AVANCES EN EL TRATAMIENTO SISTÉMICO DE LOS TUMORES DEL SISTEMA NERVIOSO CENTRAL

Transcripción

1 AVANCES EN EL TRATAMIENTO SISTÉMICO DE LOS TUMORES DEL SISTEMA NERVIOSO CENTRAL Miguel Navarro. Oncología Médica. Hospital Universitario de Salamanca.

2 Introducción Avances en el conocimiento molecular de los tumores cerebrales. Factores predictivos/pronósticos. Fármacos. Antiangiogénicos. Otros tratamientos

3 Distribution of All Gliomas by Histology Subtypes All other gliomas 10.1% incidence : 6 cases per Ependymomas 5.6% Oligodendrogliomas 9.2% Pilocytic astrocytoma 5.7% Glioblastoma 50.7%% Diffuse astrocytoma 1.7% Anaplastic astrocytoma 7.9% CBTRUS Report, All other astrocytomas 9.1%

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5 EORTC/NCIC Phase III Trial: Radiotherapy ± Temozolomide in Newly Diagnosed GBM Wk 6 Patients with newly diagnosed GBM and WHO PS 0-2 (N = 573) Focal radiotherapy 60 Gy 5 days/wk + Temozolomide* PO 75 mg/m 2 /day Focal radiotherapy 60 Gy 5 days/wk 4-wk break Adjuvant Temozolomide PO 150 mg/m 2 /day for 5 of every 28 days (cycle 1), then 200 mg/m 2 /day for up to 5 additional cycles *Plus Pneumocystic carinii prophylaxis with pentamidine or trimethoprim-sulfamethoxazole Primary endpoint: OS Secondary endpoints: PFS, safety, quality of life Did not include patients who were older than 70 years of age Mirimanoff RO, et al. J Clin Oncol. 2006;24:

6 GBM

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8 MGMT

9 GBM. MGMT Metilación

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11 GBM en ancianos NOA-08, Randomized Phase III, Aged Older Than 65 Yrs (anaplastic astrocytoma and glioblastoma) Nordic Trial, Aged Older Than 70 Yrs RT: 60 Gy / 30 F H is t o l o g y TMZ RT PD PD RT TMZ R a n d o m iz e RT: 34 Gy / 10 F TMZ x 6 TMZ: 100 mg/m 2 /day for 7 days every 14 days Focal radiotherapy: 30 x 2 Gy to a total of 60 Gy TMZ: 200 mg/m 2 Days 1-5 every 28 days

12 MGMT Ventajas Clínicas Marcador predictivo de respuesta Estudio RTOG 0525 (Validación prospectiva). Ayuda en pacientes con mal PS. Estudios en ancianos Evitar RT Pseudoprogresión Frecuente en metilados Dificultades Dificultades técnicas No tratamiento alternativo para pacientes no metilados (excepto ancianos)

13 Recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival.

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16 Can molecular markers help with decision making?

17 MUTATIONS OF THE ISOCITRATE DEHYDROGENASE GENES IN GLIOMAS

18 MOLECULAR BIOLOGY AND NEW CLASSIFICATION OF GLIOMAS

19 FÁRMACOS EN TUMORES CEREBRALES

20 Fotemustina mpfs: 6,7 meses PFS-6: 39% mos: 11,1 meses

21 Major Signaling Pathways in Malignant Gliomas and the Corresponding Targeted Agents in Development for Glioblastoma

22 Estudios Negativos

23 Angiogenesis en GBM La angiogénesis juega un papel muy importante en el crecimiento de los tumores sólidos¹. Los gliomas malignos se caracterizan por ser uno de los tumores más vascularizados y con sobreexpresión de factores proangiogénicos (como VEGF-A ) y de receptores (como VGFR-2)². 1.Chaudhry, et al. Histopathol Wong, Brem. J Natl Compr Canc Netw 2008

24 Bevacizumab 20/35 patients (57%) had radiologic response

25 AVAglio n=463 RT 2Gy; 5 days/week TMZ 75mg/m² qd TMZ mg/m² qd days 1 5 q28d Randomization N=921 Placebo q2w Placebo q2w Placebo q3w Debulking surgery or biopsy Co-primary objectives Stratification RPA class Region PFS (investigator assessed) n=458 RT 2Gy; 5 days/week TMZ 75mg/m² qd BEV 10mg/kg q2w TMZ mg/m² qd days 1 5 q28d BEV 10mg/kg q2w BEV 15mg/kg q3w OS 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

26 Baseline Characteristics* Patients, % Median age, years (range) RT/TMZ/Plb (n=463) 56.0 (18 79) RT/TMZ/BEV (n=458) 57.0 (20 84) Gender Male WHO PS RPA class MGMT status Surgical status KPS MMSE score Corticosteroids EIAEDs *Selected characteristics only III IV V Methylated Non-methylated Missing Biopsy Partial resection Complete resection <27 27 On Off On Off

27 Investigator-Assessed PFS (Co-Primary Endpoint) RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458) Probability of PFS mo 10.6 mo Stratified HR: 0.64 (95% CI: ) p< (log-rank test) Months N at risk RT/TMZ/Plb RT/TMZ/BEV BEV = bevacizumab; CI = confidence interval; HR = hazard ratio; mo = months; PFS = progression-free survival; Plb = placebo; RT = radiotherapy; TMZ = temozolomide

28 IRF-Assessed PFS (Secondary Endpoint) RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458) Probability of PFS Stratified HR: 0.61 (95% CI: ) p< (log-rank test) mo 8.4 mo Months N at risk RT/TMZ/Plb RT/TMZ/BEV BEV = bevacizumab; CI = confidence interval; HR = hazard ratio; IRF = Independent Review Facility; mo = months; PFS = progression-free survival; Plb = placebo; RT = radiotherapy; TMZ = temozolomide

29 Investigator-Assessed PFS: Subgroup Analyses* Category Subgroup Bevacizumab better Placebo better N HR # 95% CI All All Age, years < WHO PS RPA class III IV V MGMT gene promoter status Methylated Non-methylated Missing Surgical status Biopsy only Partial/complete resection MMSE score < Corticosteroid use at baseline On Off *Selected subgroups only; # Unstratified analysis HR CI = confidence interval; HR = hazard ratio; MGMT = methylguanine-dna methyltransferase; MMSE = mini-mental state examination; PFS = progression-free survival; RPA = recursive partitioning analysis; WHO PS = World Health Organization performance status

30 Median Duration Patients Maintained a KPS 70 RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458) Patients with KPS Months BEV = bevacizumab; KPS = Karnofsky performance status; Plb = placebo; RT = radiotherapy; TMZ = temozolomide

31 Corticosteroid Discontinuation in Patients ON Steroids at Baseline Patients discontinuing corticosteroids, % RT/TMZ/Plb (n=208) 47 RT/TMZ/BEV (n=187) 66 *Defined as no corticosteroid intake (0mg) for at least 5 consecutive days BEV = bevacizumab; Plb = placebo; RT = radiotherapy; TMZ = temozolomide

32 Adverse Events of Special Interest for BEV Patients, % RT/TMZ/Plb (n=447) RT/TMZ/BEV (n=464) All grades Grade 3 All grades Grade 3 Bleeding: cerebral haemorrhage mucocutaneous bleeding other Wound-healing complications Arterial thromboembolic events Venous thromboembolic events Hypertension Proteinuria GI perforation (including GI fistula/abscess) Abscesses and fistulae Congestive heart failure Posterior reversible encephalopathy syndrome Safety population BEV = bevacizumab; GI = gastrointestinal; Plb = placebo; RT = radiotherapy; TMZ = temozolomide

33 AVAglio Estudio positivo: alcanza su objetivo primario de SLP (reducción de riesgo 36%) Reforzado por datos de: Calidad de vida. Seguridad. Mantenimiento de KPS. Menor uso de corticoides. Datos de SG todavía no maduros análisis interino no es positivo.

34 Bevacizumab

35 Ongoing clinical trials.

36 OTROS TRATAMIENTOS

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39 Terapia con CAMPOS ELECTRICOS ALTERNANTES

40 NEO TTF, NOVOCURE The NovoTTF-100A device, which weighs about six pounds (three kilograms), creates a low intensity, alternating electric field within the tumor that exerts physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cancer cell death prior to division FDA approval

41 Conclusiones Marcadores moleculares son útiles en practica clínica MGMT, IDH-1, 1p19q. Eficacia de Bevacizumab (estudio AVAglio). Necesidad de nuevos fármacos. Nada real de otras terapias NovoTTF-100??

42 Gracias por su atención.