Hypoxia Imaging With the Novel Radiopharmaceutical 18F Fluoroazomycin Arabinoside (FAZA)- Prognostic Impact in Cervical Cancer
Tumor hypoxia has been shown to be a prognostic factor for local progression and prognosis
in several types of human cancers (1-4), including cervical carcinoma (5). Distribution of
oxygen within a tumor can diminish toward the less vascularized center of the tumor (6, 7).
Hypoxia is an important factor in many pathological processes, including tumor formation,
where it has been associated with resistance to radiotherapy, malignant progression, and
metastasis. Although hypoxia is toxic to both cancer and normal cells, cancer cells undergo
genetic and adaptive changes that allow them to survive and even proliferate within a
hypoxic environment. These processes contribute to the malignant phenotype and to aggressive
Hypoxia has a negative effect on anti cancer treatment (8). Radiotherapy is a major
treatment modality for advanced cervical carcinomas and requires free radicals from oxygen
to destroy target cells, and cells in hypoxic areas were found to be resistant to
radiation-induced cell death (9). The gold standard for measuring hypoxia in tumors is the
invasive technique of using computerized oxygen-sensitive electrodes. This method is
cumbersome and expensive and has not become a general clinical tool for hypoxia measurement
Positron emission tomography (PET) becomes an interesting and promising diagnostic modality
for hypoxia imaging in tumor tissue. Several tracers were developed for this purpose and
Fluoromisonidazole (18FMISO) is the most extensively hypoxia tracer studied both in humans
and animals (12-15). Previous results for imaging hypoxia using FMISO showed the regional
distribution of tumor hypoxia, expressed as fractional hypoxic volume (16). However, its
major disadvantages lie on its slow clearance kinetics and its high lipophilicity.
18Ffluoroazomycinarabinofuranoside (18FAZA) is recently synthesized and introduced as a
hypoxia tracer in various tumor-bearing mice using PET and autoradiography with promising
results. (17). 18FAZA showed also superior biokinetics in comparison to 18F-MISO in animals
(18). The safety and feasibility of FAZA was evaluated recently in 10 patients with advanced
squamous cell carcinoma of the head and neck. The authors of this study concluded that PET
imaging with FAZA appears to be safe and feasible in patients with head and neck tumors.
Aim of the study
The aim of this study is to visualize the tumor hypoxic tissue, the potential quantitative
changes and the biological behavior of cervical carcinoma (primary and / or lymph nodes)
before, during and after radiochemotherapy with the novel hypoxia PET tracer 18FAZA.
Materials and methods
Twenty-five patients with cervical carcinoma (T2Nx or TxN1) will be included in the present
study. In addition to the routine pre-therapeutical staging of cervical cancer, 18FAZA PET
will be performed before, during the planed radio/chemotherapy (short before brachytherapy)
and 3 months after the therapy.
Synthesis and quality control 18FAZA (Research Center Seibersdorf)
18FMISO will be synthesized as previously described (20). The synthesis of 18F-FAZA will be
performed as follows (21):5 mg of the precursor
1-(2,3-diacetyl-5-tosyl-a-D-arabinofuranosyl)-2-nitroimidazole in 1 mL of dimethyl sulfoxide
were reacted with the mixture of azeotropically dried 18F-fluoride, 15 mg of Kryptofix
2.2.2. (Merck), and 3.5 mg of K2CO3 at 100C for 5 min. After hydrolysis with 1 mL of 0.1 N
NaOH (2 min,30C), 0.5 mL of 0.4N NaH2PO4 was added for neutralization. The product was
purified first using an alumina cartridge (Alu N light; Waters) and then high performance
liquid chromatography (HPLC) (Phenomenex Nucleosil C18; ethanol/NaH2PO4 buffer (5:95); flow,
4mL/min; detection ultraviolet (320nm), Na(Tl)). The product was obtained in radiochemical
yields of 20.7%+-3.5% (n=12) at end of the beam. After irradiations of 1 h at 35µA, 9.1
+-1.4GBq (n=8) 18FFAZA will be isolated.
[18F]FAZA PET imaging
18FFAZA imaging will be performed in all patients after overnight fasting on a dedicated
full ring PET scanner (Advance, General Electric Medical Systems, Milwaukee, WI). The
patients will be scanned subsequent to the administration of the activity (dynamic scan) and
2 hours afterwards (static scan). For each image acquisition a 10-min transmission scan will
be performed. All images will be acquired in a 3D-mode with a matrix of 128x128. The dynamic
scan (pelvis) begins with the intravenous administration of 370 MBq 18FFAZA. Over the first
hour 21 frames will be acquired (6 frames 20s, 6 frames 30s, 2 frames 150s, 4 frames 300s, 3
frames 600s). Two hours after the application a 10-min static scan (pelvis + abdomen) will
be acquired. The images are reconstructed using an iterative algorithm (OSEM). In addition
to visual interpretation of the acquired images a semi quantitative analysis will be
performed by drawing regions of interest (ROIs) in tumor tissue (primary and lymphnodes).
For these ROIs both a standardized uptake value (SUV) and ratios to normal tissue (muscle)
will be calculated.
Simultaneously to the FAZA PET scans blood sampling (10ml) will be drawn for measurements of
protein concentrations (VEGF, Osteopontin, PAI). In total, 30 ml blood will be collected
from each patient.
The estimated radiation burden for 18FFAZA (370MBq) examination amounts about 12 mSv
(equivalent to a CT examination of the thorax).
Risks, Side effects, Toxicity
The fluorine-18(18F) labeled compound is obtained by nucleophilic substitution of a
tosylate-precursor with no-carrier-added 18F-fluoride in a specific activity of > 74 MBq /
nmol. The administration of 370 MBq 18F-FAZA will therefore correspond to < 5 nmol compound
and will not exert any pharmacologic or toxicologic effect. Similar radiopharmaceutical
such as 18FMISO showed no side effects in their clinical use in human (22)
Including criteria for patients
First diagnosis of histologically proven cervical cancer FIGO stage IB2 to IVA. Treatment
intention for the purpose of achieving cure Age < 80 years No previous standard or radical
Excluding criteria for patients
Pregnancy, breast-feeding women, patients that are not able to lie motionless for one hour.
Palliative treatment, recurrent disease, neoadjuvant chemotherapy, other pre-existing
malignancies, age > 80 years,
Results will be given as median (range). The t-test will be used for comparison of groups,
and a p value <0.05 is considered significant.
"Median SUV": stands for the median of the maximal SUVs of particular regions of interest
Observational Model: Defined Population, Time Perspective: Longitudinal, Time Perspective: Prospective
Georgios Karanikas, Prof. M.D.
Medical Universitiy of Vienna
Austria: Federal Ministry for Health and Women
EK Nr: 241/2006