Prognostic value of ADC in glioblastoma multiforme and its correlation with survival and MGMT promoter methylation status. R. Zalazar, M.D. Hernández, M. Páramo, P. Slon, M. Millor Muruzabal, J. Solorzano Rendon, M. Ribelles, J. Zubieta, M. Garcia de Eulate; Clínica Universidad de Navarra. Pamplona/ES
NIVERSITAS STVDIORV Introduction Glioblastoma multiforme is the most malignant type of glioma and has a very poor prognosis, having a mean survival of only 14 months
Patient A: 60 year old man, KPS 80 Patient B: 61 year old man, KPS 80
Patient A survival: 21 months Patient B survival: 6 months
NIVERSITAS STVDIORV Introduction Molecular Biomarkers MGMT EGFR ampl EGFRvIII Imaging Biomarkers Perfusion-MRI (rcbv) Diffusion-MRI (ADC) IDH 1/2 1p/19q PTEN p53
NIVERSITAS STVDIORV Introduction Molecular Biomarkers MGMT EGFR ampl EGFRvIII Imaging Biomarkers Perfusion-MRI (rcbv) Diffusion-MRI (ADC) IDH 1/2 1p/19q PTEN p53
NIVERSITAS STVDIORV Introduction Molecular Biomarkers MGMT EGFR ampl EGFRvIII Imaging Biomarkers Perfusion-MRI (rcbv) Diffusion-MRI (ADC) IDH 1/2 1p/19q PTEN p53
NIVERSITAS STVDIORV Objective To analyse whether apparent diffusion coefficient (ADC) values correlate with: SURVIVAL MGMT promoter methylation status in patients with glioblastoma multiforme (GBM).
NIVERSITAS STVDIORV Materials and Method Retrospective study: Oct 2007 Feb 2012 of 78 patients. Inclusion Criteria Newly diagnosed and untreated GBM Presurgical MRI At least 12 months follow-up or until their death This study was approved by the ethic committee at our institution
NIVERSITAS STVDIORV Materials and Method 78 patients with Newly diagnosed of GBM 21 patients were excluded 27 F 30 M 57 patients
MRI examination 4º SWI 1º DWI b1000 2º ADC 3º T1 + G
MRI examination 4º SWI 1º DWI b1000 2º 3º ADC T1 + G
MRI examination 4º SWI 1º DWI b1000 2º ADC 3º T1 + G
MRI examination 4º SWI 1º DWI b1000 2º ADC 3º T1 + G
MRI examination ROI 1 DWI b1000 ADC T1 + G
MRI examination ROI 2 T2 FLAIR ADC T1 + G
NIVERSITAS STVDIORV Materials and Method ADC index: ADC min SC / ADC mean NCWM
. Kaplan-Meier method. Cox regression model. ROC curves NIVERSITAS STVDIORV Materials and Method Clinical Molecular Surgical Imaging Age Sex MGMT status Pre-surgical volume Post-surgical volume ADCmin SC (solid component) Karnofsky Performance Score ADCindex: (ADC min SC/ADC mean N CWM) ADC index: ADC min SC / ADC mean NCWM Statistical analyses (SPSS 20.0)
NIVERSITAS STVDIORV Materials and Method Three groups were analysed N=19 1st group ADC-index > 0.7 MGMT-methylated-status Markers of GOOD prognosis N=10 2nd group ADC index < 0.7 MGMT non methylated status Markers of POOR prognosis N=53 3rd group MGMT-methylated status ADC index <0,7 (n=8) ADC index >0,7 (n=19) MGMT- non methylated status ADC index <0,7 (n=10) ADC index >0,7 (n=16)
NIVERSITAS STVDIORV Results PATIENT CHARACTERISTICS Age (years) Median (range) 60.5 (28-78) Sex Men 30 Women 27 KPS Median (range) 80 (40-100) Survival (months) Median (range) TUMOR CHARACTERISTICS MGMT Status n (%) Methylated 27/53 (50,94%) Unmethylated 26/53 (49,06%) Tumoral Volumen (cm 3 ) Mean ( SD) Presurgical 42,4 ( 26.7) Postsurgical 0,57(( 2,05) PFS 7,4 (2.7-41.6) OS 17.8 (3.1-42.6)
NIVERSITAS STVDIORV Results PATIENT CHARACTERISTICS Age (years) Median (range) 60.5 (28-78) Sex Men 30 Women 27 TUMOR CHARACTERISTICS MGMT Status n (%) Methylated 27/53 (50,94%) Meythylated 50,94%% Unmethylated 26/53 (49,06%) KPS Median (range) 80 (40-100) Survival (months) Median (range) PFS 7,4 (2.7-41.6) OS 17.8 (3.1-42.6)
NIVERSITAS STVDIORV Results PATIENT CHARACTERISTICS Age (years) Median (range) 60.5 (28-78) Sex TUMOR CHARACTERISTICS MGMT Status n (%) Men 30 Women 27 KPS Median (range) 80 (40-100) Survival (months) Median (range) Tumoral Volumen (cm 3 ) Mean ( SD) Presurgical 42,4 ( 26.7) Post-surgical 0,57cm 3 Postsurgical 0,57(( 2,05) PFS 7,4 (2.7-41.6) OS 17.8 (3.1-42.6)
NIVERSITAS STVDIORV Results ADC values according to MGMT status ADCmin Solid Component p=ns ADC index Methylated Non methylated Methylated Non methylated AUC: 0,55
NIVERSITAS STVDIORV Results Univariate analysis PFS OS HR (95% CI) p value HR (95% CI) p value Age 1,00 (0,98-1,03) NS 1,04 (1,0-1,07) 0,01 Sex 0,75 (0,41-1,36) NS 1,2 (0,7-2,3) NS KPS 0,99 (0,97-1,14) NS 0,98 (0,96-1,00) 0.06 MGMT 2,96 (1,5-5,7) 0,001 1,62 (0,84-3,1) 0,14 Presurgical Volumen 1,0 (0,99-1,0) NS 1,0 (0,99-1,01) NS Postsurgical Volumen 0,97 (0,82-1,14) NS 0,94 (0,78-1.12) NS ADCmin Solid Component 0,31(0,32-3,13) NS 0,01 (0,01-0,14) <0,001 ADCindex 0,72 (0,23-2,2) NS 0,05 (0,07-0,35) =0,003
NIVERSITAS STVDIORV Results Univariate analysis PFS OS HR (95% CI) p value HR (95% CI) p value Age 1,00 (0,98-1,03) NS 1,04 (1,0-1,07) 0,01 Sex 0,75 (0,41-1,36) NS 1,2 (0,7-2,3) NS KPS 0,99 (0,97-1,14) NS 0,98 (0,96-1,00) 0.06 MGMT p<0,001 p=ns% MGMT 2,96 (1,5-5,7) 0,001 1,62 (0,84-3,1) 0,14 Presurgical Volumen 1,0 (0,99-1,0) NS 1,0 (0,99-1,01) NS Postsurgical Volumen 0,97 (0,82-1,14) NS 0,94 (0,78-1.12) NS ADCmin Solid Component 0,31(0,32-3,13) NS 0,01 (0,01-0,14) <0,001 ADCindex 0,72 (0,23-2,2) NS 0,05 (0,07-0,35) =0,003
NIVERSITAS STVDIORV Results Univariate analysis PFS OS HR (95% CI) p value HR (95% CI) p value Age 1,00 (0,98-1,03) NS 1,04 (1,0-1,07) 0,01 Sex 0,75 (0,41-1,36) NS 1,2 (0,7-2,3) NS KPS 0,99 (0,97-1,14) NS 0,98 (0,96-1,00) 0.06 MGMT 2,96 (1,5-5,7) 0,001 1,62 (0,84-3,1) 0,14 Presurgical Volumen 1,0 (0,99-1,0) NS 1,0 (0,99-1,01) NS Postsurgical Volumen 0,97 (0,82-1,14) NS 0,94 (0,78-1.12) NS ADCmin Solid Component 0,31(0,32-3,13) NS 0,01 (0,01-0,14) <0,001 ADCindex 0,72 (0,23-2,2) NS 0,05 (0,07-0,35) =0,003
NIVERSITAS STVDIORV Results Univariate analysis PFS OS HR (95% CI) p value HR (95% CI) p value Age 1,00 (0,98-1,03) NS 1,04 (1,0-1,07) 0,01 Age p=ns =0,01% Sex 0,75 (0,41-1,36) NS 1,2 (0,7-2,3) NS KPS MGMT Presurgical Volumen Postsurgical Volumen ADCmin Solid Component ADCmin SC p=ns <0,001 ADCindex p=ns =0,003 0,31(0,32-3,13) NS 0,01 (0,01-0,14) <0,001 ADCindex 0,72 (0,23-2,2) NS 0,05 (0,07-0,35) =0,003
NIVERSITAS STVDIORV Results Multivariate analysis PFS OS HR (95% CI) p value HR (95% CI) p value MGMT 3,2 (1,6-6,7) 0,001 2,1 (1,04-4,2) 0,037 ADCmin Solid Component 0,40 (0,02-7,7) 0,54 0,003 (0,0-0,08) 0,001 * Adjusted for age, sex and KPS
NIVERSITAS STVDIORV Results Multivariate analysis PFS OS HR (95% CI) p value HR (95% CI) p value MGMT 3,2 (1,6-6,7) 0,001 2,1 (1,04-4,2) 0,037 ADCmin Solid Component 0,40 (0,02-7,7) 0,54 0,003 (0,0-0,08) 0,001 * Adjusted for age, sex and KPS
NIVERSITAS STVDIORV Results MGMT Status Progression-Free Survival Overall Survival p=0,002 p=ns Methylated status Methylated status Non methylated status Non methylated status MGMT-status correlated better with PFS (p=0,002)
NIVERSITAS STVDIORV Results ADC-min SC Progression-Free Survival Overall Survival <0,63 >0,63 p = 0.06 > 0.63 < 0.63 <0,63 >0,63 p=0,001 ADC-min SC correlate better with OS (p=0,001)
NIVERSITAS STVDIORV Results ADC-index Progression-Free Survival Overall Survival <0,7 >0,7 p = 0.02 <0,7 >0,7 p=0,001 ADC-index correlate better with OS (p=0,001)
NIVERSITAS STVDIORV Results Group 1 p =0,014 vs Group 2 Group 1 PROGRESSION FREE SURVIVAL Group 2 months ( months )
NIVERSITAS STVDIORV Results Group 1 p =0,001 vs Group 2 Group 1 OVERALL SURVIVAL Group 2 ( months )
NIVERSITAS STVDIORV Results OVERALL SURVIVAL MGMT-methylated ADCindex >0,7 MGMT-methylated status ADC index <0,7 ADC index >0,7 p=0,001 ADCindex <0,7 OVERALL SURVIVAL months
NIVERSITAS STVDIORV Results OVERALL SURVIVAL MGMT-methylated ADCindex >0,7 MGMT-methylated status ADC index <0,7 ADC index >0,7 p=0,001 ADCindex <0,7 OVERALL SURVIVAL months
NIVERSITAS STVDIORV Results OVERALL SURVIVAL MGMT- non methylated ADC index >0,7 MGMT- non methylated status ADC index <0,7 ADC index >0,7 p=0,027 OVERALL SURVIVAL ADCindex <0,7 months
NIVERSITAS STVDIORV Results OVERALL SURVIVAL MGMT- non methylated ADC index >0,7 MGMT- non methylated status ADC index <0,7 ADC index >0,7 p=0,027 OVERALL SURVIVAL ADCindex <0,7 months
NIVERSITAS STVDIORV Conclusions 1 ADCmin value of the SC of the tumor and the ADCindex value correlated significantly with overall survival, independently of the MGMT status.
NIVERSITAS STVDIORV Conclusions 1 ADCmin value of the SC of the tumor and the ADCíndex value correlated significantly with overall survival, independently of the MGMT status. 2 There were no significant differences in the values of ADC in the patients with MGMT methylation and MGMT non methylation status.
NIVERSITAS STVDIORV Conclusions Our findings suggest that ADC values are not useful to predict the MGMT status.. But it is strong independent predictors of survival in those patients
Laura Romina Zalazar lzalazar@unav.es