Hypoxia Response Pathways and Radiotherapy for Head and Neck Cancer
Authors: Jean Bourhis
Journal: Journal of Clinical Oncology (2006)

Tumor hypoxia has been recognized as a potential cause of failure of treatment with ionizing radiation of carcinomas, both in in vivo animal models and in human cancers such as head and neck carcinomas. The degree of hypoxia is highly variable in human tumors, and tumor reoxygenation can take place during fractionated radiotherapy, hence adding complexity to this phenomenon and making it difficult to predict the response of individual tumors to radiation exposure. In this context, the study by Koukourakis et al in this issue of the Journal of Clinical Oncology aimed to analyze by immunohistochemistry two endogeneous hypoxic tumor markers, the hypoxia inducible factor HIF-2 alpha and the carbonic anhydrase CA9, correlating expression of these markers in tissues with the outcome of patients after radiotherapy. A strong correlation between both HIF-2 alpha and CA9 immunoreactivity was found, for both locoregional control and survival, confirming the importance of tumor hypoxia in head and neck cancer. One interesting feature of their study was to address this question in the frame of the large randomized CHART (Continuous Hyperfractionated Accelerated Radiotherapy) trial, which compared two regimens of radiotherapy. The first regimen was conventional radiotherapy delivering 66 Gy in 6.5 weeks and the second was accelerated radiotherapy, delivering 54 Gy in only 12 days. The overall outcome of the patients with these two regimens was not different. However, one hypothesis to explain the absence of benefit from the more intense regimen was that the time course of this regimen was too short to allow tumor reoxygenation during the course of radiotherapy. In addition, the relatively low total dose (54 Gy) and the small dose per fraction (1.5 Gy) used in the accelerated regimen could have been relatively ineffective in overcoming radioresistance by hypoxia. Confirming this hypothesis, no benefit was found with the accelerated regimen in the group of hypoxic tumors. The number of patients analyzed (n 198) was relatively limited, and the methodology used did not allow firm conclusions. One of the drawbacks of the study was that tumor hypoxia was measured only initially and could not be neasured throughout the course of treatment. Despite these limitations, there is some suggestion from the Koukourakis study that tumors presenting with initial hypoxia, as assessed by immunohistochemistry, were more likely to experience failure with the accelerated regimen. In contrast, tumor hypoxia had no influence on the outcome after conventional radiotherapy, which may allow sufficient time for tumor reoxygenation. This hypothesis is appealing, but needs to be further investigated and confirmed. It might allow one to perform adaptive radiotherapy, and identify among tumors those that could be candidates for hypoxic modifications and/or accelerated radiotherapy. A recent work by Overgaard et al, used another hypoxiarelated marker, the serum level of osteopontin, in a randomized trial that compared in a series of head and neck cancer patients’ radiotherapy with and without an hypoxic sensitizer (nimorazole). The only group of patients who benefited from the hypoxic modification was the one in which high levels of serum osteopontin (suggesting tumor hypoxia) were found, strongly suggesting that measuring tumor hypoxia before radiotherapy may help to individualize irradiation in a more rational way. A further randomized study performed recently by Hicks et al used positron emission tomograph F18-misonidazole imaging (before the onset of radiochemotherapy) for tumor hypoxia in a series of patients with head and neck carcinomas. The patients were randomly assigned to receive tirapazamine, which is cytotoxic, specifically in hypoxic conditions. The control rate of tumors which were hypoxic and received tirapazamine was much higher than that of tumors that were hypoxic and did not receive tirapazamine, but fluorouracil instead. These results, taken together with the study of Koukourakis et al, suggest that evaluating tumor hypoxia before radiotherapy may help to identify tumor characteristics that may allow one to adapt the radiation regimen and hypoxic modifications and bring new insights to the field of radiotherapy and tumor hypoxia.