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?