Prognosis/patient selection
As shown earlier, 18F-FAZA-PET can be used to identify tumor regions with hypoxia.
Theoretically, such knowledge can be used to make a better estimation of prognosis, but also to select patients for some kind of hypoxia-targeted treatment.
For example, accelerated radiotherapy combined with the hyperoxic gas carbogen and nicotinamide (ARCON) is recently investigated in phase 3 trials50-53. For head and neck cancer, ARCON showed no benefit compared with accelerated radiation, except for regional control in T2-T4 laryngeal cancer51, but a significant gain in regional control rate was observed among the patients receiving ARCON with equal levels of toxicity53. In this study, no hypoxic imaging has been performed before the treatment, because at the time of patient selection no hypoxic image tool was available. For the future, 18F-FAZA-PET may be able to select patients with hypoxic tumors, which might indeed benefit from ARCON and consequently the true value of ARCON defined.
Tirapazamine is a drug with selective cytotoxicity for hypoxic cells. Recently, in a phase 3 trial54, 861 patients with locally advanced head and neck cancer were randomly assigned to receive chemoradiation or chemoradiation with tirapazamine. No benefit was found in terms of overall survival, failure-free survival, time to locoregional failure, or quality of life. Although in this study no advantage was found, in a substudy18 tirapazamine was found to be effective in patients with hypoxic tumors as assessed by 18F-FMISO-PET. Again, this finding suggests that introducing hypoxia imaging would better help selecting patients for additional treatment.
Radiotherapy dose escalation
In the past, several attempts have been made to overcome tumor hypoxia, such as the use of hyperbaric oxygen, radiosensitizers, vasodilators or hypoxic cytotoxins such as tirapazamine combined with (chemo)radiation. Unfortunately, generally speaking, these combined approaches have come to the expense of increased acute and late radiation-induced side-effects55.
Another approach, which may overcome hypoxic tumor resistance, is increasing the radiation dose. However, increasing the radiation dose may also increase radiation-induced side effects, especially in the head and neck area where critical structures, such as the spinal cord, carotid arteries and parotid glands,
are in close proximity to the tumor. Ideally, only hypoxic tumor cells or hypoxic cell islets should receive such a higher dose. Currently, with modern radiotherapy techniques like intensity-modulated radiotherapy, it has become possible to intensify radiation dose in specific subvolumes within the gross tumor volume56. It has been hypothesized that 18F-FAZA-PET/CT can be used to guide radiotherapy in order to substantially increase the dose to hypoxic tumor subvolumes16. This might improve local control and subsequently survival of patients with locally advanced head and neck squamous cell carcinoma. To the best of our knowledge, few clinical data are available so far to prove this hypothesis. In addition, little is known about the way hypoxic areas behave during the radiotherapy course:
hypoxic areas may disappear and subsequently appear at different locations. To achieve the most optimal hypoxic tumor subvolume dose escalation, several strategies are developed (e.g., gradual dose escalation using intensity-modulated radiation therapy with a simultaneous integrated boost, intensity modulated arc therapy, stereotactic boost, or protons). Additional information is required with regard to these possible changes.
CONCLUSIONS
Based on this review, we conclude that 18F-FAZA-PET is feasible to detect tumor hypoxia and to have superior biokinetics compared to 18F-FMISO. 18F-FAZA is a promising PET radiopharmaceutical for visualization of tumor hypoxia, although clinical studies must still confirm the exact role of 18F-FAZA-PET scanning in head and neck oncology. Also, the superior hypoxia PET radiopharmaceutical is not known yet. Therefore, a clinical study directly comparing different hypoxia radiopharmaceuticals (e.g., 18F-FMISO, 18F-FAZA, 18F-HX4) in the same patients would be desirable.
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