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Presentación - Foro de Debate en Oncologia
Tumores SNC: aspectos novedosos Dr. Manuel Benavides OMS Alto Grado T. PLEXOS COROIDES 1.- TUMORES NEUROEPITELIALES Bajo Grado T. ASTROCÍTICOS Papiloma y Carcinoma Papiloma Atípico de plexos coroides Astrocitoma pilocítico Astrocitoma pilomixoide Astrocitoma subepend. de cél. gigantes Xantoastrocitoma pleomórfico Astrocitoma difuso (Fibrilar, Protoplásmico, Gemistocítico) Astrocitoma anaplásico II Astrocitoma - Astroblastoma - Glioma cordoide del 3º ventrículo - Glioma Angiocéntrico III Glioblastoma - gliosarcoma - glioblastoma de células gigantes Gliomatosis cerebri OTROS TUMORES NEUROEPITELIALES - Neurocitoma extraventricular - T. glioneuronal papilar - T. glioneuronal con rosetas del 4º ventrículo - Gangliocitoma displásico del cerebelo, Astrocitoma desmoplásico, infantil/ganglioglioma, T. neuroepitelial disembrioplásico, Gangliocitoma, Ganglioglioma, Ganglioglioma anaplásico, Neurocitoma central, Liponeurocitoma cerebeloso, Paraganglioma Astrocitoma anaplásico T. OLIGODENDROGLIALES - Oligodendroglioma - Oligodendroglioma anaplásico IV T. NEURONALES Y MIXTOS GLIONEURONALES Glioblastoma T. REGIÓN PINEAL T. OLIGOASTROCITICOS Oligodendroglioma - Oligoastrocitoma - Oligoastrocitoma anaplásico Meduloblastoma, PNET, Pineoblastoma - T. papilar de la región pineal - Pineocitoma - Pineoblastoma - T. parenquima pineal con diferenciación intermedia Oligodendroglioma anaplásico T. EPENDIMARIOS T. EMBRIONARIOS - Subependimoma - Ependimoma Mixopapilar, Celular, Papilar, Células claras, Tanicitico, Anaplásico - Meduloblastoma (desmoplásico nodular, intensa nodularidad, anaplásico, células grandes) - PNET - T. teratoide/rabdoide Atípico Oligoastrocitoma Oligoastrocitoma anaplásico Louis DN et al. 2007. IARC, Lyon, France Distribution of Primary Brain and CNS Gliomas† by Histology Subtypes. (N:92,504), CBTRUS Statistical Report: NPCR and SEER, 2006-2010 Q.T. Ostrom et al. Neuro-Oncology, 2013 Bajo Grado OMS Alto Grado II III IV Astrocitoma Astrocitoma anaplásico Glioblastoma Aspectos Oligodendroglioma Oligodendroglioma anaplásico Oligoastrocitoma Oligoastrocitoma anaplásico Meduloblastoma, PNET, Pineoblastoma novedosos 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) 13.3 7.8 0.59 p 0.03 mPFS (yrs): 10.4 4.0 0.50 p 0.002 5 yrs survival 73 62 10 yrs survival 64 41 J.C.Buckner et al. ASCO 2014; #2000, Shaw et al: J Clin Oncol. 2012 Perfil molecular en Bajo Grado A. Alentorn et al. Neuro-Oncology 2014 Bajo Grado OMS Alto Grado II III IV Astrocitoma Astrocitoma anaplásico Glioblastoma Oligodendroglioma Oligodendroglioma anaplásico Oligoastrocitoma Oligoastrocitoma anaplásico Meduloblastoma, PNET, Pineoblastoma Astrocitomas de Alto Grado (III - IV) BTSG Soporte 3.5 BCNU 4.7 RT 9 RT + BCNU 8.7 Mediana de Supervivencia (meses) 1.978 N: 222 Walker MD y cols. J Neurosurgery 49: 333-43, 1978 AA GB GLIOMAS ALTO GRADO Metanálisis 2002 Reducción relativa del riesgo de muerte: 15% RT + QT Glioma Meta-analysis Trialists Group. Lancet RT 2002; 359:1011-18 Bajo Grado II Astrocitoma med SG: ≈ 5 año OMS Alto Grado III IV Astrocitoma anaplásico Glioblastoma Aspectos Oligodendroglioma Oligodendroglioma anaplásico novedosos Oligoastrocitoma Oligoastrocitoma anaplásico Meduloblastoma, PNET, Pineoblastoma ODA y OAA No incluyen AA SG S.L.P (mediana en años) RTOG 9402 PCV-I x 4 RT RT Cairncross G. et al. J Clin Oncol 24:2707-2714. 2006 4.9 2.6 4.7 1.7 p=.26 p .004 mediana en meses EORTC 26951 RT PCV x 6 RT Van den Bent MJ. et al. J Clin Oncol 24:2715-2722. 2006 40.3 23 30.6 13 p=.23 p .001 RTOG 9402 1p/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 31:337-343. 2012 RTOG 9402 IDH and 1p-19q by treatment group (II) PCV + RT - 14.7 yrs (95%CI 6.4 to not reached) - 5.5 yrs (95% CI 2.6-11.0) - 1.0 yrs (95% CI 0.6-1.9; p .001) RT - 6.8 yrs (95% CI 5.4- 8.6) - 3.3 yrs (95% CI 2.5-4.9) - 1.3 yrs (95% CI, 0.8-1.9;p .001) J.G. Cairncross et al. Published Ahead of Print on February 10, 2014 as 10.1200/JCO.2013.49.3726 EORTC 26951 OS PFS PFS OS 1p/19q-codeleted non–1p/19q-codeleted 1p/19q-codeleted non–1p/19q-codeleted M.J. van den Bent et al. JCO 2012 NOA04 WICK et al. JCO 2009 NOA04 WICK et al. JCO 2009 Mediana PFS (meses) 30.6 Todos 31.9 10.8 AA 18.2 52.1 OAA y ODA 52.7 NOA04 WICK et al. JCO 2009 Mediana PFS (meses) 30.6 Todos 31.9 10.8 AA 18.2 52.1 OAA y ODA 52.7 Mediana TTF (meses) 42.7 + Todos 43.8 32.0 AA 29.4 54 + OAA y ODA 54 + NOA04 WICK et al. JCO 2009 Mediana PFS (meses) 30.6 Todos 31.9 10.8 AA 18.2 52.1 OAA y ODA 52.7 Mediana TTF (meses) 42.7 + Todos 43.8 32.0 AA 29.4 54 + OAA y ODA 54 + 72.1 Mediana SG 82.6 (meses) RECOMENDACIONES DE TRATAMIENTO ASTROCITOMAS ANAPLÁSICOS IDH / MGMT ? La “mejor” evidencia (NOA 04) RT o TMZ o PCV (… pero no Stupp ????) RECOMENDACIONES DE TRATAMIENTO La mayor y mejor evidencia RTOG 9402 y EORTC 26951 Oligodendrogliomas / Oligoastrocitomas Anaplásicos IDH MUTADO IDH NATIVO 1p 19q 1p 19q Codeleccionado NO codeleccionado PCV + RT Codeleccionado PCV+RT ? MGMT ? NO codeleccionado RT RECOMENDACIONES DE TRATAMIENTO La mayor y mejor evidencia RTOG 9402 y EORTC 26951 Oligodendrogliomas / Oligoastrocitomas Anaplásicos IDH MUTADO IDH NATIVO 1p 19q 1p 19q Codeleccionado NO codeleccionado PCV + RT Codeleccionado PCV+RT ? MGMT ? NO codeleccionado RT RECOMENDACIONES DE TRATAMIENTO La mayor y mejor evidencia RTOG 9402 y EORTC 26951 Oligodendrogliomas / Oligoastrocitomas Anaplásicos IDH MUTADO IDH NATIVO 1p 19q 1p 19q Codeleccionado NO codeleccionado PCV + RT Codeleccionado NO codeleccionado PCV+RT ? RT MGMT ? 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 ? Bajo Grado II Astrocitoma Oligodendroglioma OMS Alto Grado III IV Aspectos Glioblastoma Novedosos Oligodendroglioma Meduloblastoma, PNET, Pineoblastoma Astrocitoma anaplásico med SG: ≈ 2-3 años anaplásico 1ª línea Oligoastrocitoma Oligoastrocitoma anaplásico Stupp R et al. Lancet Oncol 2009 EORTC / NCIC OS (%) Treatments at progression TMZ / RT RT TMZ / RT(%) RT(%) 2 yrs 27.2 10.9 Surg. 24 22 3 yrs 16.0 4.4 RT 5 4 4 yrs 12.1 3.0 5 yrs 9.8 1.9 CHT BSC 54 39 70 26 HR:0.6 IC95%:0.5-0.7; p<0.0001 R. Stupp et al. Lancet Oncol 2009 AVAglio Study Design RT 2Gy; 5 days/week n=463 Randomization N=921 Debulking surgery or biopsy Stratification • RPA class • Region TMZ TMZ 75mg/m² qd 150–200mg/m² qd days 1–5 q28d Placebo Placebo Placebo q2w q2w q3w RT 2Gy; 5 days/week TMZ TMZ n=458 Treatment start 4–7 weeks post-surgery 75mg/m² qd 150–200mg/m² qd days 1–5 q28d BEV BEV BEV 10mg/kg q2w 10mg/kg q2w 15mg/kg q3w Concurrent phase 6 weeks Tx break 4 weeks Maintenance phase 6 cycles 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 Monotherapy phase until PD AVAglio O.L. Chinot et al. NEJM 2014 Clasificaciones moleculares Verhaak et al. Page 19 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 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. The Cancer Genome Atlas Project (TCGA) RGW. Verhaak. Cancer Cell. 2010 Chinese Glioma Genome Atlas (CGGA) Wei Yan et al. Neuro-Oncology 2012 Intrinsic Glioma Subtypes (IGSs) Cancer Cell. Author manuscript; available in PMC 2011 January 19. L. Erdem-Eraslan et al. J Clin Oncol 2012 Correlation of molecular subtypes with survival in AVAglio. #2001^ H. Phillips et al. ASCO 2014 Verhaak et al. Page 19 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 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. 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): e12548. doi:10.1371/journal.pone.0012548 RTOG 0825 Phase III Study: Bevacizumab for the Treatment of Newly Diagnosed GBM RT TMZ 2Gy; 5 days/week 150–200mg/m2 qd days 1–5 q4w Debulking surgery N=978 RT 2Gy; 5 days/week TMZ 75mg/m2 qd Endpoints: – Co-primary: OS, PFS – Secondary : Safety, biomarkers – Exploratory: QoL 1:1 Randomisation* TMZ 75mg/m2 qd Placebo Placebo q2w q2w BEV or placebo continues RT TMZ 2Gy; 5 days/week 150–200mg/m2 qd days 1–5 q4w TMZ 75mg/m2 qd BEV BEV 10mg/kg q2w 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 Maintenance phase 4 weeks 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 NCT00884741 RTOG 0825 M. Gilbert et al. NEJM 2014 Correlation between 6-month PFS and median OS. Kelong Han et al. Neuro-Oncology 2014 Genotype-Guided Therapy in newly diagnosed GB Target Study Drug Results MGMT RTOG TMZ DD Negative RTOG VEGF Negative Bevacizumab AVAGLIO Integrin CENTRIC Positive (PFS) Cilengitide Negative Bajo Grado II Astrocitoma Oligodendroglioma OMS Alto Grado III IV Aspectos Glioblastoma Novedosos Oligodendroglioma Meduloblastoma, PNET, Pineoblastoma Astrocitoma anaplásico med SG: ≈ 2-3 años anaplásico 2ª línea Oligoastrocitoma Oligoastrocitoma anaplásico 1st line chemotherapy ± Bevacizumab in relapsed GB PFS-6 (%) BRAIN1 N:167 BELOB2 mOS (m) OS at 9 m Beva 42.6 9.2 - Beva + CPT-11 50.3 8.7 - Beva 16 8 38% Lomustina 13 8 43% Beva + Lomustina 41 11 59% N:144 1Friedman et al, JCO 2009, 2van den Bent et al, SNO 2013 Deferred use of bevacizumab for recurrent glioblastoma is not associated with diminished efficacy D.E. Piccioni et al. Neuro-Oncology 2014 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 MO28347 TAMIGA: Study Design Enrolment BEV open-label Randomisation 1L Screening BEV/PL double-blinded 2L PD1 3L PD2 PD3 Concurrent Maintenance Mono 6 weeks 28 d 6 x 28 days 21 d n=300 Patients with newly diagnosed GBM (N≈510) RT TMZ BEV TMZ BEV 4L BEV & SoC 4L BEV & LOM 2L BEV & SoC 3L BEV & SoC 4L BEV PL & LOM 2L PL & SoC 3L 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 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 MUCHAS GRACIAS A TOD@S
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