PET imaging of hypoxia using [18F]HX4: a phase I trial

Abstract

Background and purpose Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [ 18 F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging. Methods Patients with a histologically proven solid cancer without curative treatment options were eligible for this study. A study design with two dose steps was used in which a single dose of a maximum of 222 MBq (step 1) or 444 MBq (step 2) [ 18 F]HX4 was injected. Toxicity was scored on day 0 and on days 3 and 7 after injection, according to the CTCAE 3.0 scoring system. PET/CT images of the largest tumour site were acquired 30, 60 and 120 min after injection. Results Six patients with stage IV carcinoma were included, four with non-small-cell lung carcinoma, one with thymus carcinoma, and one with colon carcinoma. No toxicity was observed in any of the patients at either dose level. The median tumour to muscle ratio 120 min after injection was 1.40 (range 0.63-1.98). Conclusion The findings of this study showed that [ 18 F] HX4 PET imaging for the detection of hypoxia is not associated with any toxicity. Imaging was successful; however, future trials are needed to determine the optimal image parameters.

TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18F]HX4 Hypoxia PET Imaging

“…Tracer synthesis of [ 18 F]HX4 was performed as described previously (14). [ 18 F]HX4 PET images were acquired and analyzed using a clinical PET/CT scanner (Siemens Biograph 40, Siemens Healthcare) as previously described (13).…”

PET of Hypoxia: Current and Future Perspectives

“…An early clinical study using 18 F-fluoromisonidazole in a diverse range of tumor types found that, using this criterion to define hypoxia, 36 of 37 contained a measurable fractional hypoxic volume (2). An important caveat associated with these low tumor-to-blood ratios is that they are not entirely unexpected.…”

“…These staining patterns suggest that individual PET voxels consist of far less than 100% hypoxic elements-typically 5%-30%. Thus, 18 F-fluoromisonidazole uptake within a hypoxic tumor voxel consisting of 20% hypoxia plus 80% normoxic tissue would not be expected to yield a ratio of 6:1 but only 2:1 (0.2 · 6 1 0.8 · 1 5 2.0). By comparison, the large uptake ratio between tumor and muscle seen with 18 F-FDG is a consequence of every tumor cell, rather than a fraction, exhibiting facilitated uptake and entrapment.…”

“…These investigators pioneered the synthesis of 18 F-fluoromisonidazole and subsequently demonstrated the feasibility of 18 F-fluoromisonidazole PET for imaging the hypoxic fractions of a variety of tumors in humans. After intravenous injection, 18 F-fluoromisonidazole clears from the blood compartment relatively slowly and traverses tissue by passive diffusion. Because of these characteristics, PET protocols require imaging between 2 and 3 h after injection.…”

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

“…18 F-FAZA imaging provides similar hypoxia information to 18 F-FMISO, which may be helpful for therapy planning [96]. In addition, Lehtiö et al [97] [103,104]. Cu(II)-ATSM, a neutral lipophilic molecule, is another alternative PET probe for hypoxia imaging based on a metal complex of radioactive copper with ATSM, diacetylbis(N4-methylthiosemicarbazone), which is highly membrane permeable.…”