Hypoxia in cervical cancer: from biology to imaging

Abstract

Purpose: Hypoxia imaging may improve identification of cervical cancer patients at risk of treatment failure and be utilized in treatment planning and monitoring, but its clinical potential is far from fully realized. Here, we briefly describe the biology of hypoxia in cervix tumors of relevance for imaging, and evaluate positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques that have shown promise for assessing hypoxia in a clinical setting. We further discuss emerging imaging approaches, and how imaging can play a role in future treatment strategies to target hypoxia.

Methods: We performed a PubMed literature search, using keywords related to imaging and hypoxia in cervical cancer, with a particular emphasis on studies correlating imaging with other hypoxia measures and treatment outcome.

Results: Only a few and rather small studies have utilized PET with tracers specific for hypoxia, and no firm conclusions regarding preferred tracer or clinical potential can be drawn so far. Most studies address indirect hypoxia imaging with dynamic contrast-enhanced techniques. Strong evidences for a role of these techniques in hypoxia imaging have been presented. Pre-treatment images have shown significant association to outcome in several studies, and images acquired during fractionated radiotherapy may further improve risk stratification. Multiparametric MRI and multimodality PET/MRI enable combined imaging of factors of relevance for tumor hypoxia and warrant further investigation.

Conclusions: Several imaging approaches have shown promise for hypoxia imaging in cervical cancer. Evaluation in large clinical trials is required to decide upon the optimal modality and approach.

Keywords: Cervical cancer; Hypoxia; Imaging; Magnetic resonance imaging; Positron emission tomography; Treatment outcome.

Fig. 1

Comparison of 60CU-ATSM and 18F-FDG uptake in a hypoxic and normoxic cervix tumor. Upper hypoxic tumor. Sagittal 18F-FDG PET/CT image (right) of pelvis, showing high 18F-FDG uptake in tumor. Sagittal 60Cu-ATSM PET image coregistered with CT image (left) at same level, also showing high tumor uptake of this tracer (T/M = 4.5). Lower normoxic tumor. Sagittal 18F-FDG PET/CT image (right) of pelvis, showing high 18F-FDG uptake in tumor. Sagittal 60Cu-ATSM PET image coregistered with CT image (left) at same level, showing only mildly increased tumor uptake of this tracer (T/M = 3.0). Note that there are different patterns of 18F-FDG and 60Cu-ATSM uptake in both tumors. P tumor, B bladder. This research was originally published in JNM [62]. © by the Society of Nuclear Medicine and Molecular Imaging, Inc

Fig. 2

DCE-MRI parameter A_Brix in relationship to hypoxia gene expression and chemoradiotherapy outcome in cervical cancer. a Tumor A_Brix map superimposed on axial T2-weighted MR image of two different patients with more hypoxic (left) and less hypoxic (right) tumor. The color scale indicates A_Brix values in the range from 0 to ≥5.0. b Unsupervised clustering of 46 patients based on the expression of 31 hypoxia responsive, A_Brix-associated genes (left). Box plot of A_Brix for the two patient groups identified by clustering, displaying lower A_Brix in cluster with high gene expression (right). c Kaplan–Meier curves for progression-free survival of 78 patients with low (below median) and high (above median) A_Brix. P value from log-rank test and number of patients are indicated Reproduced with permission from Halle et al. [46]

Fig. 3

Changes in cervix tumor hypoxia by the angiogenesis inhibitor sorafenib, assessed by DCE-MRI parameter K^trans. Late-phase axial DCE-MR T1 image of pelvis (upper) and the corresponding tumor K^trans maps (lower) superimposed on the late-phase DCE-MR T1 image at baseline before any treatment (day −7; left) and after 7 days of sorafenib alone (day 0; right). Note the decrease in K^trans after sorafenib treatment. B bladder, R rectum, T tumor Reproduced with permission from Milosevic et al. [8]