Conformal Radiation Therapy

R

‘A little to a lot or a lot to a little’ the crucial question to be raised in

conformal radiation therapy

Professor Dag Rune Olsen, PhD

Institute for Cancer Research, The Norwegian Radium Hospital,University of Oslo

Conformal Radiation Therapy

Conformal radiation therapy aims at limiting the radiation dose to the targeted volume, and minimise the radiation dose to normal tissues and organs

Conformal radiation therapy offers therefore a possibility of limiting the long-term side effects following radiation therapy.

Brahme A. Int J Radiat Oncol Biol Phys. 58:603-16,2004.


“Conformity index” is a measure of how well the high dose volume is confined to the target volume:

CI=Vtarget/Vtreated

CI of conventional RT is low, for conformal RT medium, for IMRT medium-to-high, for proton therapy high.

Vtarget

Vtreated

D. Dearnaley at al. Lancet 1999


Dearnaley et al. have shown, in a CRT comparing conventional with conformal RT of prostate cancers, that conformal RT lowered the late rectal toxicity as compared to conventional RT.

Dose maps: virtual rectum unfolding

P L A R P0

25

50

75

100

Pos

ition

(%

)

DirectionOpen each orthogonal contour

66 Gy

21 Gy

9 Gy

44 Gy61 Gy

Hoogeman, MS et al. AVL, Amsterdam

Mean dose maps: conventional vs. conformal

P L A R P0

20

40

60

80

100

Direction

Pos

ition

(%

)

P L A R P

Direction

ConformalConventional

64-70 Gy

59-64 Gy

53-59 Gy48-53 Gy

42-48 Gy36-42 Gy

31-36 Gy25-31 Gy

Hoogeman, MS et al. AVL, Amsterdam


The crucial question:

‘a little to a lot or a lot to a little’

Which DVH corresponds to the

lowest NTCP

?

dose

Rectal volume

conv.

IMRT

The normal tissue volume effect

Dose response relationship for rectal bleeding following radiation therapy, demonstrating a significant volume effect. Rancati T, et al. Radiother Oncol. 73:21-32, 2004

N = total number of FSUsk = number of intact FSUs necessary to maintain organ functionk/N = critical fraction

serialk = N

k < Nparallel

N

k k < Nmix

Tissue organization and the normal tissue volume effect

The concept of Functional Sub Units (FSU)

Olsen DR, et al. Br J Radiol. 67:1218-25, 1994


Is the tissue organization and thus the volume effect an inherent biological characteristics of the tissue, or does it vary with:– end-point– location within the organ (i.e. is the tissue

organization uniform within the organ)

Tissue organization of the rectum – clinical study

• Sixty-six cancer prostate patients were treated with external radiation therapy with a mean dose to the planning target volume (PTV) of 66 Gy

• Late radiation effects in the rectum were assessed by a mailed ad hoc designed questionnaire to be completed by the patients 1–2 years after their radiotherapy

Dale E, et al. Int J Radiat Oncol Biol Phys. 43:385-91, 1999.


Descriptive values calculated from the dose-volume histograms of the 66 pts. used in the analysis.


Late toxicity in the rectum is dependent on the tissues functional architecture

Rectum

FSU

High-dose box

Prostate

FSU

High-dose box

Rectum

Prostate



Tissue organization of the rectum – experimental study

• Experimental study on the effect of irradiated volume on late normal tissue damage in the rat rectum

• Male Fischer rats (CDF[F344]/CrLBR SPF) weighing 280–300 g were used for the experiments.

• Irradiation parameters and the numbers of cases in recent experiments are summarized on the left.


• Cumulative dose-volume histograms of total rectal volume.

• "Unshielded" denotes the dose-volume histogram of the unshielded 8/2.5-mm step size configuration. "Shielded" and "Short" denote the dose-volume histograms of the shielded 8/2.5-mm step size and unshielded 2/2.5-mm step size configurations, respectively.


Dose response for single-dose and three-fractionated endocavitary irradiation with three different brachytherapy field configurations.


Histopathologic scores for:

(a) single dose and (b) three-fractionated brachytherapy, with the unshielded configuration.

U = ulcerationPCP = proctitis cystica profundaVS = vascular sclerosisF = fibrosisAER = atypical epithelial regenerationCIS = colon injury score (total score).

A B


• Modelling demonstrated a considerable volume dependence of the occurrence of rectal stenosis.

• The mean functional reserve, 50 , of 0.53 is

consistent with a typical parallel functional volume organization.

• Rectum has thus a large functional reserves and expresses a threshold-type dose-volume relationship.

Tissue organization of the rectum

• Clinical study:– Mild end-points:– Serial structure

• Experimental study– Severe end-points:– Parallel structure

Tissue organization

and thus volume effect

may thus depend on end-point !


Is the tissue organization and thus the volume effect an inherent biological characteristics of the tissue, or does it vary with:– end-point– location within the organ (i.e. is the tissue

organization uniform within the organ)

Is tissue organization uniform ?

• Radiation-induced pneumonitis in mouse lung

• Two end points:– elevated breathing rate after 22 weeks (‘elBR’)– lethality within 28 weeks (‘dead’)

• Single doses (11 - 22 Gy)

• Different subvolumes irradiated– size (% of total lung volume)– location (measured from base or apex)

• Lethality data analysed by Tucker et al. (1997)– volume effect model / target cell concept– estimated ‘target cell distribution’

base

apex

Lung:

50% base

70% apex

Travis EL, et al. Int J Radiat Oncol Biol Phys. 38:1045-54,

1997.

)/exp(1)/exp(ln11 00 DDKDDKSFp

SF = surviving fractionD = doseK and D0 : radiosensitivity parameters

ynyn

y

pp1knNpNTCPy

n

1),,,( , Nnky (1)

Normal tissue complication probability:


N = total number of FSUsn = number of irradiated FSUsk = critical number (k/N = critical fraction)p = FSU inactivation probability

)!(!!

ynyn

y

n

ynyn

y

pp1pknNNTCPy

n

1),,,(

Volume (%) measured from base of lung

0 20 40 60 80 100

Cum

ulat

ive

num

ber

of n

(F

SU

s or

targ

et c

ells

)

0

20

40

60

80

100

uniform distributionTucker's estimatesbase-elBRapex-elBRbase-deadapex-dead

Travis EL, et al. Int J Radiat Oncol Biol Phys.

38:1045-54, 1997.

Analysis performed by Sue Tucker, MD Anderson Cancer Centre, indicated a variable volume effect over the lung; could this variation be due to variation in:

– density of FSUs

– critical fraction of FSUs

– Inactivation probability of FSUs


k (critical number of FSUs)0 20 40 60 80 100

rms

err

or

0.1

0.2

0.3

0.4

base-elBR apex-elBR base-dead apex-dead

(N)


30% base 30% apex

Volume (%) measured from base of lung

0 20 40 60 80 100

FS

U in

activ

atio

n pr

obab

ility

, elB

R

0.0

0.2

0.4

0.6

0.8

14 Gy 16 Gy 18 Gy 20 Gy 22 Gy


30% base 30% apex


‘A little to a lot or a lot to a little’ ?

the question can only be answered if you know the tissue organization of the normal tissue or organ in question, and the

answer depend on the end-point chosen and may even vary within the organ

The crucial question:

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Conformal Radiation Therapy