- Email: [email protected]
From 2 Gy TO 1 Gy per fraction: Sparing effect in rat spinal cord?
Inr .I Rndralion Oncology Bml Phys.. Vol. Pnnted in the U.S.A. All rights reserved.
14. ~0. 297-300 Copyright
0360.3016/88 0 1988 Pergamon
$3.00 + .OO Journals Ltd.
??Original Contribution FROM
2 GY TO 1 GY PER FRACTION: SPARING RAT SPINAL CORD?
EMMANUEL K. KIAN ‘Department
VAN DER SCHUEREN, ANG,
M.D.,
PH.D.
M.D.,
PH.D.,’
’ AND ALBERT
WILLY
EFFECT
LANDUYT,
J. VAN DER KOGEL,
IN
B.Sc.,’ PH.D.~
of Experimental Radiotherapy, University Hospital St.-Rafael, Leuven, Belgium; and ‘Radiobiological Institute TNO, Rijswijk, The Netherlands
Recently published results, from this group, on rat cervical spinal cord, a late responding tissue, indicated no further sparing with lowering the fraction size from 2 to 1.8, 1.5, and 1.3 Gy. In the present experiments a small but probably significant rise in tolerance is suggested, when the dose per fraction was decreased from 2 Gy down to 1 Gy. This rise would however still be much less than what is predicted by the linear quadratic model, based on the experimental data obtained with fraction sizes larger than 2 Gy. Radiation tolerance of CNS. Fractionated irradiations, Isoeffect formula, Flexure dose.
when the fraction size was reduced from 2 Gy to 1.3 GY.~ Since this finding has important clinical implications with regard to the potential use of hyperfractionation in radiotherapy, a second set of experiments was carried out. The present communication shows the influence of reducing the dose per fraction from 2 Gy down to 1 Gy on the radiation response of the rat cervical spinal cord.
INTRODUCTION There is evidence that late reacting normal tissues benefit relatively more from increased fractionation than rapidly proliferating tissues.“,‘7 The fraction size region at which no further sparing of damage occurs has been described as the “flexure dose”, and estimations of this point were made for a number of normal tissues.8.‘2”6 The flexure dose is the expression of the limit of repair when increasingly smaller doses per fraction are used. The calculations of the theoretical flexure dose are based on the ratio cr/p of the coEfficients of the linear quadratic (LQ) cell survival model.’ It has been defined as & of the dose level at which cell kill induced by the N and by the p component are equal. It is expected that at this dose no significant contribution to cell kill by the 0 component can be detected.8,‘2 For late normal tissue damage the reported values for a//3 are quite small, indicating a large capacity for repairing sublethal radiation damage. For cervical spinal cord in rats a value as low as 1.7 Gy was derived from experiments using doses per fraction of 2 Gy and larger.4 Dose reductions below 2 Gy would therefore still lead to a significant increase in tolerance levels. However, recent studies on rat cervical spinal cord in our laboratory suggested no significant increase in total isoeffect doses
METHODS
AND
MATERIALS
Adult (12 to 14 weeks old) male inbred rats of the WAG/Rij strain were used. Prior to treatment, the animals were transported from the specific pathogen-free facility to conventional housing. A broad spectrum antibiotic* was added to the drinking water to prevent respiratory infection. The animals were anesthetized? to allow accurate positioning during the irradiations. These techniques have been described previously in detail.2 The radiation treatments were carried out with a linear accelerator (18 MeV photons) at a focus-skin distance of 100 cm. A length of 2 cm cervical spine (C 1 to Th 1) was irradiated, with the remaining parts of the body shielded by blocks of MCP alloy.* In the present experiments, fraction sizes of 2 Gy and 1 Gy were used. The concept of partial tolerance,3 in-
Reprint requests to: E. van der Schueren, Department of Experimental Radiotherapy, University Hospital St.-RafaEl, Capucijnenvoer 35,300O Leuven, Belgium. Acknowledgements-The present work was supported financially by grants from the “Preuss Foundation,” U.S.A., the “Algemene Spaar- en Lijfrentekas” (A.S.L.K.), Belgium and the “Koningin Wilhelmina Fond?, The Netherlands. The techni-
cal assistance of Mrs. A. Camps and the secretarial assistance of Mrs. M.-L. Detienne are acknowledged. Accepted for publication 28 August 1987. * Tylan,@ llanco, Oraganon, Belgium. t Ethrane,@ Abbott, Belgium. $ Mining and Chemical Product, melting point 70°C. 297
298
I. J. Radiation Oncology 0 Biology 0 Physics
volving a constant top-up dose of 15 Gy delivered at the end of the multiple fractionation treatment, was used to allow for halving the number of irradiations. In this way the number of fractions ranged from 26 to 41 for 2 Gy and from 58 to 88 for 1 Gy per fraction, given in an overall treatment time of 4-6 weeks. The irradiations with 2 Gy per fraction were delivered daily, while the 1 Gy radiation sessions were given twice a day with alternatingly 4 and 20 hr intervals. Following treatment, the evaluation of the neurological status was performed weekly for at least 1 year. The endpoint of the experiments was fore-leg paralysis, due to demyelination and white matter necrosis as described previously.‘4,‘5 The incidence of paralysis, with reference to the various total irradiation doses, was used for calculations of the ED50 values (radiation doses leading to paralysis in 50% of the rats) by probit analysis.
RESULTS
AND
DISCUSSION
In a further investigation of the amount of irrepairable damage in the rat spinal cord following hyperfractionated irradiation schedules, the fraction size was reduced from 2 Gy to 1 Gy. To avoid too large a number of fractions, a fixed top-up dose of 15 Gy was used in accordance with the concept of partial tolerance described previously.3 The total overall treatment time was kept within 4-6 weeks. It was previously shown in the same model that no time dependent recovery took place between 24 hr and 8 weeks.13 Similar to the observations made in our earlier experiments4 paralysis due to white matter necrosis (WMN) occurred within 6 to 10 months. However, as in the previous experiments with small fraction sizes, the present experiments showed that the WMN was occasionally accompanied by small hemorrhages. For both the experiments with 2 Gy and 1 Gy per fraction, a dose-response relationship was established using probit analysis.’ From these dose-response curves, the EDso values with 95% confidence limits were derived yielding 141.1 (127.0155.3) Gy for the 2 Gy per fraction and 159.1 (141.0177.1 ) Gy for the 1 Gy per fraction irradiations. These results are shown in Figure l.B together with the EDso values obtained in the earlier experiments4 with fraction sizes of 2.9, 2, 1.8, 1.5, and 1.3 Gy, respectively. The EDso value for the present experiment using 2 Gy per fraction was virtually identical to the value obtained in the earlier set of experiments (Fig. 1A-B and Table 1) confirming the reproducibility of the results in this model. Using the classical Fe plot’ of the reciprocal total EDs0 against the dose per fraction, the validity of the LQmodel can be tested indirectly. Based on the cervical spinal cord data of Ang et uI.~.~ involving all data related to
*D_ D ref
(culp + d ref) (aI@ + d)
.
February 1988, Volume 14. Number 2
fraction sizes of 2 Gy and larger (Fig. l.A), an o(/p ratio of 1.7 Gy was derived (correlation coefficient 0.9975). Using this a//3 ratio, in reference to a fraction size of 2 Gy and corresponding EDso of 140.5 Gy, the ED50 values predicted by the LQ-model for fraction sizes of 1.8, 1.5, 1.3, and 1 Gy were calculated.* These estimations for EDso are plotted in Fig. 1 (symbol x) and also presented in Table 1. They suggest an important increase in sparing of cervical cord even down to 1 Gy per fraction. In the earlier experiments involving doses per fraction down to 1.3 Gy4 no further sparing could be demonstrated for reduction of the fraction size below 2 Gy. The present results show a small increase in tolerance of about 12% at the EDso level when using 1 Gy instead of 2 Gy per fraction.” It needs to be specified that the confidence limits for both EDZO values are overlapping (Table 1). Using the same biological model, Hornsey et ~1.~ also reported some increased sparing as the dose per fraction is reduced from 2 to 1 Gy and to 0.6 Gy, the differences in tolerance doses remaining within the errors of the system. The sparing effect observed in our study ( 12%), is however much less pronounced than predicted on basis of the LQ-model (27%). Even when the EDso values were corrected for the possibility of incomplete repair of sublethal radiation damage for the fraction sizes given with 4 hr intervals (assuming a half-time for repair of 1.5 hr), there is still a difference of about 13% between the theoretical and experimental EDso values (Table 1). Our studies on repair kinetics have suggested the repair half-time to become shorter with smaller fraction sizes, but over the range of fraction sizes used (-4- 15 Gy) this proved not to be significant.’ If this trend would continue, however. for smaller doses per fraction of l-2 Gy as used in the present study, the correction for incomplete repair during a 4-hour interval could become even smaller. An analysis of the data for all doses per fraction below 3 Gy results in an (Y/P ratio of 4 Gy, which is similar to the result of an analysis of data obtained in experiments on repair kinetics using a direct method for analysis of quanta1 responses and an incomplete repair model.’ It can be concluded that the repair of sublethal radiation damage in the rat spinal cord actually measured in hyperfractionation experiments is less effective than predicted by the LQ-model for doses per fraction between 2 Gy and 1 Gy although probably not totally absent as was suggested earlier.4 These results suggest that the LQ-model does not adequately describe all experimentally obtained fractionation data. Therefore, our findings confirm the earlier warning for the use of LY/~ratio’s, that are extrapolated from data involving large doses per fraction, to design fractionation schedules with fraction sizes below 2 Gy.
A
200 150
100 60 t
60
5: 0 Y
40
d & I-
20
10 I
1
2 DOSE
200
III
3
4 PER
I,
5
6
76910
FRACTION
20 IGvl
B
-
> 2 :: D
160-
160 -
w
100 I 1
16
DOSE
2
PER
FRACTION
3
(Gy)
Fig. 1. Isoeffect doses for induction of foreleg paralysis (due to WMN) as a function of fraction size. A. Experiments with dose fractions down to 2 Gy (O ref. 3,4 and 0 the present study); B. Experiments with fraction sizes ranging between 1 and 3 Gy (0 ref. 3,4 and 0 the present study). At 1.3 Gy per fraction paralysis occurred even at the lowest total dose tested, and thus only the upper limit for total isoeffect dose could be estimated (for details see ref. 4). The calculated values for isoeffect, based on an a//3 ratio of 1.7 Gy and a dose fraction of 2 Gy (ED50 = 140.5 Gy) are indicated (X) for comparison.
Table 1. Comparison
of ED50 values: Experimental
results versus theoretical
calculations
Total EDso (Gy) values for rat cervical spinal cord (WMN) 2.0 GyfF Estimations* (LQ model; cu/p = 1.7 Gy) Experimental data
Experimental incomplete hr intervals
data, corrected for possible repair during the various 4 (see text)
140.0 ( 129.0- 150.8)t 141.1 (127.0-155.3) -
* Reference dose: 2 Gy/F and EDso = 140.5 Gy. t 95% confidence limits.
1.8 Gy/F
148.5 124.4 (107.8-141.2)
-128
1.5 Gy/F
162.4 137.6 (128.2-147.0)
-144
1.3 Gy/F
1.O Gy/F
173.3 <150
192.5 159.1 (141.0-177.1)
-
-167
300
I. J. Radiation Oncology 0 Biology 0 Physics
February 1988. Volume 14, Number 2
REFERENCES 1. Ang, K.K., Thames Jr., H.D., Van der Kogel, A.J., van der Schueren, E.: Is the rate of repair of radiation-induced sublethal damage in rat spinal cord dependent on the size of dose per fraction? Int. J. Radiat. Oncol. Biol. Phys. 13: 557-562, 1987. 2. Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: Inhalation anesthesia in experimental radiotherapy: A reliable and time-saving system for multifractionation studies Int. J. Radiat. Oncol. Biol. Phys. in a clinical department.
8: 145-148, 1982. 3. Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: The effect of small radiation doses on the rat spinal cord: The concept of partial tolerance. Int. J. Radiat. Oncoi. Biol.
Phys, 9: 1487-1491, 1983. 4. Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: Lack of evidence for increased tolerance of rat spinal cord with decreasing fraction doses below 2 Gy. Int. J. Radiat. 0~01. Biol. Phys. 11: 105-l 10, 1985. dose rate and iso5. Barendsen, G.W.: Dose fractionation, effect relationships for normal tissue responses. Znt. J. Radiat. Oncol. Biol. Phys. 8: 1981-1997, 1982. 6. Douglas, B.G., Fowler, J.F.: The effect of multiple small doses of X rays on skin reactions in the mouse and a basic Radiat. Res. 66: 401-426, 1976. interpretation. 7. Finney, D.J., Marcus, P.I.: Probit analysis. A Statistical Treatment qf the Sigmoid Response Curve. Cambridge, Cambridge University Press, 1952. 8. Fowler, J.F., Joiner, M.C., Williams, M.V.: Low doses per fraction in radiotherapy: A definition for “flexure dose.”
Br. J. Radiol. 56: 599-60 1, 1983.
9. Hornsey, S., Myers, R.: Is there further sparing of damage to the CNS as dose per fraction is reduced below 2 Gy per fraction (Abstract)? Int. J. Radiat. Biol. 50: 9 19, 1986. 10. Landuyt, W., Thames Jr., H.D., Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: Kinetics and extent of repair of sublethal damage in mouse lip mucosa and rat spinal cord (Abstract). Znt. J. Radiat. Biol. 50: 365, 1986. 11. Thames, H.D., Withers, H.R., Peters, L.J., Fletcher, G.H.: Changes in early and late radiation responses with altered dose fractionation: Implications for dose-survival relationships. Int. J. Radiat. Oncol. Biol. Phys. 8: 2 19-226, 1982. 12. Tucker, S.L., Thames, H.D.: Flexure dose: The low-dose limit of effective fractionation. Znt. J. Radial. Oncol. Biol. PhJ1.y.9: 1373-l 383, 1983. 13. Van der Kogel, A.J.: Late effects of radiation on the spinal cord: Dose-effect relationships and pathogenesis. Monograph, Radiobiological Institute TNO, Rijswijk, The Netherlands, 1979. 14. Van der Kogel, A.J.: The cellular basis of radiation induced damage in the CNS. In C_ytotoxic Insult to Tissue: Effects on Cell Lineages, C.S. Potten and J.H. Hendry (Eds.). Edinburgh, Churchill-Livingstone. 1983, pp. 329-
352. damage in the 15. Van der Kogel, A.J.: Radiation-induced central nervous system: An interpretation of target cell responses. Br. J. Cancer 53 (Suppl. VII): 207-2 17, 1986. 16. Withers, H.R.: Responses of tissues to multiple small dose fractions. Radial. Res. 71: 23-33, 1977. 17. Withers, H.R., Thames, H.D., Peters, L.J.: A new isoeffect curve for change in dose per fraction. Radiother. On&. 1: 187-191. 1983.
14. ~0. 297-300 Copyright
0360.3016/88 0 1988 Pergamon
$3.00 + .OO Journals Ltd.
??Original Contribution FROM
2 GY TO 1 GY PER FRACTION: SPARING RAT SPINAL CORD?
EMMANUEL K. KIAN ‘Department
VAN DER SCHUEREN, ANG,
M.D.,
PH.D.
M.D.,
PH.D.,’
’ AND ALBERT
WILLY
EFFECT
LANDUYT,
J. VAN DER KOGEL,
IN
B.Sc.,’ PH.D.~
of Experimental Radiotherapy, University Hospital St.-Rafael, Leuven, Belgium; and ‘Radiobiological Institute TNO, Rijswijk, The Netherlands
Recently published results, from this group, on rat cervical spinal cord, a late responding tissue, indicated no further sparing with lowering the fraction size from 2 to 1.8, 1.5, and 1.3 Gy. In the present experiments a small but probably significant rise in tolerance is suggested, when the dose per fraction was decreased from 2 Gy down to 1 Gy. This rise would however still be much less than what is predicted by the linear quadratic model, based on the experimental data obtained with fraction sizes larger than 2 Gy. Radiation tolerance of CNS. Fractionated irradiations, Isoeffect formula, Flexure dose.
when the fraction size was reduced from 2 Gy to 1.3 GY.~ Since this finding has important clinical implications with regard to the potential use of hyperfractionation in radiotherapy, a second set of experiments was carried out. The present communication shows the influence of reducing the dose per fraction from 2 Gy down to 1 Gy on the radiation response of the rat cervical spinal cord.
INTRODUCTION There is evidence that late reacting normal tissues benefit relatively more from increased fractionation than rapidly proliferating tissues.“,‘7 The fraction size region at which no further sparing of damage occurs has been described as the “flexure dose”, and estimations of this point were made for a number of normal tissues.8.‘2”6 The flexure dose is the expression of the limit of repair when increasingly smaller doses per fraction are used. The calculations of the theoretical flexure dose are based on the ratio cr/p of the coEfficients of the linear quadratic (LQ) cell survival model.’ It has been defined as & of the dose level at which cell kill induced by the N and by the p component are equal. It is expected that at this dose no significant contribution to cell kill by the 0 component can be detected.8,‘2 For late normal tissue damage the reported values for a//3 are quite small, indicating a large capacity for repairing sublethal radiation damage. For cervical spinal cord in rats a value as low as 1.7 Gy was derived from experiments using doses per fraction of 2 Gy and larger.4 Dose reductions below 2 Gy would therefore still lead to a significant increase in tolerance levels. However, recent studies on rat cervical spinal cord in our laboratory suggested no significant increase in total isoeffect doses
METHODS
AND
MATERIALS
Adult (12 to 14 weeks old) male inbred rats of the WAG/Rij strain were used. Prior to treatment, the animals were transported from the specific pathogen-free facility to conventional housing. A broad spectrum antibiotic* was added to the drinking water to prevent respiratory infection. The animals were anesthetized? to allow accurate positioning during the irradiations. These techniques have been described previously in detail.2 The radiation treatments were carried out with a linear accelerator (18 MeV photons) at a focus-skin distance of 100 cm. A length of 2 cm cervical spine (C 1 to Th 1) was irradiated, with the remaining parts of the body shielded by blocks of MCP alloy.* In the present experiments, fraction sizes of 2 Gy and 1 Gy were used. The concept of partial tolerance,3 in-
Reprint requests to: E. van der Schueren, Department of Experimental Radiotherapy, University Hospital St.-RafaEl, Capucijnenvoer 35,300O Leuven, Belgium. Acknowledgements-The present work was supported financially by grants from the “Preuss Foundation,” U.S.A., the “Algemene Spaar- en Lijfrentekas” (A.S.L.K.), Belgium and the “Koningin Wilhelmina Fond?, The Netherlands. The techni-
cal assistance of Mrs. A. Camps and the secretarial assistance of Mrs. M.-L. Detienne are acknowledged. Accepted for publication 28 August 1987. * Tylan,@ llanco, Oraganon, Belgium. t Ethrane,@ Abbott, Belgium. $ Mining and Chemical Product, melting point 70°C. 297
298
I. J. Radiation Oncology 0 Biology 0 Physics
volving a constant top-up dose of 15 Gy delivered at the end of the multiple fractionation treatment, was used to allow for halving the number of irradiations. In this way the number of fractions ranged from 26 to 41 for 2 Gy and from 58 to 88 for 1 Gy per fraction, given in an overall treatment time of 4-6 weeks. The irradiations with 2 Gy per fraction were delivered daily, while the 1 Gy radiation sessions were given twice a day with alternatingly 4 and 20 hr intervals. Following treatment, the evaluation of the neurological status was performed weekly for at least 1 year. The endpoint of the experiments was fore-leg paralysis, due to demyelination and white matter necrosis as described previously.‘4,‘5 The incidence of paralysis, with reference to the various total irradiation doses, was used for calculations of the ED50 values (radiation doses leading to paralysis in 50% of the rats) by probit analysis.
RESULTS
AND
DISCUSSION
In a further investigation of the amount of irrepairable damage in the rat spinal cord following hyperfractionated irradiation schedules, the fraction size was reduced from 2 Gy to 1 Gy. To avoid too large a number of fractions, a fixed top-up dose of 15 Gy was used in accordance with the concept of partial tolerance described previously.3 The total overall treatment time was kept within 4-6 weeks. It was previously shown in the same model that no time dependent recovery took place between 24 hr and 8 weeks.13 Similar to the observations made in our earlier experiments4 paralysis due to white matter necrosis (WMN) occurred within 6 to 10 months. However, as in the previous experiments with small fraction sizes, the present experiments showed that the WMN was occasionally accompanied by small hemorrhages. For both the experiments with 2 Gy and 1 Gy per fraction, a dose-response relationship was established using probit analysis.’ From these dose-response curves, the EDso values with 95% confidence limits were derived yielding 141.1 (127.0155.3) Gy for the 2 Gy per fraction and 159.1 (141.0177.1 ) Gy for the 1 Gy per fraction irradiations. These results are shown in Figure l.B together with the EDso values obtained in the earlier experiments4 with fraction sizes of 2.9, 2, 1.8, 1.5, and 1.3 Gy, respectively. The EDso value for the present experiment using 2 Gy per fraction was virtually identical to the value obtained in the earlier set of experiments (Fig. 1A-B and Table 1) confirming the reproducibility of the results in this model. Using the classical Fe plot’ of the reciprocal total EDs0 against the dose per fraction, the validity of the LQmodel can be tested indirectly. Based on the cervical spinal cord data of Ang et uI.~.~ involving all data related to
*D_ D ref
(culp + d ref) (aI@ + d)
.
February 1988, Volume 14. Number 2
fraction sizes of 2 Gy and larger (Fig. l.A), an o(/p ratio of 1.7 Gy was derived (correlation coefficient 0.9975). Using this a//3 ratio, in reference to a fraction size of 2 Gy and corresponding EDso of 140.5 Gy, the ED50 values predicted by the LQ-model for fraction sizes of 1.8, 1.5, 1.3, and 1 Gy were calculated.* These estimations for EDso are plotted in Fig. 1 (symbol x) and also presented in Table 1. They suggest an important increase in sparing of cervical cord even down to 1 Gy per fraction. In the earlier experiments involving doses per fraction down to 1.3 Gy4 no further sparing could be demonstrated for reduction of the fraction size below 2 Gy. The present results show a small increase in tolerance of about 12% at the EDso level when using 1 Gy instead of 2 Gy per fraction.” It needs to be specified that the confidence limits for both EDZO values are overlapping (Table 1). Using the same biological model, Hornsey et ~1.~ also reported some increased sparing as the dose per fraction is reduced from 2 to 1 Gy and to 0.6 Gy, the differences in tolerance doses remaining within the errors of the system. The sparing effect observed in our study ( 12%), is however much less pronounced than predicted on basis of the LQ-model (27%). Even when the EDso values were corrected for the possibility of incomplete repair of sublethal radiation damage for the fraction sizes given with 4 hr intervals (assuming a half-time for repair of 1.5 hr), there is still a difference of about 13% between the theoretical and experimental EDso values (Table 1). Our studies on repair kinetics have suggested the repair half-time to become shorter with smaller fraction sizes, but over the range of fraction sizes used (-4- 15 Gy) this proved not to be significant.’ If this trend would continue, however. for smaller doses per fraction of l-2 Gy as used in the present study, the correction for incomplete repair during a 4-hour interval could become even smaller. An analysis of the data for all doses per fraction below 3 Gy results in an (Y/P ratio of 4 Gy, which is similar to the result of an analysis of data obtained in experiments on repair kinetics using a direct method for analysis of quanta1 responses and an incomplete repair model.’ It can be concluded that the repair of sublethal radiation damage in the rat spinal cord actually measured in hyperfractionation experiments is less effective than predicted by the LQ-model for doses per fraction between 2 Gy and 1 Gy although probably not totally absent as was suggested earlier.4 These results suggest that the LQ-model does not adequately describe all experimentally obtained fractionation data. Therefore, our findings confirm the earlier warning for the use of LY/~ratio’s, that are extrapolated from data involving large doses per fraction, to design fractionation schedules with fraction sizes below 2 Gy.
A
200 150
100 60 t
60
5: 0 Y
40
d & I-
20
10 I
1
2 DOSE
200
III
3
4 PER
I,
5
6
76910
FRACTION
20 IGvl
B
-
> 2 :: D
160-
160 -
w
100 I 1
16
DOSE
2
PER
FRACTION
3
(Gy)
Fig. 1. Isoeffect doses for induction of foreleg paralysis (due to WMN) as a function of fraction size. A. Experiments with dose fractions down to 2 Gy (O ref. 3,4 and 0 the present study); B. Experiments with fraction sizes ranging between 1 and 3 Gy (0 ref. 3,4 and 0 the present study). At 1.3 Gy per fraction paralysis occurred even at the lowest total dose tested, and thus only the upper limit for total isoeffect dose could be estimated (for details see ref. 4). The calculated values for isoeffect, based on an a//3 ratio of 1.7 Gy and a dose fraction of 2 Gy (ED50 = 140.5 Gy) are indicated (X) for comparison.
Table 1. Comparison
of ED50 values: Experimental
results versus theoretical
calculations
Total EDso (Gy) values for rat cervical spinal cord (WMN) 2.0 GyfF Estimations* (LQ model; cu/p = 1.7 Gy) Experimental data
Experimental incomplete hr intervals
data, corrected for possible repair during the various 4 (see text)
140.0 ( 129.0- 150.8)t 141.1 (127.0-155.3) -
* Reference dose: 2 Gy/F and EDso = 140.5 Gy. t 95% confidence limits.
1.8 Gy/F
148.5 124.4 (107.8-141.2)
-128
1.5 Gy/F
162.4 137.6 (128.2-147.0)
-144
1.3 Gy/F
1.O Gy/F
173.3 <150
192.5 159.1 (141.0-177.1)
-
-167
300
I. J. Radiation Oncology 0 Biology 0 Physics
February 1988. Volume 14, Number 2
REFERENCES 1. Ang, K.K., Thames Jr., H.D., Van der Kogel, A.J., van der Schueren, E.: Is the rate of repair of radiation-induced sublethal damage in rat spinal cord dependent on the size of dose per fraction? Int. J. Radiat. Oncol. Biol. Phys. 13: 557-562, 1987. 2. Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: Inhalation anesthesia in experimental radiotherapy: A reliable and time-saving system for multifractionation studies Int. J. Radiat. Oncol. Biol. Phys. in a clinical department.
8: 145-148, 1982. 3. Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: The effect of small radiation doses on the rat spinal cord: The concept of partial tolerance. Int. J. Radiat. Oncoi. Biol.
Phys, 9: 1487-1491, 1983. 4. Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: Lack of evidence for increased tolerance of rat spinal cord with decreasing fraction doses below 2 Gy. Int. J. Radiat. 0~01. Biol. Phys. 11: 105-l 10, 1985. dose rate and iso5. Barendsen, G.W.: Dose fractionation, effect relationships for normal tissue responses. Znt. J. Radiat. Oncol. Biol. Phys. 8: 1981-1997, 1982. 6. Douglas, B.G., Fowler, J.F.: The effect of multiple small doses of X rays on skin reactions in the mouse and a basic Radiat. Res. 66: 401-426, 1976. interpretation. 7. Finney, D.J., Marcus, P.I.: Probit analysis. A Statistical Treatment qf the Sigmoid Response Curve. Cambridge, Cambridge University Press, 1952. 8. Fowler, J.F., Joiner, M.C., Williams, M.V.: Low doses per fraction in radiotherapy: A definition for “flexure dose.”
Br. J. Radiol. 56: 599-60 1, 1983.
9. Hornsey, S., Myers, R.: Is there further sparing of damage to the CNS as dose per fraction is reduced below 2 Gy per fraction (Abstract)? Int. J. Radiat. Biol. 50: 9 19, 1986. 10. Landuyt, W., Thames Jr., H.D., Ang, K.K., Van der Kogel, A.J., van der Schueren, E.: Kinetics and extent of repair of sublethal damage in mouse lip mucosa and rat spinal cord (Abstract). Znt. J. Radiat. Biol. 50: 365, 1986. 11. Thames, H.D., Withers, H.R., Peters, L.J., Fletcher, G.H.: Changes in early and late radiation responses with altered dose fractionation: Implications for dose-survival relationships. Int. J. Radiat. Oncol. Biol. Phys. 8: 2 19-226, 1982. 12. Tucker, S.L., Thames, H.D.: Flexure dose: The low-dose limit of effective fractionation. Znt. J. Radial. Oncol. Biol. PhJ1.y.9: 1373-l 383, 1983. 13. Van der Kogel, A.J.: Late effects of radiation on the spinal cord: Dose-effect relationships and pathogenesis. Monograph, Radiobiological Institute TNO, Rijswijk, The Netherlands, 1979. 14. Van der Kogel, A.J.: The cellular basis of radiation induced damage in the CNS. In C_ytotoxic Insult to Tissue: Effects on Cell Lineages, C.S. Potten and J.H. Hendry (Eds.). Edinburgh, Churchill-Livingstone. 1983, pp. 329-
352. damage in the 15. Van der Kogel, A.J.: Radiation-induced central nervous system: An interpretation of target cell responses. Br. J. Cancer 53 (Suppl. VII): 207-2 17, 1986. 16. Withers, H.R.: Responses of tissues to multiple small dose fractions. Radial. Res. 71: 23-33, 1977. 17. Withers, H.R., Thames, H.D., Peters, L.J.: A new isoeffect curve for change in dose per fraction. Radiother. On&. 1: 187-191. 1983.