prognostic factor>50yo: KPS most important prognostic factorMental status differentitated poor KPS groupConclusion: Older and poor KPS do worseCurran et al. J Natl Cancer Inst May 5;85(9):
72Management Bauman, Int J Radiat Oncol Biol Phys, 1994 Prospective, 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 KPSBauman GS et al. Int J Radiat Oncol Biol Phys Jul 1;29(4):835-9.
73Management Roa W, J Clin Oncol, 2004 RCT, 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 patientsRoa W et al. J Clin Oncol May 1;22(9):
74ManagementRoa W et al. J Clin Oncol May 1;22(9):
75Management Keime-Guibert, NEJM, 2007 RCT, 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 wksSurvival benefit independent of extent of surgeryNo effect on HRQoL or cognition from RTConclusion: RT is good for older, good KPS patientsKeime-Guibert et al. N Engl J Med Apr 12;356(15):
77Management Muni, Tumori, 2010 Prospective comparison study 45 patients with GBMAge ≥ 70 yo OR Age and KPS < 701:1 split of 30Gy/6 ± TMZ mg/m2 x5d q28dRT+TMZ No TMZMedian OS 9.4 mos 7.3 mos6 mo OS 95% 78%Median PFS 5.5 mos 4.4 mos6 mo PFS 45% 22%Minimal additional toxicity (≥Gr 3 = 46%)Conclusion: RT+TMZ beneficial for older or poor KPS patientsMuni R et al. Tumori Jan-Feb;96(1):60-4.
78NOA-08Wick, Lancet Oncol, 2012RCT, 412 patients with Gr III/IV astrocytomaAge ≥ 65 yo AND KPS ≥70Powered for non-inferiorityRandomized to:RT 60Gy/30vs TMZ 100mg/m2 x7d 1wk-on/1wk-offWick W et al. Lancet Oncol Jul;13(7):707-15
79NOA-08 Results Subgroups Median survival: RT=9.6 mo; TMZ=8.6 moP(non-inferiority)=0.033Event-free survival: RT=4.7mo; TMZ=3.3moP(non-inferiority)=0.043SubgroupsMGMT 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=8·4 months; RT=4·6 [4·2-5·0]),Patients without MGMT methylation did better with RTEFS for –ve methMGMT: RT=4.6 months; TMZ=3.3 monthsConclusion: TMZ alone is not inferior to RT for elderly, good KPS patients.MGMT methylation status can aid decisions.
80Wick W et al. Lancet Oncol. 2012 Jul;13(7):707-15
81RT +/- TMZ Malmstrom, Lancet Oncol, 2012 RCT, 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 vsstandard RT: 60Gy/30Malmstrom A et al. Lancet Oncol Sep;13(9):
82RT +/- TMZ Results Overall TMZ better than standard 60Gy RT median OS: TMZ=8.3 months; 60Gy RT=6.0 monthStandard 60 Gy RT not better than hypo# 34Gy RTMedian OS: 34Gy RT=7.5 mos; 60 Gy RT =6.0 mos p=0.24TMZ not better than hypo# 34Gy RTMedian OS: TMZO=8·4 mos; 34Gy RT= 7·4 mos p=0·12
83RT +/- TMZ Subset results Patients > 70 years old TMZ better than standard RTHR p<0.0001Hypo# 34Gy RT better than standard RTHR p=0.02Patients receiving TMZMethylated MGMT had better median overall survival vs non-methylated MGMTMethylMGMT = 9·7 months; nonMethylMGMT= 6·8 months p=0·02Patients receiving RTNo difference between methylMGMT and unmethylMGMTHR=0·97 p=0·81)
84All patients 60-70 years older than 70 years Figure 2 Kaplan-Meier analysis of overall survival in patients randomised across three treatment groups (A) All patients. (B) Patients aged 60?70 years. (C) Patients older than 70 years. TMZ=temozolomide. 34 Gy=hypofractionated radiotherapy. 60 .Malmstrom A et al. Lancet Oncol Sep;13(9):
85Back to CaseMr. B treated with 40Gy/15 RT aloneNo chemo