Management of Glioma: The Basics Glioma Update The clinical challenge. Glioma a malignant disease of the CNS

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1 Management of Glioma: The Basics Glioma Update 3 oger Stupp, MD Department of Oncology & Cancer Center University Hospital Zurich, Switzerland (roger.stupp@usz.ch) Bern, 3. August 3 The clinical challenge Diffuse infiltrating and migrating tumors Inflammation and edema Highly vascularized Glioma a malignant disease of the CNS June 7

2 Glioma are not all the same Genetic Pathways to GBM EGF amplification 4% p6/p4 deletion 4% LOH p&q PTEN mutations 3% telomerase activity, 6% Primary Glioblastoma mean age : 55 years p53 mutations, 6%, LOH 7p PDGF overexpression telomerase activity, % Astrocytoma II LOH 9q b alteration telomerase activity, 4% Astrocytoma III LOH q DCC loss expr, 5% PDGF amplification, <% telomerase activity, % Secondary Glioblastoma mean age : 39 years Mean Survival > 5 years -5 years year à Cave: extrapolation/generalization of results ef. Kleihues et al. 999, Hiraga et al. 998, Watanabe et al. 966 MOH. Clinical scenario 7 y. o. gentleman Inaugural seizure, right parieto-occipital tumor, à partial resection à Histology: glioblastoma Additional information required? Performance status: WHO (KPS 8%) Treatment options? EOTC 698/NCIC CE.3 Phase III Study: adiation ± Temozolomide Concomitan t TMZ/T* Adjuvant TMZ Weeks T Alone Temozolomide 75 mg/m po qd for 6 weeks, then 5- mg/m po qd day -5 q 8 days for 6 cycles Focal T daily 3 x cgy Total dose 6 Gy *PCP prophylaxis was required for patients receiving TMZ during the concomitant phase.

3 EOTC-NCIC Trial: Updated Survival T (95% ci) TMZ/T (95% ci) Median OS, mo:. (., 3.) 4.6 (3., 6.8) -yr survival:.9% ( ) 7.% (.-3.5) 5-yr survival:.9% (.6-4.4) 9.8% (6.4-4.) H [95% C.I.]:.63 [.5-.75] p < ( y e a r s ) O N N u m b e r o f p a t i e n t s a t r i s k : T r e a t m e n t T T M Z / T Stupp et al. N Engl J Med 5, 35: Stupp et al. Lancet Oncol 9, : Nordic Trial Design A N D O M I Z E 34 pts 9 random. 3 arms n= n=9 n=3 T 6 Gy ( Gy x 3) T 34 Gy (3.4 Gy x ) TMZ x 6 ( mg/m d 5 q 8d) T = radiotherapy; TMZ = temozolomide 3

4 Overall Survival MGMT methylated: TMZ longer survival than T MGMT unmethylated: T longer survival than TMZ Event-free Survival Lancet Oncol ; 3(7):77-5 All pts Overall survival Age > 7 yrs MGMT methylated: TMZ > T unmethylated: T > TMZ Lancet Oncol ; 3:96-6 For how long should we continue treatment? Duration of maintenance (adjuvant) TMZ: 6 months? months? Until progression? 4

5 73 pts registered 5 pts eligible TMZ/T 833 pts randomized EOTC TMZ = temozolomide Gilbert M et al. J Clin Oncol ;9(suppl): abstract 6 Evidence based medicine: up to 6 cycles Correlative Evidence TOG 55 EOTC NCCTG intergroup phase III study Concomitant phase Stratify by: MGMT (3% methyl. rate) Tissue TMZ daily x 6 wks adiotherapy (3 x Gy) Primary endpoint: OS Adjuvant phase (6 mo) Dose-dense TMZ (75 mg/m daily x d) Standard-dose TMZ (5 mg/m daily x 5d) Up to cylces allowed 37% of pts received >6 cycles Dose-dense regimen =double dose intensity Conclusions: No improved outcome with dose-dense TMZ No improvement over prior EOTC-NCIC trial results Comparison EOTC698 (4) and TOG 55 () EOTC 75 5 Dead 9 Total yr: 8 % 3 TMZ/T Months T Months after Trial Inclusion 5

6 Clinical scenario n n n 45y. o. lady Inaugural seizure, right frontal tumor, à partial resection à Histology: astrocytoma grade III «with some oligodendroglial features» Additional information/next steps? Histology review, molecular markers n Anaplastic Glioma (grade III) oligo astrocytoma (mixed) Anaplastic astrocytoma (GBM-O) Oligodendroglioma Panel review of anaplastic oligos (EOTC695) Kros JM van den Bent: J Neuropath Exp Neurol 7: 66, local ev ev ev3 ev4 ev5 ev6 ev7 ev8 ev9 AOD AOA AA Grade IV GBM LGG OD Grade II OA Grade II Other 6

7 Panel review of anaplastic oligos (EOTC695) Kros JM van den Bent: J Neuropath Exp Neurol 7: 66, LGG (n=8) AOD(n=48) GBM(n=6) AOA(n=8) years Pathology eview and Molecular Characterization 999; 7:76-77 LOH p/9q IDH mutations only 69% eligible histology IDH mutations carry a more favorable prognosis Variable frequency of IDH mutations Anaplastic Astrocytoma Genome sequencing within the NCCTA project identified IDH mutations in some CNS tumors 939 tumor and matched blood samples analyzed from the Duke biobank 445 CNS tumors 494 non-cns tumors Glioblastoma Yan, Parsons & Bigner. NEJM 9, 36:

8 45y. o. lady Clinical scenario Inaugural seizure, right frontal tumor, à partial resection à Histology: astrocytoma grade III «with some oligodendroglial features» Additional information required? Histology (reviewed): anaplastic oligodendrogl. Treatment options? Anplastic Glioma: Historic standard of care à adiotherapy 98; 33:33-9 All malignant glioma (no MI) % anaplastic glioma T vs Semustine Median survival doubled from 4 à 8 mo Chemotherapy for a chemosensitive disease? J. Gregory Cairncross et al JNCI 9:473-79, ; 7:

9 NOA-4-Study Wick & Weller J Clin Oncol 9; 7: Anaplastic Glioma (grade III) T Chemo- Tx progression) Chemo- Tx T Time to nd treatment failure = primary endpoint nd failure (progression) TTF ( nd progression) TTF ( nd progression) T ChemoTx (PCV v TMZ) AA AOA AO Sequence of treatment does not matter Better outcome of oligos independent of tx (sequence) NOA-4-Study Wick & Weller J Clin Oncol 9; 7: Anaplastic Glioma (grade III) T Chemo- Tx progression) Chemo- Tx T Time to nd treatment failure = primary endpoint nd failure (progression) TTF ( nd progression) Time to st progression & MGMT TTF ( nd progression) T ChemoTx (PCV v TMZ) AA AOA AO Sequence of treatment does not matter MGMT as a prognostic marker, independent of therapy Scenario : 45 y., anaplastic astrocytoma Oligo Treatment options? à adiotherapy à Chemotherapy à both Diagnosis: Anaplastic oligodendroglioma LOH p/9q 9

10 adiation Therapy Oncology Group adiation Therapy Oncology Group EOTC N=85 N=83 T (33x.8 Gy) PCV for Oligos: OS and Genetics Adjuvant PCV (6 cycles) N=48 Neo-adj. PCV x 4 cycles T (33x.8 Gy) N= weeks weeks Overall survival by genetic marker p/9q LOH p LOH 9q LOH No LOH % Alive Survival by p and 9q Status N MST p- and 9q- 9 - One/Neither 9.8 yr 75 H =.3, p < Years van den Bent et al., J Clin Oncol 6; 4:75- Cairncross et al., J Clin Oncol 6; 4:77-4 EOTC N=85 N=83 Oligos: Genetics and Chemo T (33x.8 Gy) Adjuvant PCV (6 cycles) N=48 Neo-adj. PCV x 4 cycles T (33x.8 Gy) N= weeks weeks Genetic marker and treatment Survival by Treatment Arm: Patients with p and 9q Loss PCV + PCV - 75 PCV + PCV - % Alive 5 5 n MST PCV+T 43 Not eached T Alone yr. p =.88 van den Bent et al., J Clin Oncol 6; 4: Years Cairncross et al., J Clin Oncol 6; 4:77-4 EOTC N=85 N=83 (Neo)adjuvant PCV for oligos: Long-term follow-up T (33x.8 Gy) Adjuvant PCV (6 cycles) median > years N=48 Neo-adj. PCV x 4 cycles T (33x.8 Gy) N= weeks weeks Overall Survival van den Bent et al., ASCO, abstr # Cairncross et al, ASCO, abstr #8b

11 EOTC Overall survival and molecular markers non-deleted (n=36) Overal survival H:.83, 95% CI [.6,.] p/9q co-deleted (n=8) Overal survival H:.56, 95% CI [.3,.3]] Probability of Survival Median PFS OS non-deleted P =.9 T n= 9 mo mo Probability of Survival T/PCV n=4 5 mo 5 mo P =.59 p/9q co-deleted T n=37 5 mo mo van den Bent et al. Proc ASCO T/PCV, abstr N=43 # 3 57 mo Not eached Glioma virtually always recur Clinical scenario 65 y. o. gentleman right fronto-parietal tumor, à partial resection à Histology: glioblastoma Treatment with TMZ/Tà TMZ ecurrence/progression after cycle 5 Additional information required? Treatment options?

12 Glioma Therapy esectable Unresectable Sx Bx D x st line TMZ/T TMZ st ecurrence Treatment options? Comparison: EOTC-NCIC NEJM 5 5 wks 7 months 8months 5 months GBM (glioma) recurrence: Treatment options epeat surgery ± Gliadel e-irradiation (experimental) Chemotherapy: FDA/EMEA approved: Temozolomide, Carmustine, Lomustine Only FDA Bevacizumab (Avastin ) Irinotecan (CPT) Carboplatin EGF inhibitors Progression-free survival TMZ (5d/q8) PCZ (8d/q56) Temozolomide.8 Procarbazine.6.4 PFS 6mo % vs. P=.8. 8% Time from start of treatment (mo) Yung et al. Br J Cancer ; 83: Overall Survival Overall Survival Prior chemo: n = 65 TMZ 73 PCZ OS median 6.6 mo vs. 5.9 mo No prior chemo: n = 37 TMZ 35 PCZ OS median 7.5 mo vs. 5.3 mo

13 Lomustine (CCNU) is an active agent (confirmed in 9) ; 8:68-74 Progression-free survival Overall survival Enza CCNU PFS6 % vs 9% p=.3.9% vs 4.3% p=.5 Bevacizumab VEGF Inhibition (recurrent glioma) Batchelor et al. Cediranib Cancer Cell :83-95, 7 day bevacizumab + CPT Gd-MI T FLAI Vredenburgh et al. Clin Cancer es 7 Permeability Bevacizumab ± CPT BAIN trial Design: à andomized Phase II (n=85) ecurrent GBM ( st or nd : elapse; n=67) Stratification by: KPS: 7-8, 9- st, nd relapse (n=8) Bevacizumab* Bevacizumab / CPT** at PD Optional: Bev +CPT- o Endpoint(s): % alive + progression-free at 6 mo % alive at 6 mo 3

14 N=85 Bevacizumab at PD: add CPT N=8 Bevacizumab & CPT Friedman et al. JCO 7: , 9 Waterfall plot of tumor regression } 8% } 38% N=85 N=8 Bevacizumab at PD: add CPT Bevacizumab & CPT Progression-free survial Overall survial Friedman et al. JCO 7: , 9 EGAL Study (Cediranib) andomized phase III in recurrent GBM a n d o m i z e Placebo [ mg] + Lomustine [mg/m ] (n=6) cediranib [mg] + Lomustine [mg/m ] (n=) Cediranib [3mg] (n=) Stratified by Age (>65) and esection (salvage sx) Primary endpoint: PFS o endpoints: OS, PFS6, 4

15 PFS: based on central review T + T/FLAI Batchelor on behalf of EGAL investigators. LBA#7, ESMO J Clin Oncol 3 (Aug, epub ahead of print) days Overall survival (OS) Batchelor on behalf of EGAL investigators. LBA#7, ESMO J Clin Oncol 3 (Aug, epub ahead of print) Probability of Survival months adiological changes during Cediranib therapy Brandsma and van den Bent, Curr Opin Neurol 9 baseline 6 weeks weeks 8 weeks 5

16 andomized phase II study of Bevacizumab versus Bevacizumab plus Lomustine versus Lomustine in patients with recurrent Glioblastoma st recurrence Glioblastoma Statification: age, PFS A N D O M I Z A T I O N Bevacizumab every weeks +Lomustine every 6 weeks (n=) Bevacizumab every weeks (n=5) Lomustine every 6 weeks (n=47) f o l l o w u p W. Taal MJ van den Bent, ASCO 3 Survival at 9 months % 38% 9 mo OS (95% CI) 59% 63% Bev Lom Bev/Lom 9 Bev/Lom all BELOB esults W. Taal MJ van den Bent, ASCO 3 Probability of Survival (Kaplan-Meier) EOTC 6 CCNU ± immediate vs delayed bevacizumab ecurrent GBM st recurrence/ Progression nd recurrence/ Progression 3 rd recurrence/ Progression Bevacizumab CCNU MD choice CCNU Bevacizumab TMZ / T Bevacizumab Bevacizumab CCNU CCNU MD choice Lomustine (CCNU) : mg/m² 6-weekly Bevacizumab: mg/kg -weekly Primay endpoint: OS at mo Stats: 7 pts/arm, pts alive at mo 6

17 EOTC 6 CCNU ± immediate vs delayed bevacizumab ecurrent GBM st recurrence/ Progression nd recurrence/ Progression 3 rd recurrence/ Progression Bevacizumab CCNU MD choice CCNU Bevacizumab TMZ / T Bevacizumab Bevacizumab CCNU CCNU MD choice Lomustine (CCNU) : mg/m² 6-weekly Bevacizumab: mg/kg -weekly Primay endpoint: OS at mo Stats: 7 pts/arm, pts alive at mo Take Home Messages: Glioblastoma adiation therapy combined with temozolomide followed by 6 cycles of temozolomide remains the standard of care for fit patients with GBM In elderly patients: Standard T over 6 weeks appears to be inadequate for elderly patients (>7 yrs). A hypofractionated schedule should be preferred Exclusive chemotherapy with TMZ may be an adequate treatment in elderly patients with a methylated MGMT Take Home Messages: Grade III Glioma IDH mutation status identifies patients with a better prognosis No difference in overall survival if patients treated initially with T and chemo given at recurrence vs the alternate sequence chemo first, T at recurrence Oligodendroglioma p/9q co-deletion is a prognostic and predictive marker. Longer survival for co-deleted oligo s with (PCV-) chemotherapy given early in the course of disease (adjuvant or neo-adjuvant). No benefit of adjuvant PCV in non-deleted anaplastic astrocytomas. 7

18 Take Home Messages ecurrent Glioma TMZ is the agent of first choice in chemotherapy-naive patients Nitrosoureas remain a valid treatment in malignant glioma VEGF pathway inhibitors: failed to prolong survival in recurrent GBM the value of inducing radiological response and reduction of peritumoral edema is however undisputed. 8