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How to improve effects of radiation and control its toxicity.

Radiotherapy is an important contributor to curative treatment of cancer and as the most effective nonsurgical treatment modality contributes to 18% of all cancer cures [1] and to 40% of all long term survivors [2]. In the next decade we need to build on clinical advances by optimising all treatment modalities and their combinations. In order to understand the options for clinical improvements in radiation therapy we need to understand some of the fundamental principles governing the effects of radiation on biological tissues and systems. For simplicity we will concentrate on external beam photons and exclude special forms of irradiation such as electron beams, brachytherapy and high LET irradiation. The therapeutic index of radiotherapy is a complex function influenced by technical, biological and host related parameters and augmented by the effects of additional stress such as chemotherapy, surgery or unrelated biological insults. Effects on tumours must be considered together with those on critical normal tissues. Most of the cores DNA damage that ionising radiation inflicts is repaired but if it is not it will manifest itself by cell death during subsequent divisions. Therefore the expression of this damage will be related to the magnitude of radiation dose [3], the kinetics of the irradiated tissue and the functional changes caused by cellular depopulation within the irradiated volume. Tissues respond to radiation damage in broadly two ways [4]: • Early: proliferating tissues such as gut, skin, blood and most tumours show predominantly acute radiation reactions which are due to cell depletion and can recover by repopulation from cellular reserves. Acute reactions are time limited unless the irradiated volume encompassed the critical organ as a whole. They are poor predictors of the dose limiting hallmark of radiation damage-late toxicity. • Late: lung, kidney, CNS. In most instances it is the late reactions that are dose limiting, characterised by cell loss and vascular changes causing a spectrum from necrosis to atrophy. Dense fibrosis is the clinically apparent feature. There is no recovery. Clinical relevance of these effects will be determined by the severity, site and volume of tissue affected and may not manifest itself for years. In clinical practice a course of radiation is defined by the prescribed radiation dose (including homogeneity), schedule of administration (number of fractions and overall treatment time), the volume of tissues irradiated and dose to critical tissues in the irradiated volume [5]. When reporting outcomes (tumour control and toxicity), time of and method of assessment should be stated [6]. Current schedules have been developed largely empirically by careful clinical evaluation of tumour and normal tissue effects. Durable long-term control of tumours is the prerequisite for cure and relates only indirectly to measurements such as tumour response. For safety assessment cohorts of cured patients need to be followed for a long time and for stochastic effects such as carcinogenesis, for life. The final issue is the Quality Assurance of the multi-step and multiprofessional process of clinical radiotherapy which ensures that the delivery is within specified tolerances of accuracy for dose and target m. The therapeutic ratio of a radiation course can be altered by manipulation of any of its parameters and/or addition of other therapy.