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756Stereotactic brachytherapy of craniopharyngiomas with Y90
S192 754
755
Does the dose to surrounding lung tissue influence the development of lung fibrosis in high dose regions (hot-spots): a study in minpigs.
Ablation of Prostatic Skeletal Secondary Disease using Re186 HEDP
Peter Geyer, Michael Baumann, Anne Knbrr. Lutz Voigtmann, Thomas Hcrrmann Dept. of Radiation Therapy, Technical Univcrsi .ty of Dresden. German>'
Background: In clinical radiation therapy high dose regions in normal tissues such as lung are always surrounded by larger volumes of tissue irradiated to lower doses. Only little is known about the impact of interactions of low dose- and high dose volumes on the expression of radiation damage. Purpose: We examined whether the severity, of lung fibrosis in hot-spots is influenced by the dose applied to surrounding lung tissue. Material and Methods: The right lung of 33 nunipigs was irradiated vdth 9-15 MV x-rays using parallel opposed portals and intensity modulation filters. 5 fractions were applied over 5 days to 35 Gy in the hot-spot (9cm") and 0 to 30 G:,." were given to the surrounding right lung. Positioning errors were documented by daily port films of both fields. The pigs were killed 9 month p.r. and the hydroxyprolm (liP) ratio, ic. the HP concentration in irradiated lung over udirradiated left lung, *,,,'asdetermined as a fibrosis marker (reference value=l.01 [95% upper CL 1.26l). Results: In contrast to our expectations, the HP-ratio in the hot spot increased with the surrounding dose to lung (linear regression: 0.035Gy-I d:0.008 (S.E.), p<0.001). However, even in anaesthesized animals, i~,*i~,ed under experimental cnndi*io-~ p~t'~l[m~tic~nc,f the port film~ revealed that the relauve position of the hot-spot in the same animals vaned considerably during treatment. The me~mareafully irradiated to the pre,cribed hot-spot dose ,,*,,as 28%. Because of these positioning uncertainties a mean hot-spot dose was calculated for each pig from thc hot-spot dose, the overlap area, and the surrounding lung dose using a linear approach. The mean hot-spot dose increased linearly with the dose to surrounding tissue (0.36 ± 0.01, R2=0.97, p <0.001). The liP-ratio increased as a linear function of the mean hot-spot dose (0.1±0.02 Gy-l. p<0.001). Applying partial differentiation it was found that the correlation between liP-ratios and surrounding dose could be fully explained by the dependence of the mean hot-spot dose on the surrounding dose. Conclusion: Our data do not demonstrate an impact of the dose to surrounding lung on the development of fibrosis in a hot-spot. The incidence and severity, of lung fibrosis in the hot-spot seems to depend solely on the radiation dose applied to this volume. Supported by the BMBF (FKZ 07 NBL 03)
P J FON, V R McCREADY, D P DEARNALEY Depts Nuclear Medicine and Radiotherapy, Royal Marsden Hospital, Sutton, Surrey, U.K. Background: The high tumour: background uptake of labelled diphosphonates offers the opportunity of delivering high radiation doses to prostatic skeletal secondaries. This project aims to deliver very high doses with peripheral blood stem cell transplant (PBSCT) to overcome the inevitable bone marrow toxicity. Purpose: A phase I study to ascertain the maximally tolerated dose (MTD) of Rhenium186 HEDP, to define the activity level requiring a PBSCT. Materials & Methods: Patients aged less than 70 years with bony metastases from hormone-refractory prostate cancer were treated with Rhenium186 HEDP. Three patients were treated at each activity level starting at 1500 Mbq, increasing by 500 MBq increments. Toxicity was monitored with FBC, Clotting Studies, PSA and biochemistry. Results:12 patients were analysed. At 3000 MBq, one patient developed pancytopaenia requiring transfusion with red cells and platelets. Another patient developed grade IV thrombocytopaenia. Toxicity was manifest at 6 and 4 weeks post treatment. We found that 2500 MBq was the MTD in our cohort.
Conclusion: Myelosuppression was confirmed as the only toxicity from Rhenium186 HEDP. The MTD was 2500 MBq. Further dose escalation will require peripheral blood stem cell transplantation.
756
757
STEREOTACTIC BRACHYTHERAPY OF CRANIOPHARYNGIOMAS WITH Y~
THE IMPORTANCE OF INTRINSIC HYPOXIA-INDUCED A P O P T O S I S IN C O N T R O L P R O B A B I L I T Y C A L C U L A T I O N S OF FRACTIONATED RADIOTHERAPY
JNovom.~', V. Vladyka. ILLig6Ak,J.Novom3;'Jr.. JMasopasl,l. [;up. Hospital Na Homolce. Prague. Czech Republic A stereotacticbrachytherapy using a colloid Y90 unsealedsource has been applied for the treatment of craniopharyngiomas.The whole procedure consists basically of three steps: a) a stereotactic localization of the tumor with the help of Leksell stereotactic frame; b) a tumor volume determination and Y 90 activity calculation, i. e. treatment planning; c) a
stereotacticapplicationof the calculatedactivity into the tumor volume. A stereotactic Leksell system has been used for localization of the craniopharyngioma tumors and stereotactic application of unsealed sources. It was proved by many investigators and practioners that Leksel] stereotactic system is capable of a tumor localization within +- l mm. Two methods have been employed for measurements of cyst volume: a dilution Tc99 m and a volume reconstruction from CT and MRI Lmages. A cyst volume has been calculated from the CT or MR unages using the soliware available on CT scanner or using the treatment planning system GAMMAPLAN, respectively. The agreement between a tumor volume determined from CT or MR images and from the Tc99 ~ dilutionmethod has been found acceptable only for low dense cyst fluids. It was observed that the Tc99 ~ dilution method underesamate the tmnor volume for high density cyst fluids due to very slow mixing of Tc99 ~ with liquor and therefore the measured value should be not used for activity evaluation. The average value of the effective half-lifeof Y90 in the cysts has been found to be about 50 hours on the basis of gamma camera measurements of patients from studied group. The necessary Y90 activity was determined with the help of equation derived by Loevmger applying the absorbed dose of 200 CO' to the cyst wall for all patients and using a physical half-life value for Y90. Firstclinicaldata will be also shortly discussed.
Dag R. Olsen I , Oystein Amellem 2, Erik O. Petterse 2, I Department of Medical Physics, 2 Department of Tissue Culture, The Norwegian Radium Hospital, Oslo, Norway. Background and purpose: apoptosis has in a number of papers been discussed as a positive predictor for tumour control, based on observations of correlation between apoptotic fraction and total cell kill. Clinical studies have, on the other hand, revealed an inverse correlation between local control and pre-irradiation apoptotic fraction. At our institution, we have c o n d u c t e d preliminary experiments indicating that apoptosis may also be induced by hypoxic stress. Our aim has been to develop a mathematical model for control probability calculations which take into account hypoxia induced apoptosis in fractionated radiotherapy. Materials and methods : based on our own experiments, the preirradiation hypoxia-induced apoptosis was taken as a fraction of the hypoxic fraction. A model for the hypoxic fraction throughout the irradiation regime was established, using the following parameters: the intrinsic hypoxic fraction ct and 13, OER (oxygen enhancement ratio), and the characteristic reoxygenation constant. Cell survival was calculated taking into account both mitotic cell kill and apoptotic cell inactivation, using a modified Ling equation. Control probability (CP) was calculated applying surviving fraction of cells and Poisson statistics. Results and conclusion: our calculations showed, as expected, an increased CP for larger fractions of radiation induced apoptosis, given that the apoptotic radiation susceptibility was larger than the intrinsic mitotic radiation sensitivity (ct), when no hypoxia was present. However, if an increased pre-irradiation apoptotic fraction of cells was introduced due to hypoxia, an inverse correlation between the apoptotic fraction and CP was observed. For mild hypoxia or high fractions of hypoxia-induced apoptosis, the reduction in CP was smaller. Our modelling may therefore indicate that even though apoptosis may be an important component in tumour cell kill after irradiation, one may expect an inverse correlation between CP and pre-irradiation apoptotic fraction, if this apoptosis is induced by hypoxic stress.
755
Does the dose to surrounding lung tissue influence the development of lung fibrosis in high dose regions (hot-spots): a study in minpigs.
Ablation of Prostatic Skeletal Secondary Disease using Re186 HEDP
Peter Geyer, Michael Baumann, Anne Knbrr. Lutz Voigtmann, Thomas Hcrrmann Dept. of Radiation Therapy, Technical Univcrsi .ty of Dresden. German>'
Background: In clinical radiation therapy high dose regions in normal tissues such as lung are always surrounded by larger volumes of tissue irradiated to lower doses. Only little is known about the impact of interactions of low dose- and high dose volumes on the expression of radiation damage. Purpose: We examined whether the severity, of lung fibrosis in hot-spots is influenced by the dose applied to surrounding lung tissue. Material and Methods: The right lung of 33 nunipigs was irradiated vdth 9-15 MV x-rays using parallel opposed portals and intensity modulation filters. 5 fractions were applied over 5 days to 35 Gy in the hot-spot (9cm") and 0 to 30 G:,." were given to the surrounding right lung. Positioning errors were documented by daily port films of both fields. The pigs were killed 9 month p.r. and the hydroxyprolm (liP) ratio, ic. the HP concentration in irradiated lung over udirradiated left lung, *,,,'asdetermined as a fibrosis marker (reference value=l.01 [95% upper CL 1.26l). Results: In contrast to our expectations, the HP-ratio in the hot spot increased with the surrounding dose to lung (linear regression: 0.035Gy-I d:0.008 (S.E.), p<0.001). However, even in anaesthesized animals, i~,*i~,ed under experimental cnndi*io-~ p~t'~l[m~tic~nc,f the port film~ revealed that the relauve position of the hot-spot in the same animals vaned considerably during treatment. The me~mareafully irradiated to the pre,cribed hot-spot dose ,,*,,as 28%. Because of these positioning uncertainties a mean hot-spot dose was calculated for each pig from thc hot-spot dose, the overlap area, and the surrounding lung dose using a linear approach. The mean hot-spot dose increased linearly with the dose to surrounding tissue (0.36 ± 0.01, R2=0.97, p <0.001). The liP-ratio increased as a linear function of the mean hot-spot dose (0.1±0.02 Gy-l. p<0.001). Applying partial differentiation it was found that the correlation between liP-ratios and surrounding dose could be fully explained by the dependence of the mean hot-spot dose on the surrounding dose. Conclusion: Our data do not demonstrate an impact of the dose to surrounding lung on the development of fibrosis in a hot-spot. The incidence and severity, of lung fibrosis in the hot-spot seems to depend solely on the radiation dose applied to this volume. Supported by the BMBF (FKZ 07 NBL 03)
P J FON, V R McCREADY, D P DEARNALEY Depts Nuclear Medicine and Radiotherapy, Royal Marsden Hospital, Sutton, Surrey, U.K. Background: The high tumour: background uptake of labelled diphosphonates offers the opportunity of delivering high radiation doses to prostatic skeletal secondaries. This project aims to deliver very high doses with peripheral blood stem cell transplant (PBSCT) to overcome the inevitable bone marrow toxicity. Purpose: A phase I study to ascertain the maximally tolerated dose (MTD) of Rhenium186 HEDP, to define the activity level requiring a PBSCT. Materials & Methods: Patients aged less than 70 years with bony metastases from hormone-refractory prostate cancer were treated with Rhenium186 HEDP. Three patients were treated at each activity level starting at 1500 Mbq, increasing by 500 MBq increments. Toxicity was monitored with FBC, Clotting Studies, PSA and biochemistry. Results:12 patients were analysed. At 3000 MBq, one patient developed pancytopaenia requiring transfusion with red cells and platelets. Another patient developed grade IV thrombocytopaenia. Toxicity was manifest at 6 and 4 weeks post treatment. We found that 2500 MBq was the MTD in our cohort.
Conclusion: Myelosuppression was confirmed as the only toxicity from Rhenium186 HEDP. The MTD was 2500 MBq. Further dose escalation will require peripheral blood stem cell transplantation.
756
757
STEREOTACTIC BRACHYTHERAPY OF CRANIOPHARYNGIOMAS WITH Y~
THE IMPORTANCE OF INTRINSIC HYPOXIA-INDUCED A P O P T O S I S IN C O N T R O L P R O B A B I L I T Y C A L C U L A T I O N S OF FRACTIONATED RADIOTHERAPY
JNovom.~', V. Vladyka. ILLig6Ak,J.Novom3;'Jr.. JMasopasl,l. [;up. Hospital Na Homolce. Prague. Czech Republic A stereotacticbrachytherapy using a colloid Y90 unsealedsource has been applied for the treatment of craniopharyngiomas.The whole procedure consists basically of three steps: a) a stereotactic localization of the tumor with the help of Leksell stereotactic frame; b) a tumor volume determination and Y 90 activity calculation, i. e. treatment planning; c) a
stereotacticapplicationof the calculatedactivity into the tumor volume. A stereotactic Leksell system has been used for localization of the craniopharyngioma tumors and stereotactic application of unsealed sources. It was proved by many investigators and practioners that Leksel] stereotactic system is capable of a tumor localization within +- l mm. Two methods have been employed for measurements of cyst volume: a dilution Tc99 m and a volume reconstruction from CT and MRI Lmages. A cyst volume has been calculated from the CT or MR unages using the soliware available on CT scanner or using the treatment planning system GAMMAPLAN, respectively. The agreement between a tumor volume determined from CT or MR images and from the Tc99 ~ dilutionmethod has been found acceptable only for low dense cyst fluids. It was observed that the Tc99 ~ dilution method underesamate the tmnor volume for high density cyst fluids due to very slow mixing of Tc99 ~ with liquor and therefore the measured value should be not used for activity evaluation. The average value of the effective half-lifeof Y90 in the cysts has been found to be about 50 hours on the basis of gamma camera measurements of patients from studied group. The necessary Y90 activity was determined with the help of equation derived by Loevmger applying the absorbed dose of 200 CO' to the cyst wall for all patients and using a physical half-life value for Y90. Firstclinicaldata will be also shortly discussed.
Dag R. Olsen I , Oystein Amellem 2, Erik O. Petterse 2, I Department of Medical Physics, 2 Department of Tissue Culture, The Norwegian Radium Hospital, Oslo, Norway. Background and purpose: apoptosis has in a number of papers been discussed as a positive predictor for tumour control, based on observations of correlation between apoptotic fraction and total cell kill. Clinical studies have, on the other hand, revealed an inverse correlation between local control and pre-irradiation apoptotic fraction. At our institution, we have c o n d u c t e d preliminary experiments indicating that apoptosis may also be induced by hypoxic stress. Our aim has been to develop a mathematical model for control probability calculations which take into account hypoxia induced apoptosis in fractionated radiotherapy. Materials and methods : based on our own experiments, the preirradiation hypoxia-induced apoptosis was taken as a fraction of the hypoxic fraction. A model for the hypoxic fraction throughout the irradiation regime was established, using the following parameters: the intrinsic hypoxic fraction ct and 13, OER (oxygen enhancement ratio), and the characteristic reoxygenation constant. Cell survival was calculated taking into account both mitotic cell kill and apoptotic cell inactivation, using a modified Ling equation. Control probability (CP) was calculated applying surviving fraction of cells and Poisson statistics. Results and conclusion: our calculations showed, as expected, an increased CP for larger fractions of radiation induced apoptosis, given that the apoptotic radiation susceptibility was larger than the intrinsic mitotic radiation sensitivity (ct), when no hypoxia was present. However, if an increased pre-irradiation apoptotic fraction of cells was introduced due to hypoxia, an inverse correlation between the apoptotic fraction and CP was observed. For mild hypoxia or high fractions of hypoxia-induced apoptosis, the reduction in CP was smaller. Our modelling may therefore indicate that even though apoptosis may be an important component in tumour cell kill after irradiation, one may expect an inverse correlation between CP and pre-irradiation apoptotic fraction, if this apoptosis is induced by hypoxic stress.