open questions in clinical radiobiology for ion beam tumor...

Open Questions in Clinical Radiobiologyfor Ion Beam Tumor Therapy

21.5.2011 Erice Workshop Hadrontherapy

M. ScholzGSI Darmstadt

Increased Relative Biological Effectiveness: RBE

Sur

viva

lD

ose

[Gy]

Carbon 195 MeV/u

Absorbed Dose„Effective“ Dose

Differential Effect:


Penetration depth [mm]

Sur

viva

l

Weyrather et al.

Enhancement(Peak)>>

Enhancement(Plateau)

Requirements for Treatment Planning

Challenge: Homogenous distribution of effective dose in treatment volume

Effective dose distribution in normal tissues

RBEDD PhysRBE ⋅=


RBE depends on several factors:• Particle species / LET• Dose• Cell / Tissue type• Oxygen status• ...

LET ↔ Depth Dependence of RBE


Weyrather et al. IJRB 1999

Dependence of RBE on Ion Species

V79-Cells~1 MeV/u ~15 MeV/u


Exp. Data: Belli et al., IJRB 1998

Modell: LEMIV (Elsässer et al., IJROBP 2010)

RBE is larger for light ions as compared to heavier ions at same LET

Dose Dependence of RBE

In-vitro: Cell survival / CHO-cells

RBE=4.2

RBE=5.8

In-vivo: Tolerance of Rat Spinal Cord


RBE=3.2

Karger et al. IJROBP 2006

RBE decreases with Dose

Weyrather et al., IJRB 1999

Cell type dependence of RBE

Photons


RBE is correlated with repair capacity(In terms of LQ-model: with α/β-ratio)

Weyrather et al. IJRB 1999

Oxygen Effect

X-ray, oxic

X-ray, anoxic

C peak, oxic

C peak, anoxicS

urvi

val


Staab et al.Rad.Res. 2004

OERXRAY > OERION RBEANOXIC > RBEOXIC

Sur

viva

l

Dose [Gy]

Open Questions

• Optimal Particle Species• Differential effects, tissue dependence• Hypofractionation• Volume Effects• Individual Sensitivity


• Individual Sensitivity• Role of reduced OER• Combined Radio-Chemotherapy• Secondary Cancer Induction• Modelling• …

Optimal Ion Species


Carbon ions show most prounenced increase of Effectiveness from entrance region to tumor

Advantage of Carbon Ions

R=1mmR=20mmEndpoint:HSG cell

survival in-vitro


But: optimal choice will finally depend on

tumor / normal tissue combination, hypoxia status etc.! ! !

Influence of Tissue Composition

Tumor

Normal 1Normal 2Normal 3


Tissue dependenceof RBE might lead to discontinuities of the RBE-weighted dose

distribution!

Cell type / tissue dependence


Experimental Data: Suzuki et al., IJROBP 2000

Hypofractionation: Crossing of RBE curves?

In-vivo data from neutron irradiation (Hornsey et al.)

α/β ~ 2 Gy

α/β ~ 5 Gy

Therapeutic Gain:Tumor vs. Skin

(Ando et al. 2005)


α/β ~ 5 Gy

α/β ~ 10 Gy

Dose Dependence of Tissue Dependence

Analysis of data base with ~850 survival curves:Subset of carbon ions with LET: 70...150 keV/µm


T. Friedrich, work in progress

Photon Dose response at high doses: LQ?


tttt

t

DDDDDaDSS

DDDDS

>−⋅++−=−<+=−

)()2()(lnln

ln 2

ββα

Full lines: pure LQDashed lines: modified LQ

Guerrero et al., PMB 2004

Dotted lines: LQ+Dt

(Astrahan et al. 2008)

βα⋅≈ 2tD

Ftot

FF

dD

S

ddnS

βα

βα

+=−+=−

ln

)(ln 2

Volume Effects

Photon IMRT ProtonsDose-Volume-Histogram


Torres et al., IJROBP 2009

Partial volumes differ for protonsas compared to photon IMRT plans!

Right Temporal Lobe

Reviews of Clinical Data:Emami et al., IJROBP 1991Marks et al., IJROBP 2010

Volume effects: experimental validation

Application of volume effects for tolerance doses Is largely based on simple, phenomenological NTCP models

Models need to be validated!


v. Luijk et al., IJROBP 2007

100%

75%

50%

25%

Data are represented by model, if only lung is irradiatedSimultanous irradiation of heart & lung not represented by model

Combined RadioChemotherapy

X-rayU87-MG, C 1cm SOBP+Temozolomide

U87-MG, x-ray+Temozolomide

Difference in the combined effects of radiation and chemotherapy for ion beam therapy as compared to conventional therapy?


C, 1cm SOBP

C, 11.4 MeV/u

Combs et al., IJRB 2009

Additive effect of TMZ and carbon ion irradiation

Predictive Assays for individual sensitivity?

0.2

0.4

0.6

0.8

1T

um

or

Co

ntr

ol P

rob

abili

ty

27.5 Gy 45.5Gy

30.5Gy 72G y

2.36

1.65

αααα=0.3312, α/βα/βα/βα/β=5.585, σ (α) σ (α) σ (α) σ (α)=0.18T

double = 60 days

photon

carbon(50keV/µµµµm )

3Frac/week, 18 fractionsαααα=0.66, ββββ =0.095, σ(α)σ(α)σ(α)σ(α)=0.11T

double=60 daysNSCLC (18F)

Kanai et al., IJROBP 2006

Shallow shape ofphoton TCP-curve

Variation of individual sensitivity


00 20 40 60 80 100

Total Dose (Gy)

Kanai et al., IJROBP 2006

Henriquez-Hernandez, Radiat.Oncol. 2009

Gene arrays for prediction of individual tumor and normal tissue response?

Limitations:1. Cost2. Kinetics3. …

Oxygen Effect

Wenzl & Wilkens., PMB 2011


Estimation of OER for typical clinical situation(e.g. two-field opposing field treatment) ?

Problem: LET is not a good parameter…

HeC

Ne

Secondary Cancer Induction

Neoplastic transformation in CGL1 cells in-vitro


• Link of cell tranformation to cancer induction• Balance between killing and induction• Transfer to treatment plan: volume effects

Bettega et al., IJROBP 2009

Models for prediction of RBE

Local Effect Model (LEM)Microdosimetric Kinetic

Model (MKM)


Scholz et al., Rad. Env. Biophys. 1997, Elsässer and Scholz, Rad. Res. 2007Elsässer et al., IJROBP 2008, Elsässer et al., IJROBP 2010

Hawkins, Rad. Res. 2003, Sato et al., PMB 2009, Inaniwa et al. PMB 2010

• Simultanous representation of different ion species• Choice of input parameters• Internal consistency• Systematic check with large data base

? ?

Summary & Conclusion

Carbon ion therapy has been shown already to be effective for therapy, but research is still needed to fully exploit the potential of ion beams.

• What is the optimal ion species for a given tumor / normal tissue combination?

• In which situation hypofractionation is expected to show benefits?


• In which situation hypofractionation is expected to show benefits?• Role of reduced OER• Radio-Chemotherapy with synergistic action?• Estimation of secondary cancer induction for comparison with other

treatment modalities• Validation and tests of models for most accurate implementation of

RBE- and OER-effects in treatment planning

open questions in clinical radiobiology for ion beam tumor...

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