The clinical importance of assessing tumor hypoxia: relationship of tumor hypoxia to prognosis and therapeutic opportunities

Abstract

Tumor hypoxia is a well-established biological phenomenon that affects the curability of solid tumors, regardless of treatment modality. Especially for head and neck cancer patients, tumor hypoxia is linked to poor patient outcomes. Given the biological problems associated with tumor hypoxia, the goal for clinicians has been to identify moderately to severely hypoxic tumors for differential treatment strategies. The "gold standard" for detecting and characterizing of tumor hypoxia are the invasive polarographic electrodes. Several less invasive hypoxia assessment techniques have also shown promise for hypoxia assessment. The widespread incorporation of hypoxia information in clinical tumor assessment is severely impeded by several factors, including regulatory hurdles and unclear correlation with potential treatment decisions. There is now an acute need for approved diagnostic technologies for determining the hypoxia status of cancer lesions, as it would enable clinical development of personalized, hypoxia-based therapies, which will ultimately improve outcomes. A number of different techniques for assessing tumor hypoxia have evolved to replace polarographic pO2 measurements for assessing tumor hypoxia. Several of these modalities, either individually or in combination with other imaging techniques, provide functional and physiological information of tumor hypoxia that can significantly improve the course of treatment. The assessment of tumor hypoxia will be valuable to radiation oncologists, surgeons, and biotechnology and pharmaceutical companies who are engaged in developing hypoxia-based therapies or treatment strategies.

FIG. 1.

Regulation of HIF-1α and protein signaling under normoxic and hypoxic conditions. Adapted from Xia et al. (294) and Collet et al. (50). AKT, protein kinase B; CBP/p300, CREB-binding protein/E1A binding protein p300; ERK, extracellular signal-regulated kinase; FH, fumarate hydratase; FIH-1, factor inhibiting HIF1; GLUT-1, glucose transporter 1; HIF-1α, hypoxia-inducible factor 1α; HIF-1β, hypoxia-inducible factor-1β; HRE, HIF-responsive element; LOX, lysyl oxidase; MEK, MAPK/ERK kinase; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; OPN, osteopontin; p53, tumor protein 53; PHD, prolyl hydroxylase domain containing protein; PI3K, phosphoinositide 3 kinase; PTEN, phosphatase and tensin homolog; Raf, serine/threonin-specific protein kinase; RAS, rat sarcoma; ROS, reactive oxygen species; SDH, succinate dehydrogenase; STAT3, signal transducer and activator of transcription 3; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; VHL, von Hippel-Lindau tumor suppressor; Ub, ubiquitylation.

FIG. 2.

The downstream expression of hypoxia proteins supporting the various stages of metastatic spread. VEGFA, vascular endothelial growth factor A; SNAIL, snail family zinc finger 1; TWIST, class A basic helix-loop-helix protein 38.

FIG. 3.

Predictive power of Eppendorf Histograph for 1 year survival after beginning of the radiotherapy (236). See Figure 5 for the definition of hypoxia threshold. PPV, positive predictive value; NPV, negative predictive value.

FIG. 4.

Hypoxia imaging methods and the type of information provided by each modality. BOLD MRI, blood oxygen level-dependent magnetic resonance imaging; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; EPR, electron paramagnetic resonance; HIF-1α, hypoxia-inducible factor 1α; NIRS, near-infrared spectroscopy; OMRI, Overhauser-enhanced MRI; PALI, photoacoustic lifetime imaging; PAT, photoacoustic tomography; PET, positron emission tomography; PIMO, pimonidazole.

FIG. 5.

pO₂ pressure data represented in histograph form. (A) The percent frequency of pO₂ pressures as measured in an individual head and neck cancer patient. Reprinted by permission from Lartigau et al. (158); (B) HP_2.5 distribution in the population. The hypoxic threshold is upper limit of the hypoxic range below which cellular, tissue, or organ function becomes progressively restricted (122). Reprinted by permission from Terris (262). HP_2.5, hypoxic fraction below 2.5 mmHg.

FIG. 6.

Schematic of the selective PET tracer uptake of hypoxia imaging agents in hypoxic cells. Under hypoxic conditions, accumulated 2-nitroimidazole metabolites bind to intracellular thiol-rich proteins, while reduced copper species lose their chelator and become trapped intracellularly.

FIG. 7.

¹⁸F-Tracers for PET hypoxia imaging grouped by parent radiosensitizers. ¹⁸F-EF1, monofluorinated etanidazole; ¹⁸F-EF3, trifluorinated etanidazole; ¹⁸F-EF5, pentafluorinated etanidazole; ¹⁸F-FAZA, ¹⁸F-fluoroazomycinarabinofuranoside; ¹⁸F-FENI, 1-(2-[¹⁸F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole; ¹⁸F-FETA; ¹⁸F-fluoroetanidazole; ¹⁸F-FETNIM, ¹⁸F-fluoroerythronidazole; ¹⁸F-HX4, ¹⁸F-flortanidazole.

FIG. 8.

Correlation between ¹⁸F-FMISO tumor-to-muscle ratio and electrode measurements. Reprinted by permission from Gagel et al. (96).

FIG. 9.

From left to right: transaxial ¹⁸F-FDG PET; transaxial ¹⁸F-FMISO PET of head and neck tumors. (A) normoxic (HP_2.5=13.0%; ¹⁸F-FDG_SUVmean=14.80; ¹⁸F-FMISO_T/M=1.31). (B) hypoxic (HP_2.5=37.7%; ¹⁸F-FDG_SUVmean=8.00; ¹⁸F-FMISO_T/M=1.60). Reprinted by permission from Gagel et al. (95). ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; HP_2.5, hypoxic fraction below 2.5 mmHg; SUV, standard uptake value; T/M, tumor to muscle ratio.

FIG. 10.

Danish head and neck cancer group's (DAHNCA) protocol 5 study design. Reprinted by permission from Overgaard et al. (215).

FIG. 11.

Primary outcomes by treatment group and concentration of osteopontin. Low (A); Intermediate (B); and High osteopontin (C). Reprinted by permission from Overgaard et al. (215).

FIG. 12.

DAHANCA patients stratified by hypoxia status as determined by a panel of markers. Reprinted by permission from Toustrup et al. (268).

FIG. 13.

Correlation between hypoxia [more hypoxic (A, C) vs. less hypoxic (B, D)] and HPV [HPV-pos (A, B) vs. HPV-neg (C, D)] status in head and neck tumors. Reprinted by permission from Toustrup et al. (268). HPV, human papillomavirus.

FIG. 14.

TPZ treated and untreated patients stratified by the hypoxia status as imaged by ¹⁸F-FMISO. Reprinted by permission from Rischin et al. (229). TPZ, tirapazamine.

FIG. 15.

Kaplan–Meier curves for mixed population, normoxic patients, and hypoxic patients only. ¹Hypoxia information was not used in these analyses. ²Patients were assigned their hypoxia status based on PIMO staining from tumor biopsy samples. Reprinted by permission from Janssens et al. (131). AR, accelerated radiotherapy; ARCON, accelerated radiotherapy with carbogen and nicotinamide.