4 Rs of Radiobiology

The 4 Rs are four things that happen to cells in the time between radiation fractions. Together they explain much of why splitting a dose into fractions changes its effect on tumors and normal tissues. They were first described by Withers in 1975; Steel and colleagues added a fifth in 1989.

• Repair — cells repair sublethal radiation damage between fractions.
• Redistribution (or re-assortment) — cells are not equally sensitive at every stage of the cell cycle. Cells in mitosis are mostly sensitive and cells in S-phase mostly resistant. The survivors of one fraction move on through the cycle, so some reach a more sensitive phase before the next one.
• Repopulation — surviving cells keep dividing between fractions, replacing cells that were killed.
• Reoxygenation — cells short of oxygen (hypoxic cells) are more resistant to radiation. Between fractions, surviving hypoxic cells can regain oxygen and become more sensitive. See OER.

The fifth R is radiosensitivity: the intrinsic sensitivity of the cells themselves. Steel added it because tumors' response to radiotherapy was found to correlate with how sensitive their cells were in the laboratory. Some authors propose a sixth — Boustani and colleagues suggest reactivation of the anti-tumor immune response by radiation.

The Rs pull in opposite directions. As Brown and colleagues explain, when a dose is divided into fractions, redistribution and reoxygenation increase overall cell kill, because resistant survivors move into more sensitive states over time. Repair and repopulation increase cell survival, because cells recover after each fraction and multiply between them.

Fractionation schedules are designed around this balance: to maximize tumor cell kill while avoiding normal-tissue toxicity, particularly in late-responding tissues. The difference in repair capacity between tissues is what the α/β value in BED and EQD2 describes — Brown and colleagues note the lower α/β of late-responding normal tissues compared with acute effects and most tumors (with the likely exception of prostate cancer). Repopulation is why Fowler's full BED formula includes a term for overall treatment time.

The Rs are also at the center of the debate about SRS and SBRT, which give one or a few large fractions. With so few fractions there is less opportunity for reoxygenation between them, and Brown and colleagues argue that tumor hypoxia is likely to be more important for SRS and SBRT than for conventional fractionation. Even so, they conclude that for most tumors the classic 5 Rs are sufficient to explain the clinical results, which they attribute to the much larger BEDs these treatments deliver — with the likely exception that high doses may enhance antitumor immunity in some tumors.

The Rs are not numbers you read off a plan. They are the reasoning behind tools you do use:

1. Dose per fraction and α/β — the repair side of the balance — are built into BED and EQD2, which is why a schedule's effect is never judged on total dose alone.
2. Overall treatment time — repopulation — appears as a time term in Fowler's full BED formula.
3. Hypoxia and reoxygenation are covered on the OER page.

When you compare schedules, the useful questions come straight from the Rs: how many fractions, how large, and over how long.