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0360.3016192 $5.00 Copyright 0 1992 Pergamon Press Ltd.

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@ Biology Original Contribution THE EFFECT OF HYPERFRACTIONATION ON SPINAL CORD RESPONSE TO RADIATION ROBERT S. LAVEY, M.D.,

M.P.H., ANNE K. JOHNSTONE, B. A., JEREMY M. AND WILLIAM H. MCBRIDE, D.Sc.

G. TAYLOR, PH.D.

Department of Radiation Oncology and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA The TIO-L2 level of the spinal cord of C3Hf mice was irradiated using a conventionally fractionated regimen of 2.0 Gy once daily or a hyperfractionated regimen of 1.2 Gy twice daily separated by 8 hr. After a fractionated dose of 24-60 Gy given by either regimen, a top-up dose of 15 Gy was given. Hind limb strength was then measured weekly for 15 months. The time to onset of paralysis was inversely associated with the total dose. Overall, the spinal cord was not spared by hyperfractionation to the extent predicted by the modified Ellis power law or the linear-quadratic model. The threshold dose for the development of paralysis was higher in the hyperfractionated than in the conventionally fractionated group. However, the latent period for paralysis and the dose producing hind limb paralysis in 50% of the mice (EMO) were not significantly diierent between the two regimens. The continuation of the process of sublethal damage (SLD) repair in the spinal cord beyond 8 hr after irradiation may have influenced these results. The slow component of SLD repair should be considered in the design of hyperfractionated or accelerated radiation therapy schedules for clinical use. Hyperfractionated

irradiation, Radiation tolerance of spinal cord, Radiation myelitis.

radiation doses (29, 36). The spinal cord sparing effect should allow a higher, more effective total dose to be safely delivered to the nearby tumor. To prevent tumor cell repopulation from negating the cytotoxic effect of the increased total dose, the 5 to 7 week duration of radiation therapy is maintained by treating patients twice daily. Both of the popular normal tissue isoeffect formalisms, the modified Ellis power law (17, 30) and the linear-quadratic mode1 (36), predict that the spinal cord will tolerate a substantially higher total dose when radiation is given in 1.O- 1.2 Gy than in 1.8-2.0 Gy dose fractions. The estimated increase in ED50 is approximately 25% using the linear-quadratic equation with alpha/beta = 1.7 Gy and 45% using the power law formula with an exponent for N of 0.43. These constants were derived from experimental studies in which doses of at least 2.0 Gy per fraction were delivered to segments of the rat spinal cord (32, 35). Both formulae appear applicable to the dose range between 2 and 8 Gy per fraction. However, they appear to overestimate the extent of spinal cord sparing produced by further reducing the fraction size to below 2 Gy when

INTRODUCTION

The ability to control tumors that are located in or close to the spinal cord is compromised by the limitation on radiation dose imposed by perceived spinal cord tolerance. The total radiation dose given to spinal cord tumors is directly associated not only with local control and survival rates (9) but also with the incidence of transverse myelitis (2 1). To avoid inducing radiation myelopathy, clinicians typically prescribe a maximum cumulative cord dose of 45.0-50.4 Gy in 1.8 to 2.0 Gy daily fractions (3, 9, 11). Because conventional treatment frequently fails to control central nervous system tumors, hyperfractionated radiation therapy is currently being evaluated for the treatment of tumors of the spinal cord, as well as the brain, head and neck, and lung (7, 22, 26, 27, 29). The theoretical rationale for this approach is that the use of smaller than conventional dose fractions (i.e., 1.O- 1.2 Gy) preferentially spares the slow turnover normal tissues that are responsible for late-effects by taking advantage of their large capacity to repair the sublethal damage produced by low Presented at the 33rd Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Washington, DC. 38 November 199 1. Reprint requests to: Robert S. Lavey, M.D., M.P.H., 200 UCLA Medical Plaza, Suite B265, Los Angeles, CA 90024-695 1. R.S.L. is an RSNA Research and Education Fund Scholar. Supported in part by Grant CA 3 16 12 from the National Cancer Institute. DHHS.

ilcknowlc~~~~ments-The authors thank H. Rodney Withers, M.D., D.Sc. and Willy Landuyt, M.Sc. for suggestions on the manuscript, John Thomas and Ann Nguyen for data management, and Colin McLean, Manchester Cohen, and Alex Betancourt for maintenance of the defined-flora mouse colony. Accepted for publication 5 March 1992.

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the time interval between fractions is also reduced from 24 to 4 hr (2,35). This study was undertaken to determine the extent to which hyperfractionation may spare the spinal cord as well as increase the latent period for the development of transverse myelitis. METHODS

AND MATERIALS

Animals

The experimental animals were 336 C3Hf/Sed//Kam male mice bred and maintained in our defined-flora mouse colony that weighed 25-28 grams and were 9-l 1 weeks of age on the initial day of irradiation. Four mice were housed per cage. Sterilized animal pellets and water were provided ad libitum. The hind limb strength of each mouse was measured once weekly for 15 months following the course of irradiation. The development of hind limb paralysis, defined as loss of both the limb extension reflex and the ability of one or both legs to grasp a 4 mm in diameter steel bar on repeated examinations, was the endpoint of the experiment. Euthanasia was performed at the time of development of bilateral paralysis. Irradiation

All 336 mice underwent a 5-day-a-week (Monday through Friday) course of radiation to a 17 mm segment of the thoracolumbar cord. They were randomly allocated by cage to receive either 2.0 Gy once daily at 24 hr intervals or 1.2 Gy twice daily separated by alternating periods of 8 and 16 hr. The above regimens were chosen as representative of clinically accepted conventional and hyperfractionated radiation therapy schedules. Mice received between 12 and 30 fractions of 2.0 Gy to a total dose ranging from 24 to 60 Gy in an overall time of 16-39 days or between 22 and 42 fractions of 1.2 Gy to a total dose ranging from 26.4 to 50.4 Gy over 15-29 days. The radiation start date was selected to avoid delivery of the final fraction(s) on a Monday. There were eight mice in each total dose group. The mice were anesthetized for accurate positioning during each irradiation using 60 mg/ kg of pentobarbital injected intraperitoneally. They were then placed on their side in well ventilated lucite jigs open for a length of 17 mm over the TlO through L2 vertebral bodies. The opening was 9 mm in width to allow irradiation of the spinal cord at this level. The jigs were coated with a 3 mm thick lead plate to shield the remainder of the mouse’s body from irradiation. Eight mice were irradiated simultaneously. Irradiations were given through opposed lateral portals using 250 kV x-rays filtered by 0.2 mm Cu and 2.0 mm Al to give a half-value layer of 1.3 mm of Cu. The target-to-skin distance was 32 cm, resulting in a dose rate of 258 cGy/min to the spinal cord. The jigs were turned over midway through each radiation fraction to have an equal dose given to midplane from each side. The dose rate was measured by placing thermoluminescent dosimeter chips into the thoracolumbar spinal canal of recently sacrificed mice. The chips were stan-

Volume 24, Number 4, 1992

-dardized against two calibrated ion chambers. The reproducibility of the radiation field was confirmed on a separate set of mice by x-ray films taken on a clinical simulator. The general physical condition of the mice receiving a prolonged course of twice daily anesthesia limited the number of doses that could be given to the hyperfractionated group. To halve the required number of irradiation procedures, a top-up dose of 15 Gy was given to all mice in both groups 24 hr after the last fractionated dose. Fifteen Gy was previously found to produce half of the damage leading to hind limb paralysis in 50% of mice in two-fraction experiments (19). Data analysis

The actuarial method of Kaplan and Meier was used to estimate the incidence of paralysis over time ( 18). Time to the onset of paralysis was calculated from the date of the top-up dose. The incidence of paralysis in each fractionation and total dose group within 11 months was used for calculation of the ED50 values (the radiation dose producing paralysis in 50% of mice) by logit analysis. The statistical significance of total dose and fractionation schedule were assessed by logistic regression (6) using the incidence data at 11 months and by the Cox proportional hazards model (5) using both the incidence and latency data up to 15 months. In the logistic regression model, the probability (P) of paralysis is related to the total dose (D) and the fractionation regimen (conventional, C = 1, or hyperfractionated, C = 0) by the equation log(P/( 1-P) ) = A0 + A,D + A$. Tests for coefficients in the model are obtained from likelihood ratio tests and from the second derivative of the log-likelihood. The Spearman rank correlation (28) was used to assess the association between total dose and latency in those animals that developed paralysis prior to 11 months. All model fitting was performed using the SAS statistical package. The p values were derived from two-tailed tests of significance. Eleven months beyond the date of the top-up dose was chosen as the period for quantitative analysis because the earliest animal deaths unrelated to paralysis occurred during this month. The occurrence of paralysis and death due to other causes reduced the number of mice remaining beyond the fifteenth month after irradiation to eight. RESULTS

The incidence of paralysis by total fractionated dose, excluding the 15 Gy top-up dose, over time is shown for the group that received 1.2 Gy twice daily in Figure 1 and for the group that received 2.0 Gy once daily in Figure 2. Analysis of the data both prior to the eleventh month and throughout the 15-month observation period, using the Cox proportional hazards model, indicated that the risk of paralysis was highly associated with the total dose given to the spinal cord (p < 0.00 1). However, the fractionation

Cord response to hyperfractionation 0 R. S.

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of paralysis at up to 11 months as a function of the total dose given in 1.2 Gy fractions twice daily. The doses shown on the abscissa exclude a 15 single Gy fraction top-up dose.

3.0

Fig. 1. Occurrence

schedule had no influence on the overall incidence of paralysis either within 11 months (p = 0.80) or at 15 months (p = 0.94). The dose-response curves for paralysis within 11 months in both irradiated groups are shown in Figure 3. The ED50 for the hyperfractionated regimen was 39.6 Gy (95% confidence interval 32.3-46.9 Gy) plus the 1.5Gy top-up dose and for the once daily regimen was 40.6 Gy (95% C.I. 36.5-44.7 Gy) plus the 15 Gy top-up. Although the ED50 values for the two fractionation schemes were very similar, the threshold dose for the induction of paralysis was higher with the hyperfractionated than with the conventional once-a-day schedule. Several mice became paralyzed after receiving either 24 Gy or 30 Gy in once daily fractions of 2.0 Gy, whereas none of the mice receiving 26.4 or 3 1.2 Gy in twice daily fractions of 1.2 Gy developed paralysis within 1 year. Beyond the threshold dose, the incidence of paralysis rose more steeply with increasing dose in the hyperfractionated group. The doseresponse curves of the two radiation regimens cross just above the ED50 level of approximately 40 Gy. All mice receiving a fractionated dose in excess of 50 Gy by either schedule became paralyzed within 10 months.

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Fig. 3. Probability of paralysis within 1 I months versus total dose given in 1.2 Gy fractions b.i.d. or 2.0 Gy fractions q.d. Error bars indicate the overlapping 95% confidence intervals of the ED50 estimates.

Mathematical models were constructed using logistic regression analysis to quantify the effects of total dose and fractionation regimen on the probability of paralysis prior to 11 months. The goodness of fit of the models to the actual data is inversely associated with the value of -2 X log likelihood. A “constant probability” model was constructed that assumed that neither dose nor fractionation scheme influenced the paralysis rate (-2 X log likelihood = 89.97). A second model which assumed that only total dose influenced the paralysis rate fit the data markedly better (-2 X log likelihood = 69.4 1). The model incorporating total dose was not enhanced by the addition of separate, but parallel, dose-response curves for the two fractionation schedules (-2 X log likelihood = 69.31). Assigning different slopes to the two dose-response curves significantly improved the model compared to considering the curves to be parallel (-2 X log likelihood = 65.50). The relative frequency of the latent periods between the top-up dose and the onset of paralysis are shown in Figure 4. There appear to be three waves of paralysis, the first occurring 6-8 months after irradiation, the second at lo- 11 months, and the third at 15 months. The small number of animals surviving without paralysis longer than

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15 months after the top-up dose prevents a clear definition of the third wave. The earliest occurrence of paralysis was five months after the completion of irradiation. There was no association between fractionation schedule and the latent period for the development of paralysis (I, = 0.78). Latency was inversely associated with the total fractionated dose in both the hyperfractionated (p = 0.05) and the conventionally fractionated (p = 0.12) groups. Because the two groups had similar dose-response parameters, they were combined for quantitative analysis of the dose-latency data shown in Figure 5. The mean latent period for paralysis decreased by approximately 1 month with each increase of 20 Gy in the radiation dose to the spinal cord. DISCUSSION

Latency The earliest occurrence of hind limb paralysis was at 5 months after the top-up dose. Half of the mice developing paralysis did so during the 6th or 7th month after irradiation. This timing of the mouse thoracolumbar cord response is strikingly similar to that of the rat cervical cord. Investigators have consistently found a 5 to 8 month latent period for the development of fore limb paralysis due to white matter necrosis in the rat (1, 16, 24, 34). Histological analysis was performed in our laboratory of the irradiated spinal cord of mice that developed bilateral paralysis after from one to four radiation fractions during this period. Demyelination was found in 110 of the 111 mice (99%) studied, without any demonstrable vascular or grey matter damage in 72% of cases (20). Analysis of a random sample of paralyzed mice in the present study yielded similar findings. A second wave of paralysis occurred during the 10th to 1 lth months, followed by a 2 month gap between the 12th and 15th months in which no mice became paralyzed. The later peaks in incidence of paralysis suggest the existence of an additional mechanism of radiation injury characterized by a different sensitivity to radiation and a longer latent period. A second wave of paralysis starting approximately 4 months after the end of the initial wave is also characteristic of the rat spinal cord response. This late-occurring response has

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been attributed to intramedullary vascular damage (24, 34). Our finding of an inverse association between total radiation dose and the latent period for paralysis confirms the observations of others in the mouse (10, 12, 20) and rat (4, 13, 15, 31) models, as well as in human cancer patients (25). Hyperfractionation eflect We found no significant difference in the ED50 for paralysis between the conventional and hyperfractionated radiation schedules, although the threshold dose producing paralysis appears to have been increased by hyperfractionation. This threshold region of the dose-paralysis curve is the most clinically important, as it, rather than the EDSO, defines the maximum dose that can be safely given to patients. A sparing effect at this level of response would be of great significance, even if the ED50 is not affected. The present study was not of sufficient power to determine whether the steeper slope observed in the hyperfractionated dose-response curve has a biological basis. The possibility that incomplete repair of sublethal damage (SLD) during the limited time between twice daily fractions increases the slope is being investigated. The effect of reducing radiation fraction size below 2.0 Gy has been previously investigated in the rat cervical cord. Studies using this system also found no statistically significant change in the calculated ED50 with hyperfractionation. Ang et al. (2) and van der Schueren et al. (35) compared the incidence of paralysis after 2.0 Gy given once daily to smaller dose fractions given once or twice daily at alternating 4 and 20 hr intervals, with all groups receiving at least 26 fractions followed by a single 15 Gy top-up. While Ang et al. found no suggestion of any sparing associated with fraction sizes of 1.8, 1.5, and 1.3 Gy, van der Schueren et al. calculated that fractions of 1.OGy increased the ED50 by 12% (the 95% confidence limit included 0). Even if some sparing does occur as a result of decreasing the dose per fraction from 2.0 Gy to 1.OGy, it appears to be much less than the increase in ED50 of 27% predicted by the linear-quadratic equation with alpha/beta = 1.7 or of 60% predicted by the modified Ellis power law formula using p43. These models were derived from, and are quite useful for, doses given in fractions of greater than 2 Gy, but they overestimate the effect of a reduction in fraction size below 2 Gy. It appears that the spinal cord repairs sublethal radiation damage less rapidly or completely after small doses than was anticipated based on the clinical and experimental experience with larger dose fractions. The unexpected occurrence of radiation myelitis in 4 out of the 30 cancer patients (13%) on the Mount Vernon Hospital CHART protocol who were given 45-54 Gy to the cervical cord in fractions of 1.4 to 1.5 Gy at intervals of 6 to 12 hr demonstrates the hazard of overestimating the repair kinetics of the spinal cord (23). These results call into question the value of hyperfractionation as a treatment approach for cases in which the

Cord response to hyperfractionation 0 R. S. LAVEY PIal.

spinal cord is the dose-limiting organ. The rationale for hyperfractionation assumes that the spinal cord will tolerate a substantially higher radiation dose if that dose is given in fractions of 1.O- 1.2 Gy twice daily rather than the conventional 1.8-2.0 Gy once a day. The data from rodent models indicate that this is not true. Over a large range of radiation doses, decreasing the dose diminishes the amount of residual injury to the cord. However, a constant level of unrepaired sublethal damage (SLD) may remain after doses of between 1 and 2 Gy, resulting in a plateau in the dose-response curve. Changing the fraction size and time interval between fractions may also have altered the target cell population in the spinal cord, thereby affecting the mechanism of induction of radiation myelitis. This hypothesis is supported by the apparent difference in slopes of the dose-response curves for the two radiation schedules, but not by their similar dose-latency curves.

Interval between fractions Hyperfractionation involves a reduction in both the size of the radiation fractions and the time interval between fractions. The failure of hyperfractionation to produce spinal cord sparing may be due to insufficient time for completion of SLD repair between fractions rather than a loss of the fraction size effect below 2 Gy. The halftime for SLD repair by the rat cervical and lumbar cord has been estimated to be 1.4- 1.5 hr ( 1,24, 30, 33). However, careful repair kinetics studies in two strains of rat demonstrate a continuous increase in cord tolerance as the interval between fractions is progressively increased from 0.5 to 24 hr. This finding suggests that there is a second, slower component of repair in the rat spinal cord with a half-time of at least 4 hr (8, 14). Further evidence that the time course of SLD repair is at least biphasic has recently been obtained by Landuyt, Stuben, and van der Schueren in an investigation of differing time intervals between 2 Gy fractions. The results indicated that SLD repair continues for 8 to 24 hr after irradiation (Landuyt, W. Oral communication, October, 199 1). When multifractionated regimens with a range of fraction sizes from 0.55-25 Gy given with a constant interval between fractions of 24 hr were compared, the amount of sparing produced by decreasing the fraction size below 2 Gy was as high as that predicted by the power law formula and substantially more than predicted by the linearquadratic model (37). In other words, rat cervical cord

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radiation tolerance to once-a-day fractionation increased more by decreasing the fraction size from 2 to 1 Gy than by decreasing the fraction size from 3 to 2 Gy. This study permitted variation in the number of weeks to reach a particular dose to hold the interval between fractions constant at 24 hr. In contrast, in our study and others the interval between fractions was reduced together with the fraction size to maintain a constant overall duration of treatment (2, 35). The stark contrast between the results of the two approaches may be due to the effect of the slow component of SLD repair between fractions. Repopulation during the prolonged period of once daily treatment using small fractions is unlikely to have contributed significantly to the difference in results. Two independent studies in which multiple radiation fractions separated by at least 24 hr were given to the rat cervical cord both found no change in the isoeffective dose with a range of overall treatment times from 11 to 50 days (Landuyt, W.; Ang, K. K.; van der Kogel, A. J.; Stuben, G.; van der Schueren, E. Regeneration in the rat spinal cord after irradiation, 33). The CHART protocol for human patients with squamous cell carcinoma of the head and neck included a reduction in both the interval between fractions and overall duration of therapy. The occurrence of paralysis in a significant proportion of the patients suggests that under these circumstances spinal cord tolerance to radiation decreases, despite the use of 1.4 to 1.5 Gy fraction sizes (23). Our study indicates that the ED50 of the mouse thoracolumbar cord, like the rat cervical cord (2, 35). is not substantially altered by hyperfractionation with an interval of 8 hr or less between fractions compared with conventional radiation fractionation. The latent period for the development of paralysis following irradiation was inversely associated with the total dose given to the spinal cord. The pattern of incidence of paralysis over time suggests that radiation myelitis may develop through two or three separate pathways having different response times. Data from the mouse and the rat, as well as a human clinical trial (23), do not support the use of hyperfractionated radiation schedules with short interfraction intervals to deliver higher doses to the spinal cord than would be considered safe with conventional fractionation. Additional work is required to confirm the suggestion from our study that hyperfractionation significantly increases the threshold dose for the induction of radiation myelitis.

REFERENCES 1. Ang, K. K.; Thames, H. D.; van der Kogel, A. J.; van der der Schueren, E. Is the rate of repair of radiation-induced sublethal damage in rat soinal cord deoendent 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. Lack of evidence for increased tolerance of rat spinal cord with decreasing fraction doses below 2 Gy. Int. J. Radiat. Oncol. Biol. Phys. 11:105-l 10;1985.

3. Bouchard, J. Central nervous system. In: Fletcher, G. H., ed. Textbook of radiotherapy, 3rd edition. Philadelphia, PA: Lea and Febiger; 1980:444-498. 4. Carsten, A.; Zeman, W. The control of variables in radiopathological studies on mammalian nervous tissue. Int. J. Radiat. Biol. 10:65-74;1966. 5. Cox, D. R. Regression models and life tables. J. Royal Stat. Sot. Ser. B. 34: 187-220; 1972.

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6. Cox, D. R.; Snell, E. J. Analysis of binary data, 2nd edition. London, Eng.: Chapman and Hall; 1989. 7. Davis, L. W. Presidential address: Malignant glioma-a nemesis which requires clinical and basic investigation in radiation oncology. Int. J. Radiat. Oncol. Biol. Phys. 16: 13551365;1989. 8. Feng, Y.; Guttenberger, R.; Thames, H. D.; Ang, K. K. Repair kinetics in rat cervical spinal cord: Significance for multiple fractions per day treatment (Abstr.). In: Chapman, J. D., Dewey, W. C., Whitmore, G. F., eds. Radiation research: A twentieth century perspective, Vol. I: Congress abstracts. San Diego, CA: Academic Press, Inc.; 1991: 185. 9. Garcia, D. M. Primary spinal cord tumors treated with surgery and postoperative irradiation. Int. J. Radiat. Oncol. Biol. Phys. 11:1933-1939;1985. 10. Geraci, J. P.; Jackson, K. L.; Christensen, G. M.; Thrower, P. D.; Mariano, M. RBE for late spinal cord injury following multiple fractions of neutrons. Radiat. Res. 74:382386; 1978. 11. Glanzman, C. Radiotherapy in der Behandlung von Ruckenmarksgliomen. Strahlenterie 156:6 16-625; 1980. 12. Goffinet, D. R.; Marsa, G. W.; Brown, J. M. The effects of single and multifraction radiation courses on the mouse spinal cord. Radiology 119:709-7 13; 1976. 13. Hopewell, J. W.; Morris, A. D.; Dixon-Brown, A. The influence of field size on the late tolerance of the rat spinal cord to single doses of X rays. Br. J. Radiol. 60:10991108;1987. 14. Hopewell, J. W.; van den Aardweg, G. J. M. J.; Current concepts of dose-fractionation in radiotherapy: Normal tissue tolerance. Br. J. Radiol. 22(Suppl.):88-94;1988. 15. Hopewell, J. W.; Wright, E. A. The effects of dose and field size on late radiation damage to the rat spinal cord. Int. J. Radiat. Biol. 28:325-333; 1975. 16. Hornsey, S.; Myers, R.; Jenkinson, T. The reduction of radiation damage to the spinal cord by post-irradiation administration of vasoactive drugs. Int. J. Radiat. Oncol. Biol. Phys. 18:1437-1442;1990. 17. Hornsey, S.; White, A. Isoeffect curve for radiation myelopathy. Br. J. Radiol. 53: 168- 169; 1980. 18. Kaplan, H. S.; Meier, P. Non-parametric estimation from incomplete observation. J. Am. Stat. Assoc. 55:457480;1958. 19. Lo, Y.-C. The effects of ionizing radiation and hyperthermia on mouse spinal cord. Ph.D. Thesis, UCLA. Ann Arbor, MI: University of Michigan Press; 1989. 20. Lo, Y.-C.; McBride, W. H.; Withers, H. R. The effect of single doses of radiation on mouse spinal cord. Int. J. Radiat. Oncol. Biol. Phys. 22:57-63;1992. 2 1. Marsa, G. W.; Goffinet, D. R.; Rubinstein, L. J.; Bagshaw, M. A. Megavoltage irradiation in the treatment of ghomas of the brain and spinal cord. Cancer 36:1681-1689;1975. 22. Parsons, J. T.; Mendenhall, W. M.; Cassisi, N. J.; Isaacs, J. H. Jr.; Million, R. R. Hyperfractionation for head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 14:649658;1988.

Volume 24, Number 4. I992 23. Saunders, M. I.; Dische, S.; Grosch, E. J.; Fermont, D. C.; Ashford, R. F. U.; Maher, E. J.; Makepeace, A. R. Experience with CHART. Int. J. Radiat. Oncol. Biol. Phys. 2 1: 871-878;1991. 24. Scalliet, P.; Landuyt, W.; van der Schueren, E. Repair kinetics as a determining factor for late tolerance of central nervous system to low dose rate irradiation. Radiother. Oncol. 14:345-353; 1989. 25. Schultheiss, T. E.; Higgins, E. M.; El-Mahdi, A. M. The latent period in clinical radiation myelopathy. Int. J. Radiat. Oncol. Biol. Phys. 1O:l 109-l 115;1984. 26. Seydel, H. G.; Diener-West, M.; Urtasun, R.; Podolsky, W. J.; Cox, J. D.; Zinninger, M.; Francis, M. E.; Radiation Therapy Oncology Group (RTOG). Hyperfractionation in the radiation therapy of unresectable non-oat cell carcinoma of the lung: Preliminary report of a RTOG pilot study. Int. J. Radiat. Oncol. Biol. Phys. 11:1841-1847;1985. 27. Shenouda, G.; Souhami, L.; Freeman, C. R.; Hazel, J.; Lehnert, S.; Joseph, L. Accelerated fractionation for high-grade cerebral astrocytomas. Cancer 67:2247-2252, 199 1. 28. Spearman, C. The proof and measurement of association between two things. Am. J. Psychol. 15:72-10 1;1904. 29. Thames, H. D.; Withers, H. R.; Peters, L. J.; Fletcher, G. H. Changes in early and late radiation responses with altered fractionation; Implications for dose-survival relationships. Int. J. Radiat. Oncol. Biol. Phys. 8:2 19-226; 1982. 30. van der Kogel, A. J. Radiation tolerance of the rat spinal cord: Time-dose relationships. Radiology 122:505509;1977. 3 1. van der Kogel, A. J. Late effects of radiation on the spinal cord. Dose-effect relationships and pathogenesis. Rijswijk, The Netherlands: Radiobiological Institute TNO; 1979. 32. van der Kogel, A. J. Central nervous system radiation injury in small animal models. In: Gutin, P. H., Leibel, S. A., Sheline, G. E., eds. Radiation injury to the nervous system. New York, NY: Raven Press; 199 1:9 I- 111. 33. van der Kogel, A. J.; Sissingh, H. A. Effect of misonidazole on the tolerance of the rat spinal cord to daily and multiple fractions per day of X rays. Br. J. Radiol. 56: 12 l- 125; 1983. 34. van der Kogel, A. J.; Sissingh, H. A.; Zoetelief, J. Effect of X rays and neutrons on repair and regeneration in the rat spinal cord. Int. J. Radiat. Oncol. Biol. Phys. 8:20952097; 1982. 35. van der Schueren, E.; Landuyt, W.; Ang K. K.; van der Kogel, A. J. From 2 Gy to 1 Gy per fraction: Sparing effect in rat spinal cord? Int. J. Radiat. Oncol. Biol. Phys. 14:297300;1988. 36. Withers, H. R.; Thames, H. D.; Peters, L. J. A new isoeffect curve for change in dose per fraction. Radiother. Oncol. 1: 187-191;1983. 37. Wong, C. S.; Hill, R. P. Linear quadratic model underestimates sparing effect of small doses per fraction in rat spinal cord (Abstr.). In: Chapman, J. D., Dewey, W. C., Whitmore, G. F., eds. Radiation research: A twentieth century perspective, Vol. I: Congress abstracts. San Diego, CA: Academic Press, Inc.; 199 1: 184.

The effect of hyperfractionation on spinal cord response to radiation.

The T10-L2 level of the spinal cord of C3Hf mice was irradiated using a conventionally fractionated regimen of 2.0 Gy once daily or a hyperfractionate...
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