Table 5.

Hypoxia Modification Trials, Including Trials with Hypoxia Stratification

Study ID (cancer type)	N	Hypoxia stratification	Tx	Findings	P-value or relative risk
(I) Nitroimidazole-sensitizer meta analysis(213) (bladder, cervix, head and neck, lung, esophagus, CNS)	7000	None	RT±Hypoxic sensitizer	LRC OR: 1.17	0.005
				OS OR: 1.13	0.02
(J) Hypoxia modification therapy meta-analysis (214) (head and neck)	4805	None	RT±hypoxia modifier: Normobaric O2 Hyperbaric O2 Hypoxic sensitizer	LRF OR: 0.71	<0.001
				DSD OR: 0.73	<0.001
				OD OR: 0.87	<0.001
				DM OR: 0.87	ND
(K) DAHANCA (82, 215, 216, 268) (head and neck)	422	None	RT±Nimorazole	5 year LRC: 33% (PL) vs. 49% (NM)	0.002
				10 year OS: 16% (PL) vs. 26% (NM)	0.32
	320	OPN: high (>167 g/L) moderate (69–166 g/L) low (<68 g/L)		High OPN
				5 year LRTF: 79% (PL) vs. 42% (NM)	0.19 RR (95% CI 0.08–0.44)
				5 year DSM: 79% (PL) vs. 49% (NM)	0.25 RR (95% CI 0.11–0.59)
	386	CA-IX: CA-IX<1% CA-IX 1%–10% CA-IX 10%–30% CA-IX>30%		5 year LRC
				CA-IX<1%: 35% (PL) vs. 47% (NM)	0.2
				CA-IX 1%–10%: 36% (PL) vs. 54% (NM)	0.4
				CA-IX 10%–30%: 31% (PL) vs. 47% (NM)	0.2
				CA-IX>30%: 40% (PL) vs. 43% (NM)	0.2
	414	Genetic profiling “more hypoxic” (35% of the patients) “less hypoxic” (65% of the patients)		“More hypoxic” group
				5 year LRC: 18% (PL) vs. 49% (NM)	0.001
				5 year DSS: 30% (PL) vs. 40% (NM)	0.04
				More hypoxic group, HPV+:
				5 year LRC: 47% (PL) vs. 62% (NM)	0.55
				More hypoxic group, HPV−
				5 year LRC: 9% (PL) vs. 43% (NM)	0.002
(L) Trans-Tasman TROG 98.02 Phase II (229, 230)	122	None	Arm 1: Cisplatin and radiotherapy plus 5-fluorouracil Arm 2: TPZ with chemoradiotherapy (cisplatin)	3 year FFS: 44% (R+C) vs. 55% (TPZ)	0.16
				3 year LRF 66% (R+C) vs. 84% (TPZ)	0.069
	45	18F-FMISO: signal scored 0 through 4 based on focal uptake relative to background	Hypoxic patients
				Increased LRF for R+C (HR=7.1)	0.038
				Increased LRF: R+C vs. TPZ (HR=15)	0.001
				Shorter FFS for R+C (HR=3.2)	0.095
				Increased risk of failure/death: R+C vs. TPZ (HR=4.7)	0.004
				Shorter OS: R+C vs. TPZ (HR=2.45)	0.11
(M) TROG 02.02 HeadSTART Phase III (175, 232)	861	None	Arm 1: Cisplatin and radiotherapy plus 5-fluorouracil Arm 2: TPZ with chemoradiotherapy (cisplatin)	2 year OS: 65.7% (R+C) vs. 66.2% (TPZ)	0.53
				2 year FFS: 57% (R+C) vs. 56% (TPZ)	0.96
				2 year LRFF: 74% (R+C) vs. 75% (TPZ).	0.44
	578	OPN: high (>711 ng/ml), middle (407–710 ng/ml) and low (<407 ng/ml)		Highest OPN tertile:
				2 year OS: 66% (R+C) vs. 67% (TPZ)	0.67
				LRFF HR: R+C vs. TPZ=0.84	0.57
(N) ARCON Phase III (131)	345	None	Accelerated radiotherapy (AR)±ARCON	2 year LRC: 80% (AR) vs. 83% (ARCON)	0.80
				5 year LRC: 78% (AR) vs. 79% (ARCON)	0.80
				2 year RC: 88% (AR) vs. 95% (ARCON)	0.04
				5 year RC: 86% (AR) vs. 93% (ARCON)	0.04
				DFS (HR: 0.75, 95% CI, 0.50–1.13)	0.16
				OS (HR: 1.03, 95% CI, 0.73–1.46)	0.86
	79	Pimonidazole: 2.6% cut-off for hypoxia		RC (hypoxic tumors):
				55% (AR) vs. 100% (ARCON)	0.01
				RC (normoxic tumors):
				92% (AR) vs. 96% (ARCON)	0.7
				5 year DFS (hypoxic tumors):
				40% (AR) vs. 86% (ARCON)	0.08

ARCON, accelerated radiotherapy with carbogen and nicotinamide; OR, odds ratio; LRF, locoregional failure; DSD, disease-specific death; DSS, disease-specific survival; OD, overall death; DM, distant metastasis; LRTF, locoregional tumor failure; DSM, disease-specific mortality; HPV, human papillomavirus; ¹⁸F-FMISO, ¹⁸F-fluoromisonidazole; FFS, failure-free survival; LRFF, locoregional failure free; RC, regional control; RR, relative risk; PL, placebo; AR, accelerated radiotherapy; R, radiation; R+C, radiation plus chemotherapy; NM, nimorazole; RT, radiotherapy; TPZ, tirapazamine; OPN, osteopontin; CA-IX, carbonic anhydrase IX.