Tumores SNC: aspectos novedosos. Dr. Manuel Benavides

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1 Tumores SNC: aspectos novedosos Dr. Manuel Benavides

2 1.- TUMORES NEUROEPITELIALES Bajo Grado T. ASTROCÍTICOS Astrocitoma pilocítico Astrocitoma pilomixoide Astrocitoma subepend. de cél. gigantes Xantoastrocitoma pleomórfico Astrocitoma difuso (Fibrilar, Protoplásmico, Gemistocítico) Astrocitoma anaplásico Glioblastoma - gliosarcoma - glioblastoma de células gigantes Gliomatosis cerebri T. OLIGODENDROGLIALES - Oligodendroglioma - Oligodendroglioma anaplásico T. OLIGOASTROCITICOS - Oligoastrocitoma - Oligoastrocitoma anaplásico OMS T. PLEXOS COROIDES Papiloma y Carcinoma Papiloma Atípico de plexos coroides Alto Grado OTROS TUMORES NEUROEPITELIALES - Astroblastoma - Glioma cordoide del 3º ventrículo - Glioma Angiocéntrico II III IV T. NEURONALES Y MIXTOS GLIONEURONALES - Neurocitoma extraventricular - T. glioneuronal papilar - T. glioneuronal con rosetas del 4º ventrículo Astrocitoma Astrocitoma anaplásico Glioblastoma Oligodendroglioma - Gangliocitoma displásico del cerebelo, Astrocitoma desmoplásico, infantil/ganglioglioma, T. neuroepitelial disembrioplásico, Gangliocitoma, Ganglioglioma, Ganglioglioma anaplásico, Neurocitoma central, Liponeurocitoma cerebeloso, Paraganglioma T. REGIÓN PINEAL Oligodendroglioma anaplásico Meduloblastoma, - T. papilar de la región pineal - Pineocitoma - Pineoblastoma - T. parenquima pineal con diferenciación intermedia PNET, Pineoblastoma T. EPENDIMARIOS - Subependimoma - Ependimoma Mixopapilar, Celular, Papilar, Células claras, Tanicitico, Anaplásico Oligoastrocitoma Oligoastrocitoma anaplásico T. EMBRIONARIOS - Meduloblastoma (desmoplásico nodular, intensa nodularidad, anaplásico, células grandes) - PNET - T. teratoide/rabdoide Atípico Louis DN et al IARC, Lyon, France

3 Distribution of Primary Brain and CNS Gliomas by Histology Subtypes. (N:92,504), CBTRUS Statistical Report: NPCR and SEER, Q.T. Ostrom et al. Neuro-Oncology, 2013

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5 Bajo Grado OMS Alto Grado II III IV Astrocitoma Astrocitoma anaplásico Glioblastoma Aspectos Oligodendroglioma Oligodendroglioma anaplásico novedosos Meduloblastoma, PNET, Pineoblastoma Oligoastrocitoma Oligoastrocitoma anaplásico

6 Subtotal resection, biopsy or >40 yrs Grade II astrocytoma, oligoastrocytoma, or oligodendroglioma. N:251 from 1998 to 2002 Conclusions Grade 2 glioma with less than gross total tumor resection or >40 years of age, PCV + RT prolongs both OS and PFS compared with RT alone. A or A-dominant OA have worse outcomes, as do males. IDH and 1p19q pending RT + PCV RT HR ; p mos (yrs) mpfs (yrs): yrs survival yrs survival p p J.C.Buckner et al. ASCO 2014; #2000, Shaw et al: J Clin Oncol. 2012

7 Perfil molecular en Bajo Grado A. Alentorn et al. Neuro-Oncology 2014

8 OMS Bajo Grado Alto Grado II III IV Astrocitoma Astrocitoma anaplásico Glioblastoma Oligodendroglioma Oligodendroglioma anaplásico Meduloblastoma, PNET, Pineoblastoma Oligoastrocitoma Oligoastrocitoma anaplásico

9 Astrocitomas de Alto Grado (III - IV) Soporte 3.5 Mediana de Supervivencia (meses) BTSG N: 222 BCNU RT RT + BCNU 8.7 Walker MD y cols. J Neurosurgery 49: , 1978

10 AA GB

11 GLIOMAS ALTO GRADO Metanálisis 2002 Reducción relativa del riesgo de muerte: 15% RT + QT RT Glioma Meta-analysis Trialists Group. Lancet 2002; 359:

12 OMS Bajo Grado Alto Grado II III IV Astrocitoma med SG: 5 año Astrocitoma anaplásico Glioblastoma Aspectos Oligodendroglioma novedosos Oligodendroglioma anaplásico Meduloblastoma, PNET, Pineoblastoma Oligoastrocitoma Oligoastrocitoma anaplásico

13 ODA y OAA RTOG 9402 No incluyen AA PCV-I x 4 RT Cairncross G. et al. J Clin Oncol 24: RT S G S.L.P (mediana en años) p=.26 p.004 mediana en meses RT PCV x 6 EORTC RT Van den Bent MJ. et al. J Clin Oncol 24: p=.23 p.001

14 RTOG p/19q loss is predictive of OS benefit of the addition of PCV to radiotherapy RTOG 9402 provides the strongest evidence to date that in the setting of PCV for AO/AOA, 1p/19q codeletion is both a predictive and prognostic biomarker OS by treatment for 1p/19q codeleted OS by treatment for non codeleted tumors G.Cairncross et al. J Clin Oncol 31:

15 RTOG 9402 IDH and 1p-19q by treatment group (II) PCV + RT yrs (95%CI 6.4 to not reached) yrs (95% CI ) yrs (95% CI ; p.001) RT yrs (95% CI ) yrs (95% CI ) yrs (95% CI, ;p.001) J.G. Cairncross et al. Published Ahead of Print on February 10, 2014 as /JCO

16 EORTC OS PFS OS PFS 1p/19q-codeleted 1p/19q-codeleted non 1p/19q-codeleted non 1p/19q-codeleted M.J. van den Bent et al. JCO 2012

17 NOA- 04 WICK et al. JCO 2009

18 NOA- 04 WICK et al. JCO 2009 Mediana PFS (meses) 30.6 Todos AA OAA y ODA 52.7

19 NOA- 04 WICK et al. JCO 2009 Mediana PFS (meses) 30.6 Todos AA OAA y ODA 52.7 Mediana TTF (meses) Todos AA OAA y ODA 54 +

20 NOA- 04 WICK et al. JCO 2009 Mediana PFS (meses) 30.6 Todos AA OAA y ODA 52.7 Mediana TTF (meses) Todos AA OAA y ODA Mediana SG (meses) 82.6

21 RECOMENDACIONES DE TRATAMIENTO ASTROCITOMAS ANAPLÁSICOS La mejor evidencia (NOA 04) IDH / MGMT? RT o TMZ o PCV ( pero no Stupp????)

22 RECOMENDACIONES DE TRATAMIENTO La mayor y mejor evidencia RTOG 9402 y EORTC Oligodendrogliomas / Oligoastrocitomas Anaplásicos IDH MUTADO IDH NATIVO 1p 19q 1p 19q Codeleccionado NO codeleccionado Codeleccionado NO codeleccionado PCV + RT PCV+RT? MGMT? RT

23 RECOMENDACIONES DE TRATAMIENTO La mayor y mejor evidencia RTOG 9402 y EORTC Oligodendrogliomas / Oligoastrocitomas Anaplásicos IDH MUTADO IDH NATIVO 1p 19q 1p 19q Codeleccionado NO codeleccionado Codeleccionado NO codeleccionado PCV + RT PCV+RT? MGMT? RT

24 RECOMENDACIONES DE TRATAMIENTO La mayor y mejor evidencia RTOG 9402 y EORTC Oligodendrogliomas / Oligoastrocitomas Anaplásicos IDH MUTADO IDH NATIVO 1p 19q 1p 19q Codeleccionado NO codeleccionado Codeleccionado NO codeleccionado PCV + RT PCV+RT? MGMT? RT

25 CATNON (Non-1p/19q Deleted Anaplastic Glioma.). AA ODA-OAA RT RT + TMZ (5/28) RT seguido de TMZ (5/28) RT + TMZ seguido de TMZ (5/28) En Curso NCCTG N0577 (1p/ 19q Codeleted Anaplastic Glioma). ODA-OAA RT (RT + PCV?) RT + TMZ seguido de TMZ (5/28) x 6-12 ciclos TMZ (5/28) x 12 ciclos Enmienda?

26 Bajo Grado OMS Alto Grado II III IV Astrocitoma Aspectos Astrocitoma anaplásico med SG: 2-3 años Glioblastoma Oligodendroglioma Oligoastrocitoma Novedosos Oligodendroglioma anaplásico 1ª línea Oligoastrocitoma anaplásico Meduloblastoma, PNET, Pineoblastoma

27 Stupp R et al. Lancet Oncol 2009

28 EORTC / NCIC Treatments at progression OS (%) TMZ / RT RT TMZ / RT(%) RT(%) 2 yrs Surg RT 5 4 CHT BSC yrs yrs yrs HR:0.6 IC95%: ; p< R. Stupp et al. Lancet Oncol 2009

29 AVAglio Study Design n=463 RT 2Gy; 5 days/week TMZ 75mg/m² qd TMZ mg/m² qd days 1 5 q28d Debulking surgery or biopsy Randomization N=921 Stratification RPA class Region n=458 Placebo q2w RT 2Gy; 5 days/week TMZ 75mg/m² qd BEV 10mg/kg q2w Placebo q2w TMZ mg/m² qd days 1 5 q28d BEV 10mg/kg q2w Placebo q3w BEV 15mg/kg q3w Treatment start 4 7 weeks post-surgery Concurrent phase 6 weeks Tx break 4 weeks Maintenance phase 6 cycles Monotherapy phase until PD Last patient in: March 2011 BEV = bevacizumab; PD = progressive disease; RPA = recursive partitioning analysis; RT = radiotherapy; TMZ = temozolomide; Tx = treatment; qd = daily; q28d = every 28 days; q2w = every 2 weeks; q3w = every 3 weeks

30 AVAglio O.L. Chinot et al. NEJM 2014

31 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Clasificaciones moleculares Verhaak et al. Page 19 Figure 4. Single sample GSEA scores of GBM subtypes show a relation to specific cell types. Gene expression signatures of oligodendrocytes, astrocytes, neurons and cultured astroglial cells were generated from murine brain cell types (Cahoy et al., 2008). Single sample GSEA was used The to project Cancer the four gene sets Genome on samples on the Atlas Proneural, Classical, Project Neural and(tcga) RGW. Verhaak. Cancer Cell Mesenchymal subtypes. A positive enrichment score indicates a positive correlation between genes in the gene set and the tumor sample expression profile; a negative enrichment score indicates the reverse. Also see FigureS6. Chinese Glioma Genome Atlas (CGGA) Wei Yan et al. Neuro-Oncology 2012 Intrinsic Cancer Cell. Author Glioma manuscript; available in Subtypes PMC 2011 January 19. (IGSs) L. Erdem-Eraslan et al. J Clin Oncol 2012

32 Correlation of molecular subtypes with survival in AVAglio. #2001^ H. Phillips et al. ASCO 2014 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Verhaak et al. Page 19 Figure 4. Single sample GSEA scores of GBM subtypes show a relation to specific cell types. Gene expression signatures of oligodendrocytes, astrocytes, neurons and cultured astroglial cells were generated from murine brain cell types (Cahoy et al., 2008). Single sample GSEA was used to project the four gene sets on samples on the Proneural, Classical, Neural and Mesenchymal subtypes. A positive enrichment score indicates a positive correlation between genes in the gene set and the tumor sample expression profile; a negative enrichment score indicates the reverse. Also see FigureS6. Cancer Cell. Author manuscript; available in PMC 2011 January 19.

33 NCI Repository for Molecular Brain Neoplasia Data (Rembrandt) The Proneural Molecular Signature Is Enriched in Oligodendrogliomas and Predicts Improved Survival among Diffuse Gliomas Cooper LAD et al. PLoS ONE 5(9): e doi: /journal.pone

34 1:1 Randomisation* RTOG 0825 Phase III Study: Bevacizumab for the Treatment of Newly Diagnosed GBM Debulking surgery N=978 Endpoints: Co-primary: OS, PFS Secondary : Safety, biomarkers Exploratory: QoL RT 2Gy; 5 days/week TMZ 75mg/m 2 qd RT 2Gy; 5 days/week TMZ 75mg/m 2 qd Placebo q2w RT 2Gy; 5 days/week TMZ 75mg/m 2 qd BEV 10mg/kg q2w BEV or placebo continues TMZ mg/m 2 qd days 1 5 q4w Placebo q2w TMZ mg/m 2 qd days 1 5 q4w BEV 10mg/kg q2w Data are expected in 2013 Tx start >3 to 5 weeks post-surgery RT + TMZ phase 3 weeks Concurrent phase 3 weeks TMZ break 4 weeks Maintenance phase 12 cycles maximum Cycle = 28 days. * 10 days after start of RT; Stratification by MGMT methylation status and molecular profile BEV = bevacizumab; GBM = glioblastoma; MGMT = O6-methylguanine-DNA methyltransferase; OS = overall survival; PFS = progressionfree survival; q2w = every 2 weeks; q4w = every 4 weeks; qd = daily; QoL = quality of life; RT = radiotherapy, TMZ = temozolomide NCT

35 RTOG 0825 M. Gilbert et al. NEJM 2014

36 Correlation between 6-month PFS and median OS. Kelong Han et al. Neuro-Oncology 2014

37 Genotype-Guided Therapy in newly diagnosed GB Target Study Drug Results MGMT RTOG TMZ DD Negative VEGF RTOG AVAGLIO Bevacizumab Negative Positive (PFS) Integrin CENTRIC Cilengitide Negative

38 Bajo Grado OMS Alto Grado II III IV Astrocitoma Aspectos Astrocitoma anaplásico med SG: 2-3 años Glioblastoma Oligodendroglioma Oligoastrocitoma Novedosos Oligodendroglioma anaplásico 2ª línea Oligoastrocitoma anaplásico Meduloblastoma, PNET, Pineoblastoma

39 1 st line chemotherapy ± Bevacizumab in relapsed GB PFS-6 (%) mos (m) OS at 9 m BRAIN 1 N:167 Beva Beva + CPT Beva % BELOB 2 N:144 Lomustina % Beva + Lomustina % 1 Friedman et al, JCO 2009, 2 van den Bent et al, SNO 2013

40 Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy D.E. Piccioni et al. Neuro-Oncology 2014

41 Dose and schedule Should bevacizumab be given in combination with a cytotoxic agent? When and for how long should bevacizumab be given? Retrospective investigations by Piccioni and Puduvalli and other anecdotal experience suggest that bevacizumab should be used at a later time point in the course of the disease, administered for a shorter time (e.g. 6 months only), and possibly at a lower dose, at least for the majority of patients who are eligible for more than one line of treatment

42 MO28347 TAMIGA: Study Design Enrolment BEV open-label Randomisation BEV/PL double-blinded Screening 1L 2L 3L 4L PD1 PD2 PD3 Patients with newly diagnosed GBM (N 510) Concurrent 6 weeks RT TMZ BEV Maintenance 28 d 6 x 28 days TMZ BEV Mono 21 d BEV n=300 BEV & LOM 2L PL & LOM 2L BEV & SoC 3L PL & SoC 3L BEV & SoC 4L BEV & SoC 4L PL & SoC 4L 1L = first line; 2L = second line; 3L = third line; 4L = fourth line; BEV = bevacizumab; GBM = glioblastoma; LOM = lomustine; PD = progressive disease; PD1 = first progression; PD2 = second progression; PD3 = third progression; PL = placebo; RT = radiotherapy; SoC = standard of care; TMZ = temozolomide TAMIGA protocol v3

43 Tumores SNC: aspectos novedosos Quimioterapia adyuvante establecida en Gliomas - Bajo grado: PCV - Alto grado: - Anaplásicos: PCV / TMZ - Glioblastoma: TMZ / RT Caracterización molecular pronóstica / predictiva: IDH - 1p19q - MGMT

44 MUCHAS GRACIAS A TOD@S