. 2015 Feb 23;33(10):1197–1213. doi: 10.1200/JCO.2014.55.9575

Table 5.

Potential Imaging Biomarkers of Antiangiogenic Therapy in Glioblastoma

Drug	Combination	Disease Type	No. of Patients	Imaging Modality	Technique	Response Biomarker^*	Day(s) of Imaging	Reference
Bevacizumab	—	rGBM	16	MRI	DSC	↓CBV_HPV^†	42	Sawlani et al⁹⁴
Bevacizumab	—	rGBM	9	MRI	DWI	↓ADC ↓RSI	16-112	Kothari et al¹⁵⁶
Bevacizumab	Irinotecan	rGBM	14	MRI	DSC	↓CBV	56	Reiger et al¹⁸¹
Bevacizumab	Irinotecan	rGBM	42	MRI	DSC	↑CBV^†	56	Eoli et al¹⁹
Bevacizumab	Irinotecan	rGBM	20	MRI	DCE	↓K_trans ↓V_e	1-14 1	Ferl et al¹⁸²
Bevacizumab	Irinotecan	rGBM	20	MRI	DCE	↓K_trans ↓V_e	1-14 1	Hsu et al¹⁸⁷
Bevacizumab	Irinotecan	rGBM	13	MRI	DCE	↓K_trans	1-14	Desjardins et al¹⁸⁸
Bevacizumab	Irinotecan	rGBM	41^§	MRI	DWI	↑ADC_L^†	baseline	Pope et al¹⁸⁹
Bevacizumab	Irinotecan	rGBM	14	MRI	DWI	↓ADC	56	Rieger et al¹⁸¹
Bevacizumab	Irinotecan	rGBM	16^‡	MRI	DWI	↑ADC_NEL^†	42	Jain et al¹⁸³
Bevacizumab	Irinotecan	rGBM	6	MRI	DWI	↑ADC_hist^†	56-84	Nowosielski et al¹⁸⁴
Bevacizumab	Irinotecan	rGBM	16	MRI	DWI	↓fDM^†	30-90	Ellingson et al^189a,189b
Bevacizumab	Irinotecan	rGBM	70^‡	MRI	DWI	↓fDM^†	30-90	Ellingson et al^189a,189b
Bevacizumab	Irinotecan	rGBM	22	MRI	DWI	↓L_ADC^†	40	Hwang et al^189c
Bevacizumab	Irinotecan	rGBM	13^‡		MRS	↑NAA/Cho^† ↓Cho/Cr^† ↑NAA/Cr^†	56-168	Ratai et al¹⁸⁶
							112
							112
Bevacizumab	Irinotecan	rGBM	41	MRI	DWI	↑ADC_L^†	baseline	Pope et al¹⁵⁵
Bevacizumab	Irinotecan	rGBM	36^‡^§	CT	Cal	→ Not present^†	56	Bähr et al¹²²
Bevacizumab	Irinotecan	rGBM	17	PET	[¹⁸F]-FLT	↓SUV^†	7-49	Chen et al et al¹⁹⁰
Bevacizumab	Irinotecan	rGBM	11	PET	[¹⁸F]-FLT	↓SUV^†	7-49	Schiepers et al¹⁹¹
Bevacizumab	Irinotecan	rGBM	16	PET	[¹⁸F]-FLT	↓SUV^†	7-49	Wardak et al¹⁹²
Bevacizumab	Irinotecan	rGBM	24^‡	PET	[¹⁸F]-FLT	↓SUV^†	7-49	Schwarzenberg et al¹³⁴
Bevacizumab	Irinotecan	rGBM	18^‡	PET	[¹⁸F]-FLT	↓SUV^†	7-49	Harris et al¹³⁵
Bevacizumab	Irinotecan	rGBM	5	PET	[¹⁸F]-FET	↓SUV^†	56-96	Hutterer et al¹⁹³
Bevacizumab	Irinotecan	rGBM	5	PET	[¹⁸F]-FET	↓SUV_vol^†	20	Galldiks et al¹⁹⁵
Bevacizumab	Irinotecan	rGBM	20	PET	[¹⁸F]-FDG	↓SUV_max^†	baseline	Colavolpe et al¹⁹⁴
Bevacizumab	Irinotecan	rGBM	18^‡	PET	[¹⁸F]-FDOPA	↓SUV^†	7-49	Harris et al¹³⁵
Bevacizumab	Fotemustine	rGBM	9^‡	CT	PCT	↓CBV	21	Vidiri et al¹⁹⁶
Bevacizumab	Carboplatin	rGBM	26^‡	MRI	DQT₂	↓ΔT₂^†	28-42	Ellingson et al^196a
Bevacizumab	Temozolomide	rGBM	27^‡	MRI	DSC	↓CBV	60	Gupta et al¹⁹⁷
Bevacizumab	Temozolomide	rGBM	23^§	MRI	DSC	↓ΔAVOL^†	38	LaViolette et al¹⁹⁹
Bevacizumab	Temozolomide	rGBM	14^‡	MRI	DWI	→RDL (yes)^†	baseline, control	Mong et al¹⁹⁸
Bevacizumab	Temozolomide	nGBM	40^§	MRI	DSC	↓CBV	42-120	Grommes et al²⁰⁰
Bevacizumab	Temozolomide	nGBM	56^§	MRI	DWI	↓ADC_L^†	baseline, control	Pope et al^200a
Bevacizumab	Temozolomide	nGBM	40^§	MRI	[¹⁸F]-FDG	↓SUV^†	180	Grommes et al²⁰⁰
Cediranib	—	rGBM	16	MRI	DSC	↓CBV	1-28	Batchelor et al³²
Cediranib	—	rGBM	30	MRI	DSC	↑CBV^† ↑CBF^†	1	Sorensen et al¹⁷
Cediranib	—	rGBM	30	MRI	DSC	↑CBV^† ↑CBF^†	1-56	Sorensen et al¹⁷
Cediranib	—	rGBM	16	MRI	DSC	↓VCI^†	1	Batchelor et al³²
Cediranib	—	rGBM	30	MRI	DSC	↓VCI^† ↑VNI^†	1	Sorensen et al⁹²
Cediranib	—	rGBM	30	MRI	DSC	↓VCI^† ↑VNI^† ↑A/V^† ↓ΔSO₂^†	1	Emblem et al^151,200b
							1
							1-56
							1-56
Cediranib	—	rGBM	30	MRI	DCE	↓K_trans^†	1-112	Sorensen et al⁹²
Cediranib	—	rGBM	16	MRI	DCE	↓K_trans^† ↓V_e	1-112 1-56	Batchelor et al³²
Cediranib	—	rGBM	30	MRI	DCE	↓K_trans^†	1-112	Gerstner et al¹⁵⁹
Cediranib	—	rGBM	30	MRI	ASL	↑CBF^†	1-56	Sorensen et al¹⁷
Cediranib	—	rGBM	30	MRI	MRS	↑NAA/Cho^†	1-56	Kim et al³⁸
Cediranib	—	rGBM	30	MRI	DWI	↓ADC	1-112	Batchelor et al³²
Cediranib	—	rGBM	30	MRI	DWI	↓ADC	1-112	Gerstner et al¹⁵⁹
Cediranib	—	rGBM	30	MRI	DWI	↑ADC_sub^†	1-112	Gerstner et al¹⁵⁹
Cediranib	Temozolomide	nGBM	40^§	MRI	DSC	↑CBF^† ↓VCI ↓ΔSO₂^†	1-50	Batchelor et al¹⁶
Cediranib	Temozolomide	nGBM	40^§	MRI	DSC	↓ΔSO₂^† ↓A/V^†	1-50	Emblem et al^200c
Cediranib	Temozolomide	nGBM	40^§	MRI	DSC	↓ΔSO₂^† ↓A/V^†	1-50, control	Emblem et al^200c
Cediranib	Temozolomide	nGBM	40^§	MRI	DCE	↓K_trans	1-50	Batchelor et al¹⁶
Cediranib	Temozolomide	nGBM	40^§	MRI	DWI	↓ADC	1-50	Batchelor et al¹⁶
Vatalanib	—	rGBM	47	MRI	DSC	↓CBV	2-30	Conrad et al¹⁸
Vatalanib	—	rGBM	47	MRI	DCE	↓K_trans	2-30	Conrad et al¹⁸
Ramucirumab	—	rGBM		MRI	DSC	↓CBV	1	O'Neill Blakeley et al²⁰²
Ramucirumab	—	rGBM		MRI	DWI	↓ADC	28	O'Neill Blakeley et al²⁰²
Cabozantinib	—	rGBM	38	MRI	DCE	↓K_trans	28	Sorensen et al^202a
Cabozantinib	—	rGBM	38	MRI	MRS	↑NAA/Cho ↓Lipids	28	Sorensen et al^202a
Pazopanib	—	rGBM	11	MRI	DSC	↓CBV^†	28-56	Iwamoto et al⁷⁵
Pazopanib	—	rGBM	11	MRI	DCE	↓K_trans^†	28-56	Iwamoto et al⁷⁵
Enzastaurin	Temozolomide	nGBM	35^§	MRI	DSC	↓PH^† ↑PR^†	60	Essok-Burns et al²⁰⁴
Enzastaurin	Temozolomide	nGBM	25^§	MRI	SWI	↑%SWI-h^†	baseline	Lupo et al²⁰³
Thalidomide	Carboplatin	rGBM	15	MRI	DSC	↓CBV	60	Cha et al²⁰⁵
Cilengitide	—	rGBM	24	MRI	DSC	↓CBF	56-280	Akella et al²⁰⁶
Cilengitide	—	rGBM	37	MRI	DSC	↓CBF	56-280	Nabors et al²⁰⁷
Olaratumab	—	rGBM	17	MRI	DSC	↓CBV	28	O'Neill Blakeley et al²⁰²
Sunitinib	—	rGBM	7	MRI	DSC	↓CBF	28	Chaskis et al¹³⁴
Sunitinib	—	rGBM	14	MRI	DSC	↓CBV ↓CBF	28 28	Neyns et al²⁰⁹
Aflibercept	—	rGBM	14	MRI	DCE	↓K_trans	1	De Groot et al⁶²

NOTE. ↑, increase; →, no change/presence; ↓, decrease.

Abbreviations: A/V, arteriovenous ratio; ADC, apparent diffusion coefficient; ADC_hist, ADC histogram features; ADC_L, lower curve mean of two-peak ADC histogram; ADC_NEL, ADC in nonenhancing lesion; ADC_sub, volume of subthreshold ADC in tumor; ASL, arterial spin labeling; Cal, calcifications; CBF, cerebral blood flow; CBV, cerebral blood volume; CBV_HPV, CBV hyperperfusion volume; Cho, choline; Cr, creatinine; CT, computed tomography; DCE, dynamic contrast-enhanced [MRI]; DQT₂, differential quantitative T₂ relaxometry mapping; DSC, dynamic susceptibility contrast [MRI]; DWI, diffusion weighted imaging; fDM, functional diffusion map; [¹⁸F]-FLT, [¹⁸F]fluorothymidine; [¹⁸F]-FET, O-(2-¹⁸F-fluoroethyl)-l-tyrosine; [¹⁸F]-FDG, [¹⁸F]fluorodeoxyglucose; [¹⁸F]-FDOPA, 3,4-dihydroxy-6-[¹⁸F]-fluoro-l-phenylalanine; K_trans, capillary permeability transfer constant; L_ADC, tumor ADC lower-than-normal cortex; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; NAA, N-acetylaspartate; nGBM, newly diagnosed glioblastoma; PCT, perfusion computed tomography; PET, positron emission tomography; PH, peak height of tissue relaxivity (a pseudoestimate of vascular density); PR, percent recovery of tissue relaxivity (a pseudoestimate of leakage); RDL, restricted-diffusion lesions with well-demarcated high signal intensity on DWI; rGBM, recurrent glioblastoma; RSI, restriction spectrum imaging; SUV, standardized uptake value (g/mL); SUV_vol, tumor volume by SUV; SWI, susceptibility-weighted imaging; SWI-h, fraction of SWI hypointensity in total contrast-enhanced volume; T₂, transverse (proton spin-spin) magnetic relaxation; VCI, vessel caliber imaging; V_e, extravascular extracellular space volume; VNI, vascular normalization index; ΔAVOL, change in arteriovenous overlap; ΔSO₂, change in relative oxygen saturation.

Limited to antiangiogenic studies reporting significant patient group effects from univariable advanced imaging parameters (beyond Macdonald's/RANO criteria) and compared with pretherapy baseline or controls.

^†

Response in a subgroup of patients with favorable outcome (radiologic response, progression-free survival, or overall survival).

^‡

Other combination drugs used in some patients.

^§

Radiotherapy.