- Email: [email protected]
32 Final results of in vitro tests of the equivalence between pulsed dose rate and continuous low dose rate irradiation
S8
30
29 HDR- and LDR- interstitial irradiation (IRT) in rat spinal effect of decreasing the d&se rate and the impact of a rapid ON over the spinal cord.
cord: the dose fall
L.A.M. Pop, M. van der Plas, A. E. J. Hanssen and A.J.van der Kogel. Institute of Radiotherapy, University of Nijmegen, 6500 HB Nijmegen. The Netherlands. Introduction: Detailed knowledge of radiobiological parameters of the different tissues involved are warranted before HDR- and recently PDRbrachytherapy can be successfully introduced in clinical practice -as an alternative to LDR- brachvtherauv. The o-se of this studv is to determine the c@ ratio a& half time of ;ep& of rat spinal cbrd during continuous irradiation at different dose rates and to investigate the impact of a rapid dose fall off over the spinal cord thickness. Material and methods: Two parallel catheters are inserted on each side of the vertebral bodies from the level of Th,O to L,. These catheters were afterloaded with two ‘921r- wires of 4 cm length each (activity I- IO mCi/cm) or connected to the HDR- microSelectron. Serial experiments have been carried out to obtain complete dose response curves at 5 different dose rates, resp. 0.5, 0.9, 1.6, 2.6 and 120 Gyih. Paralysis of the hlndlegs after 5-6 months and histopatbological examination of the spinal cord of each animal are used as experimental endpoints. Dosevolume histograms of each irradiated rat have been analyscd to evaluate the correlation between dose distribution and biological response and the hlstopathological damage seen. Results: The distribution of the histological damage was a good reflection of the rapid dose fall-off over the spinal cord. with white matter necrosis or demyelination predominantly seen in the dorsal tracts of the spinal cord or dorsal roots. With each reduction of the dose rate, spinal cord tolerance was significantly increased, with a maximum dose rate factor of 4.3 if the dose rate was reduced from 120 Gyih to 0.53 Gyih. Estimates of the repair parameters using different types of analysis revealed an o& ratio of 2.44 Gv and a (mono- exwnential) half time of repair (=tl/Z) df 1.43 hours; forihe maximum of i50 % of the prescribed dose these values were 3.67 Gv and I .43 hours resoectivelv. Conclusions: Spinal cord radi&m tolerance is sig’tificantfy increased by a reduction in dose rate. In dependence of the dose prescription, the a/l3 ratio varies between 2.44 and 3.67 Gv. while the half time of reualr is I.43 hours. No indication was found for a biphasic pattern of the kihetxs of rep&r. The distribution of histopathological damage in the spinal cord as a reflection of the rapid dose tall off will be discussed.
Bicitogicat effect of Pulsed Doaa Rate braahytherapy wiul m somces Erik F M Van Limbergen. MD, PhD. and Jack F Fcwier. PhD, DSc Department of Oncology. University Hospital Gaathuiirg. 3ooo Leuven, Belgium. Putpoaa: To explore the possible increase of radiation effed in tissues irradiated by puked brachytherapy (PDR). fw local tisaua doae*tes between those “averaged over the whole pulse” and the instantaneous high dose rates close to the dwell positions. A” earlier publication (Fowier 8 Mount 1992) had shown that, for dose rates (averaged for the duration of the pulse) up to 3 Gyh, little change of i&act doses from continuous low dose rate (CLDR) are expected, unless larger doses per fraction than 1 Gy are used, and especially if components of very rapid repair are present with half-times of less than about 0.5 hours. However, local and transient dose rates close to stepping sourcea can be up to several Gy par muwte. Methods: Calculations were done assuming the linear quadratic formula for radiation damage. in which only the dose-squared term is subject to repair, at a constant exponential rate. The formula developed by Dale for fractionated lowdose-rate radiotherapy was used. A COnstant overall time of 140 hours and constant total dose of 70 Gy were assumed throughout, the eo”ti”uous low dose-rate of 0.5 Gylh (CLDR) providing the unitary standard effects for each PDR condition. Effects of dose-rates ranging from 4 Gylh to 120 Gylh (HDR at 2 Gy/min) were studied, and T l/Z from 4 minutes to 1.5 hours Results: Curves are presented relating the ratio of increased biological effect (proportional to log cell kill) calculated for PDR relative to CLDR. Ratios as high as 1.5 can be found for large doses per pulse (> 1 Gy) at high instantaneous dose-rates if T l/2 in tissues is as short as a few minutes The major influences on effect are dose per pulse, half-time of repair in the bssue. and -when T 112 is short-the iristantaneous dose-rate. Maximum ratios of PDRKLDR effect occur when the dose-rate is such that pulse duration is approximately equal to T 1R of repair. Results are presented for late-responding tissues, the differences from CLDR being 2 or 3 times smaller for early-responding tissues and most tumors. Restricting the doss par pulse to 0.5 cf 0.6 Gy should avoid Conclusions: rabos of increased effecl larger than about 1 .I, which is a 10 % increase in log cell kill compared with CLDR, probably clinically detectable.. Ratios increase rapidly as instantaneous dose rate is increased. tending towards a plateau at dose-rates above about 20 Gyh. with which a substantial proportion of the dose in PDR is given. Therefore PDR delivered by stepping Source might behave more like HDR than LDR. especially for tissues with a substantial component of repair of very short half time. That is why using small doses per pulse is important.
31
32
THE EFFECTS OF PENTOXIF’YLLlNE ON BRACHYTHERAPY INDUCED LATE NORMAL TISSUE REACTIONS
FINAL RESULTS OF IN VITRO TESTS OF THE EQUlVALENCE BEIWEEN PULSED DOSE RATE AND CONTINUOUS LOW DOSE RATE lRRADL4TlON
Aslay I., Yal~m S., Alath C.. Kemlkler G.. Kurdoglu Taa@ N.. Di$$l R.. Erseven G.. T&e G. tstanbal University Oacology Insmute.
B., &bilen
S..
istanbd. TURKiYE
Irradiation is known to stimulate the relcasc of platelet derived grwth factor (F’DGF) from irradiated platelets. PDGF causes the migration aad proliferation of vascular smooth muscle and endothelial elements. and is thought to be a cause of late radiation vasculopathy. Irradiation also causes a significant release of tmmboxane that is a potent vasoconstrictor and a strong stimulator of platelet aggregation. On the other hand petoxifyllmc increases red blood cell deformability and pmstwyclinc release from platelets, and inhibits neatmphil activity. If damage to micmvawlaturc is responsible for late radiation injury. pcnto.xifylline (PENTO). by improving blood supply and by increasing the level of pmstocycline on irradiated tissue may pwent late radiation rcactloas.Tbe effects of PENT0 on the brachytherapy (BT) indaccdiate normal tissue mjuq were tested using If ‘*’ wire (2.378 mCi/cm activity) application via the plastic tube method and the Dosimetric System of Paris in the hind legs of BALBic mice. 7.5 Ciy were given in 6.98 dais. and were divided into saline (0.01 ml/g/day. SC) and PENT0 injeztion (50 mglkgiday, SC) groups. At the end of three months animals were killed by cervical dislocation, and 40 slices in only BT. 48 slices in BT+PENTO groups were evaluated with light microscopy by the same pathologists. Vascalariration, vascular hyalinization endothehal pmliferation. inllammatory infiltration. fibrosis. muscle degeneration and mast cell iatiltration were graded from 0 to 3+ In the BT+PENTO group were found statistically significant decreases in vasculatiation. fibrosis and murk degeneration. Preliminary results of this shady arc Promising and I” favor of using PENT0 after brachytlwapy to reduce late Abrow and muscle degeneration.
Beth Erickson, J&ey Shadly Medical College of Wiscoasin,
Milwaukee,
Wl
USA
Introduction: pulsed low dose rate (PDR) iradiation is being investigated as an alternative to c~ltiiaoas low dose rate (CLDR) irradiation for the trcabncnt of certain malignancies. Mathematical modeling by B-and Hall suggests that the hvo irmLatioll regimem will be equivalent under catain ccnditioas. Materials & Metbcds: We have tested these predictions directly usi the rodent/SCC VII m vim-m tiw tumx model. This study involved in titro irradiations which would not be expected to severely stress the assumptions oftbe matbematxal model. The cytotoxicity of CLDR was canpared to that for PDR rcgimcns consisting of hourly radiation pllses of 5,1O,oT 20 minutes, acd a 20 minute radiation pulse every two bows. A total dose of 15.7 Cy of”Cn gamma rays was deliverul over the same total tinx for all irradiations.. confluent calhrres were lrradiatcd in low serum at room temperature to minim& eEwts of cell proliferation and cell cycling. Sixty-one expmiments were pert&& that an average of Results & Discussion: Flow cytometric analysis dawnstrati 180% of cells were in G~GI, with 55% incorporating bwdiae. Also, mitotic mdices averaged ~0.2%. ‘Ihere were no sign&ant di&cmes between the mean values for these cell cycle measures ixtwen CLDR and PDR OT behveen PDR rcgimem All PDR regimens showed increased cell kill relative to the CLDR, but in no case were the inweasea statistic+ significant. The iwease Incell kill wasbyfactasof 1.14 to2.00, tithtlxgreatesti iIlCellkilliIl thePDRregimen~~iag5mi1aiteinutepllsesonceperho Thisin-incellkill, even if real, would not appear to be sutlicieat to violate the criteria for being “climcally indistinguishable” as suggested by Band Hall. Conclusion:. Ahbough these. results genaally suppat the modeling ofBand Hall, this experimental model does show &cased cell killing in the PDR reginrms and his m vim m&l does not strews the awmptioas of the BrcnaerHall model as swcxely as in viw mcdels or clinical use. would.
30
29 HDR- and LDR- interstitial irradiation (IRT) in rat spinal effect of decreasing the d&se rate and the impact of a rapid ON over the spinal cord.
cord: the dose fall
L.A.M. Pop, M. van der Plas, A. E. J. Hanssen and A.J.van der Kogel. Institute of Radiotherapy, University of Nijmegen, 6500 HB Nijmegen. The Netherlands. Introduction: Detailed knowledge of radiobiological parameters of the different tissues involved are warranted before HDR- and recently PDRbrachytherapy can be successfully introduced in clinical practice -as an alternative to LDR- brachvtherauv. The o-se of this studv is to determine the c@ ratio a& half time of ;ep& of rat spinal cbrd during continuous irradiation at different dose rates and to investigate the impact of a rapid dose fall off over the spinal cord thickness. Material and methods: Two parallel catheters are inserted on each side of the vertebral bodies from the level of Th,O to L,. These catheters were afterloaded with two ‘921r- wires of 4 cm length each (activity I- IO mCi/cm) or connected to the HDR- microSelectron. Serial experiments have been carried out to obtain complete dose response curves at 5 different dose rates, resp. 0.5, 0.9, 1.6, 2.6 and 120 Gyih. Paralysis of the hlndlegs after 5-6 months and histopatbological examination of the spinal cord of each animal are used as experimental endpoints. Dosevolume histograms of each irradiated rat have been analyscd to evaluate the correlation between dose distribution and biological response and the hlstopathological damage seen. Results: The distribution of the histological damage was a good reflection of the rapid dose fall-off over the spinal cord. with white matter necrosis or demyelination predominantly seen in the dorsal tracts of the spinal cord or dorsal roots. With each reduction of the dose rate, spinal cord tolerance was significantly increased, with a maximum dose rate factor of 4.3 if the dose rate was reduced from 120 Gyih to 0.53 Gyih. Estimates of the repair parameters using different types of analysis revealed an o& ratio of 2.44 Gv and a (mono- exwnential) half time of repair (=tl/Z) df 1.43 hours; forihe maximum of i50 % of the prescribed dose these values were 3.67 Gv and I .43 hours resoectivelv. Conclusions: Spinal cord radi&m tolerance is sig’tificantfy increased by a reduction in dose rate. In dependence of the dose prescription, the a/l3 ratio varies between 2.44 and 3.67 Gv. while the half time of reualr is I.43 hours. No indication was found for a biphasic pattern of the kihetxs of rep&r. The distribution of histopathological damage in the spinal cord as a reflection of the rapid dose tall off will be discussed.
Bicitogicat effect of Pulsed Doaa Rate braahytherapy wiul m somces Erik F M Van Limbergen. MD, PhD. and Jack F Fcwier. PhD, DSc Department of Oncology. University Hospital Gaathuiirg. 3ooo Leuven, Belgium. Putpoaa: To explore the possible increase of radiation effed in tissues irradiated by puked brachytherapy (PDR). fw local tisaua doae*tes between those “averaged over the whole pulse” and the instantaneous high dose rates close to the dwell positions. A” earlier publication (Fowier 8 Mount 1992) had shown that, for dose rates (averaged for the duration of the pulse) up to 3 Gyh, little change of i&act doses from continuous low dose rate (CLDR) are expected, unless larger doses per fraction than 1 Gy are used, and especially if components of very rapid repair are present with half-times of less than about 0.5 hours. However, local and transient dose rates close to stepping sourcea can be up to several Gy par muwte. Methods: Calculations were done assuming the linear quadratic formula for radiation damage. in which only the dose-squared term is subject to repair, at a constant exponential rate. The formula developed by Dale for fractionated lowdose-rate radiotherapy was used. A COnstant overall time of 140 hours and constant total dose of 70 Gy were assumed throughout, the eo”ti”uous low dose-rate of 0.5 Gylh (CLDR) providing the unitary standard effects for each PDR condition. Effects of dose-rates ranging from 4 Gylh to 120 Gylh (HDR at 2 Gy/min) were studied, and T l/Z from 4 minutes to 1.5 hours Results: Curves are presented relating the ratio of increased biological effect (proportional to log cell kill) calculated for PDR relative to CLDR. Ratios as high as 1.5 can be found for large doses per pulse (> 1 Gy) at high instantaneous dose-rates if T l/2 in tissues is as short as a few minutes The major influences on effect are dose per pulse, half-time of repair in the bssue. and -when T 112 is short-the iristantaneous dose-rate. Maximum ratios of PDRKLDR effect occur when the dose-rate is such that pulse duration is approximately equal to T 1R of repair. Results are presented for late-responding tissues, the differences from CLDR being 2 or 3 times smaller for early-responding tissues and most tumors. Restricting the doss par pulse to 0.5 cf 0.6 Gy should avoid Conclusions: rabos of increased effecl larger than about 1 .I, which is a 10 % increase in log cell kill compared with CLDR, probably clinically detectable.. Ratios increase rapidly as instantaneous dose rate is increased. tending towards a plateau at dose-rates above about 20 Gyh. with which a substantial proportion of the dose in PDR is given. Therefore PDR delivered by stepping Source might behave more like HDR than LDR. especially for tissues with a substantial component of repair of very short half time. That is why using small doses per pulse is important.
31
32
THE EFFECTS OF PENTOXIF’YLLlNE ON BRACHYTHERAPY INDUCED LATE NORMAL TISSUE REACTIONS
FINAL RESULTS OF IN VITRO TESTS OF THE EQUlVALENCE BEIWEEN PULSED DOSE RATE AND CONTINUOUS LOW DOSE RATE lRRADL4TlON
Aslay I., Yal~m S., Alath C.. Kemlkler G.. Kurdoglu Taa@ N.. Di$$l R.. Erseven G.. T&e G. tstanbal University Oacology Insmute.
B., &bilen
S..
istanbd. TURKiYE
Irradiation is known to stimulate the relcasc of platelet derived grwth factor (F’DGF) from irradiated platelets. PDGF causes the migration aad proliferation of vascular smooth muscle and endothelial elements. and is thought to be a cause of late radiation vasculopathy. Irradiation also causes a significant release of tmmboxane that is a potent vasoconstrictor and a strong stimulator of platelet aggregation. On the other hand petoxifyllmc increases red blood cell deformability and pmstwyclinc release from platelets, and inhibits neatmphil activity. If damage to micmvawlaturc is responsible for late radiation injury. pcnto.xifylline (PENTO). by improving blood supply and by increasing the level of pmstocycline on irradiated tissue may pwent late radiation rcactloas.Tbe effects of PENT0 on the brachytherapy (BT) indaccdiate normal tissue mjuq were tested using If ‘*’ wire (2.378 mCi/cm activity) application via the plastic tube method and the Dosimetric System of Paris in the hind legs of BALBic mice. 7.5 Ciy were given in 6.98 dais. and were divided into saline (0.01 ml/g/day. SC) and PENT0 injeztion (50 mglkgiday, SC) groups. At the end of three months animals were killed by cervical dislocation, and 40 slices in only BT. 48 slices in BT+PENTO groups were evaluated with light microscopy by the same pathologists. Vascalariration, vascular hyalinization endothehal pmliferation. inllammatory infiltration. fibrosis. muscle degeneration and mast cell iatiltration were graded from 0 to 3+ In the BT+PENTO group were found statistically significant decreases in vasculatiation. fibrosis and murk degeneration. Preliminary results of this shady arc Promising and I” favor of using PENT0 after brachytlwapy to reduce late Abrow and muscle degeneration.
Beth Erickson, J&ey Shadly Medical College of Wiscoasin,
Milwaukee,
Wl
USA
Introduction: pulsed low dose rate (PDR) iradiation is being investigated as an alternative to c~ltiiaoas low dose rate (CLDR) irradiation for the trcabncnt of certain malignancies. Mathematical modeling by B-and Hall suggests that the hvo irmLatioll regimem will be equivalent under catain ccnditioas. Materials & Metbcds: We have tested these predictions directly usi the rodent/SCC VII m vim-m tiw tumx model. This study involved in titro irradiations which would not be expected to severely stress the assumptions oftbe matbematxal model. The cytotoxicity of CLDR was canpared to that for PDR rcgimcns consisting of hourly radiation pllses of 5,1O,oT 20 minutes, acd a 20 minute radiation pulse every two bows. A total dose of 15.7 Cy of”Cn gamma rays was deliverul over the same total tinx for all irradiations.. confluent calhrres were lrradiatcd in low serum at room temperature to minim& eEwts of cell proliferation and cell cycling. Sixty-one expmiments were pert&& that an average of Results & Discussion: Flow cytometric analysis dawnstrati 180% of cells were in G~GI, with 55% incorporating bwdiae. Also, mitotic mdices averaged ~0.2%. ‘Ihere were no sign&ant di&cmes between the mean values for these cell cycle measures ixtwen CLDR and PDR OT behveen PDR rcgimem All PDR regimens showed increased cell kill relative to the CLDR, but in no case were the inweasea statistic+ significant. The iwease Incell kill wasbyfactasof 1.14 to2.00, tithtlxgreatesti iIlCellkilliIl thePDRregimen~~iag5mi1aiteinutepllsesonceperho Thisin-incellkill, even if real, would not appear to be sutlicieat to violate the criteria for being “climcally indistinguishable” as suggested by Band Hall. Conclusion:. Ahbough these. results genaally suppat the modeling ofBand Hall, this experimental model does show &cased cell killing in the PDR reginrms and his m vim m&l does not strews the awmptioas of the BrcnaerHall model as swcxely as in viw mcdels or clinical use. would.