Estudios Neo-adyuvantes en Neurooncología
Nuestra experiencia como grupo
Carmen Balañá
Diciembre 2015
Tipos de pacientes
Paciente irresecable
• Localizaciones elocuentes
• Gran tamaño
• Multicéntricos
• Profundos
Paciente resecable
• Localizaciones no elocuentes
• Pequeños
• No multicéntricos
BIOPSIA o RESECCIÓN MÍNIMA •Inestables neurológicamente •Sintomáticos •Precisan DXM •No efecto debulking •Toleran peor quimio-radio
RESECCIÓN PARCIAL AMPLIA O COMPLETA •Estables neurológicamente • ¿Menos sintomáticos? •Puede retirarse DXM •Efecto debulking previo: •Toleran mejor quimio-radio
Survival Nomogram
Gorlia T, et al. Lancet Oncol. 2008;9:29-38.
Table 1: Type of surgery reported frequencies
Author/country
N Source Period Biopsy %
Partial resectio
n %
Complete resection
%
Bauchet/France◊
952 French Brain Tumor DataBase
2004-2006 43.9 24.2 31.7
Scoccianti/italy*
1059 18 RDT UNIT 2002-2007 11.6% 41 45.8
Graus/Spain 833 Retrospective study
2008-2010 33.6 28.5 37.4
Gan/Australia 315 Victorian Cancer Registry
2006-2008 24 37 32
Chang/USA ∆ 418 Glioma Outcomes Project
1997-2000 21.1 78.9 % resection
◊ first or second surgery, *only patients who were sent for treatment. ∆ 78.5% craniotomies
Is it Possible To Define Optimal Surgery for Brain Tumors?
• A topographical staging system with the integration of
– Location
– Size
– Eloquence of the brain
Topographical Staging for GBM
STAGE 1: surgery as radical as possible
STAGE 2: risky surgery, more careful and meticulous careful planning (new technology)
STAGE 3: resection is not recommended at present
Pros y contras estudios neoadyuvantes
• Atenuación efectos confusión en la valoración de respuesta: ausencia de efectos de irradiación.
• Administración de tratamiento adecuado a la diana molecular presente en el momento de iniciar el tratamiento.
• Posibilidad de estudios ‘pick-up de winner’: test de eficacia terapéutica
• Retraso del tratamiento con irradiación.
• Paciente inestable neurológicamente: no resección previa.
Estudios Neo-adyuvantes de GEINO
Participación multicéntrica
Investigador
2 1,4 1,4 1,4
41 28,5 28,5 29,9
10 6,9 6,9 36,8
8 5,6 5,6 42,4
4 2,8 2,8 45,1
2 1,4 1,4 46,5
6 4,2 4,2 50,7
1 ,7 ,7 51,4
7 4,9 4,9 56,3
7 4,9 4,9 61,1
5 3,5 3,5 64,6
12 8,3 8,3 72,9
1 ,7 ,7 73,6
11 7,6 7,6 81,3
7 4,9 4,9 86,1
11 7,6 7,6 93,8
2 1,4 1,4 95,1
2 1,4 1,4 96,5
1 ,7 ,7 97,2
1 ,7 ,7 97,9
2 1,4 1,4 99,3
1 ,7 ,7 100,0
144 100,0 100,0
Dr. J. L. García López
Dra. Balaña
Dr. Berrocal
Dr. López Pousa
Dr. Yayatur
Dr. Martín
Dr. Herrero
Dr. Bernav ides
Dr. Reynes
Dr. Gallego
Dr. Perez Segura
Dr. Gil
Dr. Verger
Dr de las Peñas
Dra. Luque
Dr. Sepulv eda
Dr. Peralta
Dra. Garcia
Dra. Martinez
Dr. Vazquez
Dr. Vieitez
Dra. Fernandez
Total
Válidos
Frecuencia Porcentaje
Porcentaje
válido
Porcentaje
acumulado
Table 1: Trials’ description Characteristic GENOM-99
Phase II GENOM008
Phase II GENOM009
Randomized phase II
Trial identification /Pub
Oct 1999-Jan 2001
JNO 2004.
EUDRACT: 2008-006728-73
NCT01100177 Target Oncol 2014
EUDRACT: 2009-010337-45 NCT01102595.
ASCO meeting 2014
NA treatment 3 cycles /28d TMZ&CDDP
Sunitinib 8 weeks
2 cycles TMZ/ 28d
2 cycles TMZ & BEV/28d
Num. Eval Patients 39 12 45 48
Radiotherapy with concurrent TMZ
NO YES YES YES
Response criteria MacDonald RANO RANO RANO
Central review histology
YES YES YES YES
Central review radiology
YES YES
YES
YES
MGMT analysis Optional Optional Mandatory Mandatory
Table 2: Patients’ characteristics (1) Characteristic GENOM99
Phase II N(%)
GENOM008 Phase II
N(%)
GENOM009 Randomized phase II
N(%)
TOTAL N(%)
Num pat 39 12 45 48 144
NA treatment TMZ&CDDP Sunitinib 2 cycles TMZ 2 cycles TMZ
Sex (female) 18 (46.2) 5 (41.7) 25 (55.6) 31 (64.6) 79 (54.9)
Stereotactic biopsy only
14 (35.9) 12 (100) 35 (77.8) 42 (87.5) 103 (71.5)
PS≥2 16 (41.0) 4 (33.3) 13 (28.9) 13 (27.1) 46 (31.9)
MMS <27* UNK 4 (33.3) 20 (44.4) 13 (27.1) 37 (25.7)
Barthel <75/100 5 (12.8) 4 (33.3) 12 (27.2) 8 (17.3) 29 (20.1)
Anticonvulsants No EIA EIA
29 7
22
1 1 0
26 26 0
17 16 1
74 51 23
Neurological impairment
24 (61.5) 5 (41.7) 28 (62.2) 28 (58.3) 85 (59.0)
Basal > DXM2mg/d
36 (92.3)
8 (66.7)
30 (66.7)
31 (64.6)
105 (72.9)
Table 2: Patients’ characteristics (2) Characteristic GENOM9
9 Phase II N(%)
GENOM008 Phase II
N(%)
GENOM009 Randomized phase II
N(%)
TOTAL N(%)
RPA classification III IV ≥V
4 (10.3) 9 (23.1)
26 (66.7)
1 (8.3) 1 (8.3)
10 (83.3)
1 (2.2)
7 (15.6) 37 (82.2)
0 (0.0) 4 (8.3)
44 (91.7)
8 (4.2)
21 (14.6) 117 (81.3)
MGMT Unmet Met Unknown
7 (17.9) 5 (12.8)
27 (69.3)
- -
12 (100.0)
18 (40.0) 12 (26.6) 15 (33.4)
17 (35.4) 20 (41.6) 11 (23.0)
42 (29.2) 37 (25.7) 65 (45.1)
Concurrent Rxt with TMZ
0 (100.0) 3 (25.0) 32 (71.1) 39 (81.3) 74 (51.4)
Completed Radiotherapy
29 (74.4) 6 (50.0) 30 (66.7) 37 (77.1) 102 (70.8)
Bevacizumab at recurrence
0(0.0) 0 (0.0) 11 (24.4) 16 (33.3) 27 (18.8)
Table 3: Response and OS Characteristic GENOM99
Phase II GENOM008
Phase II GENOM009
Randomized phase II TOTAL
Num pat 39 12 45 48 144
NA treatment 3 cycles /28d TMZ&CDDP
Sunitinib 8 weeks
2 cycles TMZ/ 28d
2 cycles TMZ & BEV/28d
Response** CR PR SD P NE
3 ( 7.7)
15 (38.5) 4 (10.3)
14 (35.9) 3 (7.7)
0 ( 0.0) 0 ( 0.0) 6 (50.0) 6 (50.0) 0 ( 0.0)
0 ( 0.0) 4 ( 8.9) 6 (13.3)
33 (73.3) 2 ( 4.4)
0 ( 0.0)
11 (22.9) 17 (35.4) 15 (31.3) 5 (10.4)
3 ( 2.1)
30 (20.8) 33 (22.9) 68 (47.2) 10 ( 6.9)
Clinical Benefit#
22(56.4)
6 (50%)
10 (22.2)
28 (58.3)
66 (45.8)
Median survival (m)
12.46 (11.5-13.4) 3.7 (1.9-5.4)
8.3 (6.3-10.3)
11.2 (7.8-14.5)
10.3 (8.7-12.0)
**OVER CENTRALIZED REVIEW OF RESPONSE # OVER ALL PATIENTS (INCLUDING NON EVALUABLE- CR+PR+SD)
Estudios paralelos
• Valor de la respuesta objetiva para impactar la Supervivencia (Poster SNO 2015)
• ¿Fue la cirugía óptima en los pacientes GENOM 009? (Poster SNO 2015)
• GENOM 009: MGMT suero versus tejido: oral ESMO 2014
Table 4: OS and prognostic factors All patients N=144
(P) Biopsy only patients N= 103
(P)
Overall survival 10.3 (8.7-12.0) 9.1 (7.5-10.6)
By MGMT Unmet Met
6.9 (2.2-11.5) 14.0 (11.6-16.5)
0.001
5.9 (5.0-6.8) 13.8 (8.2-19.4)
0.003
By BEV at recurrence
Yes No
20.0 (15.7-24.4) 8.6 (7.1-10.2)
0.0001
20.3 (15.7-24.9) 7.6 (6.0-9.1)
0.0001
By RPA
III&IV V
15.2 (12.5-17.9) 9.5 (8.0-11.0)
0.05
15.1 (10.4-19.8) 8.4 (6.9-9.9)
0.11
By response to NA treatment
No response Obj response
SD&P PR&CR
8.4 (6.1-10.6) 16.4 (14.0-18.9)
0.0001
7.9 (6.0-9.8) 16.4 (12..0-20.8)
0.01
Progression Clinical Benefit
PR&CR&SD 6.4 (4.6-8.1) 13. 8 (11.0-16.5)
0.0001
6.0 (4.7-7.4) 12.7 (9.4-16.0)
0.0001
Talbe 4: Multivariate analyses
All patients (N= 144) Biopsy patients (n=103)
Protocol NS NS
RPA (III&IV vs V NS NS
MGMT met 0.36 (0.20-0.68) P=0.001 0.31 80.15-0.63) P=0.001
Bev at recurrence 0.28 (0.13-0.57) P=0.0001 0.25 (0.11-0.56) P=0.001
Objetive response (OR+PR) 2.3 (1.15-4.9) P=0.01 1.3 (0.54-3.46) P=0.49
Protocol NS NS
RPA (III&IV vs V NS NS
MGMT met 0.39 (0.21-0.71) P=0.002 0.38 (0.18-0.80) P=0.01
Bev at recurrence 0.34 (0.17-0.68) P=0.002 0.32 (0.13-0.76) P=0.01
Clinical benefit(OR+PR+SD)
0.43 (=.23-0.77) P=0.005 0.42 (0.18-0.97) P=0.04
SD and P: 8.4 (6.1-10.6); P=0.0001
PR and CR: 16.4 (14.0-18.9)
PR + CR +SD: 13. 8 (11.0-16.5)
P: 6.4 (4.6-8.1)
Non evaluable 9.5 (0.0-22.4); P=0.0001
Fig. 2: Survival curves
• MGMT is an important prognostic factor to consider in NA trials.
• RANO criteria are more demanding than MacDonald’s criteria.
• Objective Response to NA treatment is related with OS both by RANO and for MacDonald’s criteria.
• The evaluation of response at the NA setting, is easiest than at the recurrent setting. This is mostly due to the absence of the confounding factors on imaging of radiotherapy (pseudoprogression).
Is unresected glioblastoma truly unresectable? An analysis of basal MRI’s of patients with unresected glioblastoma included in the GENOM009 trial and
the variability of surgical approaches.
Jaume Capellades, Pilar Teixidor, Cristina
Hostalot, Gloria Villalba, Gerard Plans, Roser Garcia-Armengol, Juan Jose García, Anna
Estival, Ramón de las Penas, Raquel Luque, Miguel Gil, Juan Sepúlveda, Carmen Balana.
Background
• The percentatge of patients with unresected glioblastoma (biopsy only) ranges from 20 to 40% in different series. (Table 1).
• There exists variability in the selection of the best surgical approach depending on:
– Technical availability of the team
– Skills of the neurosurgeon
– Conviction on the role of radical surgery to increase survival in glioblastoma patients
– Different weighting about post-surgical aftermaths
Fig 1: Study Schema
Pre-surgical MRI’s uploaded
5 different NS from 3 University Centers
Blinded to patients’ clinical status and age
QUESTIONS. 1. Which surgical approach would you perform? -Biopsy (B) -Partial resection (PR) -Radical Resection (RR) 2. Which pre-operative /intraoperative assessments Would you ask for to perform this surgery?
Blinded to each other answers
T1Gd +T2 (FLAIR): 68p (3D: 36p and 2D:41p) T1Gd only: 9p
Table 2: Surgical approach evaluation by the investigators (first evaluation)
Real surgery
NS 1 N (%)
NS 2 N (%)
NS 3 N (%)
NS 4 N (%)
NS 5 N (%)
Biopsy 68 (88.3) 44 (57.1) 47 (61.0) 56 (72.7) 26 (33.8) 45 (58.4)
CompleteResecion
0 9 (11.7) 6 ( 7.8) 4 ( 5.2) 28 (36.4) 26 (33.8)
Partial Resection
9 (11.7) 24 (31.2) 24 (31.2) 17 (22.1) 23 (29.9) 5 ( 6.5)
Fleiss Kappa statistics 0.234 ; 95% CI-0.156-0.312; P=0.0001 (FAIR, LESS THAN MODERATE)
Mi diseño ideal
Mi diseño ideal (1)
PET AA RMN
GLIOBLASTOMA
MUESTRA HISTOLÓGICA ESTUDIO MOLECULAR
BIOPSIA 8 SEMANAS DE TRATAMIENTO TTO EXPERIMENTAL
TTO STANDARD
PET AA RMN
PET AA RMN
CRITERIOS RANO/IRANO CRITERIOS NANO
¿BEVACIZUMAB PARA CONTENER EDEMA?
¿TTO ANTIDIANA?