Int. 1. Radiation
Oncdogy
Bid
Phys.. 1976. Vol. 1. pp. 651-657.
RADIATION
Pcrpunon Press.
MYELOPATHY
HIJIBERT S. REINHOLD, M.D., and KOBY
Printed in Ik U.S.A.
OF THE CORD
THORACIC
SPINAL
Ph.D., Jos G. A. H. KAALEN, Ph.D.? UNGER-GILS, B.A.
Department of Experimental Radiotherapy, Erasmus University Rotterdam, c/o Rotterdam Radiotherapeutical Institute, Groene Hilledijlc, Rotterdam, The Netherlands Theauthors reviewed and readculated the dose, number of fractions, and overall b-eatmcnt time of 19 patknts who developed radiation myclopatby of the tboracic spinal cord after radiation therapy far carcinoma of the lung. The 19 patknts represented the “usabk” yieid of 4~nthorplwSopcral~ycaperlod,~mtlw18lcsottbcreiarti~o~the~ timcpaiod,tBc&~of24potksPtswhonaived~~yt8c~-ntbrtdldnot devebped radWon myefopatby were analyzed. Tbeee were no signf&ant dfffefencea between tbc~donOcsrspplgcd,tbcnlunbtrof~~ortbedo&perfnctiolr.Thcrcw~ however, a dffferemcein tbe overall treatment tin, in the muse tbat tbe treamnt of those patients who later developed radMo0 myelopatby was longa tbaa that of the aomnyeiopatby W. in contrast to expectation, the bfood pressure of tbe patknts wbo later devetoped radiathtion myelopathy was lower tbaa tbat of the wnmydopatby cases. Radiation myeiopatby, Thorn&spinalcord,Radiation tberapy.
INTRODUCTION The increased survival of patients with malignancies treated by radiation is accompanied by an increased incidence of side effects. One of the most notorious side effects of a full of course of radiation is the development radiation myelopathy, sometimes called radiation myelitis.‘“*‘7.‘g The incidence of radiation myelopathy in one center in Holland, the Rotterdam Radiotherapeutical Institute, has been reported previously.5 The awareness of this unfortunate complication resulted in the suggestion (Prof. Dr. H. C. Stam, written communication, 1971) that it might be worthwhile to collect the total number of cases with radiation myelopathy in Holland, in order to gain a better insight into the dose-time-effect relationship.15*‘6 In order to do so, not only data on patients with radiation myelopathy, but also data on those patients who received similar treatment and apparently escaped the danger of developing radiation myelopathy had to be collected.
Data on 19 patients with and 24 patients without radiation myelopathy could be collected. After an initial survey, we restricted the type of treatment to that for carcinoma of the lung. Other cases such as patients with malignancies in the head and neck area or with diseases like Hodgkin’s sarcoma were excluded from the present series because of the possibilities of overlapping fields, etc. Our results indicate that the patient’s blood pressure as well as the overall treatment time is of importance in the development of radiation myelopathy.
tDepartment of Statistics, Radiotherapeutical Institute, Rotterdam, The Netherlands. Acknowledgements-The authors wish to thank
Thomas, the late Dr. W. Th. Evers, Dr. J. de Jong, Dr. S. den Hoed-Sijtsema, Dr. J. A. van der Peel, Dr. H. P. Hamers for making available and recalcu-
Prof. Dr. H. C. Stam for his suggistion to pool the available data in the Netherlands. Also Prof. Dr. P.
lation of the patient data.
METHODS AND MATERIALS Four hospitals reported cases of radiation myelopathy that warranted further The diagnosis “radiation investigation. myelopathy” was invariably made by experienced neurologists. The diagnosis was made on the clinical symptoms only, including myelography for the majority of the cases. No cases were included in which there was the
651
652
Radiation.Oncology 0 Biology 0 Physics
slightest reason to assume that the neurological symptoms could be the result of other causes, i.e. malignant involvement. The extended follow-up time between the onset of the neurological symptoms and the final diagnosis of radiation myelopathy averaged 4 months. This was sufficient to prevent a false diagnosis resulting from malignant invoivement. Moreover, a false diagnosis on clinical symptoms is highly unlikely.‘* The files over the periods for which the myelopathy cases were reported (generally from 1960 to 1971) were also scrutinized for those patients who did not dtvclop myelopathy. All patients surviving for 30 months after treatment for carcinoma of the lung without showing signs of myelopathy were accepted as “nonmyelopathy” patients. The procedure for data collection for the myelopathy and nonmyelopathy patients was identical. The records wer3 analyzed for total dose, dose ptr fraction, overall treatment time, number of fractions and blood pressure. Blood pressure as mentioned in this paper refers to the systolic blood pressure, as it was recorded in the patients history, i.e. in the period of initial work-up. The X-ray films and treatment films were reviewed and only those casts in which it was certain that the spinal cord received the (re)calculattd dose were included in the series. Moreover, only patients treated with Ttltcobalt or mtgavoltagt therapy were taken into account. One and another resulted in a considerable reduction in the number of “reliable” nonof myelopathy casts. In the (rt)calculations the dose applied to the spinal cord, no corrtction for bone absorption was made. This is in agreement with every day practice, and no systematic error in the results can bt expected from deleting the bone absorption of the vertebrae in the dose calculations. RESULTS The patient data art given in Table 1. Only patients who did not receive a split-dose trtatment were included in the final series. This left us with 19 mytlopathy and 24 nonmyelopathy patients. A summary of the statistical data is given in Table 2A and Fig. 1. There is a barely significant difference in total dose (P = O&4),
1976, Vol. 1, Number 7 and Number 8
50
7000 TM0
d 5CQOmd
30
Overall time
3Odays
I5
Number d Length - fractions-
2Ofracbs
km
175
1Blood 'PnSSUR
.I !OOmmHg
Fig. 1. Statistical data of the myelopathy (M+) and nonmyelopathy CM-) patients. From left to right; Total Myelum Dose (TMD), overall treatment time, number of fractions, length of spinal cord treated (field length) and systolic blood pressure. Vertical bars indicate 95% confidence limits of the mean. and no dittertnct in the number of fractions. There is, however, a difference in the overall treatment time (2P = 0.03). The mean treatment time of mytlopathy patients is 42.42 days; this is longer than the mean treatment time of 37.6 days for the nonmyelopathy patients. The mean blood pressure of the mytlopathy casts is 128 mm Hg which is lower than the mtan blood pressure of 148 mm Hg for the nonmytlopathy casts. This difference is sign&ant (2P = 0.0024). The difference between the average dose per fraction (259 vs 236) was not significant (2P = 0.06). Finally, the mean latent period was 19 months with a range of 5.5 months-4 years. DISCUSSION Some of our findings differ from what one would expect. The differences in total dose, average dose per fraction, and number of fractions are non, or barely significant; however, they move in the expected direction, that is, that the mytlopathy patients received a somewhat higher dose in fewer fractions. It was, very surprising, however, to find that the overall treatment time for the mytlopathy patients was longer than that for the nonmytlopathy patients. One then of course becomes suspicious that the overall treatment exerts some influence upon the survival time of the patients, introducing a bias in the selection of the non-
Radiation myelopathy of the thoracic spinal cord 0 H. S. Rawuo~~ et al.
653
Table 1. Data of the myelopatby and nonmyelopathy patients, arranged in order of magnitude of the total myelum dose (TMD) Patient No.
Blood pressure (mm Hg)
23R9R14R20R18R15R8R’ 7R1 IR’ 22D’ lOR32L9R’ 2R’ 14R’ 22R4R’ 2OL’ 8R6R12R24L’ 19R28G16G’ 21R13R15G’ 16R_ 12R’ 27G3OD23D’ 29GSR6R’ 18G’ 3R’ 210’ 25G17G’ 26G25G’
145 150 180 155 160 140 140 ? 140 140 130 130 110 135 110 140 120 150 165 130 150 130 180
t 110 155 140 140 160 140 120 140 140 175 125 85 95 t 145 125 150 160 t
Length (cm)
TMD (tad)
Time (days)
Fraction No.
Latent per. (months)
10 12 10 14 20 10 10 17 10 9 9.5 10 10 10.5 13 14 12.5 9.5 10 12 11.5 10.5 7 16 15 10 9 13 14 10 16 9 11 11 12.5 9 14 11 14 10 10 14 12
4317
30 32 30 27 36 35 37 37 26 48 29 41 33 37 35 39 44 42 44 36 36 40 32 44 43 39 43 40 36 43 45 53 64 40 40 43 47 42 55 40 46 40 41
21 24 20 19 25 25 26 26 20 19 23 30 24 27 25 28 29 18 29 24 23 18 24 30 30 26 31 30 24 31 30 23 23 30 30 29 30 28 22 30 30 30 29
3
4895 5143 5222 5239 5342 5570 5609 5782 6003 6161 6174 6186 6286 6282 6354 6368 6387 6429 6453 6504 6515 6536 6537 6562 6571 6633 6686 6702 6727 6769 6787 6884 6895 6912 6953 6961 7091 7223 7394
: : $ 30 $ IO 13 : 13 22 26 $ 18 29 : $ 29 : 10 $ $ 10 $ 48 : : $ 6 13 39 12 $ 22 $ 5.5
tNo information available. SDid not develop disease.
myelopathy group. However, we have been unable to find any trace of an influence of the overall treatment time on the survival time of the nonmyelopathy cases. Neither did extension of this number to a group of 288 patients surviving for over 1 year show any indication
in this direction. It seems unlikely, therefore, that the composition of our nonmyelopathy series is biassed via the overall treatment time and patients survival, and we have been unable to explain this rather absurd phenomenon.
654
Radiation Oncology 0 Biology 0 Physics
In a recent publication on the treatment of carcinoma of the lung, Eichhorn et al.’ were also puzzled by the finding that, from three series of different treatments, the one with the longest overall treatment time and the lowest total dose showed the highest incidence of radiation myelopathy. The fractionation schedule, however, was very unusual and the observation was not statistically significant. The only experimental report known to the authors in which the effect was found to be decreased by prolongation of the interval between two fractions comes from Withers et al.” They found a decreased survival of stem cells of the rat testis when the interval between the dose increased from 4 hr to 14 days. “Strandquist” slopes for radiation myelopathy for dose against time were given for humans by Boden (Atkins and Tretter) as 0.26,’ Phillips and Buschke as 0.75,” Maier et al. as 0.277,14 and for rats by Van der Kogel and Barendsen as 0.44.= In our material, a value of 0.23 was found with a least-squares (double logarithm) regression for the myelopathy patients. This is somewhat low, but certainly not outside the expected range. In Table 2(b) two derived values are tabulated, the first representing the generally used exponents for time of - 0.11 and - 0.24 for the number of fractions. The dserence between the values is barely significant (P = 0.026). The second row on Table 2(b) represents values that were calculated via a search routine’. for the optimal separation between the two groups, as judged by the Student’s t-test. The highest t-values were determined with initial incremental steps of 0.1 for the t, as well as for the N exponents, covering the range from - 2 through + 2. This was followed by a search with 0.005 incremental steps in the area in which the highest t values were found. The optimal separation was found (P = 0.0037) for a time exponent of 0.52 and an for the number of exponent of -0.67 fractions. Using these values for transformation, a probit-analysis could be performed, as shown in Fig. 2. The dose, as indicated on the abcissa, was recalculated from the transformed individual date, but now for the average treatment time (40 days) and the average number of
1976, Vol. 1, Number 7 and Number 8
r; 8
,/ 0
cc @‘q/2 30
40
dose
in rad x 100 hcalcubted
SO
60
70
60
60
for 40 doyr,
too
26 Actions)
Fig. 2. Percentage radiation myelopathy against dose, assuming an average treatment time of 40 days and 26 fractions. The dosages (and incidences) The upper and are grouped for 850 rad intervals. lower 95% dose limits are also indicated. This curve refers only to our 43 patients. fractions (26 fr). The dose-effect relationship, as shown in Fig. 2, is based only on the data of the 43 patients we have collected so far and all the data were used, regardless of the patient’s blood pressure. It should be cautioned, therefore, that this dose-effect relationship may not be generally applicable. Incidence, as calculated on Fig. 2 is deduced from the numbers of myelopathy patients versus the numbers of “controls”. The size of the latter group can be influenced not only by the size of the population one selects to investigate, but also by the restrictions that one unavoidably has to make. (1) It should be realized that the “control” group also consisted of patients with lung carcinoma. Factors influencing the survival rate may therefore also influence the eventual number of “controls”. (2) The number of hospitals included in the search may be of some importance; only hospitals reporting myelopathy cases were included. (3) The same applied for the observation period; only the time periods over which myelopathy cases were reported were scrutinized for “controls” (on which 2 additional cases of myelopathy were found!). (4) Period of time following irradiation after
ztcT-O-”
* N-O*’
K = TMD * T+.” * N-o.6’
K = TMD
6094.2 (+ 791.8) 37.6 (+ 5.9) 26 (+ 3.6) 12.02(? 3.1) 147.9 (2 17.9)
( f SD)
( 2 SD)
1870.6 (+ 195.7) 4536.5 (-c 670.0)
Nonmyelopathy
Table 2(b). Derived values of the myelopathy
Total myelum dose (rad) Overall treatment time (days) Number of fractions Length of spinal cord treated (cm) Systolic blood pressure (mm Hg) Latent period (months)
Nonmyelopathy
Table 2(a). Statistical data of the myelopathy
6468.9 42.4 25.7 11.3 128.2 19.1
24 24
n
( 2 SD)
patients
(k SD) 1974.5 (k 129.1) 5229.9 (k 943.9)
Myelopathy
patients
(2523.0) (+- 8.1) (2 4.5) (2 1.8) (+ 19.6)
Myelopathy
and nonmyelopathy
24 24 24 24 22
n
and nonmyelopathy
P < 0.05
19 I9 19 19 17 19
Significance P < 0.05 P < 0.005
n 19 19
2P :‘“6.005
2P < 0.05 ns.
Significance
n
656
Radiation Oncology 0 Biology 0 Physics
which one assumes that no myelopathy will develop, will influence the number of “controls” (see point 1), but may also influence the yield of patients with myelopathy. A 50% incidence seems to correlate with an average dose of 6500 rad (95% range, 5l300-7900 rad) if given in an average number of 26 fractions, over a mean time period of 40 days. The finding that the average value for the blood pressure of patients with radiation myelopathy is lower than that on nonpatients was completely myelopathy unexpected. We included the blood pressure in our investigation because of the available experimental evidence that hypertension increases the radiation damage to the CNS. Asscher and Anson’ induced hypertension in rats by a clip around a renal artery 2 weeks before irradiation of the spinal cord with dosages from 1500 to 3000 rad. Only hypertensive .animals developed spinal cord lesions with a latent period ranging from 25 to 270 days, the average value probably being about 4 months. In addition, Hopewell and Wright found that induced hypertension shortened the lifespan of rats that received moderate dosages of radiation to the brain.’ These experiments were all done with rats with induced hypertension. The latent period between radiation and the development of neurological symptoms (or death) was, however, rather short in these investigations. The same applies to the results obtained by Asbell and Kramer in determining the relationship between the dose to the spine and the latent period.’ Their latent period is invariably shorter than 1 year. Van der Kogel and Barendser?’ inferred that there may be a threshold dose of 2000rad (single dose). He concludes that, rather than a continuous relationship between dose and latent period, one rapidly approaches a minimum latent period of about 4-5 months when the dose is increased. Whether or not the aforementioned experimental data are directly applicable to the human situation is as yet unknown. It should be mentioned, however, that, in our material, the shortest latent period was 5.5 months and therefore in agreement with the
1976, Vol. 1, Number 7 and Number 8
observations of Van der Kogel and Barendsen.M However, the longest latent period was 4 years, while the average value was about 19 months. This is in agreement with clinical experience and is essentially longer than the majority of the aforementioned experimental determinations. This discrepancy may also be of importance in the difference in influence of blood pressure upon the development of radiation myelopathy in experimental and clinical determinations. Surprisingly, there was no correlation between blood pressure and latent period in our material, Few reports deal with the blood pressure of patients in relation to their response to radiation. Jellinger and Sturm”’ mention that no correlation could be found between hypertension and radiation myelopathy. Jet&in and Stryker” and Hierlihy, Jenkin, and Stryker’ conclude from their series of patients with cervival carcinoma that patients with high blood pressure (> 140.9) showed recurrences, also fewer more but complications, than patients with a lower blood pressure. Complications in their cases were of the intestinal/gyneacological type rather than of a neurological nature. Their findings seem to indicate that the tumour cure rate was better with lower blood pressures, but that the incidence of complications was also higher. Our results seem to agree with their finding of a higher complication incidence with a lower blood pressure. Whether or not the survival rate of patients treated with irradiation for carcinoma of the lung is also influenced by the pressure is presently under blood investigation. It is tempting to speculate whether the individual sensitivity, as suggested by Jellinger and Sturm,‘” Dynes and Smedal,6 and Locksmith and Powers,” bears any relationship to the blood pressure of the patient. Accepting that the level of the blood pressure may in itself be the result of many factors, one could think not only of protecting or enhancing factors for damage to, e.g. blood vessels during the treatment, but also during the latent period. In conclusion, our serious attempts to collect and compare two groups of patients, with
Radiation myclopathy of the thoracic spinal cord 0 H. S. REINHOLDet nl.
and without radiation myelopathy, yielded two unexpected features . developed radiation Patients who myelopathy received their treatment in a longer overall treatment time and their mean blood pressure was lower than the average. These puzzling findings may be incidental,
657
resulting from interfering factors in the colletting procedure; they may also be correct. Data from other institutions will be required to evaluate this. In the meantime, our results show unambiguously that one should be extremely cautious in accepting any simplified prescription for a “safe” dose level.
REFERENCES 13. Locksmith, J.P., Powers, W.E.: Permanent radiation myelopathy. Am. J. Roentgenol. 102: 916-926, 1968. 14. Maier, C.J.G., Perry, R.H., Saylor, W., Sulak, C.M.H.: Radiation myelitis of the dorsolumbar spinal cord. Radiology 93: 153-160, 1%9. 15. Mendelsohn, M.L.: The biology of dose-limiting tissues. In Time and Dose Relationships in Radiation Biology as Applied to Radiotherapy. NCI-AEC Conference, Cannel, Calij. 1969, Brookhaven National Laboratories, Upton, New York, pp. 154-173. 16. Moore, D.H., Mendelsohn, M.L.: Optimal treatment levels in cancer therapy. Cancer 30: 97-106, 1972. 17. Phillips, Th., Buschke, F.: Radiation tolerance of the thoracic spinal cord. Am. J. Roenfgenol. 105: 659-664, 1%9. Einflusz verschiedener Bestrahlungsrhytrnen 18. Reagan, ThJ., Thomas, J-E., Colby, MY.: auf tumor- und normalgewebe in viw. Chronic progressive radiation myelopathy. Stmhhthempie 143: 614629, 1972. J.A.M.A. 263: 128-132, 1968. 8. Hierlihy, P., Jenkin, R.D.T., Stryker, J.A.: 19. Van der Brenk, H.A.S., Richter, W., Hurl&y, Anenima as a prognostic factor in cancer of the R.H.: Radiosensitivity of the human oxygenated cervix: A preliminary report. Can. Med. Assoc. cervical spinal cord based on analysis of 357 J. 100: 1100-1102, 1%9. cases receiving 4 MeV X-rays in hyperbaric 9. Hopewell, J.W., Wright, E.A.: The nature of oxygen. Br. J. Radiol. 41: 205-214, 1968. latent cerebral irradiation damage and its 19. Van den Brenk, H.A.S., Richter, W., Hurley, R.H.: Radiosensitivity of the human oxygenated modification by hypertension. Br. J. Radiol. 43: 161-167, 1970. cervical spinal cord based on analysis of 357 cases receiving 4 MeV X-rays in hyperbaric 10. Jellinger, K., Sturm, K.W.: Delayed radiation myelopathy in man. Report of twelve necropsy oxygen. Br. J. Radiol. 41: 205-214, 1968. cases. J. Neural. Sci. 14: 389-408, 1971. 20. Van der Kogel, AJ., Barendsen, G.W.: Late 11. Jenkin, R.D.T., Stryker, J-A.: The influence of effects of spinal cord irradiation with 300 kV the blood pressure on survival in cancer of the X-rays and 15 MeV neutrons. Br. J. Radiol. 47: cervix. Br. J. Radiol. 41: 913-920, 1968. 393-398, 1974. 12. Kagan, A.R., Lee, K.H., Wollin, M., Norman, 21. Withers, H.R., Hunter, N., Barkley, H.T., Reid, A.: An examination of some dose-time relationB.O.: Radiation survival and regeneration ships in therapeutic radiology. Bt. J. Radiol. 46: characteristics of spermatogenic stem cells of 354-359, 1973. mouse testis. Radiat. Res. 57: 88-103, 1974. 1. Asbell, S.O., Kramer, S.: Oxygen effect on the production of radiation-induced myelitis in rats. Radiology 98: 678-681, 1971; 2. Asscher, A.W., Anson, S.G.: Arterial hypertension and irradiation damage to the nervous system. Lancer 2: 1343-1346, 1%2. 3. Atkins, H.L., Tretter, P.: Time-dose considerations in radiation myelopathy. Acta Radial. 5: 79-94,1%6. 4. Boden, G.: Radiation myelitits of the cervical spinal cord. Br. J. Radiol. 21: 464-469, 1948. 5. Den Hoed-Sijtsema, S., Kaalen, J.G.A.H., Crezee, P.: The influence of the dose per fraction on radiation damage to the myelium. Radiol. Clin. Biol. 40: 89-99, 1971. 6. Dynes, J.B., Smedal, M.I.: Radiation myelitis. Am. J. Roentgenof. 83: 78-87, 1960. 7. Eichhom, H.J., Lessel, A., Rotte, K.H.:
Oncdogy
Bid
Phys.. 1976. Vol. 1. pp. 651-657.
RADIATION
Pcrpunon Press.
MYELOPATHY
HIJIBERT S. REINHOLD, M.D., and KOBY
Printed in Ik U.S.A.
OF THE CORD
THORACIC
SPINAL
Ph.D., Jos G. A. H. KAALEN, Ph.D.? UNGER-GILS, B.A.
Department of Experimental Radiotherapy, Erasmus University Rotterdam, c/o Rotterdam Radiotherapeutical Institute, Groene Hilledijlc, Rotterdam, The Netherlands Theauthors reviewed and readculated the dose, number of fractions, and overall b-eatmcnt time of 19 patknts who developed radiation myclopatby of the tboracic spinal cord after radiation therapy far carcinoma of the lung. The 19 patknts represented the “usabk” yieid of 4~nthorplwSopcral~ycaperlod,~mtlw18lcsottbcreiarti~o~the~ timcpaiod,tBc&~of24potksPtswhonaived~~yt8c~-ntbrtdldnot devebped radWon myefopatby were analyzed. Tbeee were no signf&ant dfffefencea between tbc~donOcsrspplgcd,tbcnlunbtrof~~ortbedo&perfnctiolr.Thcrcw~ however, a dffferemcein tbe overall treatment tin, in the muse tbat tbe treamnt of those patients who later developed radMo0 myelopatby was longa tbaa that of the aomnyeiopatby W. in contrast to expectation, the bfood pressure of tbe patknts wbo later devetoped radiathtion myelopathy was lower tbaa tbat of the wnmydopatby cases. Radiation myeiopatby, Thorn&spinalcord,Radiation tberapy.
INTRODUCTION The increased survival of patients with malignancies treated by radiation is accompanied by an increased incidence of side effects. One of the most notorious side effects of a full of course of radiation is the development radiation myelopathy, sometimes called radiation myelitis.‘“*‘7.‘g The incidence of radiation myelopathy in one center in Holland, the Rotterdam Radiotherapeutical Institute, has been reported previously.5 The awareness of this unfortunate complication resulted in the suggestion (Prof. Dr. H. C. Stam, written communication, 1971) that it might be worthwhile to collect the total number of cases with radiation myelopathy in Holland, in order to gain a better insight into the dose-time-effect relationship.15*‘6 In order to do so, not only data on patients with radiation myelopathy, but also data on those patients who received similar treatment and apparently escaped the danger of developing radiation myelopathy had to be collected.
Data on 19 patients with and 24 patients without radiation myelopathy could be collected. After an initial survey, we restricted the type of treatment to that for carcinoma of the lung. Other cases such as patients with malignancies in the head and neck area or with diseases like Hodgkin’s sarcoma were excluded from the present series because of the possibilities of overlapping fields, etc. Our results indicate that the patient’s blood pressure as well as the overall treatment time is of importance in the development of radiation myelopathy.
tDepartment of Statistics, Radiotherapeutical Institute, Rotterdam, The Netherlands. Acknowledgements-The authors wish to thank
Thomas, the late Dr. W. Th. Evers, Dr. J. de Jong, Dr. S. den Hoed-Sijtsema, Dr. J. A. van der Peel, Dr. H. P. Hamers for making available and recalcu-
Prof. Dr. H. C. Stam for his suggistion to pool the available data in the Netherlands. Also Prof. Dr. P.
lation of the patient data.
METHODS AND MATERIALS Four hospitals reported cases of radiation myelopathy that warranted further The diagnosis “radiation investigation. myelopathy” was invariably made by experienced neurologists. The diagnosis was made on the clinical symptoms only, including myelography for the majority of the cases. No cases were included in which there was the
651
652
Radiation.Oncology 0 Biology 0 Physics
slightest reason to assume that the neurological symptoms could be the result of other causes, i.e. malignant involvement. The extended follow-up time between the onset of the neurological symptoms and the final diagnosis of radiation myelopathy averaged 4 months. This was sufficient to prevent a false diagnosis resulting from malignant invoivement. Moreover, a false diagnosis on clinical symptoms is highly unlikely.‘* The files over the periods for which the myelopathy cases were reported (generally from 1960 to 1971) were also scrutinized for those patients who did not dtvclop myelopathy. All patients surviving for 30 months after treatment for carcinoma of the lung without showing signs of myelopathy were accepted as “nonmyelopathy” patients. The procedure for data collection for the myelopathy and nonmyelopathy patients was identical. The records wer3 analyzed for total dose, dose ptr fraction, overall treatment time, number of fractions and blood pressure. Blood pressure as mentioned in this paper refers to the systolic blood pressure, as it was recorded in the patients history, i.e. in the period of initial work-up. The X-ray films and treatment films were reviewed and only those casts in which it was certain that the spinal cord received the (re)calculattd dose were included in the series. Moreover, only patients treated with Ttltcobalt or mtgavoltagt therapy were taken into account. One and another resulted in a considerable reduction in the number of “reliable” nonof myelopathy casts. In the (rt)calculations the dose applied to the spinal cord, no corrtction for bone absorption was made. This is in agreement with every day practice, and no systematic error in the results can bt expected from deleting the bone absorption of the vertebrae in the dose calculations. RESULTS The patient data art given in Table 1. Only patients who did not receive a split-dose trtatment were included in the final series. This left us with 19 mytlopathy and 24 nonmyelopathy patients. A summary of the statistical data is given in Table 2A and Fig. 1. There is a barely significant difference in total dose (P = O&4),
1976, Vol. 1, Number 7 and Number 8
50
7000 TM0
d 5CQOmd
30
Overall time
3Odays
I5
Number d Length - fractions-
2Ofracbs
km
175
1Blood 'PnSSUR
.I !OOmmHg
Fig. 1. Statistical data of the myelopathy (M+) and nonmyelopathy CM-) patients. From left to right; Total Myelum Dose (TMD), overall treatment time, number of fractions, length of spinal cord treated (field length) and systolic blood pressure. Vertical bars indicate 95% confidence limits of the mean. and no dittertnct in the number of fractions. There is, however, a difference in the overall treatment time (2P = 0.03). The mean treatment time of mytlopathy patients is 42.42 days; this is longer than the mean treatment time of 37.6 days for the nonmyelopathy patients. The mean blood pressure of the mytlopathy casts is 128 mm Hg which is lower than the mtan blood pressure of 148 mm Hg for the nonmytlopathy casts. This difference is sign&ant (2P = 0.0024). The difference between the average dose per fraction (259 vs 236) was not significant (2P = 0.06). Finally, the mean latent period was 19 months with a range of 5.5 months-4 years. DISCUSSION Some of our findings differ from what one would expect. The differences in total dose, average dose per fraction, and number of fractions are non, or barely significant; however, they move in the expected direction, that is, that the mytlopathy patients received a somewhat higher dose in fewer fractions. It was, very surprising, however, to find that the overall treatment time for the mytlopathy patients was longer than that for the nonmytlopathy patients. One then of course becomes suspicious that the overall treatment exerts some influence upon the survival time of the patients, introducing a bias in the selection of the non-
Radiation myelopathy of the thoracic spinal cord 0 H. S. Rawuo~~ et al.
653
Table 1. Data of the myelopatby and nonmyelopathy patients, arranged in order of magnitude of the total myelum dose (TMD) Patient No.
Blood pressure (mm Hg)
23R9R14R20R18R15R8R’ 7R1 IR’ 22D’ lOR32L9R’ 2R’ 14R’ 22R4R’ 2OL’ 8R6R12R24L’ 19R28G16G’ 21R13R15G’ 16R_ 12R’ 27G3OD23D’ 29GSR6R’ 18G’ 3R’ 210’ 25G17G’ 26G25G’
145 150 180 155 160 140 140 ? 140 140 130 130 110 135 110 140 120 150 165 130 150 130 180
t 110 155 140 140 160 140 120 140 140 175 125 85 95 t 145 125 150 160 t
Length (cm)
TMD (tad)
Time (days)
Fraction No.
Latent per. (months)
10 12 10 14 20 10 10 17 10 9 9.5 10 10 10.5 13 14 12.5 9.5 10 12 11.5 10.5 7 16 15 10 9 13 14 10 16 9 11 11 12.5 9 14 11 14 10 10 14 12
4317
30 32 30 27 36 35 37 37 26 48 29 41 33 37 35 39 44 42 44 36 36 40 32 44 43 39 43 40 36 43 45 53 64 40 40 43 47 42 55 40 46 40 41
21 24 20 19 25 25 26 26 20 19 23 30 24 27 25 28 29 18 29 24 23 18 24 30 30 26 31 30 24 31 30 23 23 30 30 29 30 28 22 30 30 30 29
3
4895 5143 5222 5239 5342 5570 5609 5782 6003 6161 6174 6186 6286 6282 6354 6368 6387 6429 6453 6504 6515 6536 6537 6562 6571 6633 6686 6702 6727 6769 6787 6884 6895 6912 6953 6961 7091 7223 7394
: : $ 30 $ IO 13 : 13 22 26 $ 18 29 : $ 29 : 10 $ $ 10 $ 48 : : $ 6 13 39 12 $ 22 $ 5.5
tNo information available. SDid not develop disease.
myelopathy group. However, we have been unable to find any trace of an influence of the overall treatment time on the survival time of the nonmyelopathy cases. Neither did extension of this number to a group of 288 patients surviving for over 1 year show any indication
in this direction. It seems unlikely, therefore, that the composition of our nonmyelopathy series is biassed via the overall treatment time and patients survival, and we have been unable to explain this rather absurd phenomenon.
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Radiation Oncology 0 Biology 0 Physics
In a recent publication on the treatment of carcinoma of the lung, Eichhorn et al.’ were also puzzled by the finding that, from three series of different treatments, the one with the longest overall treatment time and the lowest total dose showed the highest incidence of radiation myelopathy. The fractionation schedule, however, was very unusual and the observation was not statistically significant. The only experimental report known to the authors in which the effect was found to be decreased by prolongation of the interval between two fractions comes from Withers et al.” They found a decreased survival of stem cells of the rat testis when the interval between the dose increased from 4 hr to 14 days. “Strandquist” slopes for radiation myelopathy for dose against time were given for humans by Boden (Atkins and Tretter) as 0.26,’ Phillips and Buschke as 0.75,” Maier et al. as 0.277,14 and for rats by Van der Kogel and Barendsen as 0.44.= In our material, a value of 0.23 was found with a least-squares (double logarithm) regression for the myelopathy patients. This is somewhat low, but certainly not outside the expected range. In Table 2(b) two derived values are tabulated, the first representing the generally used exponents for time of - 0.11 and - 0.24 for the number of fractions. The dserence between the values is barely significant (P = 0.026). The second row on Table 2(b) represents values that were calculated via a search routine’. for the optimal separation between the two groups, as judged by the Student’s t-test. The highest t-values were determined with initial incremental steps of 0.1 for the t, as well as for the N exponents, covering the range from - 2 through + 2. This was followed by a search with 0.005 incremental steps in the area in which the highest t values were found. The optimal separation was found (P = 0.0037) for a time exponent of 0.52 and an for the number of exponent of -0.67 fractions. Using these values for transformation, a probit-analysis could be performed, as shown in Fig. 2. The dose, as indicated on the abcissa, was recalculated from the transformed individual date, but now for the average treatment time (40 days) and the average number of
1976, Vol. 1, Number 7 and Number 8
r; 8
,/ 0
cc @‘q/2 30
40
dose
in rad x 100 hcalcubted
SO
60
70
60
60
for 40 doyr,
too
26 Actions)
Fig. 2. Percentage radiation myelopathy against dose, assuming an average treatment time of 40 days and 26 fractions. The dosages (and incidences) The upper and are grouped for 850 rad intervals. lower 95% dose limits are also indicated. This curve refers only to our 43 patients. fractions (26 fr). The dose-effect relationship, as shown in Fig. 2, is based only on the data of the 43 patients we have collected so far and all the data were used, regardless of the patient’s blood pressure. It should be cautioned, therefore, that this dose-effect relationship may not be generally applicable. Incidence, as calculated on Fig. 2 is deduced from the numbers of myelopathy patients versus the numbers of “controls”. The size of the latter group can be influenced not only by the size of the population one selects to investigate, but also by the restrictions that one unavoidably has to make. (1) It should be realized that the “control” group also consisted of patients with lung carcinoma. Factors influencing the survival rate may therefore also influence the eventual number of “controls”. (2) The number of hospitals included in the search may be of some importance; only hospitals reporting myelopathy cases were included. (3) The same applied for the observation period; only the time periods over which myelopathy cases were reported were scrutinized for “controls” (on which 2 additional cases of myelopathy were found!). (4) Period of time following irradiation after
ztcT-O-”
* N-O*’
K = TMD * T+.” * N-o.6’
K = TMD
6094.2 (+ 791.8) 37.6 (+ 5.9) 26 (+ 3.6) 12.02(? 3.1) 147.9 (2 17.9)
( f SD)
( 2 SD)
1870.6 (+ 195.7) 4536.5 (-c 670.0)
Nonmyelopathy
Table 2(b). Derived values of the myelopathy
Total myelum dose (rad) Overall treatment time (days) Number of fractions Length of spinal cord treated (cm) Systolic blood pressure (mm Hg) Latent period (months)
Nonmyelopathy
Table 2(a). Statistical data of the myelopathy
6468.9 42.4 25.7 11.3 128.2 19.1
24 24
n
( 2 SD)
patients
(k SD) 1974.5 (k 129.1) 5229.9 (k 943.9)
Myelopathy
patients
(2523.0) (+- 8.1) (2 4.5) (2 1.8) (+ 19.6)
Myelopathy
and nonmyelopathy
24 24 24 24 22
n
and nonmyelopathy
P < 0.05
19 I9 19 19 17 19
Significance P < 0.05 P < 0.005
n 19 19
2P :‘“6.005
2P < 0.05 ns.
Significance
n
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Radiation Oncology 0 Biology 0 Physics
which one assumes that no myelopathy will develop, will influence the number of “controls” (see point 1), but may also influence the yield of patients with myelopathy. A 50% incidence seems to correlate with an average dose of 6500 rad (95% range, 5l300-7900 rad) if given in an average number of 26 fractions, over a mean time period of 40 days. The finding that the average value for the blood pressure of patients with radiation myelopathy is lower than that on nonpatients was completely myelopathy unexpected. We included the blood pressure in our investigation because of the available experimental evidence that hypertension increases the radiation damage to the CNS. Asscher and Anson’ induced hypertension in rats by a clip around a renal artery 2 weeks before irradiation of the spinal cord with dosages from 1500 to 3000 rad. Only hypertensive .animals developed spinal cord lesions with a latent period ranging from 25 to 270 days, the average value probably being about 4 months. In addition, Hopewell and Wright found that induced hypertension shortened the lifespan of rats that received moderate dosages of radiation to the brain.’ These experiments were all done with rats with induced hypertension. The latent period between radiation and the development of neurological symptoms (or death) was, however, rather short in these investigations. The same applies to the results obtained by Asbell and Kramer in determining the relationship between the dose to the spine and the latent period.’ Their latent period is invariably shorter than 1 year. Van der Kogel and Barendser?’ inferred that there may be a threshold dose of 2000rad (single dose). He concludes that, rather than a continuous relationship between dose and latent period, one rapidly approaches a minimum latent period of about 4-5 months when the dose is increased. Whether or not the aforementioned experimental data are directly applicable to the human situation is as yet unknown. It should be mentioned, however, that, in our material, the shortest latent period was 5.5 months and therefore in agreement with the
1976, Vol. 1, Number 7 and Number 8
observations of Van der Kogel and Barendsen.M However, the longest latent period was 4 years, while the average value was about 19 months. This is in agreement with clinical experience and is essentially longer than the majority of the aforementioned experimental determinations. This discrepancy may also be of importance in the difference in influence of blood pressure upon the development of radiation myelopathy in experimental and clinical determinations. Surprisingly, there was no correlation between blood pressure and latent period in our material, Few reports deal with the blood pressure of patients in relation to their response to radiation. Jellinger and Sturm”’ mention that no correlation could be found between hypertension and radiation myelopathy. Jet&in and Stryker” and Hierlihy, Jenkin, and Stryker’ conclude from their series of patients with cervival carcinoma that patients with high blood pressure (> 140.9) showed recurrences, also fewer more but complications, than patients with a lower blood pressure. Complications in their cases were of the intestinal/gyneacological type rather than of a neurological nature. Their findings seem to indicate that the tumour cure rate was better with lower blood pressures, but that the incidence of complications was also higher. Our results seem to agree with their finding of a higher complication incidence with a lower blood pressure. Whether or not the survival rate of patients treated with irradiation for carcinoma of the lung is also influenced by the pressure is presently under blood investigation. It is tempting to speculate whether the individual sensitivity, as suggested by Jellinger and Sturm,‘” Dynes and Smedal,6 and Locksmith and Powers,” bears any relationship to the blood pressure of the patient. Accepting that the level of the blood pressure may in itself be the result of many factors, one could think not only of protecting or enhancing factors for damage to, e.g. blood vessels during the treatment, but also during the latent period. In conclusion, our serious attempts to collect and compare two groups of patients, with
Radiation myclopathy of the thoracic spinal cord 0 H. S. REINHOLDet nl.
and without radiation myelopathy, yielded two unexpected features . developed radiation Patients who myelopathy received their treatment in a longer overall treatment time and their mean blood pressure was lower than the average. These puzzling findings may be incidental,
657
resulting from interfering factors in the colletting procedure; they may also be correct. Data from other institutions will be required to evaluate this. In the meantime, our results show unambiguously that one should be extremely cautious in accepting any simplified prescription for a “safe” dose level.
REFERENCES 13. Locksmith, J.P., Powers, W.E.: Permanent radiation myelopathy. Am. J. Roentgenol. 102: 916-926, 1968. 14. Maier, C.J.G., Perry, R.H., Saylor, W., Sulak, C.M.H.: Radiation myelitis of the dorsolumbar spinal cord. Radiology 93: 153-160, 1%9. 15. Mendelsohn, M.L.: The biology of dose-limiting tissues. In Time and Dose Relationships in Radiation Biology as Applied to Radiotherapy. NCI-AEC Conference, Cannel, Calij. 1969, Brookhaven National Laboratories, Upton, New York, pp. 154-173. 16. Moore, D.H., Mendelsohn, M.L.: Optimal treatment levels in cancer therapy. Cancer 30: 97-106, 1972. 17. Phillips, Th., Buschke, F.: Radiation tolerance of the thoracic spinal cord. Am. J. Roenfgenol. 105: 659-664, 1%9. Einflusz verschiedener Bestrahlungsrhytrnen 18. Reagan, ThJ., Thomas, J-E., Colby, MY.: auf tumor- und normalgewebe in viw. Chronic progressive radiation myelopathy. Stmhhthempie 143: 614629, 1972. J.A.M.A. 263: 128-132, 1968. 8. Hierlihy, P., Jenkin, R.D.T., Stryker, J.A.: 19. Van der Brenk, H.A.S., Richter, W., Hurl&y, Anenima as a prognostic factor in cancer of the R.H.: Radiosensitivity of the human oxygenated cervix: A preliminary report. Can. Med. Assoc. cervical spinal cord based on analysis of 357 J. 100: 1100-1102, 1%9. cases receiving 4 MeV X-rays in hyperbaric 9. Hopewell, J.W., Wright, E.A.: The nature of oxygen. Br. J. Radiol. 41: 205-214, 1968. latent cerebral irradiation damage and its 19. Van den Brenk, H.A.S., Richter, W., Hurley, R.H.: Radiosensitivity of the human oxygenated modification by hypertension. Br. J. Radiol. 43: 161-167, 1970. cervical spinal cord based on analysis of 357 cases receiving 4 MeV X-rays in hyperbaric 10. Jellinger, K., Sturm, K.W.: Delayed radiation myelopathy in man. Report of twelve necropsy oxygen. Br. J. Radiol. 41: 205-214, 1968. cases. J. Neural. Sci. 14: 389-408, 1971. 20. Van der Kogel, AJ., Barendsen, G.W.: Late 11. Jenkin, R.D.T., Stryker, J-A.: The influence of effects of spinal cord irradiation with 300 kV the blood pressure on survival in cancer of the X-rays and 15 MeV neutrons. Br. J. Radiol. 47: cervix. Br. J. Radiol. 41: 913-920, 1968. 393-398, 1974. 12. Kagan, A.R., Lee, K.H., Wollin, M., Norman, 21. Withers, H.R., Hunter, N., Barkley, H.T., Reid, A.: An examination of some dose-time relationB.O.: Radiation survival and regeneration ships in therapeutic radiology. Bt. J. Radiol. 46: characteristics of spermatogenic stem cells of 354-359, 1973. mouse testis. Radiat. Res. 57: 88-103, 1974. 1. Asbell, S.O., Kramer, S.: Oxygen effect on the production of radiation-induced myelitis in rats. Radiology 98: 678-681, 1971; 2. Asscher, A.W., Anson, S.G.: Arterial hypertension and irradiation damage to the nervous system. Lancer 2: 1343-1346, 1%2. 3. Atkins, H.L., Tretter, P.: Time-dose considerations in radiation myelopathy. Acta Radial. 5: 79-94,1%6. 4. Boden, G.: Radiation myelitits of the cervical spinal cord. Br. J. Radiol. 21: 464-469, 1948. 5. Den Hoed-Sijtsema, S., Kaalen, J.G.A.H., Crezee, P.: The influence of the dose per fraction on radiation damage to the myelium. Radiol. Clin. Biol. 40: 89-99, 1971. 6. Dynes, J.B., Smedal, M.I.: Radiation myelitis. Am. J. Roentgenof. 83: 78-87, 1960. 7. Eichhom, H.J., Lessel, A., Rotte, K.H.:
