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1
A study on the effect of set up errors and organ motion in patients treated
with IMRT for prostate cancer
S.C. Radioterapia
Laboratorio di Fisica Medica e Sistemi Esperti
I.F.O. Istituto Regina Elena, Roma
B. Saracino, V. Landoni
2
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Radiotherapy is one of the most important and evolving therapeutic strategies in localized prostate cancer
Dose escalation studies employing the newest techniques (conformal therapy and IMRT) have shown to improve local control and DFS in patients with favourable, intermediate and unfavourable prognosis
3
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
The probability of tumor control (TCP) is a function of the dose received by CTV, whilst the probability of normal tissue complication (NTCP) is a function of the dose absorbed by organs at risk (ORs)
TCP and NTCP are dose-dependent and the dose-response relationships are described by sigmoid-shaped curves
4
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Clinical data have shown that the amount of rectal and bladder wall receiving high doses is significantly lower employing IMRT than in patients treated with conventional 3DRT
As rectal and bladder toxicities exhibit a volume-effect, even high dose IMRT allows a decrease of acute and late toxicities ORs
5
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Tumor control curves are usually at the lower dose levels relative to normal tissue toxicity curves
The decrease of the amount of ORs within the treatment field induces a translation of NTCP curve toward the high dose region
This allows the treatment of the tumor with high doses in a dose escalation program, without a significant increase of toxicity of the organs at risk
6
.
3D-IMRT
3D-CRT:
Hypothetical Model
0
Prescribed Dose
0.2
0.4
0.6
0.8
1.0
Tum
or C
ontr
ol P
roba
bilit
y
0.2
0.4
0.6
0.8
TCP/NTCP Model
Prescribed Dose
Nor
mal
Tis
sue
Com
plic
atio
n P
roba
bilit
y
ConventionalRadiotherapy
Dose Escalation with 3D-IMRT
7
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
IMRT is a dose-delivery technique that provides high gradient dose distributions
An adequate level of treatment accuracy is mandatory in IMRT dose-escalation studies, in order to define the extent of the safety margins and DVHs constraints
Treatment accuracy depends on both daily repositioning uncertainties and random internal organ motion
8
IMRT
• adequate immobilization system• accuracy and set-up reproducibility• evaluation of internal organ motion
Matching portal images on DRR(reference anatomical structures)
C.T. scans taken also at the middle and at the end of RT courseContours re-outlined
DVH evaluation
Study design
Safety margin for PTV
9
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Patients selection:
12 patients at intermediate risk prostate cancer,
without clinical evidence of lymph node and distant
metastases entered our study
10
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Technical procedures:
• Baseline C.T. simulation in prone position in a customized immobilization cradle, including the whole trunk and with a wedge cushion under the ankles
• C.T. scans were acquired with a spiral C.T. and the slides were reconstructed at 5 mm increments
• Digitally reconstructed radiographs (DRR) generated from C.T. data were used as reference images
11
Baseline C.T. simulation in prone position in a customized immobilization cradle with a wedge
cushion under the ankles
12
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Technical procedures:
• The pubic symphysis and the ischiatic bone on L-L DRR, the ilium bone, the ileo-pubic branch and the ischio-pubic branch on A-P DRR were chosen as reference structures
• The evaluation of set-up errors was achieved by means of daily orthogonal portal images
• An online matching of the anatomical structures on portal images allowed a daily isocenter check
13
Comparison between reference images (DRR) and orthogonal portal images
14
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Technical procedures:
• The evaluation of organ motion was achieved by means of two further C.T. scans taken on each patient during radiation therapy course
• The volumes of interest (CTVs and ORs) were re-contoured • In order to eliminate intra-observer variability, CTVs and ORs were
always outlined by the same radiation oncologist
• The new data were transferred to the planning system and the dose distribution was recalculated by using the original beams parameters
15
CTVs volumes outlined on three T.C. scans
CT 1
CT 3
CT 2CTV (L-L view)
CTV (A-P view)
16
Comparison between rectal wall volumes outlined on the three C.T. scans
Rectum (A-P view)
Rectum (L-L view)
CT 1
CT 2
CT 3
17
Modification of volumes of interest and shifts of internal organs
CT 1
CT 3
CT 2
18
DISTRIBUTION OF SYSTEMATIC SET UP ERRORS IN THE THREE DIRECTIONS
-5,0-4,0-3,0-2,0-1,00,0
1,02,03,04,05,06,0
0 1 2 3 4 5 6 7 8 9n.patients
-5,0-4,0-3,0-2,0-1,00,01,02,03,04,05,06,0
0 1 2 3 4 5 6 7 8 9n. patients
-5,0-4,0-3,0-2,0-1,00,01,02,03,04,05,06,0
0 1 2 3 4 5 6 7 8 9n.patients
*J.C. Stroom et al.: Geometrical uncertainties, radiotherapy planning margins, and ICRU-62 report; Radiotherapy and Oncology 64 (2002) 75-83.
LATERAL ANTERIOR-POSTERIOR
CRANIO-CAUDAL
19
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Results and conclusions:
• Our study has shown that the mean shift for the population of the
treatment isocentre with respect to the planning one in the 3
directions was less than 2 mm
• Errors within 2 mm did not significantly influence the behaviour of
both CTV and rectal wall DVHs
• Therefore, margins adopted for PTV seem to be adequate
20
Volumes (cm3) of rectal wall, CTV and PTV to rectal wall intersection calculated from baseline, intermediate and final CT scan
Volumes (cm3)
rectal wall CTV PTV to rectal wall intersection
patient initial intermediate final initial intermediate final initial intermediate final
1 32,56 27,37 32,08 82,54 63,67 61,00 9,29 3,93 2,71
2 38,89 37,27 39,51 56,98 58,59 57,58 5,39 5,55 4,81
3 30,21 29,66 31,03 52,64 53,28 51,97 3,25 3,64 2,55
4 31,72 24,98 32,92 61,23 43,81 52,11 8,14 5,08 6,68
5 53,79 56,28 69,58 63,09 70,05 71,44 6,03 5,85 4,03
6 34,69 32,81 42,53 59,98 62,49 69,24 2,97 2,78 3,20
7 42,59 49,40 49,64 93,39 82,22 93,16 6,44 5,46 6,27
8 39,06 52,61 55,68 74,95 76,79 58,93 5,69 2,26 5,88
9 29,95 47,68 50,00 87,96 72,42 71,65 3,81 8,82 5,84
10 43,18 44,88 49,17 43,11 34,08 42,23 3,22 2,22 3,23
11 29,42 43,18 45,43 95,11 102,8 97,84 4,82 5,42 4,03
12 33,58 37,85 40,12 99,92 108,5 96,84 2,97 3,25 3,3
median value 34,14 40,52 43,98 69,02 66,86 65,12 5,11 4,51 4,03
std deviation 7,23 10,27 11,08 18,87 21,81 18,56 2,08 1,89 1,47
21
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Results and conclusions:
The analysis of CTV and rectal wall volumes has shown
• a slight decrease of CTV (prostate and seminal vesicles) by tumor cell killing
• a slight increase of rectal wall by aedema and congestion, during the treatment course
22
A study on the effect of set-up errors and organ motion in patients treated with IMRT for
prostate cancer
Toxicity:
Acute toxicity: Gr 1 Gr 2 Gr 3
Rectal 4 (33%) 3 (25%) -
Vesical 5 (42%) 3 (25%) 1 (8%)
No late rectal or vesical toxicity was found
23
20-30%
40-50%
60-70%
80-90%
90-100%
100-105%
RATIONALE FOR TREATMENT PLANNING
Five field sliding window technique
IMRT plans were developed using Helios 6.3 on CadPlan v 6.3.5
24
RATIONALE FOR TREATMENT PLANNING
• Prescription: 80 Gy in 40 fractions to the ICRU reference point,
with percent minimum and maximum dose to the PTV of 95%
and 107% respectively. Dose-volume constraints on normal tissues
were: doses ≥ of 70 Gy (V70) and ≥ of 40 Gy (V40) to less than
35% and 60% of rectal wall volume respectively and doses ≥ of 70
Gy (V70) and ≥ of 50 Gy (V50) to less than 50% and 70% of
bladder volume respectively.
• Treatment was delivered by 15 MV photon beams from VARIAN
2100CD linear accelerators, all equipped with Millenium (0.5 cm
leaf width) multileaf collimators (MLC).
25
EFFECT OF SET UP ERRORS ON DVHs
• Original plan was recalculated with the isocentre
shifted from the original one of a quantity equal to the
systematic error measured
• Random errors were assumed averaging to zero
26
EFFECT OF SET UP ERRORS ON DVHs
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90Gy
initial CTV
initial rectal wall
recalculated CTV
recalculated rectal wall
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90Gy
V %
initial rectal wall
recalculated CTV
recalculated rectalwallinitial CTV
3.4 MM IN CRANIAL DIRECTION
1.8 MM IN ANTERIOR DIRECTION
27
EFFECT OF ORGAN MOTION ON DVHs
• At the middle and at the end of treatment, two more CT scans
were taken on each patient (i.e. intermediate and final)
• The volumes of interest were re-contoured by the same radiation
oncologist and the new data transferred to the planning system
• Dose distribution was recalculated on the new CT data by using
the original beam parameters.
28
EFFECT OF ORGAN MOTION ON DVHs
0
10
20
30
40
50
60
70
80
90
100
50 55 60 65 70 75 80 85 90Gy
V %
planning CTV (from initial treatment plan)
treatment CTV (from recalculated plans)
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90Gy
V %
planning rectal w all (from initial treatment plan)
treatment rectal w all (from recalculated plans)RECTAL WALL DVHs
CTV DVHs
Planning DVHs• dose to the 50% of CTV: from 76.8 to 81.2 Gy• dose to the whole CTV: from 75.6 to 84.8 Gy Treatment DVHs • dose to the 50% of CTV: from 75.6 to 81.6 Gy• dose to the whole CTV: from 54.4 to 85.6 Gy
Planning DVHs• median V70 = 26.3 ± 5.8 %• median V40 = 67.4 ± 9.8 %Treatment DVHs • median V70 = 26.0 ± 11.1 % • median V40 = 69.4 ± 12.8 %
29
FREQUENCY HISTOGRAMS OF V70 AND V40 VALUES
0
1
2
3
4
5
6
10 15 20 25 30 35 40 45 50 55 60 65 %
intermediate CTinitial CTfinal CT
0
1
2
3
4
5
6
20 30 40 50 55 60 65 70 75 80 85 90 95 100 %
intermediate CTinitial CT
final CT
PERCENTAGE RECTAL WALL RECEIVING 70 Gy
PERCENTAGE RECTAL WALL RECEIVING 40 Gy
V70 moves beyond the maximum initial volume constraint obtained of
35 % in 5 out of 12
V40 moves beyond the maximum initial volume constraints obtained of
85 % in 3 patients out of 12
No time dependance
30
Vref = whole organ;v = fraction of volume irradiated with a dose D;TD50(1) = tolerance dose that gives 50% probability of damage for whole organ irradiation;m = parameter that gives the slope of the dose-response curve;n = parameter that gives the dependance of TD50 on the fraction of volume irradiated;
n
ref
t
vTDvTD
VV
v
)v(TD*m)v(TDD
t
dt/texpNTCP
1
22
1
50
50
2
• NTCP was calculated from normalized DVHs obtained converting the total physical dose into the biologically
equivalent total dose normalized to 2 Gy per fraction according to the Lyman-Burman-Kutcher model.[1]
RADIOBIOLOGICAL ANALISYS
NORMAL TISSUE COMPLICATION PROBABILITY
[1] Burman C., Kutcher G.J., Emami B., and Gotein M. Fitting of normal tissue tolerance data to an analytic function. Int. J. Radiation Oncology Biol. Phys. 1991; 21: 123-135.
31
• We assumed = 3 Gy for rectum and we used the recently fitted
parameters of TD50=81.9 Gy, n=0.23 and m=0.19 [2]. These
parameters were calculated for a group of patients with minimum
follow-up of 18 months and considered as bleeders if showing
grade ≥ 2 late complication according to a slightly modified
RTOG/EORTC scoring system.
[2]: T.Rancati, Fiorino C., Gagliardi G.M. et al. Analysis of clinical complication data on late rectal bleeding: fitting to different NTCP models.Abstracts of ESTRO. Geneva 12-18 Sept 2003.
RADIOBIOLOGICAL ANALISYS
NORMAL TISSUE COMPLICATION PROBABILITY
32
RADIOBIOLOGICAL ANALISYS
TUMOR CONTROL PROBABILITY
• TCP was calculated by using the Poisson model without taking into account tumor
repopulation. Since patients recruited for this study were those classified at the
intermediate risk group (i.e. PSA=10-20 ng/ml, or Gleason ≥ 7 ,or stage ≥ T2b) we
fitted clinical data for external beam irradiation reported by Fowler et al. [1].
[1] Fowler J., Chappel R. and Ritter M. Int. J. Radiation Oncology Biol. Phys. 2001; 50: 1021-1031.
i
iii DN/DexpvexpTCP
= initial density of clonogenic cells; Di = total dose delivered to the volume vi ;
N = number of fractions; and : parameters of the linear-quadratic model for cell survival
33
RADIOBIOLOGICAL ANALISYS
TUMOR CONTROL PROBABILITY
• The number of clonogenic cells (N0) was estimated by using a Matlab
code according to Starev et al. [2]. For = 0.0391 Gy-1 and = 1.5
Gy our esteem was N0 =253 ± 34
• A mean prostate volume of 72.58 ± 18.87 cm3 was estimated from our
patient population, giving a mean clonogenic cellular density
= 3.48 ± 1.37 cells/cm3
• TCPs were calculated by assuming a costant clonogenic cellular
density and taking into account each patient’s CTV volume
[2] Stavrev P., Nemierko A., Stavreva N., M. Goitein. The Application of Biological Models to Clinical Data. Physica Medica April-June 2001; vol. XVII: 71-82.
34
TCP AND NTCP CALCULATED FROM PLANNING AND TREATMENT DVHS
TCP (%) TCP (%) TCP (%) NTCP norm (%) NTCP norm (%) NTCP norm (%)
patient (planning) (intermediate) (final) (planning) (intermediate) (final)
1 86,08 88,03 88,20 11,04 6,49 2,94
2 87,60 88,27 87,95 8,25 6,92 5,69
3 87,30 89,51 89,37 5,16 10,02 4,27
4 87,67 92,49 90,42 11,61 15,01 5,32
5 85,60 81,18 85,96 4,85 11,60 0,58
6 87,58 86,99 86,05 4,09 3,25 10,32
7 76,56 83,42 82,16 5,47 10,68 10,35
8 78,28 73,45 59,18 9,37 3,76 3,92
9 83,96 83,63 87,22 7,55 22,14 19,16
10 89,31 93,98 92,44 6,56 4,33 11,52
11 71,27 68,27 70,85 6,62 14,43 6,24
12 80,95 77,81 81,46 3,95 5,95 3,44
mean TCP mean TCP mean NTCP mean NTCP
planning treatment planning treatment
83.51±5.57 83.62±7.53 7.04±2.58 7.86±4.65
35
PERCENTAGE DEVIATION FROM INITIAL NTCP
VALUE
-20-17,5
-15-12,5
-10-7,5
-5-2,5
02,5
57,510
12,515
0 1 2 3 4 5 6 7 8 9 10 11 12 13n. patients
PERCENTAGE DEVIATION FROM INITIAL TCP
VALUE
-20-17,5
-15-12,5
-10-7,5
-5-2,5
02,5
57,510
12,515
0 1 2 3 4 5 6 7 8 9 10 11 12 13n. patients
Variations in NTCP are mostly limited to within ± 10 % of the initial value. In only
one patient the intermediate and final NTCP showed values of 11.6 % and 14. 6
% higher than the initial one
Variations in TCP are mostly limited to within ± 5% of the initial
value. In only one patient final TCP was 19.1 % lower than initial
one
36
Results and conclusions
• DVH modification due to organ motion is more considerable than
that produced by set-up errors
• Contrary to the latter, which can be easily detected and quantified
by precise measurement of the shift between rigid structures (i.e.
pelvic bones), organ motion does not occur by a simple translation
of rigid organs but involves several other mechanisms of organ
modification, such as changes in volume, shape and position
produced by different levels of organs filling
• Furthermore, the level of bladder filling can easily be controlled
before each treatment session, whilst rectal filling depends on
several factors (diet, individual intestinal habits, etc.)
37
Results and conclusions
•The analysis of DVHs has shown that CTVs were irradiated by a
homogeneous dose distribution and are not influenced by organ
motion, whilst larger shifts of the rectal wall were observed
•There aren’t significant differences between initial and late TCP
values, whilst the percent deviation from initial values was larger for
NTCP
38
Results and conclusions
Longer follow-up will be necessary to further substantiate our
considerations:
•The prediction of a grade 2 toxicity of ≈ 10%, despite the rectal wall
modifications
•The prediction of the 83% local control, despite the CTV motion