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Advancements in Neuro-Oncology: Glioblastoma Treatment and Management

This conference discusses the latest developments in the treatment and management of glioblastomas, a type of brain cancer, with a focus on the role of chemotherapy, MGMT status, and antiangiogenic therapy.

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Advancements in Neuro-Oncology: Glioblastoma Treatment and Management

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  1. Rabat 31.10.2015 Journée de Neuro-Oncologie Prise en charge des glioblastomes Olivier Chinot Aix-Marseille Université AP-HM, Centre Hospitalo-Universitaire Timone Service de Neuro-Oncologie Marseille

  2. Gliomas: a recent story withsomeprogress 1980 2005 2015 Walker, NEJM 1980 Chinot, NEJM 2014 Stupp, NEJM 2005

  3. Pré-requis • Traitement de première ligne • MGMT et réversion de la résistance • Traitement de première ligne sujets âgés • Traitements à la récidive • Antiangiogéniques

  4. Gliomacancerologyvs neurology ? A cancer as others A cancer different from others biology: Proliferation Invasion Neoangiogenesis • symptoms • Complexity • Functional impact • treatment • Limited options • evaluation • Neurological • MRI • management • Centralised • Restricted teams

  5. Primary and secondary GBM 1p19q IDH1 IDH1 IDH1 EGFR

  6. Age reproductible +++ KPS reproductible + Surgery reproductible +/- MGMT status (GBM) Reproductible ? But why ? (Biology?) Prognostic factors in GBM

  7. Pré-requis pour la décision thérapeutique

  8. Benefit of adding PCV to RT in codel AO: trends for PFS and OS van den Bent, JCO, 2006; ASCO 2012 Cairncross, JCO 2006; ASCO 2012

  9. Pré-requis • Traitement de première ligne • MGMT et réversion de la résistance • Traitement de première ligne sujets âgés • Traitements à la récidive • Antiangiogéniques

  10. GBM first line treatmentstandard and limits estimate %: 15% 65% 8% 12%

  11. GBMTraitement standard 1ère ligne 14.5 mths Stupp, Lancet 2009

  12. EORTC/NCIC Treatment Platform Chemotherapy: Temozolomide PCP Prophylaxis 6 1 10 14 18 22 RT 30 x 2 Gy Control Arm PCP Prophylaxis 5d 5d 5d x 6 cycles 4 wks 4 wks TMZ daily x 42 days 6 1 10 14 18 22 RT 30 x 2 Gy Experimental Arm Radiotherapy: Focal, 60 Gy in 6 wks to tumor volume plus 2- to 3-cm margin TMZ: During radiotherapy: 75 mg/m2/day (including weekends) for up to 49 days; administered 1-2 hrs before radiotherapy in morning on days without radiotherapy Maintenance: 150-200 mg/m2/day x 5 days, for up to 6 cycles; antiemetic prophylaxis Stupp R, et al. N Engl J Med. 2005;352:987-996.

  13. GBMadjuvant time RT RT+TMZ First line 7 mths Stupp et al., NEJM 2005

  14. Stupp et al., NEJM 2005

  15. Stupp et al., NEJM 2005

  16. Stupp et al., NEJM 2005

  17. En pratique

  18. En pratique

  19. BCNU Polymer bénéficeincertain non confronté au TMZ 100 90 ITT Analysis (N = 240) HR: 0.73 95% CI: 0.56-0.95 Log-rank P < .05 80 70 60 50 Survival (%) GBM (N = 207) patients did not achieve survival benefit (P = .10) 40 30 Median SurvivalBCNU: 13.9 mos Placebo: 11.6 mos P = .03 BCNU Polymer 20 10 Placebo 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Mos From Implant Surgery • Westphal M, et al. Neurooncol. 2003;5: 79-88.

  20. TTF: nouveau standard?

  21. TTF: nouveau standard?

  22. TTF: nouveau standard?

  23. TTF: nouveau standard?

  24. Traitement de première ligne • MGMT et réversion de la résistance • Traitement de première ligne sujets âgés • Traitements à la récidive • Antiangiogéniques

  25. Resistance to alkylating agents: implication of MGMT activity Esteller et al., NEJM 2000

  26. Effect of MGMT Promoter Methylation Status on Survival Following TMZ Plus RT Hegi ME, et al. N Engl J Med. 2005;352:997-1003

  27. MGMT status (promotermethylation MGMT M)pronostic and predictive value • Prognostic: • OS: 22mths in M vs 12mths in UM • Predictive: • Benefit of TMZ restricted to pts with MGMT M But • dosage to be validate • MGMT M vary (30-50%) • Key biologic event to be determined Not decisional to date Hegi, NEJM, 2005; Noushmehr, Cancer Cell 2010; van den Bent, Clin Cancer Res 2011

  28. RTOG 0525: Outcomes by Treatment MGMT Unmethylated vs methylated MGMT Unmethylated MGMT methylated

  29. Traitement de première ligne • MGMT et réversion de la résistance • Traitement de première ligne sujets âgés • Traitements à la récidive • Antiangiogéniques

  30. GLIOME MALIN DU SUJET AGÉ : ÉTAT ACTUEL • Incidence en augmentation • 20% des gliomes (>70 ans) • Données limitées : • patients exclus des analyses pronostiques (RPA du RTOG) et des études thérapeutiques (EORTC-NCIC) • Pronostic médiocre • Médiane de survie : 4-6 mois • Morbidité importante • Retentissement rapide sur autonomie • Tolérance aux traitements diminuée

  31. Qui est âgé? Faut-il traiter? Qui traiter? Place de la chirurgie ? Comment traiter ? Pour quelle qualité de vie ? Limite d’âge ? 60, 65, ou 70 ; comorbiditées Survie limitée 3/3 facteurs pronostiques - Population homogène ? pas de facteur pronostique établi Diagnostique, thérapeutique Standard (RT) remis en cause Soins de support radiothérapie chimiothérapie +/- radiothérapie Quels critères EORTC QOL, compliance, … QUESTIONS NON RÉSOLUES

  32. RT+SP vs SP ANOCEF phase III Logrank p = 0.004Hazard Ratio = 0.49 (0.30–0.80) Probability of Survival BSC BSC + RT Median follow-up: 17.7 weeks (0.3 to 93.1) N of subjectsMedian Survival (95% CL)One year survival BSC 444.1(13.4 – 21.9)2.6 % (SE = 0.06) BSC + RT406.7 (17.6 – 35.9)13.8 % (SE = 0.03) Keime, NEJM 2007

  33. Whichschedule of radiotherapy? OS 40 Gy/ 15 f/ 3s 5.1 (5.9) RT interrompue: 10% stéroides augmentés: 23% • GBM • 70y • KPS 60-80 60 Gy/ 30 f/ 6s 5.6 (6.1) RT interrompue: 26% stéroides augmentés : 49% N = 100 Roa, JCO 2004

  34. Clinical benefit: Impact on fonctional status • Improvement of KPS and/or MMSE with stable or decrease level of steroids n = 16/ 32 pts (50%) • Significant decrease of steroid level (25-100%) n = 14/ 29 pts (52%) Chinot, Cancer 2004

  35. TAG: Pronostic impact of MGMT (methyl) in elderly pts with GBM • Amélioration fonctionnelle: • 23 pts (32.9%) • Median: +20 pts (10-40) Perez, et al. JCO 2011

  36. TMZ vs RT: essai de non infériorité (n=412) Wick, et al. Lancet Oncol 2012

  37. Traitement de première ligne • MGMT et réversion de la résistance • Traitement de première ligne sujets âgés • Traitements à la récidive • Antiangiogéniques

  38. GBMRecurrence time Subsequent lines 7.5 mths Stupp, Lancet 2009

  39. Recurrent Glioblastoma: Treatment • Surgery • BCNU polymer • Re-resection • Radiation • Hypofractionated reirradiation • Radiosurgery • Chemotherapy • Nitrosoureas (CCNU, BCNU) • Lomustine (CCNU) • PFS 6: 19% to 25% after previous radiation ± temozolomide • Bevacizumab • Clinical trials

  40. Prognosticfactors in recurrent HHG 458 pts 8 trials Singe center: MD Anderson Study period: 1986-1995 Drugs of limited activity (carbo, 13cis RA, PCZ, 5FU) Wong JCO. 1999

  41. Recurrent GBMincreasingresistance to alkylating agents via MGMT? Metellus, Cancer 2009

  42. BCNU Polymer Recurrent malignant glioma, 65% GBM (N = 222) BCNU Wafer + Tumor Resection Placebo Wafer + Tumor Resection Brem H, et al. Lancet. 1995;345:1008-1012.

  43. TMZ in GBM: PFS Rates 1.0 TMZPCB PFS at6 months (%) 21 8* Median PFS, weeks (months)† 12.4 (2.89) 8.32 (1.88)‡ 0.8 TMZ PCB 0.6 PFS rate 0.4 0.2 0 12 0 2 4 6 8 10 *P=0.008. †Hazard ratio=1.47. ‡P=0.00063. PCB = procarbazine. . Months from start of treatment Yung Br J Cancer. 2000.

  44. Rechallenge TMZ dose denseRESCUE study 3 groups: B1, early: PD during adjuvant C1-C6 TMZ n=33 B2, extended: PD during adjuvant > C6 n=29 B3, rechallenge: after TMZ free interval >2 mois n=29 Perry, JCO 2010

  45. Update assessement of nitrosoureasLomustine (vsenzastaurin)

  46. GBM trt 2st line: current optionssingle agents

  47. Traitement de première ligne • MGMT et réversion de la résistance • Traitement de première ligne sujets âgés • Traitements à la récidive • Antiangiogéniques

  48. Targeting VEGF in GBM: Rational VEGF expression in tumor Normal tissues Pancreatic Breast Lung (NSC) Colon Glioma Gastric Liver Kidney VEGF inhibition in vivo Anti-VEGF inhibits growth of GBM xenograft additive anti-tumoreffect of Bev +TMZ in U87 xenograft Personal unpublished data Nature, Vol 362, 29 April 1993

  49. Bevacizumab +/- irinotecana signal of activity in recurrent GBM Friedman, et al. JCO 2009; Wick, JCO 2010; Wong, et al. JCO 1999

  50. Bevacizumab in the upfront settingSupra-additive effect of RT + BEV • BEV combined to RT microvessel density apoptosis > additive effect on TGD - Independant of hypoxia Effect of BEV on tumor growth delay (TGD) Lee, Cancer Res, 2000

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