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Role of free radicals in the mechanisms of radiation pneumonitis
247
Proceedings of the 32nd Annual ASTRO Meeting
1045 HYPERFRACTIONATION WIT>T>
IM PROPHYr,AKIS CRANIA', IRRADIATION DEC?'?ASE TO DP'WRIORATION A HYPOTHSSIS DERIVED FROM CURRgNT RADIOBIOr,OGICAr, MODET,S. R. Muller-Runkel, Ph.D.a and S. Vijayakumar, M.D.b
a. Saint Margaret Hospital and Health Centers, for Radiation Therapy, Chicago, Jr> 60616
Hammond,
IN 46320,
b. Michael
IN CHILDREN
Reese/University
WITH ALL
of Chicago
?
Cntr
Prophylactic cranial irradiation (PCRT) is an important component in the treatment of childhood lymphocytic leukemia (AT,T,). A dreaded complication of PCRT, however, is long-term IQ deterioration, particularly in younger children (1). A hyperfractionated (HF) treatment scheme may avoid this lrnwanted sequelae. Based on the linear-quadratic(J>Q) model (2): E/cx = D(l+d,' d/,13) (E/x-biological effective dose (BED), D= total dose, d= dose/fraction), a conventional and a HF treatment schedule are compared: Schedule
late BED (Gy) z/p:
18 Gy/lO
Fr
19.8 Gy/22 (bid)
Fr
1.5
acute BED (Gy) 2
3
ID
15
20
39.6
34.2
28.8
21.2
20.2
19.6
3!.7
28.7
25.7
21.6
21.0
20.7
Low values of a/$ apply for late effects (2). IQ deterioration should be considered as a late effect since it is manifested at least one year after PCRT (I), and can take as long as 2 to 5 years (I). The mechanism/pathogenesis is not known. Acute effects, as well as trrmor response are associated with high LX/~ values (2). For leukemic cells O/p of IO - 20 can be assumed (3). The table illustrates that the effect on late reacting tissue is weaker with a HF treatment scheme as compared to conventional fractionation (e.g. 28.7134.2 =.839 for a/p = 2) whereas the effect on tumor is almost unchanged (e.g. 21.0/20.2 = 1.04 for d/p =15), implying a therapeutic gain (1.04/.839 = !.24 or 24%)for the HF treatment schedule. A similar gain can be derived from the NSD concept: it was shown (4) that an exponent of -.44 should be applied to N, the number of fractions, for late reacting brain tissue, vs. -.24 for acute effects. Clinically, it was demonstrated (I) that growth hormone deficiency, another long-term sequela from PCRT, was markedly improved when fractional doses were decreased from 2.4 Gy to 1.2 Gy per day. in PCRT may decrease IQ deterioration Based on these arguments, it is suggested that hyperfractionation in children with AT,T,and need to be tested prospectively in clinical trials. (1) Duffner, P.K. et al. Cancer 56,1841-1846 (1985). (2) Fowler, J.F. Br. J. Rad. 62, 679-694 (1989). (3) Withers, H.R. in Radiation Oncology, C. Perez and L. Brady ed. 67-98 (1987). (4) Sheline, G.E. et al. Int. .J. Rad. One. Biol. Phys. 6, 1215-1228 (1980).
1046 ROLE
OF
FREE
RADICALS
IN
THE
MECHANISMS
OF
RADIATION
PNEUMONITIS
Hashimura, M.D., Michio Kono, M.D., Kazufumi Imanaka, M.D., Toshinori Soejima, M.D., and Kazuyuki Yonezawa, M.D. School of Medicine, Kobe, Japan Department of Radiology, Kobe University
Takahisa
complications of recognized as Radiation pneumonitis are well (RP) of RP the thoracic malignancies. However, the pathoqenesis radiotherapy for to define the role of free this has poorly understood. In study, been radicals in mechanism of RP, we measured lipid peroxides experimentally the counts to the development of contribution of qranulocyte and examined roentqenoqraphic RP clinically. of lipid peroxides, the activities measured Experimental studies: we C4 and D4 (LTC4 and LTD4) in glutathione peroxidase (GSH pex.), leukotriene Eight-week-old female ICR mice were sacrificed irradiated lungs of mice. the after to 5 days) following the 10 Gy at various periodswit;iy;f;Etely time The lipid peroxides and the irradiation gamma rays. whole-body the irradiation, but pex. increased after GSH immediately activities of level 1 hour after the irradiation. And then, the control returned to the from 1 day after the irradiation, while the also increased lipid peroxides LTC4 and LTD4 in pex. decreased below the control level. GSH activities of were also significantly higher than those of lungs of mice the irradiated we investigated effects of Coenzyme controls. Furthermore, non-irradiated Lungs of ICR mice after 10 Gy Azelastine for the prevention of RP. Q-10 and were compared with the irradiation treated with those drugs whole-thorax Intraperitoneal administration of those drugs pathologically. control lungs such as vacuole formation and stripping decreased the damages for endothelium, This basement membrane whch were recognized by electron microscope. off the the initial damages of irradiated lungs may be experimental data suggests
248
Radiation Oncology, Biology, Physics
October 1990, Volume 19, Supplement
1
induced by lipid peroxides, which are produced by the radiation-generated free radicals. Clinical studies: Pre-radiotherapy granulocyte counts and the development of chest roentogenographic RP were analized in 46 patients with lung cancer retrospectively. These patients were divided into 4 groups (negative, mild, moderate and severe) with the chest roentogenographic development of RP 1, 3 and 6 months after the completion of radiotherapy. Mean granulocyte counts were 2,048 in negative group, 4,210 in mild grup, 4,234 in moderate and 4,785 in severe group. The pre-radiotherapy granulocyte counts are increasing with the severity of RP. This clinical data shows that pre-radiotherapy granulocyte counts is one of contributing factors to the development of RP and free radicals produced by granulocytes may interact with those generated by radiotherapy in the mechanisms of RP. In conclusion, both of experimental and clinical study suggest that free radicals play an important role in the mechanisms of RP. may
1047 NEW DEVELOPMENT OF AN INTEGRATED AND CLINICAL APPLICATION.
CT SIMULATION
SYSTEM
FOR RADIATION
Kazufumi Imanaka, M.D., Michio Kono, M.D., Takeyuki Kushima, Takahisa Hashimura, M.D., Toshiya Sakaguchi, M.D., Toshinori Kazuyuki Yonezawa, M.D., Masao Sako, M.D. Department of Radiology, School of Medicine Kobe University,
M.D., Soejima, Kobe
THERAPY
M.D.,
650, Japan
To more precise radiotherapy into practice, we newly developed a CT Put simulation system which consisted of a CT scanner (GE 9800 quick highlight), a work station to decide radiation fields, an isocenter marking system (Yokogawa RT marker), a treatment planning device RTD system), auxiliary (Modulex storage and a linear accelerator (Mitubishi ML-20MDX). All of these components are connected on line except for a linear accelerator. Procedure of this system is as follows: Multiple CT images up to 39 slices are transferred to the work station to determine the target area and the critical normal structures on CRT. After dose calculation and optimization of treatment planning, planned data in each axial image is reformatted into a projection film showing a radiation field (computed simulation film: CS film). Finally, The positioning only the isocenter is marked on the patient's skin. of the patient the and isocenter of the tumor is aligned with three laser beams in the treatment room. The contour of radiation field is reproduced on the patient's skin surface using the CS film which is put on the shadow tray of the linear accelerator. We applied 186 patients (70 head and neck lesions, 86 this system to thoracic lesions, 21 abdominal lesions and 11 pelvic lesions). In order to evaluate were taken the reproducibility in each treatment, linacographs periodically during the treatment course putting a specific scale device on the head of the gantry. A comparative evaluation of each linacography in the same patient showed excellent accuracy and reliability in this system. A integrated CT simulation has been developped in our new system department. The advantages of this system are: (1)Target area and the geometrical relation with critical organs can be established in a three dimentional definition with CT images. (2)Isocenter marking method make it unnecessary to draw a contour of radiation field on the patient's skin. (3)Connection of a work station and a treatment unit on line enables to carry out the treatment efficiently and accurately.
Proceedings of the 32nd Annual ASTRO Meeting
1045 HYPERFRACTIONATION WIT>T>
IM PROPHYr,AKIS CRANIA', IRRADIATION DEC?'?ASE TO DP'WRIORATION A HYPOTHSSIS DERIVED FROM CURRgNT RADIOBIOr,OGICAr, MODET,S. R. Muller-Runkel, Ph.D.a and S. Vijayakumar, M.D.b
a. Saint Margaret Hospital and Health Centers, for Radiation Therapy, Chicago, Jr> 60616
Hammond,
IN 46320,
b. Michael
IN CHILDREN
Reese/University
WITH ALL
of Chicago
?
Cntr
Prophylactic cranial irradiation (PCRT) is an important component in the treatment of childhood lymphocytic leukemia (AT,T,). A dreaded complication of PCRT, however, is long-term IQ deterioration, particularly in younger children (1). A hyperfractionated (HF) treatment scheme may avoid this lrnwanted sequelae. Based on the linear-quadratic(J>Q) model (2): E/cx = D(l+d,' d/,13) (E/x-biological effective dose (BED), D= total dose, d= dose/fraction), a conventional and a HF treatment schedule are compared: Schedule
late BED (Gy) z/p:
18 Gy/lO
Fr
19.8 Gy/22 (bid)
Fr
1.5
acute BED (Gy) 2
3
ID
15
20
39.6
34.2
28.8
21.2
20.2
19.6
3!.7
28.7
25.7
21.6
21.0
20.7
Low values of a/$ apply for late effects (2). IQ deterioration should be considered as a late effect since it is manifested at least one year after PCRT (I), and can take as long as 2 to 5 years (I). The mechanism/pathogenesis is not known. Acute effects, as well as trrmor response are associated with high LX/~ values (2). For leukemic cells O/p of IO - 20 can be assumed (3). The table illustrates that the effect on late reacting tissue is weaker with a HF treatment scheme as compared to conventional fractionation (e.g. 28.7134.2 =.839 for a/p = 2) whereas the effect on tumor is almost unchanged (e.g. 21.0/20.2 = 1.04 for d/p =15), implying a therapeutic gain (1.04/.839 = !.24 or 24%)for the HF treatment schedule. A similar gain can be derived from the NSD concept: it was shown (4) that an exponent of -.44 should be applied to N, the number of fractions, for late reacting brain tissue, vs. -.24 for acute effects. Clinically, it was demonstrated (I) that growth hormone deficiency, another long-term sequela from PCRT, was markedly improved when fractional doses were decreased from 2.4 Gy to 1.2 Gy per day. in PCRT may decrease IQ deterioration Based on these arguments, it is suggested that hyperfractionation in children with AT,T,and need to be tested prospectively in clinical trials. (1) Duffner, P.K. et al. Cancer 56,1841-1846 (1985). (2) Fowler, J.F. Br. J. Rad. 62, 679-694 (1989). (3) Withers, H.R. in Radiation Oncology, C. Perez and L. Brady ed. 67-98 (1987). (4) Sheline, G.E. et al. Int. .J. Rad. One. Biol. Phys. 6, 1215-1228 (1980).
1046 ROLE
OF
FREE
RADICALS
IN
THE
MECHANISMS
OF
RADIATION
PNEUMONITIS
Hashimura, M.D., Michio Kono, M.D., Kazufumi Imanaka, M.D., Toshinori Soejima, M.D., and Kazuyuki Yonezawa, M.D. School of Medicine, Kobe, Japan Department of Radiology, Kobe University
Takahisa
complications of recognized as Radiation pneumonitis are well (RP) of RP the thoracic malignancies. However, the pathoqenesis radiotherapy for to define the role of free this has poorly understood. In study, been radicals in mechanism of RP, we measured lipid peroxides experimentally the counts to the development of contribution of qranulocyte and examined roentqenoqraphic RP clinically. of lipid peroxides, the activities measured Experimental studies: we C4 and D4 (LTC4 and LTD4) in glutathione peroxidase (GSH pex.), leukotriene Eight-week-old female ICR mice were sacrificed irradiated lungs of mice. the after to 5 days) following the 10 Gy at various periodswit;iy;f;Etely time The lipid peroxides and the irradiation gamma rays. whole-body the irradiation, but pex. increased after GSH immediately activities of level 1 hour after the irradiation. And then, the control returned to the from 1 day after the irradiation, while the also increased lipid peroxides LTC4 and LTD4 in pex. decreased below the control level. GSH activities of were also significantly higher than those of lungs of mice the irradiated we investigated effects of Coenzyme controls. Furthermore, non-irradiated Lungs of ICR mice after 10 Gy Azelastine for the prevention of RP. Q-10 and were compared with the irradiation treated with those drugs whole-thorax Intraperitoneal administration of those drugs pathologically. control lungs such as vacuole formation and stripping decreased the damages for endothelium, This basement membrane whch were recognized by electron microscope. off the the initial damages of irradiated lungs may be experimental data suggests
248
Radiation Oncology, Biology, Physics
October 1990, Volume 19, Supplement
1
induced by lipid peroxides, which are produced by the radiation-generated free radicals. Clinical studies: Pre-radiotherapy granulocyte counts and the development of chest roentogenographic RP were analized in 46 patients with lung cancer retrospectively. These patients were divided into 4 groups (negative, mild, moderate and severe) with the chest roentogenographic development of RP 1, 3 and 6 months after the completion of radiotherapy. Mean granulocyte counts were 2,048 in negative group, 4,210 in mild grup, 4,234 in moderate and 4,785 in severe group. The pre-radiotherapy granulocyte counts are increasing with the severity of RP. This clinical data shows that pre-radiotherapy granulocyte counts is one of contributing factors to the development of RP and free radicals produced by granulocytes may interact with those generated by radiotherapy in the mechanisms of RP. In conclusion, both of experimental and clinical study suggest that free radicals play an important role in the mechanisms of RP. may
1047 NEW DEVELOPMENT OF AN INTEGRATED AND CLINICAL APPLICATION.
CT SIMULATION
SYSTEM
FOR RADIATION
Kazufumi Imanaka, M.D., Michio Kono, M.D., Takeyuki Kushima, Takahisa Hashimura, M.D., Toshiya Sakaguchi, M.D., Toshinori Kazuyuki Yonezawa, M.D., Masao Sako, M.D. Department of Radiology, School of Medicine Kobe University,
M.D., Soejima, Kobe
THERAPY
M.D.,
650, Japan
To more precise radiotherapy into practice, we newly developed a CT Put simulation system which consisted of a CT scanner (GE 9800 quick highlight), a work station to decide radiation fields, an isocenter marking system (Yokogawa RT marker), a treatment planning device RTD system), auxiliary (Modulex storage and a linear accelerator (Mitubishi ML-20MDX). All of these components are connected on line except for a linear accelerator. Procedure of this system is as follows: Multiple CT images up to 39 slices are transferred to the work station to determine the target area and the critical normal structures on CRT. After dose calculation and optimization of treatment planning, planned data in each axial image is reformatted into a projection film showing a radiation field (computed simulation film: CS film). Finally, The positioning only the isocenter is marked on the patient's skin. of the patient the and isocenter of the tumor is aligned with three laser beams in the treatment room. The contour of radiation field is reproduced on the patient's skin surface using the CS film which is put on the shadow tray of the linear accelerator. We applied 186 patients (70 head and neck lesions, 86 this system to thoracic lesions, 21 abdominal lesions and 11 pelvic lesions). In order to evaluate were taken the reproducibility in each treatment, linacographs periodically during the treatment course putting a specific scale device on the head of the gantry. A comparative evaluation of each linacography in the same patient showed excellent accuracy and reliability in this system. A integrated CT simulation has been developped in our new system department. The advantages of this system are: (1)Target area and the geometrical relation with critical organs can be established in a three dimentional definition with CT images. (2)Isocenter marking method make it unnecessary to draw a contour of radiation field on the patient's skin. (3)Connection of a work station and a treatment unit on line enables to carry out the treatment efficiently and accurately.