Post on 05-Feb-2016
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‘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.
Conformal Radiation Therapy
“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
Conformal Radiation Therapy
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
Conformal Radiation Therapy
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
Tissue organization and the normal tissue volume effect
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.
Tissue organization of the rectum – clinical study
Descriptive values calculated from the dose-volume histograms of the 66 pts. used in the analysis.
Dale E, et al. Int J Radiat Oncol Biol Phys. 43:385-91, 1999.
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 – clinical study
Dale E, et al. Int J Radiat Oncol Biol Phys. 43:385-91, 1999.
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.
Tissue organization of the rectum – experimental study
• 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.
Tissue organization of the rectum – experimental study
Dose response for single-dose and three-fractionated endocavitary irradiation with three different brachytherapy field configurations.
Tissue organization of the rectum – experimental study
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
Tissue organization of the rectum – experimental study
• 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 !
Tissue organization and the normal tissue volume effect
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:
Is tissue organization uniform ?
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
Is tissue organization uniform ?
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)
Is tissue organization uniform ?
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
Is tissue organization uniform ?
30% base 30% apex
Is tissue organization uniform ?
‘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: