The risk of cancer following high, and very high, doses of ionising radiation.

It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose-response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens-for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons-may be properly assessed.