radiobiology - sefm filedisclosures Ø i have no clinical experience in the use of...

Radiobiology

Damián Guirado Llorente

Hospital Clínico de Granada

Disclosures

Ø I have no clinical experience in the use of radiopharmaceuticals for therapeutic purposes.

Ø I came here to learn from my colleagues .

Ø I think I've got myself into a mess.

Ø If this does not work, you should lay the blame on Luis and Raquel for inviting me.

Dosimetría en terapia con radiofármacos Radiobiology

30 40 50 60 70 800,00

0,25

0,50

0,75

1,00A

Prescribed dose (Gy)

TCP, NTCP

30 40 50 60 70 800,00

0,25

0,50

0,75

1,00B


TCP, NTCP

)1(CWC NTCPTCPP −×=

Goal of radiotherapy

Ø How can we open the therapeutic window?

Ø Improving treatment technique.

Ø Improving treatment fractionation.

Ø …


30 40 50 60 70 800,00

0,25

0,50

0,75

1,00A


TCP, NTCP

30 40 50 60 70 800,00

0,25

0,50

0,75

1,00B


TCP, NTCP

)1(CWC NTCPTCPP −×=

Goal of radiotherapy

Ø We need a theoretical framework:

Ø Dose-response modeling for targeted radiotherapies.


Overview

Ø Linear-quadratic approach. Isoeffect.

Ø Relevant radiobiological aspects of therapywith radiopharmaceuticals.

Ø Repair (dose rate).

Ø Fractionation.

Ø Low dose hyper-radiosensitivity.

Ø LET.

Ø Proliferation.

Ø Heterogeneity in the dose distributions.

Ø From BED to EUD.

Ø A dose-response model.

Ø Dosimetric uncertainties and radiobiology.

Ø Conclusions.


LQ Isoeffect

• Effect is related to cell survival:

nddes

= −− )( 2βα

0 5 10 15 200.001

0.010

0.100

1.000

α/β=3 Gy

α/β=20 Gy

Dosis total (Gy)

Fracción de supervivencia



)()(ln dndsEEffect βα +=−==

)( 2ndndes βα −−=

0 5 10 15 200.001

0.010

0.100

1.000

α/β=3 Gy

α/β=20 Gy

Dosis total (Gy)

Fracción de supervivenciaLQ Isoeffect



We have several ways of writing a isoeffect formula for fractionatedradiotherapy, being the most common one BED:

)( 2ndndes βα −−=

)()(ln dndsEEffect βα +=−==

0 5 10 15 200.001

0.010

0.100

1.000

α/β=3 Gy

α/β=20 Gy

Dosis total (Gy)

Fracción de supervivencia

)/

1(βααd

ndE

BED +==

Biologically effective dose (BED)

(Fowler 1989).

LQ Isoeffect


0 1 2 3 4 525

50

75

100

α /β=15 Gy

α /β=3 Gy

DBE=100 Gy

Dosis por fracción (Gy)

Dosis total (G

y)

0 5 10 15 200.001

0.010

0.100

1.000

α/β=3 Gy

α/β=20 Gy

Dosis total (Gy)Fracción de supervivencia

)/

1(βαd

ndBED +=

LQ Isoeffect

• BED has units of absorbed dose.

• BED is aditive.

• It distinguishes between different tissue responses.

• Tumours and acute reactions ofnormal tissues, a/b ~ 10 -15 Gy.

– Rapidly-proliferating tissues.

• Late reactions of normal tissues, a/b ~ 2 - 4 Gy.

– Also for some tumours.


0 1 2 3 4 525

50

75

100

α /β=15 Gy

α /β=3 Gy

DBE=100 Gy

Dosis por fracción (Gy)

Dosis total (G

y)

0 5 10 15 200.001

0.010

0.100

1.000

α/β=3 Gy

α/β=20 Gy

Dosis total (Gy)Fracción de supervivencia

)/

1(βαd

ndBED +=

• BED has units of absorbed dose.

• BED is aditive.

• It distinguishes between different tissue responses.

• Tumours and acute reactions ofnormal tissues, a/b ~ 10 -15 Gy.

– Rapidly-proliferating tissues.

• Late reactions of normal tissues, a/b ~ 2 - 4 Gy.

– Also for some tumours.

LQ Isoeffect

The dose per fraction effect is much more important for late reactionsthan for early reactions.


Radiobiological aspectsof therapy with

radiopharmaceuticals


0 200 400 600 800 1000 1200

102

103

104

105

Tipo I

Tipo II

Daño inicial

Daño residual

tiempo (min)

número de lesiones

( )ttT

∆−=

∆−= µϑ exp2ln

exp2/1

Repair

Núñez et al, 1995


)()(ln 2DGDsEEffect βα +=−==

tttxpetDttDD

GT t

′′−−′= ∫ ∫ d)]([)(d)(2

0 02

λ&&

Exponetial decrease of dose rate:

0 2 4 6 80.000001

0.00001

0.0001

0.001

0.01

0.1

1

aguda

rep. incompleta

rep. completa

d d

α=0.3 Gy-1

β=0.15 Gy-2

ϑd

Dosis (Gy)

Supervivencia

Incomplete repair

++==

)/)((1 00

βαλµλαRRE

BED

R0 Ø initial dose-rate.lØ overall rate constant: decay+clearance.m Ø repair constant.


Incomplete repair and dose rate

a/b=10 Gy a/b=3 Gy

Dale 1996


Incomplete repair and dose rate

Dale 1996

RERRR

BEDλβαλµλ000

)/)((1 =

++=


++==

)/)((1 00

βαλµλαRRE

BED

Linear Energy Transfer (LET)

++==

)/)((

0max

0

βαλµλαR

RBERE

BED

Dale and Carabe-Fernandez 2005


RFBEDBED −= 0

Proliferation during irradiation

RF Ø repopulation factor.TD Ø doubling time.lØ overall rate constant: decay+clearance.

DTRF

α2ln

= DT

RD

αλ2ln0 −=

Dale 1996


Fractionation

Mínguez et al. 2016Reasons for fractionation:

• To give a tissue sparing effect.

• To use the knowledge of distributionin first administration to the rest.

• Legal considerations.

• Radiological protection of staff.

The expession for BDE takes intoaccount the interplay betweensubletal damages corresponding todifferent administrations.


Other aspects

Ø Several sources (MIRD schema).Ø Baechler et al. 2008

Ø Low dose hyper-radiosensitivity.

Ø …

Guirado et al. 2012


From isoeffect model todose-response model


From dose to a dose-response relationship

Amro et al. 2010Non-Hodgkin lymphoma patients treated with 131I-labeled tositumomab

D, R, Q(R), l

a/b, a, m, l

BED, P(BED) EUD

20 30 40 50 60 70 80 900,00

0,25

0,50

0,75

1,00

EUD (Gy)

TCP, NTCP


++==

)/)((1 00

βαλµλαRRE

BED

Perhaps BED is not sufficient

D, R, Q(R), l

a/b, a, m, l

BED, P(BED) EUD

20 30 40 50 60 70 80 900,00

0,25

0,50

0,75

1,00

EUD (Gy)

TCP, NTCP

−−= ∑

i

iV

EUD )exp(1

ln1

αψα

−−= ∫

∞

0d)exp()(ln

1ψαψψ

αPEUD

BED≡ψ

14

501)(

−

+=γ

EUD

EUDEUDPCT

Logistic model

O’Donoghue 1999

++==

)/)((1 00

βαλµλαRRE

BED

−−= ∫

∞

0d)exp()(ln

1ψαψψ

αPEUD

14

501)(

−

+=γ

EUD

EUDEUDPCT

++==

)/)((1 00

βαλµλαRRE

BED

−−= ∫

∞

0d)exp()(ln

1ψαψψ

αPEUD


Clinical evidence: kidney response. BED works

Wessels et al. 2008, MIRD Pamphlet 20.Radionuclide data are for peptide therapy (90Y-DOTATOC)External beam data are for standard fractionation

Model predictions, using both the multiregion kidney and linear quadratic models, may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.


BED is not sufficient

−−= ∫

∞

0d)exp()(ln

1ψαψψ

αPEUD

Prideaux et al. 2007

The key is the nonuniformity of dose distribution


Clinical evidence

Amro et al. 2010

Non-Hodgkin lymphoma patients treated with 131I-labeled tositumomab


Finally, uncertainties and radiobiology!


A simulation exercise

We assume that there is a dose-response relationship between cure and EUD1

4

501)(

−

+=γ

EUD

EUDEUDPCT

−−= ∫

∞

0d)exp()(ln

1ψαψψ

αPEUD

Fixed parameters:a=0.35 Gy-1

a/b=3Gym=ln(2)/1 h-1

EUD0=29 Gy

Random parameters:R0=1.5 Gy/h --- 20%

te=ln(2)/l=12h --- 20 %sBED=20% --- 20 %Normal distributions

++=

)/)((1 00

βαλµλRR

BED

D, R, Q(R), l

a/b, a, m, l

BED, P(BED) EUD PCT



12.7929 1.17396 21.667 0.168451 33.0124 27.6007 0.355846 0

12.846 1.27434 23.6171 0.245115 37.0451 23.1957 0.0641674 0

10.6081 1.19019 18.2148 0.1591 27.7421 24.3329 0.108553 0

9.22329 1.80324 23.9946 0.201222 42.7669 29.8797 0.588698 0

13.9424 1.68831 33.9597 0.203639 59.6865 34.6773 0.895245 1

10.5378 1.8937 28.7895 0.184911 52.7351 36.1612 0.933906 1

200 virtual patients

.

.

.

.

te R0 D sBED BED EUD PCT cure

We have introduced a true dose-response relationship. Can we recover it from a clinical trial if there was an uncertainty?

12345....

.

.

.

.

.

.

.

.



12.7929 1.17396 21.667 0.168451 33.0124 27.6007 0.355846 0

12.846 1.27434 23.6171 0.245115 37.0451 23.1957 0.0641674 0

10.6081 1.19019 18.2148 0.1591 27.7421 24.3329 0.108553 0

9.22329 1.80324 23.9946 0.201222 42.7669 29.8797 0.588698 0

13.9424 1.68831 33.9597 0.203639 59.6865 34.6773 0.895245 1

10.5378 1.8937 28.7895 0.184911 52.7351 36.1612 0.933906 1

200 patients with physical and biological parameters with uncertainty

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

te R0 D sBED BED EUD PCT cure

We have introduced an aditional uncertainty of 5% and 10%

12.1819 1.1629 20.4378 0.13267 31.0003 28.0401

11.8738 1.08354 18.5613 0.286692 27.4819 17.3748

9.55945 1.27899 17.639 0.160821 27.4607 24.0476

8.6336 1.85072 23.0519 0.2 41.4386 29.4701

13.5748 1.75755 34.4204 0.211329 61.5166 33.5358

12345....


Statistical analysis of the virtual data

5% of uncertainty



10% of uncertainty



10% of uncertainty


Dose-response model

10 20 30 40 50 60

0

25

50

75

100

Simulation (10%)

Model

EUD (Gy)

TCP

Statisticalanalysis

Without Uncertainty,without EUD


Statisticalanalysis

Without Uncertainty,without EUD


-4 -3 -2 -1 0 1 2 3 4 5

0.00

0.05

0.10

0.15

0.20

0.25

Dose

BED

BED-2

D or BED normalized

Fre

qu

en

cy

Conclusions

• Variability is a fundamental aspect of radiotherapy and especially

in targeted radiotherapy.

• Despite its limitations, the isoeffect LQ equation is appropiate for

quantitative analysis of therapy with radiopharmaceuticals.

• It is not necessary to introduce too many ingredients in the

model, remember the case of external radiotherapy.

• We need to know well (low uncertainty) the most important

aspects of temporal dose distribution to establish a dose-

response model in therapy with radiopharmaceuticals.

• The reports of treatment should be complete and need to include

the radiobiological aspects, only in this way we can generate

useful knowledge and information to share.


Acknowledgements

• I thank Jose Manuel de la Vega for his assistance with

statistical calculations.

• I am grateful to Ana M Tornero López for reviewing this

presentation. “Las bibliotecas más eficientes del mundo son

los berenjenales”.


References (I)

• Amro H, Wilderman SJ, Dewaraja YK, Roberson PL.. Methodology to incorporate biologically

effective dose and equivalent uniform dose in patient-specific 3-dimensional dosimetry for non-

Hodgkin lymphoma patients targeted with 131I-tositumomab therapy. J Nucl Med 2010;51:654-9.

• Baechler S, Hobbs RF, Prideaux AR, et al. Extension of the biological effective dose to the MIRD

schema and possible implications in radionuclide therapy dosimetry. Med Phys 2008;35:1123-34.

• Dale RG. Dose-rate effects in targeted radiotherapy. Phys Med Biol 1996;41:1871-84.

• Dale R, Carabe-Fernandez A. The radiobiology of conventional radiotherapy and its application to

radionuclide therapy. Cancer Biother Radiopharm 2005;20:47-51.

• Guirado D, Aranda M, Ortiz M, et al. Low dose radiation hyper-radiosensitivity in multicellular

tumour spheroids. Br J Radiol 2012;.

• Mínguez P, Gustafsson J, Flux G, Gleisner KS. Biologically effective dose in fractionated

molecular radiotherapy-application to treatment of neuroblastoma with (131)I-mIBG. Phys Med

Biol 2016;61:2532-51.

• Núñez MI, McMillan TJ, Valenzuela MT, et al. Relationship between DNA damage, rejoining and

cell killing by radiation in mammalian cells. Radiother Oncol 1996;39:155-65.

• O'Donoghue JA. Implications of nonuniform tumor doses for radioimmunotherapy. J Nucl Med

1999;40:1337-41.


References (II)

• Prideaux AR, Song H, Hobbs RF, et al. Three-dimensional radiobiologic dosimetry: application of

radiobiologic modeling to patient-specific 3-dimensional imaging-based internal dosimetry. J Nucl

Med 2007;48:1008-16.

• Wessels BW, Konijnenberg MW, Dale RG, et al. MIRD pamphlet No. 20: the effect of model

assumptions on kidney dosimetry and response--implications for radionuclide therapy. J Nucl Med

2008;49:1884-99.


radiobiology - sefm filedisclosures Ø i have no clinical experience in the use of...

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