Tumour hypoxia continues to remain one of the greatest challenges in the treatment of solid tumours. An important avenue to follow with both radiotherapy and chemotherapy is the development of hypoxic cytotoxins such as tirapazamine. The present review covers the history of tirapazamine from preclinical models to clinical trials. The biochemistry as well as the pharmacokinetics of this bioreductive agent are presented. Laboratory data demonstrating the enhanced effect of radiation and cisplatin when combined with tirapazamine are also discussed. There is considerable evidence supporting the potentiation of anti-tumour effect of cisplatin by tirapazamine. Several clinical trials for various tumour sites have been testing the synergistic effect of cisplatin-tirapazamine with and without radiotherapy. These are also reviewed in the present paper. The current literature data on tirapazamine leaves unanswered questions about its action and toxicity. While the current number of phase III trials limits comprehensive conclusions about the administration of this drug, there is a unanimous indication that further clinical studies are warranted.

A review of the published literature has been undertaken to ascertain the trends in treatment schedules of unresectable head and neck cancer (HNC) using cisplatin in conjunction with radiotherapy. In addition, four trials were reviewed where cisplatin was examined as a single agent without radiotherapy, demonstrating that cisplatin alone has a palliative effect only, and for a curative intent should be used in combination with radiation. Of the numerous clinical trials published on such combined chemo-radiotherapy, 16 were selected for analysis fulfilling the following criteria: cisplatin used as the sole chemotherapeutic agent in combination with radiation for patients with unresectable squamous cell carcinomas of the head and neck, with no previous treatment for the same malignancy. Daily low-dose cisplatin performed in 6 out of the 16 trials demonstrated increased tumour control with less toxicity as compared to weekly high-dose drug delivery. The increased tumour control with a daily low-dose schedule reflects the observation that cisplatin dissociates from the DNA in 24 h. Other cisplatin properties (e.g. radiosensitizing) also have the potential to influence chemo-radiotherapy treatment outcomes. There is significant scope to further optimize the treatment schedule for the unresectable HNC through detailed study of the pharmacokinetics and radiobiology of combined chemo-radiotherapy.

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.