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116 oral Impact of uncertainties on rectal NTCP modelling: fitting clinical data with the Lyman model
$54
Monday, October 25, 2004
using the linear quadratic model for cell survival. The effects of reoxygenation, necrosis and acute and chronic hypoxia were included in the modelling process, and the optimum dose distributions with respect to TCP were determined as a function of the model parameters.
Results: The constraint of constant mean dose to the tumor made the dose to the hypoxic compartment a steep function of the size of the hypoxic volume fraction, hence, for small to moderate hypoxic volume fractions, a large increase in dose to the hypoxic compartment could be achieved for a small decrease in dose to the well-oxygenated compartment. The potential gain in TCP from dose redistribution selectively targeting the hypoxic cells was found to be strongly dependent on the degree of reoxygenation assumed present during the course of radiotherapy. An inhomogeneous dose distribution resulted in the optimum TCP for tumors in which no or incomplete reoxygenation occurred, while a homogeneous dose distribution gave maximum TCP in the case of complete or hyper-reoxygenation. Acute hypoxia, which cannot be targeted based on information obtained from imaging modalities, was found to give only a small decrease in TCP for no reoxygenation with moderate acute hypoxic fractions, but to be of increasing importance with increasing degree of reoxygenation and increasing acute hypoxic fraction. TCP decreased sharply as a function of the fraction of chronic hypoxic cells erroneously included in the well-oxygenated compartment, underlining the need for a high degree of accuracy in dose delivery. A case study of a spontaneous canine head and neck tumor, in which tumor pretreatment oxygenation levels were assessed with dynamic contrast enhanced MRI and used as input information in the modelling process, will be presented.
Conclusion: Redistributing dose according to tumor oxygenation status might result in increased TCP when tumor response to radiotherapy is limited by chronic hypoxia, but further work is needed on the realization and evaluation of targeted, inhomogeneous dose distributions. 115 oral Modelling the biological effect around an isotropic lowenergy x-ray source used for intraoperative tumour bed irradiation
C. Herskind, V. Steil, U. Kraus-Tiefenbacher, F. Wenz Mannheim Medical Center, University of Heidelberg, Dept. of Radiation Oncology, Mannheim, Germany Purpose: Intraoperative radiotherapy (IORT) with isotropic lowenergy x-rays is undergoing randomised clinical trial for local tumour bed irradiation in low-risk breast cancer patients. The biological effect of this modality may differ from conventional radiotherapy owing to the increased relative biological effectiveness (RBE) of low-energy photons, the steep dose gradient of the source and repair during protracted single-dose irradiation. The purpose was to assess the influence of these parameters by modelling the distribution of biological effect as a function of distance in the tumour bed for normal tissue and tumour cells. Method: Spherical applicators of different diameters are used for tumour bed irradiation with a miniaturized x-ray machine (Intrabeam®, Carl Zeiss Oberkochen) emitting 30-50 kV x-rays from the target at the end of a 0.3 x 10 cm drift tube. A modification of the linear-quadratic formalism by Brenner et al. (Phys.Med.Biol. 44:323-33, 1999) was used to calculate RBE as a function of dose with and without the effect of repair. A single fraction of 50 kV x-rays with a dose of 20 Gy at the applicator surface was assumed. The biological response was modelled as a function of distance in the tissue based on dose,
Proffered papers
RBE and published dose-response data for conventional highenergy photons.
Results: RBE values calculated for late reaction (o~/l~ =3 for conventional photon irradiation) increased with distance from the applicator surface (RBE=0.92-1.13) reaching a value of 1.5 at 13-21 mm, depending on applicator diameter and repair. The depth for EDs0 yielded values in the range 6-11 mm for pneumonitis and 3-7 mm for subcutaneous fibrosis. The RBE for tumour cells (~/~ =10 for conventional photons) was higher than for late-reacting tissue. At small distances from the applicator, control of tumour cells was estimated to be higher than for conventional radiotherapy but decreased with increasing distance. Conclusion: The applicator diameter is an important parameter for the depth profile of biological effect. However, normal-tissue reaction is expected to be limited owing to the thickness of the thorax wall and to the volume effect. For control of recurrence within the tumour bed, the modelling suggests the existence of a "sphere of equivalence" between tumour bed irradiation and conventional irradiation comprising a major part of the first 10 mm of depth in the tumour bed. Supported by a grant from Carl Zeiss Oberkochen. 116 oral
Impact of uncertainties on rectal NTCP modelling: fitting clinical data with the Lyman model
T. Rancatf, F. Foppiano 3, M. Pasquino 4, M. Stasl~, C. Fiorino 2 ~Univ of Milan, Physics Dept, Milan, Italy 2H.S. Raffaele, Medical Physics, Milan, Italy 3National Institute of Cancer, Medical Physics, Genova, Italy 40spedale Civile, Medical Physics, Ivrea, Italy 51stituto per la Ricerca e Cura del Cancro, Medical Physics, Candiolo, Italy Purpose: estimate the impact of uncertainties (contour!ng, organ motion, set-up errors) on best fitted (bf) parameters calculated fitting the Lyman-Kutcher-Burman (LKB) model to the clinical outcome on late rectal bleeding (Irb) after radiotherapy (RT) for prostate cancer. Materials/Methods: within the Italian AIRO working group on prostate RT, rectal dose-volume histograms (DVH) and clinical data of 547 patients (pts) pooled from 5 institutions were analyzed. Pts were treated mainly at 70-78 Gy: both radically treated pts (rad-pts) and pts who underwent prostatectomy before RT (surg-pts) were included. Rectum (including filling) was contoured from anal verge up to sigmoid. Minimum followup was 18 months. Pts were considered as bleeders if showing grade 2/3 Irb (slightly modified RTOG/EORTC scoring system) within 18 months after the end of RT. The bf parameters for the LKB model were fitted to pt data using a maximum likelihood analysis: results were recently presented (IJROBP 2003(57(s2)) $392 and RO 2003(68(sl)) $66). The impact of uncertainties on the model bf parameters was investigated by an iterative approach: the fitting procedure was repeated several (1000) times and each time and for each patient a new DVH was sampled (to take uncertainties into account) according to a simple Gaussian-like deformation of the DVHs. In this way, a distribution of bf parameters is obtained. This simple modelling of uncertainties was derived from a number of studies previously undertaken within the working group: a study on contouring uncertainty (IJROBP 2003(57) 573) showing that DVH modifications due to inter-observer variability can be described trough a gaussian distribution with s=3.5% between 40Gy and the 95% of prescribed dose, and with s=5% in the high-dose region; and two studies on organ motion (rad-pts and surg-pts considered separately). These studies individuated an approximately constant s value for random error around 5-6%
Proffered papers
between 40Gy and Dmax: both investigations also detected an average systematic shift between planned DVHs and the average DVHs during therapy in the two studied populations. Set-up error was estimated to have s=5%. Starting from the s values reported above, a sensitivity study was conducted; s were varied between 50% and 150% of their absolute value, with and without the presence of average systematic shift due to organ motion. Different values of average systematic shift were considered Results: Grade 2/3 Irb were considered in this analysis (38/547 Irb). The impact of the uncertainties resulted in a gaussian distribution of bf parameters for LKB model. As expected, mean values of bf parameter distributions were equa! to the originally derived values (i.e. calculated without including DVH uncertainties): n=0.23, m=0.19 and D50=81.9Gy, the half-width of bf parameter distributions varies between 2% and 10%; the introduction of possible systematic shifts due to organ motion induces a variation of the bf parameters; depending on the entity of the average shift, n varies between 0.19 and 0.23, m between 0.16 and 0.19 and D50 between 78.2 Gy and 82 Gy. When only grade 3 Irb are considered, the spread of the distribution of bf parameters becomes relatively high, probably due to the low number of grade 3 events (9/547). Conclusions: the results of this study showed that the bf parameters calculated fitting the LKB model to Irb are robust enough when grade 2/3 tox are considered together, and that the introduction of uncertainties in DVH values do not change in a significant way bf results. The simple method of DVH deformation here used could simply be modified to further model the impact of uncertainties, even using more refined error distributions
Monday, October 25, 2004 $55
Monday, October 25, 2004
using the linear quadratic model for cell survival. The effects of reoxygenation, necrosis and acute and chronic hypoxia were included in the modelling process, and the optimum dose distributions with respect to TCP were determined as a function of the model parameters.
Results: The constraint of constant mean dose to the tumor made the dose to the hypoxic compartment a steep function of the size of the hypoxic volume fraction, hence, for small to moderate hypoxic volume fractions, a large increase in dose to the hypoxic compartment could be achieved for a small decrease in dose to the well-oxygenated compartment. The potential gain in TCP from dose redistribution selectively targeting the hypoxic cells was found to be strongly dependent on the degree of reoxygenation assumed present during the course of radiotherapy. An inhomogeneous dose distribution resulted in the optimum TCP for tumors in which no or incomplete reoxygenation occurred, while a homogeneous dose distribution gave maximum TCP in the case of complete or hyper-reoxygenation. Acute hypoxia, which cannot be targeted based on information obtained from imaging modalities, was found to give only a small decrease in TCP for no reoxygenation with moderate acute hypoxic fractions, but to be of increasing importance with increasing degree of reoxygenation and increasing acute hypoxic fraction. TCP decreased sharply as a function of the fraction of chronic hypoxic cells erroneously included in the well-oxygenated compartment, underlining the need for a high degree of accuracy in dose delivery. A case study of a spontaneous canine head and neck tumor, in which tumor pretreatment oxygenation levels were assessed with dynamic contrast enhanced MRI and used as input information in the modelling process, will be presented.
Conclusion: Redistributing dose according to tumor oxygenation status might result in increased TCP when tumor response to radiotherapy is limited by chronic hypoxia, but further work is needed on the realization and evaluation of targeted, inhomogeneous dose distributions. 115 oral Modelling the biological effect around an isotropic lowenergy x-ray source used for intraoperative tumour bed irradiation
C. Herskind, V. Steil, U. Kraus-Tiefenbacher, F. Wenz Mannheim Medical Center, University of Heidelberg, Dept. of Radiation Oncology, Mannheim, Germany Purpose: Intraoperative radiotherapy (IORT) with isotropic lowenergy x-rays is undergoing randomised clinical trial for local tumour bed irradiation in low-risk breast cancer patients. The biological effect of this modality may differ from conventional radiotherapy owing to the increased relative biological effectiveness (RBE) of low-energy photons, the steep dose gradient of the source and repair during protracted single-dose irradiation. The purpose was to assess the influence of these parameters by modelling the distribution of biological effect as a function of distance in the tumour bed for normal tissue and tumour cells. Method: Spherical applicators of different diameters are used for tumour bed irradiation with a miniaturized x-ray machine (Intrabeam®, Carl Zeiss Oberkochen) emitting 30-50 kV x-rays from the target at the end of a 0.3 x 10 cm drift tube. A modification of the linear-quadratic formalism by Brenner et al. (Phys.Med.Biol. 44:323-33, 1999) was used to calculate RBE as a function of dose with and without the effect of repair. A single fraction of 50 kV x-rays with a dose of 20 Gy at the applicator surface was assumed. The biological response was modelled as a function of distance in the tissue based on dose,
Proffered papers
RBE and published dose-response data for conventional highenergy photons.
Results: RBE values calculated for late reaction (o~/l~ =3 for conventional photon irradiation) increased with distance from the applicator surface (RBE=0.92-1.13) reaching a value of 1.5 at 13-21 mm, depending on applicator diameter and repair. The depth for EDs0 yielded values in the range 6-11 mm for pneumonitis and 3-7 mm for subcutaneous fibrosis. The RBE for tumour cells (~/~ =10 for conventional photons) was higher than for late-reacting tissue. At small distances from the applicator, control of tumour cells was estimated to be higher than for conventional radiotherapy but decreased with increasing distance. Conclusion: The applicator diameter is an important parameter for the depth profile of biological effect. However, normal-tissue reaction is expected to be limited owing to the thickness of the thorax wall and to the volume effect. For control of recurrence within the tumour bed, the modelling suggests the existence of a "sphere of equivalence" between tumour bed irradiation and conventional irradiation comprising a major part of the first 10 mm of depth in the tumour bed. Supported by a grant from Carl Zeiss Oberkochen. 116 oral
Impact of uncertainties on rectal NTCP modelling: fitting clinical data with the Lyman model
T. Rancatf, F. Foppiano 3, M. Pasquino 4, M. Stasl~, C. Fiorino 2 ~Univ of Milan, Physics Dept, Milan, Italy 2H.S. Raffaele, Medical Physics, Milan, Italy 3National Institute of Cancer, Medical Physics, Genova, Italy 40spedale Civile, Medical Physics, Ivrea, Italy 51stituto per la Ricerca e Cura del Cancro, Medical Physics, Candiolo, Italy Purpose: estimate the impact of uncertainties (contour!ng, organ motion, set-up errors) on best fitted (bf) parameters calculated fitting the Lyman-Kutcher-Burman (LKB) model to the clinical outcome on late rectal bleeding (Irb) after radiotherapy (RT) for prostate cancer. Materials/Methods: within the Italian AIRO working group on prostate RT, rectal dose-volume histograms (DVH) and clinical data of 547 patients (pts) pooled from 5 institutions were analyzed. Pts were treated mainly at 70-78 Gy: both radically treated pts (rad-pts) and pts who underwent prostatectomy before RT (surg-pts) were included. Rectum (including filling) was contoured from anal verge up to sigmoid. Minimum followup was 18 months. Pts were considered as bleeders if showing grade 2/3 Irb (slightly modified RTOG/EORTC scoring system) within 18 months after the end of RT. The bf parameters for the LKB model were fitted to pt data using a maximum likelihood analysis: results were recently presented (IJROBP 2003(57(s2)) $392 and RO 2003(68(sl)) $66). The impact of uncertainties on the model bf parameters was investigated by an iterative approach: the fitting procedure was repeated several (1000) times and each time and for each patient a new DVH was sampled (to take uncertainties into account) according to a simple Gaussian-like deformation of the DVHs. In this way, a distribution of bf parameters is obtained. This simple modelling of uncertainties was derived from a number of studies previously undertaken within the working group: a study on contouring uncertainty (IJROBP 2003(57) 573) showing that DVH modifications due to inter-observer variability can be described trough a gaussian distribution with s=3.5% between 40Gy and the 95% of prescribed dose, and with s=5% in the high-dose region; and two studies on organ motion (rad-pts and surg-pts considered separately). These studies individuated an approximately constant s value for random error around 5-6%
Proffered papers
between 40Gy and Dmax: both investigations also detected an average systematic shift between planned DVHs and the average DVHs during therapy in the two studied populations. Set-up error was estimated to have s=5%. Starting from the s values reported above, a sensitivity study was conducted; s were varied between 50% and 150% of their absolute value, with and without the presence of average systematic shift due to organ motion. Different values of average systematic shift were considered Results: Grade 2/3 Irb were considered in this analysis (38/547 Irb). The impact of the uncertainties resulted in a gaussian distribution of bf parameters for LKB model. As expected, mean values of bf parameter distributions were equa! to the originally derived values (i.e. calculated without including DVH uncertainties): n=0.23, m=0.19 and D50=81.9Gy, the half-width of bf parameter distributions varies between 2% and 10%; the introduction of possible systematic shifts due to organ motion induces a variation of the bf parameters; depending on the entity of the average shift, n varies between 0.19 and 0.23, m between 0.16 and 0.19 and D50 between 78.2 Gy and 82 Gy. When only grade 3 Irb are considered, the spread of the distribution of bf parameters becomes relatively high, probably due to the low number of grade 3 events (9/547). Conclusions: the results of this study showed that the bf parameters calculated fitting the LKB model to Irb are robust enough when grade 2/3 tox are considered together, and that the introduction of uncertainties in DVH values do not change in a significant way bf results. The simple method of DVH deformation here used could simply be modified to further model the impact of uncertainties, even using more refined error distributions
Monday, October 25, 2004 $55