Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma

H.S. Nguyen; N. Milbach; S.L. Hurrell; E. Cochran; J. Connelly; J.A. Bovi; C.J. Schultz; W.M. Mueller; S.D. Rand; K.M. Schmainda; P.S. LaViolette

doi:10.3174/ajnr.A4898

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Fig 1.
Demonstration of the creation of a patient-specific brain mold for minimizing tissue distortion during fixation. The patient's MR imaging is used to generate a brain mask, which is then used as a guide for generating the mold in 3D modeling software. Molds are then 3D-printed in plastic.
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Fig 2.
Demonstration of the use of a custom 3D-printed slicing jig for sectioning the brain in the same axial orientation as the imaging. Shown on the lower right are examples of gyri and sulci that align well with the imaging (yellow arrows).
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Fig 3.
The brain section and corresponding imaging from a representative patient. The diffusion-restricted lesion (red arrows) was growing between the 2 imaging sessions, shown 2 months and 1 month before death. Histology revealed coagulative necrosis surrounded by viable hypercellular tumor (lower section). T1+C indicates T1 + gadolinium contrast.
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Fig 4.
Examples of stable and progressive diffusion-restricted lesions occurring following the onset of bevacizumab treatment.
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Fig 5.
Survival analyses comparing groups. Upper Section, Overall survival is significantly greater in patients with stable diffusion restriction compared with those with no diffusion restriction (P < .05). OS is significantly lower in patients with progressive diffusion restriction compared with those with stable diffusion restriction (P < .05). Middle Section, Unmethylated tumors show survival trends similar to those in the overall population, in which patients with stable diffusion restriction survived longer than those with no diffusion restriction and progressive diffusion restriction (P < .05). Lower Section, Patients with unmethylated stable diffusion restriction show survival similar to those with no diffusion-restriction methylation. DR indicates diffusion restriction; PrDR, progressive diffusion restriction; NDR, no diffusion restriction; StDR, stable diffusion restriction; Meth, methylation; Unmeth, no methylation.

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Table 1:

Patient clinical summaries for the 6 patients included in the autopsy study

Patient No.	Last MRI to Death (day)	Age at Death (yr)	Tumor Type	Surgery	XRT	TMZ	Location of Focal Region of Diffusion Restriction	Bevacizumab (day)
Patient No.	Last MRI to Death (day)	Age at Death (yr)	Tumor Type	Surgery	XRT	TMZ	Location of Focal Region of Diffusion Restriction	Before Death	Before Focal Region Appears	Between Focal Region and Death
1	10	40	Grade III mixed glioma	+	+	+	Corpus callosum	44	34	10
2	3	68	GBM	+	+	+	Corona radiata	435	306	129
3	23	53	GBM	+	+	+	Corona radiata	85	34	51
4	37	65	GBM	+	+	+	Centrum semiovale	343	264	79
5	29	58	GBM	+	+	+	Corpus callosum	827	728	99
6	62	42	GBM	+	+	+	Centrum semiovale	700	534	166

Note:—XRT indicates radiation therapy; TMZ, temozolomide; +, yes.

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Table 2:

Demographics for the retrospective bevacizumab study

	NDR (n = 45),^{^a} (Meth [n = 8]/Unmeth [n = 10])	StDR (n = 10),^{^b} (Unmeth [n = 7])	PrDR (n = 9),^{^c} (Unmeth [n = 4])
Age at death (yr) (mean) (SD)	55 (13) (58/63)	55 (11) (55)	52 (8) (58)
Sex
Male	23 (4/4)	6 (4)	8 (4)
Female	22 (4/6)	4 (3)	1 (0)
Days between bevacizumab initiation and death (median) (lower/upper CI)	256 (213–298) (524–352)	516 (197–835) (484)	183 (125–241) (252)
Recurrences/progression (median) (range)	2 (1–5) (2.5/2.2)	2 (1–5) (2.57)	2 (1–3) (1.5)
Initial pathology
Grade II	5 (1/1)	1 (1)	0 (0)
Grade III	2 (0/1)	2 (2)	1 (0)
GBM	38 (7/8)	7 (4)	8 (4)
Therapeutic regimen
Surgery + XRT/TMZ + adjuvant TMZ	45 (8/10)	10 (7)	9 (4)
Reoperation	22 (2/5)	6 (4)	2 (0)
Bevacizumab	45 (8/10)	10 (7)	9 (4)
Stopped?^{^a}	10 (1/3)	3 (1)	1 (0)
Irinotecan	6 (0)	2 (0)	3 (0)
Isotretinoin	15 (2/3)	2 (2)	1 (0)
CCNU/BCNU	8 (3/1)	2 (2)	3 (2)
Interferon	2 (0)	0 (0)	0 (0)
Optune^{^d} TTF	0 (0)	1 (1)	0 (0)
PLDR	12 (5/4)	5 (4)	3 (2)

Note:—PLDR indicates pulsed low-dose rate radiation; NDR, no diffusion restriction; StDR, stable diffusion restriction; PrDR, progressive diffusion restriction; TTF, tumor treating fields; Meth, methylation; Unmeth, no methylation; CCNU/BCNU, carmustine/lomustine; XRT, radiation therapy; TMZ, temozolomide.
↵a Bevacizumab was stopped for further surgery (for resection, n = 5; for infection, n = 1; for shunting, n = 1; for hemorrhage, n = 1; buttock abscess, n = 1; and hip fracture, n = 1).
↵b Bevacizumab was stopped for neutropenia/thrombocytopenia (n = 1), fatigue (n = 1), and hemorrhage (n = 1).
↵c Bevacizumab was stopped for further surgery (resection, n = 1).
↵d Novocure, Portsmouth, New Hampshire.

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Table 3:

Summary of the ADC values within regions of DRN and hypercellularity

Patient No.	ADC DRN	DRN Nvox	ADC HypCel	HypCel Nvox	Scanner	Field Strength
1	0.578	142	0.694	256	Optima^{^a}	1.5T
2	0.552	122	1.000	143	Symphony^{^b}	1.5T
3	0.622	88	1.076	72	Optima^{^a}	1.5T
4	0.786	237	1.170	950	Discovery^{^a}	3T
5	0.699	96	0.775	584	Symphony^{^b}	1.5T
6	0.743	121	0.838	129	Espree^{^b}	1.5T
Average	0.663	134	0.926	356

Note:—DRN indicates diffusion restricted necrosis; Nvox, number of voxels; HypCel, hypercellular.
↵a GE Healthcare, Milwaukee, Wisconsin.
↵b Siemens, Erlangen, Germany.