Biological Uncertainties in Proton (Ion) Therapy

Harald Paganetti PhD

Definition of RBE M

. Krä

mer

, W. K

. Wey

rath

er, M

. Sch

olz:

Tec

hn. C

ance

r R

es. T

reat

m. 2

, 427

-436

, 200

3

€

RBE =Dγ

Dion

effect

RBE values in vitro (center of SOBP; relative to 60Co)

Endpoint: Cell Survival

Paga

netti

et a

l.: In

t. J.

Rad

iat.

Onc

ol. B

iol.

Phys

. 200

2; 5

3, 4

07

1.21 ± 0.20

RBE from experimental data Clinical RBE Pr

oton

s

RB

E

Mice data: Lung tolerance, Crypt regeneration, Acute skin reactions, Fibrosarcoma NFSa

Paga

netti

et a

l.: In

t. J.

Rad

iat.

Onc

ol. B

iol.

Phys

. 200

2; 5

3, 4

07

RBE values in vivo (center of SOBP; relative to 60Co)

1.07 ± 0.12

RBE from experimental data Clinical RBE Pr

oton

s

RB

E

Experimental data in vivo are supporting the use of a clinical RBE of 1.1 in proton therapy

Our clinical experience does not indicate that the RBE of 1.1 for proton therapy is incorrect Pr

oton

s

Lesion complexity

Lesions can be repairable or non-repairable

High-LET radiation produces more non-repairable lesions

Hypoxic cells are more radio-resistant than well oxygenated cells for low-LET radiation

Oxygen Enhancement Ratio RBE as a function of particle energy / LET

Paganetti H:

Med Phys 2005: 32, 2548-2556

Dose = Fluence [1/cm2] × LET [keV/cm] / ρ [g/cm3]

RBE as a function of particle energy / LET

RBE as a function of particle energy / LET

Carbon ion RBE at 2Gy for various endpoints

Car

bon

Ions

Implication of RBE(LET) for RBE(depth)

Dose = Fluence [1/cm2] × LET [keV/cm] / ρ [g/cm3]

RBE as a function of particle energy / LET

1

1

2

2

3

3

Wou

ters

et a

l. Ra

diat

Res

199

6; 1

46, 1

59-1

70

RBE as a function of particle energy / LET Pr

oton

s

Fit of all available RBE values: RBE increased by 5% at 4 mm from the distal edge RBE increased by 10% at 2 mm from the distal edge

RBE (depth)

RBE as a function of particle energy / LET

depth in water [cm] 1.5 2.0 2.5 3.0 3.5 0

20 40 60 80

100 120

physical dose

biological dose

Prot

ons

RBE (depth) for Carbon beams RBE as a function of particle energy / LET C

arbo

n Io

ns

depth in water [cm] 1.5 2.0 2.5 3.0 3.5

0 20 40 60 80

100 120

physical dose

biological dose

2 Gy

An increasing RBE with depth cause an extended biologically effective range (1-2 mm)

Paga

netti

, Goi

tein

: Med

. Phy

s. 20

00: 2

7, 1

119-

1126

RBE as a function of particle energy / LET Pr

oton

s

Increased effectiveness as a function of depth (affects the entire Bragg curve for Carbon beams)

Extended beam range (causes range uncertainty; to be considered when pointing a field towards a critical structure)

RBE in the target is significantly higher than in the OAR for heavy ions*

RBE as a function of particle energy / LET

Dose [Gy]

Surv

ivin

g Fr

actio

n

M. Belli et al. 1993

X-rays

p (3.2 MeV)

p (1.4 MeV)

RBE=2/1=2 RBE=5/3=1.7

RBE as a function of dose

in vitro in vivo

RBE as a function of dose Pr

oton

s

RB

E

RB

E

RB

E

RB

E

RB

E

Dose [Gy] Dose [Gy] Dose [Gy]

Dose dependency of RBE values for Carbon RBE as a function of dose

Carbon ion beams; RBE in vitro

Car

bon

Ions

  RBE decreases with increasing dose   The lower the LET, the smaller the effect

Weyrather et al., IJRB 1999

Dose dependency of RBE values for Carbon RBE as a function of dose

Wilkins and Oelfke, IJROBP 2008

RBE as a function of dose

RBE increases with decreasing dose; effect seems to be very small for protons in vivo

Indicates higher RBE for OAR

RBE values in vitro (center of SOBP; relative to 60Co)

Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407-421

RBE as a function of tissue Pr

oton

s

V79 cells only R

BE

RBE values in vivo (center of SOBP; relative to 60Co)

Mice data: Lung tolerance,Crypt regeneration,Acute skin reactions,Fibrosarcoma NFSa Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407-421

RBE as a function of tissue Pr

oton

s

In vitro; non-V79 cells only R

BE

human cells

Proton beams of < 10 MeV; RBE in vitro

Belli et al. 2000 Bettega et al. 1979

RBE as a function of tissue Pr

oton

s

  Do cells with higher repair capacity show higher RBE?

Carbon ions Photons

S(D) = e-(αD+βD2)

Car

bon

Ions

RBE as a function of repair capacity (α/β)

high (α/β)x (> 5 Gy) early responding

tumor tissue

low (α/β)x (≤ 5 Gy) late responding healthy tissue

RBE as a function of repair capacity (α/β) Pr

oton

s

We have to be careful when using V79 cell data to estimate RBE effects in clinical scenarios

RBE seems to be higher for tissues with a low α/β ratio (organs at risk, prostate)

RBE seems to be higher for non-lethal injuries

Oxygen Enhancement Ratio is an advantage of heavy ions

RBE as a function of tissue

Before we can implement RBE variations in proton therapy we need to understand them in vivo

RBE variations are typically small in proton therapy

We have to consider RBE variations in heavy ion radiation therapy, which does lead to considerable uncertainties

We need more in vivo experiments !

CONCLUSIONS

“high-LET radiation” versus “low-LET radiation”

High RBE is not an advantage per se

It is an advantage if it affects mainly the target area (consider LET, dose, and tissue dependency)

Hypofractionation might be advantageous for high-LET radiation (less tumor repopulation) because it causes a lack of cellular repair, i.e. reduces the advantage of fractionation

CONCLUSIONS