Tumour
hypoxia is well recognised as a major factor contributing to radioresistance. This article examines the role of
hypoxia in influencing the treatment outcome following
radiotherapy (RT), and reviews the rationale and results of clinical trials that utilise hypoxic sensitizers or
cytotoxins in the treatment of head and neck
carcinoma. Histologic evidence for tumour
hypoxia in human
neoplasms was first reported in 1955. Since then, direct measurement by
microelectrodes has revealed heterogeneity in intratumoural
oxygen concentrations, and low
oxygen concentrations are associated with poor local-regional control by RT. These findings coupled with the result of nuclear imaging studies employing radiolabelled
imidazoles, provide strong evidence for the existence of tumour
hypoxia which influences RT treatment outcome. Hyperbaric
oxygen (HBO) trials for
head and neck cancer, conducted in the early 1970s, demonstrated that HBO improved local control and survival rates in patients with
head and neck cancer receiving
radiotherapy (RT). Since the mid-1970s, clinical research in overcoming tumour
hypoxia was mainly centred on the use of nitro-
imidazoles as hypoxic cell sensitizers. However, the results from several major clinical trials remain inconclusive. Specifically, the
Radiation Therapy Oncology Group (RTOG)
misonidazole head and neck trial (298 patients) showed no benefit. The Danish
misonidazole trial (626 patients) showed no overall benefit, however positive results were observed in a subgroup (304
pharyngeal cancer patients). Although the European Organisation for Research and Teaching of
Cancer (EORTC)
misonidazole trial with hyperfractionated RT showed no benefit, the Danish
nimorazole trial demonstrated an overall benefit in survival as well as local control. The European
etanidazole (ETA) trial (374 patients) showed no advantage of adding the
drug to RT. The RTOG ETA trial (504 patients) showed no global benefit. However, positive results were observed in a subset of patients with early nodal disease (197 patients). In addition, a recent meta-analysis by Overgaard, utilising pooled results in the literature demonstrated that modification of tumour
hypoxia significantly improved local-regional control in head and
neck cancers with an odds ratio of 1.23 (95% confidence limits 1.09 to 1.37). Hypoxic
cytotoxins, such as
tirapazamine, represent a novel approach in overcoming radioresistant hypoxic cells.
Tirapazamine is a bioreductive agent which, by undergoing one electron reduction in hypoxic conditions, forms cytotoxic
free radicals that produce
DNA strand breaks causing cell death. In vitro and in vivo laboratory studies demonstrate that
tirapazamine is 40 to 150 times more toxic to cells under hypoxic conditions as compared to oxygenated conditions and that
tirapazamine is superior to ETA in enhancing fractionated irradiation in mouse SCCVII and other tumour types with an enhancement ratio of 1.5 to 3.0. Phase I studies demonstrated that therapeutic doses of
tirapazamine can be given safely. A multi-institutional phase II trial using
tirapazamine with concurrent RT for
head and neck cancer is now in progress.