AVANCES EN EL TRATAMIENTO SISTÉMICO DE LOS TUMORES DEL SISTEMA NERVIOSO CENTRAL Miguel Navarro. Oncología Médica. Hospital Universitario de Salamanca.
Introducción Avances en el conocimiento molecular de los tumores cerebrales. Factores predictivos/pronósticos. Fármacos. Antiangiogénicos. Otros tratamientos
Distribution of All Gliomas by Histology Subtypes All other gliomas 10.1% incidence : 6 cases per 100 000 Ependymomas 5.6% Oligodendrogliomas 9.2% Pilocytic astrocytoma 5.7% Glioblastoma 50.7%% Diffuse astrocytoma 1.7% Anaplastic astrocytoma 7.9% CBTRUS Report, 2004-2005. All other astrocytomas 9.1%
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;24:2563-2569.
GBM
MGMT
GBM. MGMT Metilación
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
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)
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.
Can molecular markers help with decision making?
MUTATIONS OF THE ISOCITRATE DEHYDROGENASE GENES IN GLIOMAS
MOLECULAR BIOLOGY AND NEW CLASSIFICATION OF GLIOMAS
FÁRMACOS EN TUMORES CEREBRALES
Fotemustina mpfs: 6,7 meses PFS-6: 39% mos: 11,1 meses
Major Signaling Pathways in Malignant Gliomas and the Corresponding Targeted Agents in Development for Glioblastoma
Estudios Negativos
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 2001 2.Wong, Brem. J Natl Compr Canc Netw 2008
Bevacizumab 20/35 patients (57%) had radiologic response
AVAglio n=463 RT 2Gy; 5 days/week TMZ 75mg/m² qd TMZ 150 200mg/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 150 200mg/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
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 64 62 WHO PS RPA class MGMT status Surgical status KPS MMSE score Corticosteroids EIAEDs *Selected characteristics only 0 1 2 III IV V Methylated Non-methylated Missing Biopsy Partial resection Complete resection 50 80 90 100 <27 27 On Off On Off 52 48 16 60 23 26 51 23 10 48 42 30 70 24 76 45 55 20 80 50 50 17 57 26 26 49 25 13 46 41 33 67 24 76 41 59 19 81
Investigator-Assessed PFS (Co-Primary Endpoint) RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458) 1.0 0.9 Probability of PFS 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 6.2 mo 10.6 mo Stratified HR: 0.64 (95% CI: 0.55 0.74) p<0.0001 (log-rank test) 0 3 6 9 12 15 18 21 24 27 30 33 36 Months N at risk RT/TMZ/Plb 463 349 247 170 110 77 47 23 8 RT/TMZ/BEV 458 424 366 278 189 104 71 25 13 BEV = bevacizumab; CI = confidence interval; HR = hazard ratio; mo = months; PFS = progression-free survival; Plb = placebo; RT = radiotherapy; TMZ = temozolomide 4 2 0 1 0 0 0 0
IRF-Assessed PFS (Secondary Endpoint) RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458) 1.0 0.9 Probability of PFS 0.8 0.7 0.6 0.5 0.4 0.3 0.2 Stratified HR: 0.61 (95% CI: 0.53 0.71) p<0.0001 (log-rank test) 0.1 0.0 4.3 mo 8.4 mo 0 3 6 9 12 15 18 21 24 27 30 33 36 Months N at risk RT/TMZ/Plb RT/TMZ/BEV 463 458 297 396 168 298 109 212 76 148 46 70 30 44 14 14 6 7 4 1 0 0 0 0 0 0 BEV = bevacizumab; CI = confidence interval; HR = hazard ratio; IRF = Independent Review Facility; mo = months; PFS = progression-free survival; Plb = placebo; RT = radiotherapy; TMZ = temozolomide
Investigator-Assessed PFS: Subgroup Analyses* Category Subgroup Bevacizumab better Placebo better N HR # 95% CI All All 921 0.65 0.56 0.75 Age, years <50 229 0.64 50 59 323 0.69 60 69 296 0.59 70 73 0.78 0.47 0.86 0.54 0.88 0.46 0.77 0.46 1.33 WHO PS 0 465 0.71 0.58 0.88 1 2 455 0.57 0.46 0.69 RPA class III 151 0.64 IV 540 0.62 V 229 0.72 MGMT gene promoter status Methylated 237 0.76 Non-methylated 461 0.56 Missing 223 0.61 0.44 0.93 0.51 0.74 0.54 0.96 0.56 1.04 0.46 0.68 0.46 0.82 Surgical status Biopsy only 104 0.81 Partial/complete resection 817 0.62 MMSE score <27 214 0.74 27 696 0.63 0.53 1.26 0.54 0.73 0.55 0.99 0.53 0.75 Corticosteroid use at baseline On 395 0.69 0.55 0.85 Off 522 0.63 0.51 0.76 *Selected subgroups only; # Unstratified analysis HR 0.1 0.2 0.4 0.6 1 2 3 4 5 6 10 20 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
Median Duration Patients Maintained a KPS 70 RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458) Patients with KPS 70 6 9 0 2 4 6 8 10 Months BEV = bevacizumab; KPS = Karnofsky performance status; Plb = placebo; RT = radiotherapy; TMZ = temozolomide
Corticosteroid Discontinuation in Patients ON Steroids at Baseline Patients discontinuing corticosteroids, % 80 60 40 20 0 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
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 2.2 8.9 8.1 0.7 0.4 2.6 26.7 11.6 1.5 0.4 0.6 Wound-healing complications 2.2 0.7 3.7 1.5 Arterial thromboembolic events 1.6 1.3 5.0 4.1 Venous thromboembolic events 9.6 8.1 7.8 7.3 Hypertension 13.0 2.0 37.5 10.3 Proteinuria 4.0 14.0 3.7 GI perforation (including GI fistula/abscess) 0.2 0.2 1.7 1.1 Abscesses and fistulae 0.4 0.4 0.6 0.6 Congestive heart failure 0.2 0.4 0.4 Posterior reversible encephalopathy syndrome Safety population BEV = bevacizumab; GI = gastrointestinal; Plb = placebo; RT = radiotherapy; TMZ = temozolomide
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.
Bevacizumab
Ongoing clinical trials.
OTROS TRATAMIENTOS
Terapia con CAMPOS ELECTRICOS ALTERNANTES
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
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??
Gracias por su atención.