In vivo assessment of hypoxia in gastro-intestinal cancer using 18F-HX4-PET: an optimization and reproducibility study

Several studies have shown that tumour hypoxia may have a negative impact on
the outcome of anticancer treatment. Assessment of tumor hypoxia at baseline or
shortly after start of treatment may serve as a predictive marker to determine
treatment efficacy at an early stage. Preferably, such an assessment is
performed in vivo and non-invasively.Non-invasive imaging with positron
emission tomography (PET) using the 2-nitroimidazole nucleoside analogue,
3-18F-fluoro-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-
yl)propan-1-ol (18F-HX4), was tested as a new marker of tumor hypoxia. Before
hypoxia-measurements can be clinically implemented for response prediction, the
reproducibility of the technique should be assessed for each specific tumor
type. Knowledge of reproducibility is needed to determine what change in
parameters between two examinations can be considered relevant in an individual
patient. Assessment of reproducibility becomes even more important in early
response monitoring since the changes in the tumor induced by the treatment may
be smaller during the treatment compared to response monitoring after
completion of treatment. Also, as image quality of 18F-HX4-PET increases with
increasing time intervals after injection, determination of the optimal time
point for measurement of hypoxia is warranted.

In this study, we first intend to investigate the optimal time point for
measurement of hypoxia in esophageal, pancreatic and rectal cancer using
18F-HX4-PET and then assess reproducibility of hypoxia measurements in these
tumor types.

In this study two steps will be taken.
1) First, as 18F-HX4-PET image quality may improve when allowing for relatively
longer time intervals after injection, in three patients with esophageal,
pancreatic or rectal cancer 18F-HX4-PET scans will be performed 90, 180 and 240
minutes after injection of 18F-HX4. The time-point with the best image quality
(in terms of tumor-to-background-ratio) will be chosen for the reproducibility
study.
2) In the second step, patients with proven esophageal, pancreatic or rectal
cancer will undergo an 18F-HX4-PET twice within one week before start of
treatment. 18F-HX4-PET will be performed at 90, 180 or 240 minutes after
injection of 18F-HX4, depending on the results of the first part of the study.
Reproducibility of hypoxia measured by 18F-HX4-PET will be assessed. In those
patients for whom tumor tissue is available which has not been treated with
radiation or chemotherapy, levels of hypoxia measured by 18F-HX4-PET will be
compared with endogenous hypoxia markers (HIF1-alfa, CA9, GLUT1, PAI-1, VEGF)
using immunohistochemistry. In those patients that underwent 18F-HX4-PET before
start of neoadjuvant treatment, levels of hypoxia measured by 18F-HX4-PET will
be compared to pathological response after neoadjuvant treatment.

The patient will not have a direct benefit from the study The proposed 18F-HX4
dose is chosen based on the phase 1 study with 18F-HX4.22 In this phase I study
no toxicities were observed except for a mild, grade I headache one day after
18F-HX4 injection, which was considered unlikely to be related to the
injection. In view of previous experiences with 18F-HX4, conventional PET-CT
and other nitroimidazole drugs, we expect no unforeseen side effects.
Nevertheless, it cannot be excluded that patients will experience an acute
allergic reaction to 18F-HX4. Therefore, all patients will be monitored
carefully during and directly after administration of the labelled 18F-HX4 by
trained caregivers.
Participation in the study will involve radiation exposure which is
estimated to be maximally 12,4 mSV for the two scans together. The theoretical
chance for radiation induced cancer induction is 5% per Sievert. For a
radiation exposure of 10 mSv this implies a chance of 1 in 2000. This number
applies to patients of 30 years old. The risk reduces with ~50% for a typical
oncological population of patients aged 55-70 years. Moreover, all patients
with rectal cancer and esophageal cancer in this protocol will be treated with
radiotherapy according to the current clinical guidelines. Radiation exposure
due to the 18F-HX4 scans is negligible compared to radiation exposure because
of the clinically indicated radiotherapy.
Finally, patients will have to come to the hospital twice for a
18F-HX4-PET scan. One hour after injection of 18F-HX4 patients will be scanned
for approximately 15 minutes. The total extra time spent in the hospital will
be ~4 hours at most on two separate days.