Radiobiology of fractionated treatments: the classical approach and the 4 Rs

Vischioni Barbara MD, PhD

Centro Nazionale Adroterapia Oncologica

Radiobiology

It is fundamental in radiation oncology

Radiobiology in radiation oncology

First fractionation experiments

In multifraction radiotherapy schemes the dayly patients treatment dose is of 1.8-2 Gy

It contributes to the definition of optimal radiotherapy schemes for patients

Radiobiology in radiation oncology

Tumor control

• Sigmoid curve

• Each radiation dose destroys the same proportion of clonogenic cells. The success of a radiotherapy scheme depends on the distruction of all the surviving clonogenic cells within the tumor

Tumor control probability%

dose

0%

100%

Therapeutic gain

• Normal tissue complication probability compared to tumor control probability

• Therapeutic gain when the 2 curves are separated

4R in radiobiology(Whiters 1975)

• REPAIR

• REPOPULATION

• REDISTRIBUTION

• REOXYGENATION

Radiation effect

• DNADNA• Liysosomes, endoplasmic reticulum, cytoplasmic and nuclear membrane, etc.)• proteins

Radiation effect

1 ÷ 2 Gy • extensive base damage

• 1000 SSB

• 50 DSB

Appr. 30% of cells dies and the rest has been repired or are able to survive with

a damaged genome

Radiation effect at the DNA level

• Base damage• Nucleotide damage• SSB• DSB • Bulky lesions

Bulky Lesions

Double Strand Breaks

Base Damage

Single Strand Breaks

Cell fate after radiation

Error-free repair Faulty repair No repair

The damage is totally removed

The damage causes mutations not lethal or lethal

but in the long-term

The damage is lethal for the cell

Cell survival Neoplasia Cell death

First R: Repair

Repair mechanisms in normal tissues works much better than in tumor tissues. It is convenient to fractionate the dose since more cells of the healthy tissue than tumor cells will survive after each fraction

Therapeutic index: Healthy tissue tolerance

dose

Tumor lethal dose

Damaged DNA is enzimatically repaired after each fraction of a multifraction radiotherapy scheme

Single Strand Break (SSB) repair

• Error-free mechanism of repair

• Unrepaired SSBs contribute to DBS damage

Double strand break (DSB) repair

Non-HomologousEnd joining

HomologousRecombination

Clonogenic activity study

In vitro test for clonogenic activity

Cell survival curves considers

• Radiation dose

• Cell clonogenic activity (surviving fraction of irradiated clonogenic cells)

Clonogenic activity study

The shape of the curve is

characteristic for each cell population and express

specific radiosensitivi

ty

• Cell population type

• Radiation quality

• Oxygen level and temperature

• drugs

Clonogenic activity study

Dose response curve depends on:

Cell fate after IR

Permanent Permanent arrestarrest

Permanent Permanent arrestarrest

Short-term arrest and Short-term arrest and attempted DNA-repairattempted DNA-repair

ApoptosisApoptosisApoptosisApoptosis Reversible Reversible arrest and DNA arrest and DNA

repairrepair

Reversible Reversible arrest and DNA arrest and DNA

repairrepair

Resumed Resumed proliferationproliferation

Resumed Resumed proliferationproliferation

OKOK

Attempt to resume Attempt to resume proliferationproliferation

Attempt to resume Attempt to resume proliferationproliferation

Gudkov, Nature 2003 / modifiedMitotic Mitotic

catastrophecatastropheMitotic Mitotic

catastrophecatastrophe

lymphocytes/ lymphocytes/ endothelial cellsendothelial cells

fibroblasts/ fibroblasts/ pneumocytespneumocytes

many tumor many tumor cellscells

many normal many normal cellscells

Mathematical models of the radiobiological effect

They have assumptions:

• Cell death after radiation connected to abrogation of cell reproductive activity

• At least one DSB in DNA is responsible for cell death

Radiobiological models can help to predict clinical outcomes when treatment parameters are altered

Cell survival curves and the linear-quadratic model

component

• Linear variation with dose (Gy-1)

• Lethal damage

• DSB

• Especially for cells with impaired DDR

machinery

• Predominant for high LET radiation

component• Quadratic variation with dose (Gy-2)• Damage can be repaired• SSB• Especially for cells with good DDR machinery

Cell survival curves and the linear-quadratic model

/ ratio

/ ratio defines the bending of the survival curve

/ ratio is the dose at which the linear component of the damage is equal to the quadratic component

/ ratio high

Lethal damageCurve linear at origin

/ ratio low

Damage can be repairedCurve with shoulder at the beginning

/ ratio highEarly responding normal tissues Proliferating tissues

skinMucosaeBone marrow

Fast growing tumor

/ ratio lowLate responding normal tissuesTissues not proliferating

kidneyliverCentral nervous system

Slow growing tumor

/ ratio

/ ratio and isoeffect relationship

/ ratio highNo fractionation sensitivity

/ ratio lowFractionation sensitivity

• To calculate isoeffect relationship

• To compare different fractionation schemes

• To sum up doses given to the same patients with different fractionation

BED (biologically equivalent dose)

D = dose totale

d = dose per frazione

Linear-quadratic model and BED

Cell survival curves and the linear-quadratic model

Radiobiological basis of fractionation

/ RATIO

• high / Ratio- early reacting tissues squamous cell ca acute normal tissues

--total dose

• Low / Ratio- Late reacting tissues late normal tissues

--total dose and dose/fraction

• Hypofractionation

• Hyperfractionation - low dose/fraction- higher total dose- more fraction/day (6 h)

- less total time (accelerated)

• Continuous Hyperfractionation

Altered fractionation schemes

Large dose/fraction (hypofractionation) increase the RT effect

Less in the tissues with high / RATIO

Less damage can be repaired within each fraction

Large dose/fraction more toxic to tissues with low / ratio compared to tissues with high / ratio

Radiobiological basis of fractionation

• Small dose/fraction (hyperfractionation) has reduced effect

– in the tissues with low / RATIO

– More damage can be repaired within each fraction

Small dose/fraction protects tissues with low / ratio compared to tissues with high / ratio

Radiobiological basis of fractionation

Fractionation sensitivity of different tumors in the clinical setting

Tumor fractionation sensitivity

Definition Optimal fractionation schedule

Clinical level of evidence

Reference

Low / ratio of ca higher than that of late responding healthy tissues

More, smaller-sized fr. with higher total dose, or fr. given over a shorter time course-> improves LC, same late tox, more acute tox.

Level I evidence for improved therapeutic ratio in head and head and neck and lung neck and lung caca

Nguyen et al.,2002

Overgaard et al., 2003

Saunders et al., 1999

Moderate Moderate to highto high

/ ratio of ca similar or slightly higher than that of late responding healthy tissues

Fewer, larger-sized fractions might achieve same LC and late toxicity as conventional fractionation

Level IIII evidence for therapeutic ratio equivalent to conventional scheme in BREAST CABREAST CA

Yarnold et al., 2005

Owen et al., 2006

Whelan et al., 2002

START A, 2008

START B, 2008

High / ratio of ca lower than that of late responding healthy tissues

Fewer, larger-sized fr-> improve LC with similar or reduced late and acute tox effects

Level III evidence for therapeutic ratio equivalent to conventional fr. In prostate ca prostate ca

Fowler, 2005

1. Repair of the damage

2. Repopulation:

Dose fractionation and the 4 R

• For tumour cells this repopulation partially counteracts the cell killing effect of radiotherapy

• The repopulation time of tumour cells appears to vary during radiotherapy - at the commencement it may be slow (e.g. due to hypoxia), however a certain time after the first fraction of radiotherapy repopulation accelerates.

• Repopulation must be taken into account when protracting radiation e.g. due to scheduled (or unscheduled) breaks such as holidays.

• Also normal tissue repopulate - this is an important mechanism to reduce acute side effects from e.g. the irradiation of skin or mucosa

Dose fractionation and the 4 R

3. Redistribution

4. Reoxygenation: at each fraction oxygenated cells will be killed and hypoxic cells will replace the dead cells in more oxygenated parts of the tumor progressively reducing the final tumor mass

New frontiers to increase the therapeutic gain:hadrontherapy

• No fractionation sensitivity

• Effect not dependent on cell cycle, oxygenation

New frontiers to increase the therapeutic gain:radiogenomics

• Research on factors that increase sensitivity to different fraction size and radiation type

• Allow to add drugs to treatment