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64 Invited The essential parameters used in treatment planning of endovascular brachytherapy
$20 Wednesday, 18 September 2002
Conclusions: In our study hif-la immunoreactivity was a predictive marker for clinical complete remission after radiotherapy and an independent prognostic marker for overall surivaL From correlation with anemia and the histological staining pattern hif-la may be used as a marker for hypoxia, which can attribute to radioresistance, 63
Oral
Hypoxia-indueed metastasis in human melanoma xenografts E.K. Rofstad The Norwegian Radium Hospital, Department of Biophysics, Os/o, Norway Hypoxic regions are present in many experimental and human tumors, and hypoxia is associated with poor prognosis in human cancer. The significance of hypoxia in the primary tumor for the development of metastatic disease was investigated in the present work by using D-12 and R-18 human melanoma xenograffs as models of cancer in humans. D-12 tumors give rise to pulmonary metastases and R-18 tumors metastasize to lymph nodes when growing intradermally in BALB/c-nu/nu mice. Pimonidazole was used as a hypoxia marker, and hypoxia and hypoxia-induced gone up-regulation were studied in adjacent histological sections by immunohistochemistry. Interleukin-8 (IL-8)-positive regions showed a high degree of colocalization with hypoxic regions in D-12 tumors, and urokinase-type plasminogen activator receptor (uPAR)-positive regions showed a high degree of colocalization with hypoxic regions in R-18 tumors. There was a strong correlation between IL-8 positive fraction and hypoxic fraction in individual D-12 tumor and between uPAR-positive fraction and hypoxic fraction in individual R-18 tumors. Vascular hot spots were found to be induced in hypoxic loci in D-12 tumors, owing to hypoxia-induced up-regulation of IL-8. Metastatic D-12 tumors showed a significantly higher hypoxic fraction, a significantly higher IL-8 positive fraction, and a significantly higher density of vascular hot spots than nonmetastatic D-12 tumors of the same size. Similarly, metastatic R18 tumors showed a significantly higher hypoxic fraction and a significantly higher uPAR positive fraction than nonmetastatic R-18 tumors. Treatment with neutralizing antibody against IL-8 inhibited metastasis in D-12 tumors significantly, and treatment with neutralizing antibody against uPAR provented metastasis in R-18 tumors almost completely. The present work demonstrates that hypoxia promotes spontaneous pulmonary metastasis in D-12 human melanoma xenografts by up-regulating IL-8 and promotes spontaneous lymph node metastasis in R-18 human melanoma xenografts by up-regulating uPAR. Consequently, hypoxia in the primary tumor may induce metastatic disease by up-regulating the expression of gone products involved in the metastatic cascade by activating oxygen sensors, hypoxia signal transduction pathways, and DNA transcription factors,
NEW BRACHYTHERAPY APPLICATIONS 64
Invited
The essential parameters used in treatment planning o f endovascular brachytherapy C. Kirisits 1, R. Schmid 1, B. Syeda 2, B. Pokrajac 1, D. G/ogat2, R. P6tter 1, D. Georg 1
1University of Vienna, Dept. of radiotherapy and radiobio/ogy, Vienna, Austria 2University of Vienna, Dept. of cardiology, Vienna, Austria The EVA GEC ESTRO working group introduced a general concept for target and dose specification in endovascular brachytherapy. Important parameters for treatment planning in longitudinal direction are the amount of safety margin to be added to the Interventional Length (IL) and the Referonce Isodose Length (RIL). Dose prescription and reporting is based on the reference dose rate and the radial dose profile of the sources used. Determination of the reference dose rate, the RIL and the radial dose profile was performed by using GafChromic film dosimetry and Monte Carlo (EGSnrc) calculations for commercial devices. In order to estimate the positioning inaccuracies of the delivery catheter a retrospective study was performed using the angiographic documentation of 116 treatments. The IL was determined by analysing the documented dilation balloons and was related to the RIL of the ac'(ual active source positions. Lengths in angiography were measured by using balloon markers, source edges or catheter markers, all of known geometry as a reference scale, Monte Carlo calculated dose distributions are in good agreement to the film measurements. The radial dose profiles are close to the values given by the manufactures for distances more than 2 mm from the source axis. The absolute dose rate at the reference distance was within + 5% for the 90St seed train used in a 5F delivery system, but shows deviations up to 15 % in
Proffered papers
case of the 90Sr seed train for the 3.5F system and the 32P wire source. The analysis of the angiographic documentation of tL and RIL shows the amount of "geographic miss" directly related to the applied safety margin i.e. the difference between IL and RIL. A margin of at least 10 mm resulted in an adequate coverage in more than 90% of the analysed cases. Based on the determined RIL and the evaluation of safety margins it is recommended to allow a maximum IL of 25 mm and 45 mm for a 40 and 60 mm 90Sr seed train and 26 mm and 46 mm for 2 or 3 steps with a 20 mm 32P wire source. In case of IL values exceeding these values a multisegment treatment has to be performed. The complete radial dose curves allows to use proper prescription concepts and reporting of dose at reference points related to the vessel anatomy. The determination of the referonce dose rate shows inaccuracies and additional work has to be performed to ensure proper calibration and verification methods to be used in clinical practice. 65
Invited
CT/MRI assisted brachytherapy in gynaecology R. Pdtter, S. Wachter, N. Gerstner-Wachter, C. Kirisits, C. Fe//ner, T.H. Knocke Department of Radiotherapy and Radiobiology, University of Vienna, Vienna, Austria. For more than a decade the importance of MRI on staging for patients with cervical carcinoma has been demonstrated. Since 1998 MRI &ssisted brachytherapy treatment planning has been systematically explored and then introduced into the day to day treatment planning process at Vienna University due to a dedicated low cost low-field MRI-system (Magnetom Open Viva, -500.000 ~;, 0.2 T, Siemens) which was then installed in the division of brachytherapy. The clinical experience was based on the traditional treatment strategy in cervix carcinoma at Vienna University: EBT: 45-50 Gy, (ICRU-point) and intracervical HDR-brachytherapy (3-6 fractions, 6- 9 Gy at point A), depending on the initial tumour size and stage (POtter et al. Cancer Radiother., 2000). Since 1998/99 more than 130 patients underwent a systematic MRt assisted 3D treatment planning for HDR-brachytherapy with a MRI compatible ring-tandem applicator in place (altogether >300 MRI examinations). Organ contouring was systematically introduced first for the rectum, bladder, sigma and bowel. Dose constraints for the rectum and bladder ICRU point were based on the clinical experience collected with radiography based individual dosimetry (ICRU points for rectum and bladder), where a total close of 120-130 Gy3 was found to be a critical dose value for significant late side effects. This dose was related to a fixed volume of the critical organ which was assumed to be relevant for the induction of late side effects: 2 cc and 5 cc. The next step was to explore and introduce the contouring of the GTV and CTV based on the signal alteration on T2-weighted MR images at the time of brachytherapy with the applicator in place, taking into account the tumour extension before treatment. A total dose of 80-90 Gy (6-8 Gy per fraction) was individually prescribed to this CTV and reported additionally in point A. For patients with parametrial residual disease after EBT beyond the treated volume, MRI assisted parametrial needle placement was performed. MR-images were directly sent to the treatment planning system after contouring of GTV, CTV and organs at risk (OAR). HDR treatment was only performed after adaptation of source positions and dwell times and evaluation of dose-volume histograms (DVH) for all relevant structures based on the actual MRI examination for each fraction. Tumour delineation with MRI-compatible applicators in situ was feasible in the majority of patients. Enhanced soft tissue representation and multiplanar visualisation of tumour at time of brachytherapy and OAR improved plan adaptation significantly. Plan evaluation based on MRI assisted treatment planning and DVH analysis indicated an improvement as compared to radiography-based treatment planning and also to CT-based treatment planning, which had been the standard procedure until 1998. Dose escalation became possible from 80 Gy in point A (1993-1997) to mean 87 Gy (19982002) in advanced disease. Morbidity at the same time was remarkably reduced with 10/187 grade Ill/IV late side effects at the digestive system in the old period and only 1/130 in the recent period. MRI-based brachytherapy treatment planning offers a new and challenging approach to high conformal dose-escalated brachytherapy for patients with cervical carcinoma, even with unfavourable tumour size or parametrial involvement. However, extensive requirements with regard to personnel, time and complex organisation procedures are at present major challenges which have to be overcome.
Conclusions: In our study hif-la immunoreactivity was a predictive marker for clinical complete remission after radiotherapy and an independent prognostic marker for overall surivaL From correlation with anemia and the histological staining pattern hif-la may be used as a marker for hypoxia, which can attribute to radioresistance, 63
Oral
Hypoxia-indueed metastasis in human melanoma xenografts E.K. Rofstad The Norwegian Radium Hospital, Department of Biophysics, Os/o, Norway Hypoxic regions are present in many experimental and human tumors, and hypoxia is associated with poor prognosis in human cancer. The significance of hypoxia in the primary tumor for the development of metastatic disease was investigated in the present work by using D-12 and R-18 human melanoma xenograffs as models of cancer in humans. D-12 tumors give rise to pulmonary metastases and R-18 tumors metastasize to lymph nodes when growing intradermally in BALB/c-nu/nu mice. Pimonidazole was used as a hypoxia marker, and hypoxia and hypoxia-induced gone up-regulation were studied in adjacent histological sections by immunohistochemistry. Interleukin-8 (IL-8)-positive regions showed a high degree of colocalization with hypoxic regions in D-12 tumors, and urokinase-type plasminogen activator receptor (uPAR)-positive regions showed a high degree of colocalization with hypoxic regions in R-18 tumors. There was a strong correlation between IL-8 positive fraction and hypoxic fraction in individual D-12 tumor and between uPAR-positive fraction and hypoxic fraction in individual R-18 tumors. Vascular hot spots were found to be induced in hypoxic loci in D-12 tumors, owing to hypoxia-induced up-regulation of IL-8. Metastatic D-12 tumors showed a significantly higher hypoxic fraction, a significantly higher IL-8 positive fraction, and a significantly higher density of vascular hot spots than nonmetastatic D-12 tumors of the same size. Similarly, metastatic R18 tumors showed a significantly higher hypoxic fraction and a significantly higher uPAR positive fraction than nonmetastatic R-18 tumors. Treatment with neutralizing antibody against IL-8 inhibited metastasis in D-12 tumors significantly, and treatment with neutralizing antibody against uPAR provented metastasis in R-18 tumors almost completely. The present work demonstrates that hypoxia promotes spontaneous pulmonary metastasis in D-12 human melanoma xenografts by up-regulating IL-8 and promotes spontaneous lymph node metastasis in R-18 human melanoma xenografts by up-regulating uPAR. Consequently, hypoxia in the primary tumor may induce metastatic disease by up-regulating the expression of gone products involved in the metastatic cascade by activating oxygen sensors, hypoxia signal transduction pathways, and DNA transcription factors,
NEW BRACHYTHERAPY APPLICATIONS 64
Invited
The essential parameters used in treatment planning o f endovascular brachytherapy C. Kirisits 1, R. Schmid 1, B. Syeda 2, B. Pokrajac 1, D. G/ogat2, R. P6tter 1, D. Georg 1
1University of Vienna, Dept. of radiotherapy and radiobio/ogy, Vienna, Austria 2University of Vienna, Dept. of cardiology, Vienna, Austria The EVA GEC ESTRO working group introduced a general concept for target and dose specification in endovascular brachytherapy. Important parameters for treatment planning in longitudinal direction are the amount of safety margin to be added to the Interventional Length (IL) and the Referonce Isodose Length (RIL). Dose prescription and reporting is based on the reference dose rate and the radial dose profile of the sources used. Determination of the reference dose rate, the RIL and the radial dose profile was performed by using GafChromic film dosimetry and Monte Carlo (EGSnrc) calculations for commercial devices. In order to estimate the positioning inaccuracies of the delivery catheter a retrospective study was performed using the angiographic documentation of 116 treatments. The IL was determined by analysing the documented dilation balloons and was related to the RIL of the ac'(ual active source positions. Lengths in angiography were measured by using balloon markers, source edges or catheter markers, all of known geometry as a reference scale, Monte Carlo calculated dose distributions are in good agreement to the film measurements. The radial dose profiles are close to the values given by the manufactures for distances more than 2 mm from the source axis. The absolute dose rate at the reference distance was within + 5% for the 90St seed train used in a 5F delivery system, but shows deviations up to 15 % in
Proffered papers
case of the 90Sr seed train for the 3.5F system and the 32P wire source. The analysis of the angiographic documentation of tL and RIL shows the amount of "geographic miss" directly related to the applied safety margin i.e. the difference between IL and RIL. A margin of at least 10 mm resulted in an adequate coverage in more than 90% of the analysed cases. Based on the determined RIL and the evaluation of safety margins it is recommended to allow a maximum IL of 25 mm and 45 mm for a 40 and 60 mm 90Sr seed train and 26 mm and 46 mm for 2 or 3 steps with a 20 mm 32P wire source. In case of IL values exceeding these values a multisegment treatment has to be performed. The complete radial dose curves allows to use proper prescription concepts and reporting of dose at reference points related to the vessel anatomy. The determination of the referonce dose rate shows inaccuracies and additional work has to be performed to ensure proper calibration and verification methods to be used in clinical practice. 65
Invited
CT/MRI assisted brachytherapy in gynaecology R. Pdtter, S. Wachter, N. Gerstner-Wachter, C. Kirisits, C. Fe//ner, T.H. Knocke Department of Radiotherapy and Radiobiology, University of Vienna, Vienna, Austria. For more than a decade the importance of MRI on staging for patients with cervical carcinoma has been demonstrated. Since 1998 MRI &ssisted brachytherapy treatment planning has been systematically explored and then introduced into the day to day treatment planning process at Vienna University due to a dedicated low cost low-field MRI-system (Magnetom Open Viva, -500.000 ~;, 0.2 T, Siemens) which was then installed in the division of brachytherapy. The clinical experience was based on the traditional treatment strategy in cervix carcinoma at Vienna University: EBT: 45-50 Gy, (ICRU-point) and intracervical HDR-brachytherapy (3-6 fractions, 6- 9 Gy at point A), depending on the initial tumour size and stage (POtter et al. Cancer Radiother., 2000). Since 1998/99 more than 130 patients underwent a systematic MRt assisted 3D treatment planning for HDR-brachytherapy with a MRI compatible ring-tandem applicator in place (altogether >300 MRI examinations). Organ contouring was systematically introduced first for the rectum, bladder, sigma and bowel. Dose constraints for the rectum and bladder ICRU point were based on the clinical experience collected with radiography based individual dosimetry (ICRU points for rectum and bladder), where a total close of 120-130 Gy3 was found to be a critical dose value for significant late side effects. This dose was related to a fixed volume of the critical organ which was assumed to be relevant for the induction of late side effects: 2 cc and 5 cc. The next step was to explore and introduce the contouring of the GTV and CTV based on the signal alteration on T2-weighted MR images at the time of brachytherapy with the applicator in place, taking into account the tumour extension before treatment. A total dose of 80-90 Gy (6-8 Gy per fraction) was individually prescribed to this CTV and reported additionally in point A. For patients with parametrial residual disease after EBT beyond the treated volume, MRI assisted parametrial needle placement was performed. MR-images were directly sent to the treatment planning system after contouring of GTV, CTV and organs at risk (OAR). HDR treatment was only performed after adaptation of source positions and dwell times and evaluation of dose-volume histograms (DVH) for all relevant structures based on the actual MRI examination for each fraction. Tumour delineation with MRI-compatible applicators in situ was feasible in the majority of patients. Enhanced soft tissue representation and multiplanar visualisation of tumour at time of brachytherapy and OAR improved plan adaptation significantly. Plan evaluation based on MRI assisted treatment planning and DVH analysis indicated an improvement as compared to radiography-based treatment planning and also to CT-based treatment planning, which had been the standard procedure until 1998. Dose escalation became possible from 80 Gy in point A (1993-1997) to mean 87 Gy (19982002) in advanced disease. Morbidity at the same time was remarkably reduced with 10/187 grade Ill/IV late side effects at the digestive system in the old period and only 1/130 in the recent period. MRI-based brachytherapy treatment planning offers a new and challenging approach to high conformal dose-escalated brachytherapy for patients with cervical carcinoma, even with unfavourable tumour size or parametrial involvement. However, extensive requirements with regard to personnel, time and complex organisation procedures are at present major challenges which have to be overcome.