# The four Rs and accelerated repopulation

Source: https://onco.cc/technologies/fractionation-repopulation-models/  
OnCo record `fractionation-repopulation-models` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Radiotherapy works through repair, redistribution, reoxygenation and repopulation between fractions; the discovery that tumours speed up their regrowth during a course explained why gaps in treatment cost cures and led to accelerated schedules.

## Summary

Rodney Withers set out in 1975 the four Rs of radiobiology that fractionation exploits: repair of sublethal damage (favouring normal tissue), redistribution of cells through the cell cycle, reoxygenation of hypoxic cells and repopulation of surviving clonogens. In 1988 Withers, Taylor and Maciejewski showed from head and neck cancer series that repopulation accelerates about four weeks into a course, so every extra day costs roughly 0.6 Gy of control, which is why treatment breaks are made up, overall time is kept short and accelerated schedules (DAHANCA 6 and 7, CHART in lung cancer) were tested. Time factors now sit in biologically effective dose calculations for fast-growing tumours.

## Fields

- Kind: Technology
- Status: established
- Last checked: 2026-09-17
- Tags: mathematical-model
- Principle: Tumour control depends on total dose, dose per fraction and overall time; loss of control per day of prolongation beyond a kick-off time reflects accelerated repopulation of clonogens.
- Since: 1975
- Strengths: Explains the cost of treatment gaps; Led to accelerated and hyperfractionated schedules with proven benefit; Incorporated into BED for fast tumours
- Limitations: Time factors vary by tumour and are uncertain; Less relevant to slow-growing cancers; Molecular basis still incompletely understood

## Sources

- Withers, Taylor and Maciejewski 1988, Acta Oncologica: https://doi.org/10.3109/02841868809090333

## Connected records

- cancers: [Cervical cancer](https://onco.cc/cancers/cervical/), [Head and neck squamous cell carcinoma](https://onco.cc/cancers/head-and-neck/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- fronts: [AI & Computation](https://onco.cc/fronts/ai-computation/), [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/)
- technologies: [Hypofractionated radiotherapy](https://onco.cc/technologies/hypofractionated-radiotherapy/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [The linear-quadratic model and fractionation](https://onco.cc/technologies/linear-quadratic-model/)

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