J.J. Wilkens - TUM Department of Radiation Oncology

The biological rationale of hadron therapy

Jan J. Wilkens Department of Radiation Oncology www.radonc.med.tum.de

ICMP 2013

J.J. Wilkens - TUM Department of Radiation Oncology

Introduction

Recent developments in radiotherapy: biologically adaptive treatment strategies • functional imaging • TCP/NTCP calculations and optimization • … Hadrons (protons, ions, neutrons): „biological effects“ due to changes in radiation quality

J.J. Wilkens - TUM Department of Radiation Oncology

Bragg peak

rela

tive

dose

(%)

depth (cm)

megavoltage x-rays protons

exponential falloff

SOBP

rela

tive

dose

(%)

depth (cm)

The physical advantage of protons (and ions)

J.J. Wilkens - TUM Department of Radiation Oncology

Biological effectiveness

low LET high LET biologically more effective

rela

tive

dose

(%)

depth (cm)

J.J. Wilkens - TUM Department of Radiation Oncology

The relative biological effectiveness (RBE)

The RBE depends on:

• particle type (p, n, 12C, …), LET / local energy spectrum, dose • tissue type, biological endpoint

RBE(proton) ≈ 1.1 RBE(carbon ions, neutrons) ≈ 2 … 5

hadron

photon

DD

RBE =

for the same biological effect

Definition of the RBE:

dose (Gy)

survival photons

hadrons

J.J. Wilkens - TUM Department of Radiation Oncology

RBE-weighted absorbed dose

“RBE-weighted absorbed dose” = RBE(x,y,z) × dose(x,y,z)

• units: Gy(RBE) [ICRU] (formerly: GyE or CGE)

• hypothetical (!) photon dose distribution with the same biological effect

J.J. Wilkens - TUM Department of Radiation Oncology

Biological optimization for carbon ions

optimize RBE×dose instead of the dose

Chen et al. 1979 IJROBP 5(10) 1809-19

physically optimized SOBP biologically optimized SOBP

(Gy(

RB

E))

J.J. Wilkens - TUM Department of Radiation Oncology

Techniques for biological optimization

Two main parts: a) biological model to calculate RBE e.g. “local effect model” LEM (GSI Darmstadt/Germany) b) incorporation of this model into optimization / objective function to optimize RBE×dose in treatment planning Problem: RBE depends nonlinearly on dose

J.J. Wilkens - TUM Department of Radiation Oncology

Example: carbon ion planning

RBE x dose (100% = 3 Gy(RBE)) dose (100% = 1 Gy)

Single field plan

(RBE for chordoma cells/LEM) Wilkens et al. 2006 Phys

Med Biol 51(12) 3127-40

J.J. Wilkens - TUM Department of Radiation Oncology

Problems with RBE

• RBE>1 is not necessarily an advantage

• If (and only if) RBE(target) > RBE(normal tissue), the therapeutic window widens

• Large uncertainties in clinical RBE values

J.J. Wilkens - TUM Department of Radiation Oncology

Versions of the “local effect model”

Elsässer et al. 2008 IJROBP 71(3) 866-872

target normal tissue normal tissue

1997 2007 2008

J.J. Wilkens - TUM Department of Radiation Oncology

Most recently: LEM IV

Grün et al. 2012 Phys Med Biol 57 7261-74

optimized with LEM I recalculated with LEM IV

J.J. Wilkens - TUM Department of Radiation Oncology

Potential validation of RBE models

• Pre-clinical studies in vitro and in vivo

• Clinical studies

• Advance radiobiology to better understand the mechanisms

“From molecules to life”

J.J. Wilkens - TUM Department of Radiation Oncology

γ-H2AX foci

Focussed protons show elevated RBE

4.5 MeV/u carbon 20 MeV protons 20 MeV protons (single ions) (homogeneous) (sub-µm focussed)

higher RBE than homogeneous protons

Schmid et al. 2012 Phys Med Biol 57 5889-907

5 µm

J.J. Wilkens - TUM Department of Radiation Oncology

EMRP project: Biologically weighted quantities in radiotherapy (BioQuaRT) A Joint Research Project within the European Metrology Research Programme EMRP Apply micro- and nanodosimetric methods to measure track structure and “radiation quality” define a measureable quantity that is relevant for the biological effectiveness

http://www.ptb.de/emrp/bioquart.html

J.J. Wilkens - TUM Department of Radiation Oncology

Neutron therapy

• no physical dose advantage • high LET • high RBE gives benefit for

selected patients

depth [mm]

dose

neutrons

gamma Munich: fast neutrons (mean energy: 2 MeV) from nuclear reactor

J.J. Wilkens - TUM Department of Radiation Oncology

Summary

Biology matters in radiation therapy RBE effects can be additional advantage for ions or neutrons But: • RBE models difficult to validate • better understanding of radiobiological mechanisms

desirable

Foliennummer 1IntroductionThe physical advantage of protons (and ions)Biological effectivenessThe relative biological effectiveness (RBE)RBE-weighted absorbed doseBiological optimization for carbon ionsTechniques for biological optimizationExample: carbon ion planningProblems with RBEVersions of the “local effect model”Most recently: LEM IVPotential validation of RBE modelsFocussed protons show elevated RBEEMRP project: Biologically weighted quantities in radiotherapy (BioQuaRT)�Neutron therapySummary