1 A study on the effect of set up errors and organ motion in patients treated with IMRT for prostate...

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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

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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

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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

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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

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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

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.

3D-IMRT

3D-CRT:

Hypothetical Model

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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

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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

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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

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prostate cancer

Patients selection:

12 patients at intermediate risk prostate cancer,

without clinical evidence of lymph node and distant

metastases entered our study

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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

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Baseline C.T. simulation in prone position in a customized immobilization cradle with a wedge

cushion under the ankles

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prostate cancer


• 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

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Comparison between reference images (DRR) and orthogonal portal images

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prostate cancer


• 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

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CTVs volumes outlined on three T.C. scans

CT 1

CT 3

CT 2CTV (L-L view)

CTV (A-P view)

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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

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Modification of volumes of interest and shifts of internal organs

CT 1

CT 3

CT 2

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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

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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

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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

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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

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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

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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

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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).

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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

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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

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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.

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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 %

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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

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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

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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.

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• 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.


NORMAL TISSUE COMPLICATION PROBABILITY

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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

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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.

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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

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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

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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.)

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•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

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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

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