a review
GB Halmosa, L Bruine de Bruina,b,†, JA Langendijkd, BFAM van der Laana,#, J Pruimc, RJHM Steenbakkersd
aDepartment of Otorhinolaryngology/Head and Neck Surgery,University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
bDepartment of Pathology and Medical Biology,University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
cDepartment of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, The Netherlands and Department of Nuclear Medicine, Tygerberg Hospital, Stellenbosch University, Stellenbosch, South-Africa
dDepartment of Radiation Oncology,University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
†Current affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, Hospital St Jansdal, Harderwijk/Lelystad, The Netherlands
#Current affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, Haaglanden Medical Center, The Hague, The Netherlands
Published in: Clinical Nuclear Medicine. 2014 Jan;39(1):44-48
ABSTRACT
Tumor hypoxia is known to be associated with poor clinical outcome; therefore, patients with hypoxic tumors might benefit from more intensive treatment approaches. This is particularly true for patients with head and neck cancer. Pre-treatment assessment of hypoxia in tumors would be desirable, not only to predict prognosis but also to select patients for more aggressive treatment.
As an alternative to the invasive polarographic needle electrode method, there is the possibility of using PET with radiopharmaceuticals visualizing hypoxia. Most hypoxia imaging studies on head and cancer have been performed using 18F-labeled fluoromisonidazole (18F-FMISO). A chemically related molecule, 18 F-fluoroazomycin-arabinoside (18F-FAZA), seems to have superior kinetic properties and may therefore be the radiopharmaceutical of choice.
This minireview summarizes the published literature on animal and human
18F-FAZA-PET studies. Furthermore, future perspectives on how individualized treatment could be applied in patients with hypoxic head and neck tumors are discussed, for instance the use of hypoxia sensitizers or special intensity modulated radiation therapy techniques achieving tumor subvolume dose escalation.
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INTRODUCTION
Tumor hypoxia
Tumor hypoxia is a well-recognized adverse prognostic factor in patients with solid tumors treated with radiotherapy1 and is associated with a number of unfavorable biological characteristics, including increased genetic instability, increased invasiveness, enhanced metastatic potential and decreased radiosensitivity2,3. Poorer clinical outcome of hypoxic tumors has been observed in patients with head and neck cancer treated by radiotherapy4,5 and surgery6. From this point of view, patients with hypoxic tumors might benefit from more intensive treatment approaches to counterbalance the radioresistance. It has been estimated that tumor hypoxia is present in about half of the solid tumors regardless of the tumor volume or histological type7. Unfortunately, patients with head and neck cancer tend to present themselves with tumors in advanced stages, which increase the likelihood of developing hypoxia8.
Detection of hypoxia
Although tumor hypoxia is usually defined as a tumor region with a partial oxygen pressure (pO2) less than 10 mm Hg9, there is no consensus over the interpretation and analysis of hypoxia-positive areas of different imaging modalities. For instance, some of the PET studies use the tumor-to-background ratio (T/B), others the tumor-to-muscle ratio (T/M) and there are also self-developed scoring systems.
Unfortunately, these differences make it difficult to compare studies.
Polarographic needle electrode sampling is considered the gold standard to assess hypoxia in vivo10,11. However, assessing tumor hypoxia using the Eppendorf electrodes is invasive, requires sophisticated skills and technical demands and may be subject to sampling error because of the known heterogeneity in tumor hypoxia12,13. In addition, the results of these measurements cannot be used for radiotherapy treatment planning, for example, for escalating the dose to hypoxic regions within a tumor.
Therefore, assessing tumor hypoxia with metabolic imaging techniques such as PET, using specific radiopharmaceuticals visualizing hypoxia, is an attractive alternative, at least theoretically. Several studies have been published and several different radiopharmaceuticals have been applied. Due to the different analysis techniques applied, however, it is difficult to compare studies even using the same PET radiopharmaceuticals (Table 1).
Table 1. Summary of studies on human 18F-FAZA-PET
Publication No. patients Tumor site (n) Definition of
hypoxic volume Percentage of patients with increased 18F-FAZA uptake
(ie, hypoxia) Grosu et al.16 and
Souvatzoglou et al.43 18 Head and neck
(18) T/M ≥ 1.5* 83
Garcia-Parra et al.47 14 Prostate (14) T/B ratio‡ 0
Mortensen et al.48 40 Head and neck
(40) T/M ≥ 1.4§ 63
Bollineni et al.49 11 Lung (11) T/B ratio ≥ 1.2 and
T/B ratio ≥ 1.4 100
*Tumor SUV/muscle SUVmean ratio ≥ 1.5.
†Tumor SUVmax/muscle SUVmax ratio ≥ 1.2.
‡Tumor SUVmax/benign prostate SUV.
§Tumor SUVmax/muscle SUV mean ratio ≥ 1.4.
18F-FMISO for hypoxia imaging
A number of PET radiopharmaceuticals for hypoxia imaging have been identified, of which the group of nitroimidazoles is the largest. These compounds undergo reduction under hypoxic conditions and form highly reactive oxygen radicals.
After binding to intracellular macromolecules, they are trapped inside the hypoxic cells. Among the radiolabeled nitroimidazoles, 18F-FMISO is the most frequently used. Troost et al.14 found a significant correlation between 18F-FMISO-PET imaging of tumor hypoxia in head and neck cancer and the extrinsic hypoxic cell marker pimonidazole. Pimonidazole is a nitroimidazole-like robust exogenous hypoxia marker, which needs to be injected 2 hours before biopsy. The distribution of pimonidazole is visualized by immunohistochemistry. In another validation study, only a week correlation was found between 18F-FMISO uptake and pO2 histography15. These apparently conflicting results are most likely due to heterogeneity in intratumoral hypoxia16. In a study of 73 patients with head and neck cancer, hypoxia, defined by increased 18F-FMISO uptake, was found in almost 80% of the patients. Moreover, increased 18F-FMISO uptake found to be associated with significant worse overall survival17. Rischin and co-workers18 also found 18F-FMISO effective in determining hypoxic regions in head and neck carcinoma. In that study,
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tirapazamine (a hypoxic cytotoxin), was found to be effective in patients with hypoxic tumors as assessed by 18F-FMISO-PET. Pre-treatment dynamic 18 F-FMISO-PET scanning has also found to be successful in predicting radiotherapy outcome in non-small cell lung cancer and head and neck cancer19,20. Moreover, a later study of the same group21 showed that the same imaging technique is also suitable for following the radio-induced reoxygenation of head and neck cancer during radiotherapy. A recent study by Zips et al.22 investigated the change of hypoxia and the predictive value of it for survival during radiotherapy in patients with head and neck cancer using 18F-FMISO-PET scan. Each patient has been scanned before and three times during radiotherapy. The scan parameters performed at week 1 (8-10 Gy) and 2 (18-20 Gy) strongly correlated with the local progression-free survival endpoints, suggesting good prognostic value of 18F-FMISO-PET at these time points and not at baseline.
Most of the studies investigating hypoxia by PET scans using static scans, as technically static scans are easier to perform. However, dynamic scans are more informative as they allow kinetic modeling and estimation of some rate constants, which can discriminate between tumor and background.
Alternatives to 18F-FMISO
Although hypoxia imaging using 18F-FMISO-PET is feasible and has prognostic value, there are also some disadvantages using this PET radiopharmaceutical. One of the problems is the relatively short half-life time (110 minutes) of 18F-FMISO, which hampers late imaging that could enhance good contrast between hypoxia and normal tissues23. There is ongoing intensive research in order to find alternative hypoxia PET radiopharmaceuticals with better kinetics. 18F-HX4, another new potential marker for hypoxia PET scanning has recently been described24. Preclinical studies showed advantageous biodistribution and dosimetry properties, which make 18F-HX4 a promising hypoxia radiopharmaceutical candidate. A pilot PET study on hypoxia imaging using 18F-HX4 as a radiopharmaceutical in head and neck cancer patient has recently been published25. Although this study included only 12 patients, the data are promising; higher sensitivity, specificity, faster clearance, and shorter injection-imaging time were found compared to 18F-FMISO. 18F-EF5 is another nitroimidazole that has been evaluated in imaging hypoxia in patients with head and neck squamous cell carcinoma. Data showed that the later uptake and binding of 18F-EF5 are hypoxia specific. The optimal scanning time and the appropriate T/M have also been established26. Head and neck tumor hypoxia has
also been assessed by 18F-FETNIM27. In a later study, high uptake of 18F-FETNIM seemed to correlate with poorer radiotherapy outcome, although firm conclusions are difficult to draw due to small study population28. Beside these nitroimidazoles, other molecules have been also tested, like the dithiosemicarbazones. One of them is 64Cu-ATSM, which is also a PET radiopharmaceutical developed to accumulate in hypoxic tumors. It found to be feasible for radiotherapy planning in a pilot study, and the biokinetic properties seems to be superior to 18F-FMISO, as a hypoxic tumor subvolume could be identified as early as 10 minutes after injection29.
Purpose of the present review
In this review, we will focus on the possible applicability of PET scanning with a relatively new hypoxia radiopharmaceutical, 18F-FAZA, in radiotherapy treatment planning based on tumor hypoxia determination in head and neck cancer.
More specifically, the purposes of this review are to assess whether hypoxia as determined with 18F-FAZA-PET correlates with histological or biological parameters, to investigate whether the presence of hypoxia as demonstrated with 18F-FAZA predicts outcome and to investigate how 18F-FAZA could be used in clinical practice.