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 Tumor Control Probability TCP/NTCP Model Prescribed Dose Normal Tissue Complication Probability Conventional Radiotherapy 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 course Contours 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 2 CTV (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 *J.C. Stroom et al.: Geometrical uncertainties, radiotherapy planning margins, and ICRU-62 report; Radiotherapy and Oncology 64 (2002) LATERALANTERIOR-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 (cm 3 ) 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 patientinitialintermediatefinalinitialintermediatefinalinitialintermediatefinal 132,5627,3732,0882,5463,6761,009,293,932,71 238,8937,2739,5156,9858,5957,585,395,554,81 330,2129,6631,0352,6453,2851,973,253,642,55 431,7224,9832,9261,2343,8152,118,145,086,68 553,7956,2869,5863,0970,0571,446,035,854,03 634,6932,8142,5359,9862,4969,242,972,783,20 742,5949,4049,6493,3982,2293,166,445,466,27 839,0652,6155,6874,9576,7958,935,692,265,88 929,9547,6850,0087,9672,4271,653,818,825, ,1844,8849,1743,1134,0842,233,222,223, ,4243,1845,4395,11102,897,844,825,424, ,5837,8540,1299,92108,596,842,973,253,3 median value 34,1440,5243,9869,0266,8665,125,114,514,03 std deviation 7,2310,2711,0818,8721,8118,562,081,891,47

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 1Gr 2Gr 3 Rectal 4 (33%) 3 (25%) - Vesical 5 (42%) 3 (25%) 1 (8%) No late rectal or vesical toxicity was found

% 40-50% 60-70% 80-90% % % 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 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 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 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 V ref = whole organ; v = fraction of volume irradiated with a dose D; TD 50 (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 TD 50 on the fraction of volume irradiated; 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:

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 Sept 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:  = initial density of clonogenic cells; D i = total dose delivered to the volume v i ; 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 (N 0 ) was estimated by using a Matlab code according to Starev et al. [2]. For  = Gy-1 and  = 1.5 Gy our esteem was N 0 =253 ± 34 A mean prostate volume of ± cm 3 was estimated from our patient population, giving a mean clonogenic cellular density = 3.48 ± 1.37 cells/cm 3 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:

34 TCP AND NTCP CALCULATED FROM PLANNING AND TREATMENT DVHS

35 PERCENTAGE DEVIATION FROM INITIAL NTCP VALUE PERCENTAGE DEVIATION FROM INITIAL TCP VALUE 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 % 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