Predictive models validated by clinical data:

new strategies for fractionation

Dr. M. Benassi

Dr. S. Marzi

Surviving Cell FractionSF

N0= initia cell number

before irradiation

SF =N/ N0

N = surviving cell number

after irradiation

D(Gy)

SF

)/

d1(Dexp)d(Dexp)d,D(SF

LQ Model and Dose Fractionaction Schedules

a fractionated delivery of total dose D in equal fractions of dose d is assumed

damage repair and cell proliferation are absent

linear term attribuited to non-reparaible DNA lesions

quadratic term attribuited to two reparaible lesions interacting to kill the cell

involves the efficacy of different dose fractionations :

Surviving cell fraction

large values of damage depends on D

small values of damage is affected by both D and d

LQ Model and Dose Fractionaction Schedules

)/

d1(DBED

Biological

Effective Dose

same BED results in the same SF

drops out of BED

BED depends only on the better-known

for a single tissue:

BEDexp)d,D(SF

Hypofractionation Schedules

Rationale

Example: tumor be 1.5 Gy (*)

late-responding tissue be 3 Gy

same late complications

Dstd be the total dose in 2 Gy fractions

DHF be the total dose in 3 Gy fractions

Prostate

Damage to the tumor is sensitive

to the dose per fraction

(*)FOWLER J., CHAPPELL R. and RITTER M., 2001 Is for prostate tumors really low? Int. J. Radiation Oncology Biol. Phys., 50(4) 1021-1031

3D)5.1

31(DBED

33.2D)5.1

21(DBED

HFHFHF

stdstdstd

07.1288.183.033.2

3

D

D

BED

BED

std

HF

std

HF

Tumor:

stdstdHF

HFstd

HFstd

D83.02

66.1DD

)3

31(D)

3

21(D

BEDBED

Normal tissues:

BED Calculations

same late complications ---> lower dose prescribtionin spite of this the tumor BED increases

Hyperfractionation Schedules

Rationale Damage to the tumor is insensitive

to the dose per fraction

Example: tumor be 10 Gy

late-responding tissue be 3 Gy

same late complications

Dstd be the total dose in 2 Gy fractions

DHF be the total dose in 1.2 Gy fractions

Head and Neck

12.1D)10

2.11(DBED

2.1D)10

21(DBED

HFHFHF

stdstdstd

11.12.1

12.119.1

2.1

12.1

D

D

BED

BED

std

HF

std

HF

Tumor:

stdstdHF

HFstd

HFstd

D19.14.1

66.1DD

)3

2.11(D)

3

21(D

BEDBED

Normal tissues:

(!) acutely respondig tissues, for ex. mucosa, also experience increased BED

BED Calculations

same late complications ---> higher dose prescribtion---> increased tumor BED

NTDNormalized total dose

)/

1()/

1(d

Dd

D

BEDBED

refd

dd

ref

ref

ref

d d/

d/DD

ref

If the fraction size is different from dref = 2 Gy the physical total

dose can be converted to the biologically equivalent total dose

normalized to 2 Gy per fraction (NTD) using BED:

NTD

Normalized dose-volume histogram

With the advent of 3DCRT (three dimensional conformal radiation therapy) the dose delivery is often characterized by steep dose gradients and inhomogeneous dose distributions, especially within sensitive structures;

NTD formulation may be used to take into account the actual fractionation for each structure at each voxel:

NormalizedDVH

A Time-dependent Effect:Repopulation

refrefad

lag

ud

lag

d

d

d

nd

ref

T

TT

T

T

dSFSF

/

/

)(2 ,,

refref d

d

d

nd

refdSFddnSF

/

/

2 )()(exp

MOHAN R., WU Q., MANNING M., SCHMIDT-U. R., 2000 Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers Int J Radiat Oncol Biol Phys 46 (3) 619-630

adT ,

lagTudT ,

n number of fractions

lag time before accelerated repopulation begins

unperturbed doubling time

accelerated tumor clonogen doubling time

overall treatment durationT

),(),( refdNTDSFdDSF

refrefad

NTDttref d

dD

dSFT

TTdNTD

/

/

)(ln(

)2ln(

,

,

NTDIncluding Repopulation

2)5

(,

NTDNTDNTDt

refNTD

nnT

d

NTDn

number of days in all the weekends

the equation system can be solved adopting an iterative

search of nNTD and Tt,NTD

For a given fractionation strategy for which repopulation is considered, the

corresponding NTD can be derived from the new SF:

Simultaneous Integrated Boost

Conventional treatments:

are often divided into two phases, initial large photon fields followed by a boost to a reduced volume

IMRT techniques:

allow a simultaneous treatment

(SIB simultaneous integrated boost)

produce more conformal dose distributions

reduce normal tissue doses

are biologically more effective

Standard radiotherapy:

D 70 Gy to gross tumor (in 2 phases, photon + electron fields)

50 Gy D 70 Gy to surrounding tissues (photons)

D 50 Gy to lymph nodes at risk (photons)

dose per fraction d = 1.8 - 2 Gy

Treatment time Tt 7 weeks

Head and neck (HN):

parotid

spinal cord

brainstemGTV

Limphnodes

Head and neck (HN):IMRT

7 or more IMRT fields

Head and neck (HN): tumor parameters

• MOHAN R., WU Q., MANNING M., SCHMIDT-U. R., 2000 Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers Int J Radiat Oncol Biol Phys 46 (3) 619-630• WU Q., MANNING M., SCHMIDT-ULLRICH R. and MOHAN R., 2000 The potential for sparing of parotids and escalation of biologically dose with intensity-modulated radiation treatments of head and neck cancers: a treatment design study Int J Radiat Oncol Biol Phys 46 (1) 195-205

HN : normal tissue values

dose per fraction is significant

are affected by the total dose

same or lower doses and lower dose per fraction are delivered to normal tissues outside the target volume

dose to normal tissues embedded within the target volume may be significantly higher and possible late effects need to be investigated

SIB:

Example:Nasopharynx carcinoma

GTV: 69.3 Gy/2.1GyCTV: 60 Gy/1.8 Gy

GTV

GTV(positive nodes)

CTV

parotid

Dose-Volume Histograms

left parotid

right parotidbrainstem

spinal cord

PTV 60 Gy

PTV 69.3Gy

Normalized Dose-Volume Histograms

left parotid

right parotid

spinal cord

Example:Prostate carcinoma

Prostate: 77 Gy/2.2 GyLymph nodes: 59.5 Gy/1.7 Gy

lymph nodes

prostate

Uterus: 70.4 Gy/2.2 GyLymph nodes: 57.5 Gy/1.8 Gy

Example: Pelvic irradiation

lymph nodes

uterus

bowel

VisibleTumor: 66 Gy/2.2 GyLymph nodes : 54 Gy/1.8 Gy

Example: Pelvic and para-aortic irradiation

Kidneys

para-aortic lymph nodes

GTV

Physical and Biolgical Conformality

Rationale for the adoption of IMRT is also the ability to spatially customize 3D-dose delivery to supposed tumor foci of increased radioresistence or proliferative capabilities

new imaging techniques are necessary to define more precisely the edges of the visible tumor and its surroundings BTV (biological target volume) is derived from metabolic, functional and genotypic data

a better knowledge of tumor radiobiologic characteristics not only improve the target identification but also support the choice of different dose prescribtions in each tumor subvolumes

Some approaches are described in literature to convert the physical dose into an “effective” dose transforming the biological image (PET, fMRI, ect) into a dose efficiency distribution;

a relative dose efficiency (0 <e(x)< 1) may be introduced to represent the radiation effect on the tumor at each point x (*) ;

the optimization algorithm can be forced to compensate for regionally variable radiosensitivity in order to achieve the best intensity modulation;

the assumption is that the effective dose should be homogeneous:

(*) ALBER M., PAULSEN F., ESCHMANN S.M. and MACHULLA H. J., 2003 On biologically conformal boost dose optimization Phys. Med. Biol. 48 N31-N35

)()( xdxe effective dose

Biologically conformal boost dose optimization

The cumulative dose-volume histogram of the target volume and the histogram showing the effective dose distribution

nMkDnD pp 0

nKDnD tt 0

(It was supposed a linear relation between the metabolic information and the prescribed dose but the formalism can be extended to any other relation)

(*) XING LEI et al., 2002 Inverse planning for functional image-guided intensity-modulated radiation therapy Phys. Med. Biol. 47 3567-3578

A similar approach has been proposed(*) to integrate the information coming from metabolic and functional images within the inverse planning process:

)(

,0

0

nK

nM

k

D

Dt

p

conventional prescription dose

conventional tolerance dose

empirical coefficients

correlated with metabolic informations

correlated with functional informations

Biologically conformal boost dose optimization

Sensitive structures

Tumor

Conclusions

LQ-model may be used to design the most appriopriate fractionation schedules (iperfractionation or ipofractionation depending on values)

for some tumors (short doubling time) the repopulation effect has to be included on SF formalism

high conformality of IMRT plans allows to deliver simulateneous boost (SIB), that may be advantageous in different clinical situations

SIB techniques force to account for altered fractionations (different doses are delivered in the same number of fractions)

the lack of reliable radiobiological data has limited until now their use for making clinical predictions but

the integration of physical and biological conformality

will greatly improve the efficacy of radiotherapy