The 5 R's Of Fractionation

The five (historically four) R's of radiobiology are concepts that explain the rationale behind fractionation of radiotherapy.


Repair is the one of the primary reasons to fractionate radiotherapy. As discussed in DNA Damage and Repair, there are three types of damage that ionising radiation can cause to cells:

  • Lethal Damage, damage which is fatal to the cell
  • Sublethal Damage, damage which can be repaired before the next fraction of radiation is delivered
  • Potentially Lethal Damage, damage which can be repaired under certain circumstances (usually when the cell is paused in the cell cycle due to external factors)

By splitting radiation dose into small parts, cells are allowed to repair sublethal damage. The amount of damage that is repaired depends on the ability of the cell to recognise the damage and activate a) repair pathways and b) cell cycle arrest. Malignant cells have often suppressed these pathways, often through mutation or inhibition of TP53, preventing them from undergoing efficient repair. Normal tissue cells with intact repair pathways are able to repair the sublethal damage by the time the next fraction is delivered.

Repair Half Life

Intefraction interval and the repair half life is an important consideration when fractionating radiotherapy. Some tissues, notably the spinal cord, appear to have a slow repair mechanism with a half life of about 4 hours. It is important to separate dose by at least 6 hours and preferably 8 hours if two fractions are given on the same day.

Repair and Low Dose Rate treatment

If the dose rate is sufficiently low, repair may be able to take place during radiotherapy treatment. This considerably reduces the cell death due to sublethal damage and is one reason low dose treatments show reduced effectiveness at identical doses to high dose rate treatment.


When radiotherapy is given to a population of cells, they may be in different parts of the cell cycle. Cells in S-phase are typically radioresistant, whereas those in late G2 and M phase are relatively sensitive. A small dose of radiation delivered over a short time period (external beam or high dose brachytherapy) will kill a lot of the sensitive cells and less of the resistant cells. Over time, the surviving cells will continue to cycle. If a second dose of radiation is delivered some time later, some of these cells will have left the resistant phase and be in a more sensitive phase, allowing them to be killed more easily.

Redistribution and Low Dose Rate Treatments

Redistribution occurs during low dose rate treatment. Cells are constantly exposed to a relatively low level of radiation through all phases of the cell cycle. This may increase cell killing, although this is minimal compared to the increased repair that can take place as well as repopulation below.


Tumours may be acutely or chronically hypoxic. This oxygenation status may change during treatment.

Acute Hypoxia

Acute hypoxia is due to transient closure of capillaries or arterioles servicing parts of the tumour. While this vessel is closed, the tumour cells become hypoxic and resistant to the indirect action of radiation. These vessels are usually only closed for short times but may occur during a fractionated dose of radiation. Splitting the dose into fractions raises the possibility of the closed vessel being open the next time around, and therefore allowing the tumour cells to be killed.

Chronic Hypoxia

Chronic hypoxia is due to the poor vasculature of tumours and the distance oxygen must travel to reach cells that are far from the capillaries. These chronically hypoxic cells are also resistant to radiation. Fractionated radiotherapy kills cells that lie close to the capillary more effectively. As these cells are removed, the chronically hypoxic cells are able to move closer to their nutrient source, and therefore become relatively oxic. Oxic cells can be killed.


Repopulation is the last of the classical 4 R's. Repopulation is the increase in cell division that is seen in normal and malignant cells at some point after radiation is delivered.

Repopulation of normal tissues

Repopulation occurs in different speeds depending on the tissue. In general, early responding tissues begin repopulation at about 4 weeks. By increasing treatment time over this amount, it is possible to reduce early toxicity in that tissue. Late responding tissues only begin repopulation after a conventional course of radiation has been completed, and therefore repopulation has minimal effect on these effects (the repair 'R' is more important for late tissues).

Repopulation of malignant tissues

Some tumours exhibit accelerated repopulation, a marked increase in their growth fraction and doubling time, at 4 - 5 weeks. This is seen most notably in squamous cell carcinoma of the head and neck as well as the cervix. Accelerated repopulation is a dangerous phenomenon that must be countered if treatment time extends over five weeks. Methods to do this include accelerated treatment with hyperfractionation to minimise late effects.


Radiosensitivity is a newer member of the R's. It reminds us, that apart from repair pathways, redistribution of cells, reoxygenation of malignant cells and repopulation there is an intrinsic radiosensitivity or radioresistance in different cell types. Radiosensitive cells include haemotological cells, epithelial stem cells, gametes and tumour cells from haemotological or sex organ origin. Radioresistant cells include myocytes, neurons and tumour cells such as melanoma or sarcoma.