. 2017 Jan 25;7:10. doi: 10.3389/fonc.2017.00010

Table 1.

Oxymetric studies linking hypoxia and radiation therapy outcome.

Oxymetric technique	Animal studies	Reference	Clinical studies	Reference	Cross-validation with quantitative oxymetric methods?	Reference
Eppendorf electrodes	C3H mammary tumors: significant difference in local tumor control between the fraction of hypoxic values (<2.5 mmHg) and less hypoxic tumors	(36)	Prostate cancer study (n = 57): 8-year survival is 78% for moderately hypoxic tumors and 46% for severe hypoxic tumors	(16)	n.a.

			Head and neck cancer study (n = 35): 2-year locoregional control is two times lower for hypoxic tumors (i.e., with 15% of readings <2.5 mmHg)	(15)

PET ¹⁸F-MISO	FaDu hSCC xenografts: prognostic value of pretreatment ¹⁸F-MISO hypoxic volume; SUVmax was not associated with local control	(25)	5 head and neck studies (n = 45; 73; 12; 17; 15)	(21, 24, 26, 27, 29)	Mixed results	(23)
PET ¹⁸F-MISO		(25)	4 studies reported correlation between ¹⁸F-MISO hypoxia and outcome 1 study reported a lack of correlation	(21, 24, 26, 27, 29)	Lack of correlation with Eppendorf measurements in head and neck tumors	(23)

PET ¹⁸F-FAZA	Rhabdomyosarcoma: lower uptake linked to better local tumor control at 90 days post-irradiation	(36)	Head and neck cancer study: DAHANCA trial (n = 40), high tumor uptake is correlated to lower disease-free survival	(38)	Positive results	(38)
PET ¹⁸F-FAZA		(36)		(38)	Validated with EPR oximetry in the preclinical setting (rat rhabdomyosarcomas)	(38)

	9L glioma and rhabdomyosarcoma: significant correlation between ¹⁸F-FAZA T/B and tumor growth delay	(37)

PET ¹⁸F-FETNIM			1 head and neck cancer study (n = 21)	(21)	NO (but compared with other nitroimidazoles)	(44, 45)
			2 lung cancer studies (n = 26; 32)		Comparison with F-MISO: positive response under hyperoxic breathing challenge in C3H murine tumors Comparison with FAZA: positive correlation in murine mammary tumors
			1 cervical cancer study (n = 16)
			1 esophageal cancer study (n = 28)
			High fractional hypoxic volumes, uptake, or baseline SUVmax correlated with PFS, OS, or clinical response

PET ⁶⁰CU-ATSM	Canine sinonasal tumors: lack of correlation between Cu-ATSM uptake and outcome	(51)	3 cervical cancer studies (n = 14; 15; 38)	(21, 48–50)	Mixed results	(40, 57–63)
			2 head and neck cancer studies (n = 15; 11)		Comparison with F-MISO, EF5, or pimonidazole: no link with hypoxia in different tumor models or in response to hyperoxic challenges Comparison with Eppendorf electrodes: correlation with hypoxia in FaDu tumors but not in HT29 tumors
			3 lung cancer studies (n = 19; 22; 7)		Potential link with tumor redox status
			1 rectal cancer study (n = 19)
			Tumor uptake is inversely related to PFS or disease specific free survival Hypoxic tumor volume and hypoxic burden (=HTV × SUVmean) related to PFS

Dynamic contrast-enhanced magnetic resonance imaging	Melanoma xenografts: low k^trans is correlated with increased radioresistance	(78)	Cervical cancer study: k^trans and A_Brix parameters correlated with poor outcome	(80)	Mixed results	(82)
Dynamic contrast-enhanced magnetic resonance imaging		(78)		(80)	Comparison with Eppendorf electrodes: correlation between max DCE signal enhancement and median pO₂ in cervical cancer patients	(82)

	Cervical cancer xenografts: basal k^trans correlated to the outcome of RT; skewness (heterogeneity) in k^trans distribution correlated with poorer outcome	(79)			Comparison with pimonidazole Correlation between “poor perfusion” parameters and hypoxia (pimonidazole staining) in head and neck cancer patients Lack of correlation in glioma mice xenografts and glioma patients	(83, 84)

	Mouse fibrosarcoma: none of the tested DCE parameters (k^trans, v_p, K_ep, % of perfused voxels) were related to RT outcome	(69)

$R_{2}^{} - T_{2}^{}$	G3H prolactinomas (rats)	(100)	Cervical cancer study: basal $R_{2}^{*}$ was predictive for RT response	90	Mixed results	(96–98)
	RIF-1 fibrosarcomas (mice)				Lack of quantitative relationship between fluorescence quenching fiber optic probes pO₂ values and $Δ T_{2}^{}$ values Correlation between pimonidazole and high $R_{2}^{}$ in prostate cancer Inverse correlation between pimonidazole and $R_{2}^{*}$ in mammary tumors
	$Δ R_{2}^{}$ was predictive for a transient reduction in tumor size; low baseline $R_{2}^{}$ was linked to a small reduction in tumor size

R₁–T₁ of water protons	Dunning R3327-AT1 rat prostate	(92)			Mixed results
R₁–T₁ of water protons	A large increase in R₁ response to hyperoxic challenge was linked to a longer tumor growth delay after radiation therapy	(92)			No study addressing potential correlations between R₁–T₁ and quantitative pO₂ measurements

R₁–T₁ of lipid protons	9L glioma	(101)			Mixed results	(101, 123)
R₁–T₁ of lipid protons	Water and lipids T₁ are less predictive of RT outcome than $R_{2}^{*}$ in this model	(101)			Comparison with EPR oximetry Positive correlation in mammary tumors Lack of correlation in rat rhabdomyosarcoma and 9L glioma	(101, 123)

Combined R₁ and $R_{2}^{*}$ MRI	Dunning rat prostate tumors	(121)
Combined R₁ and $R_{2}^{*}$ MRI	Useful factors to predict tumor response to hypofractionation	(121)

EPR oximetry	C6 and 9L glioma	(151)
EPR oximetry	pO₂ assessed after a first course of RT was a prognostic indicator of differential response to RT between the two glioma models	(151)

	TLT and FSaII syngeneic tumors	(69, 76, 130, 132, 136–146, 148)
	pO₂ assessed during/after administration of treatments able to alleviate tumor oxygenation was predictive of the outcome of RT when administered during this window of reoxygenation	(69, 76, 130, 132, 136–146, 148)