Physical Factors
Physical factors include the type of radiation used, the dose, and other physical factors such as the temperature of the treated volume.
The total dose is perhaps the most important physical factor. Very low doses are unlikely to lead to any visible response, whereas very high doses (single dose over 20 Gy) have the potential to kill most human cells. Fractionation of dose is also an important physical factor. Changes in fraction dose size can lead to widening of the responses seen in tissues, particularly late effects.
High LET radiation will usually have a greater biological effect. This is due to increased cell killing as radiation induced damage is more closely spaced. As LET increases over 100 keV/μm, cell killing decreases as the energy delivered exceeds that needed to kill the cell.
The rate at which dose is delivered will also impact on cell survival, as low dose rates allow for DNA repair to occur during radiation delivery. Very low dose rates may also allow reoxygenation or redistribution to occur.
Increased temperature leads to an increase in cell killing. This is due to deficiency in DNA double strand break repair that occurs at higher temperatures. For temperatures between 40 and 43oC, where heat has minimal cytotoxicity, the increased effect is seen in a loss of the shoulder on the cell survival curve. For temperatures over 45oC, where cell killing from heat is common, the cell survival curve is also steepened.
Chemical Factors
Chemical factors are due to the presence or absence of particular molecules, both naturally occurring in the body or administered.
The oxygen effect refers to the increased cell killing in oxic conditions. Anoxic cells are between 2 – 3 times more resistant to low LET radiation than oxic cells. Therefore, the addition or reduction in oxygen will have effects on the radiation reaction.
Radiosensitisers, such as cisplatin or 5-fluorouracil, function by increasing the cellular damage caused by radiation. Cisplatin causes interstrand and intrastrand crosslinks in DNA, making it more difficult for cells to repair nearby double strand breaks. 5-fluorouracil restricts cellular repair by interfering with synthesis of thymidine, an important base in DNA structure. The presence of these chemicals leads to an increase in the observed radiation effect.
Radioprotectors, such as amifostine, reduce the effect ionising radiation has on cells. This is often by increasing the availability of anti-oxidants which prevent ‘fixing’ of radiation damage.
Biological Factors
Biological factors are due to the cell being irradiated or the organism as a whole.
Different organisms have different tolerances to radiation. Most eukaryotic cell cultures demonstrate significant cellular death at doses of 1 – 2 Gy. Bacteria are relatively radioresistant, requiring doses far above those in mammalian cells before significant cell death occurs. Although this has minimal relevance to tissue reactions seen in humans it is important in other areas that use radiation (eg. food sterilisation).
The different cells within an organism may also show differing radiosensitivity. Haemopoietic cells typically respond to low doses of radiation, whereas well differentiated skin cells do not suffer ill consequences except at very high doses. If a cell is undergoing the cell cycle, its current stage is also relevant to radiosensitivity and the resulting radiation reaction. Cells in S-phase are typically resistant, whereas those undergoing M-phase are generally much more radiosensitive.
The arrangement of a tissue may also play a role in the radiation reaction. Tissues with a serial organisation of their functional sub-units may demonstrate a significant response if only one of their units is damaged (eg. spinal cord). Tissues with a parallel arrangement (eg. liver, kidney) typically only show clinical effects if a significant volume is irradiated.
In humans, the age of a person may also impact on their response to radiation. Children are much more likely to suffer from second malignancies due to radiation exposure. Children also have developing tissues (such as cartilage) which can be permanently damaged by low doses of radiation (10 – 20 Gy). Gender has minimal role to play, aside from the differing locations of reproductive organs and increased susceptibility of males to X-linked chromosomal abnormalities.
Other host factors, such as the presence of radiosensitivity syndromes (ataxia-telangiectasia, Fanconi anaemia) also alter the radiation reaction.
Finally, the amount of tissue in the organism that is irradiated can have a significant impact. If the entire body is treated, then there can be no region spared and significant toxicity can result. For example, bone marrow is one of the most sensitive tissues but is also able to re-establish itself if sufficient bone marrow is left untouched. If the entire body is irradiated then there may be insufficient surviving bone marrow stem cells for recovery to occur. This may be desirable but can also occur radiological accidents or attacks.
Technical Factors
Technical factors are due to inaccuracies in treatment delivery.
Treatment inaccuracies may include ‘hot spots’, which receive a larger dose per fraction as well as a larger overall dose. This increases the rate of both early and late reactions seen in normal tissues.
Alternatively, due to insufficient margins to account for internal movement or setup errors, a geographic miss may occur. A geographic miss is when the tumour is not completely covered by the prescribed fields. This leads to insufficient treatment of the tumour, and potentially treatment of a normal tissue to high dose.
