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Cortisone and the treatment of radiation sickness
68
JOURNAL
OF
THE
FACULTY
OF
RADIOLOGISTS
Cortisone and the Treatment of Radiation Sickness R. FINNEY, M.B., B.S., F.R.C.S. (Edin.), D.M.R.T. Radiotherapist, Newcastle General Hospital THE t e r m ' r a d i a t i o n s i c k n e s s ' is applied to a general constitutional upset following irradiation. Characteristically, s y m p t o m s are gastro-intestinal, varying from nausea to prolonged vomiting and often associated with headache, lassitude, and mental depression. T h i s s y m p t o m - c o m p l e x is allied to the general radiation syndrome found to follow exposure to radiation produced by nuclear fission, as exemplified by the populations of H i r o s h i m a and Nagasaki. I n both, a fairly well-defined pattern of events occurs and we are indebted to Court Brown (1953) and Court Brown and M a h l e r (1953, a, b, 1954) for a great deal of important work in relation to the analysis of these symptomatic disturbances and the correlation of the related syndromes. T h e constitutional symptoms following irradiation have been recognized by therapists for years, and indeed m a y be of such severity as to be a limiting factor in radiotherapy treatment. M u c h has been written on the subject both in regard to the aetiology and to treatment, and the literature is filled with a mass of confused and often equivocal data dealing with various clinical and pathological findings in humans and animals. T h e r e is still no complete answer to either the aetiology or the treatment. In recent years interest has been focused on the role played by the adrenal cortex in this syndrome. In 1941 Ellinger emphasized the importance of adrenal cortical insufficiency i n radiation sickness. His results were based on metabolic phenomena, but in the light of more recent knowledge it has become difficult to interpret these results f r o m the specific action of radiation alone. Langendorff, Koch, and Sauer (1954) have demonstrated a small but definite protective effect in mice with D O C A or total extracts from the adrenal, but only if sublethal' doses of irradiation are given. 'Weichert (1942) noted the striking similarity between A d d i s o n ' s disease and severe radiation sickness and suggested that the toxic products of protein breakdown resulting from irradiation produces a relative adrenal insufficiency. L e b l o n d and Segal (1949) showed that heavy irradiation of lymphatic tissue with adequate shielding of the rest of the body p r o d u c e d hypertrophy of the adrenal cortex and involution of distant lymphatic organs. T h i s failed to occur in adrenalectomized animals. T h e s e findings a r e in keeping with the observations of therapists who have noted that irradiation of lymphatic tissue m a y produce decrease in the size of distant nodes.' It is also a c o m m o n clinical finding that irradiation of the u p p e r a b d o m e n with large fields results in radiation sickness in a high percentage of cases. I n this site lymphatic tissue occurs in large quantities and coupled with the known sensitivity of this tissue would appear to give further support to Weichert's suggestion that the breakdown products of irradiation are released into the circulation; resulting in the syndrome of radiation sickness.
Porter (1952), in a series of cases, estimated adrenal functions by means of 17 keto-steroid urinary excretion and total eosinophil counts, specifying that at least a 50 per cent fall in count m u s t occur to represent adrenal cortical response. T h e results f r o m this investigation were : - a. A fall in total eosinophil count or rise in 17 keto-steroid excretion is evident only following the onset of radiation sickness. b. Sickness occurred more readily if t h e initial eosinophil count was low. c. W h e n adrenal cortical activity became present, sickness s y m p t o m s abated. Porter concluded that those patients undergoing irradiation fitted in with the Selye adaptation theory (195o a, b) in that the radiation acted as stress, producing sickness as an alarm reaction and an adrenal response as a 'counter shock ' phase. In those cases in which there was evidence of cortical response during the remainder of the therapy course, it was assumed that the patient was ' in a stage of resistance ' and in those cases with a lowered adrenal reserve there was a greater susceptibility to alarm stimuli. It was assumed that the natural response to irradiation stress is a h y p e r t r o p h y of the adrenal cortex following a chain of e v e n t s - - t h e initial one being a release into the circulation of tissue breakdown products. Lasser and S t e n s t r o m (1954), in a controlled series employing a modification of the T h o r n A C T H eosinophil response as an indication of adrenal cortical function, came to the conclusion that the adrenal cortex undergoes changes in the course of irradiation but doubt the relationship to radiation sickness. Cronkite (I953) and K o h n (I95I) go so far as to state that it is impossible to f o r m a clear picture of the participation of the pituitary and adrenals in radiation sickness, and Bacq and Alexander (1955), in a comprehensive review of the whole subject, came to the conclusion that it is difficult to interpret all aspects of radiation sickness in the light of the adaptation syndrome in spite of a large amount of data on the subject. T h e y point out that one of the drawbacks of the adaptation theory is its very versatility, and that if a series of symptoms cannot be explained by adrenal insufficiency then they are fitted to be explained by adrenal hyperactivity. T h e m a i n difficulties therefore in deciding the relationship of adrenal cortical function and the syndrome of radiation sickness would appear to be : - a. T h e relative crudeness of the tests as yet to hand in estimating adrenal function. Bacq and Alexander have emphasized that all biochemical as well as biological findings should be surveyed before drawing any conclusions and not accept two or even one sign as evidence of pituitary-adrenal reaction. b. T h e difficulties in correlating the findings in experimental animals with those in man.
CORTISONE
AND
THE
TREATMENT
It was felt, however,, t h a t in spite of t h e i n c o m plete evidence for a n d against t h e p a r t p l a y e d b y the adrenal cortex in relation to t h e r a d i a t i o n syndrome, t h a t a series of cases s h o u l d b e i n v e s t i g a t e d employing cortisone in t h e t r e a t m e n t . F r o m this it was h o p e d i n f o r m a t i o n w o u l d b e g a i n e d w h i c h might help in clarifying a n d possibly v e r i f y i n g some of the data already obtained. INVESTIGATION
PROCEDURE
T h e original investigation was to have dealt w i t h the effect of cortisone in .treating r a d i a t i o n sickness developing after irradiation of the b r e a s t area following m a s t e c t o m y for c a r c i n o m a of t h e breast. T h e suggestion was made, however, t h a t t h e lytic properties of cortisone m i g h t exert a n u n f a v o u r a b l e effect o n t h e m a l i g n a n t processes b y allowing metastases to occur far m o r e readily in t h e absence of a protective fibrous m e s h w o r k . I t was t h e r e f o r e decided to deal only w i t h n o n - m a l i g n a n t c o n d i t i o n s and 32 cases were i n c l u d e d i n the series, all of w h i c h were of spinal a r t h r i t i s - - a n k y l o s i n g spondylitis or o s t e o - a r t h r i t i s - - n e c e s s i t a t i n g t r e a t m e n t to t h e w h o l e spine a n d sacro-iliac joints. T h e series was r a n d o m ized b y Dr. D. D. R e i d of t h e D e p a r t m e n t of M e d i c a l Statistics a n d E p i d e m i o l o g y in t h e U n i v e r s i t y of London, 16 cases b e i n g t r e a t e d b y cortisone a n d 16 by identical ' d u m m y ' tablets. T h e dosage of cortisone e m p l o y e d was 15o mg. daily in divided dosage, c o m m e n c i n g 48 h o u r s before the course of irradiation. T h i s dosage c o n t i n u e d t h r o u g h o u t the 14 days of the course of t r e a t m e n t , after w h i c h 75 rag. in divided dosage was given for 3 days, t h e n 25 mg. for a f u r t h e r 3 d a y s . T h i s gradual decrease in dosage reduced the possibility of cortisone w i t h d r a w a l effects. Some p a t i e n t s were t r e a t e d in the R a d i o t h e r a p y D e p a r t m e n t of St. T h o m a s ' s Hospital a n d some at the D e p a r t m e n t of t h e Newcastle G e n e r a l Hospital. In b o t h places a similar X - r a y m a c h i n e was u s e d at a kilovoltage of 220 kV., a half-value layer of 1'75 m m . Cu, a n d an o u t p u t of a b o u t 30 r p e r minute. A total dosage of 15oo r was g i v e n to t h e whole spine a n d sacro-iliac joints, g i v e n i n five t r e a t m e n t s over 14 days' overall time. T h e integral volume dose for t h e series as calculated b y t h e M a y n e o r d f o r m u l a was 2-2"9 m e g a g r a m m e r o e n t g e n s per t r e a t m e n t , the dosage v a r y i n g w i t h the thickness of the patient. E a c h case was t r e a t e d at t h e same time of day a n d o n t h e same days of t h e w e e k a n d detailed b l o o d - c o u n t s were carried o u t o n all cases t h r o u g h o u t t h e course. C o u n t s were t a k e n at t h e same time of day in each case to r e d u c e t h e effect of the diurnal variations in c o u n t a n d carried o u t b y one t e c h n i c i a n in each of t h e above hospitals. It was originally p l a n n e d for all cases to b e t r e a t e d for the first t r e a t m e n t as i n - p a t i e n t s to facilitate observation a n d enable c o m p a r i s o n w i t h C o u r t - B r o w n ' s series dealing w i t h single exposures to irradiation. Unfortunately, owing to difficulties in o b t a i n i n g beds, this p l a n was a b a n d o n e d a n d instead t h e p a t i e n t s were k e p t u n d e r o b s e r v a t i o n in a w a r d for t h e day of the first t r e a t m e n t - - u s u a l l y eight h o u r s following the initial irradiation t r e a t m e n t . S u b s e q u e n t l y each patient was i n t e r r o g a t e d daily t h r o u g h t h e t r e a t m e n t course. A detailed f o r m was filled in at each
OF
RADIATION
69
SICKNESS
i n t e r v i e w i n w h i c h the s y m p t o m s , if any, were noted, t h e t i m e of onset a n d cessation of each r e c o r d e d a n d t h e severity g r a d e d as f o l l o w s : + + Severe, + M o d e r a t e , ± M i n i m a l , -- Nil. I n all cases n o leading questions were asked a n d contact w i t h o t h e r r a d i o t h e r a p y cases was avoided. Latent P e r i o d . - - T h e l a t e n t p e r i o d in each case i n w h i c h s y m p t o m s were r e c o r d e d was calculated Table
L--LATENT
PERIOD
AFTER EACH
CONTROL
CORTISONE (31 R e a d i n g s ) I
2
3
4-
I
5
TREATMENT
(54 Readings)
2
3
4
5
2
2
I
2
2
I½
3½
2
2
2
2
2
6
8½
4 28
21
2
i½
2
2
2½
I
2½
~½
i½
31 24
I4
48
2
28 3
5
4
4 26
8
~
4
2½
12
i 2
3
2
2½
2
2½
2~
2
2
2
4½
2
4-
3
2
2
3 i½
2 4
2
3
5
I
4
¼
~½ 2
3
I
½
3
½
½
f r o m t h e t i m e of c o m m e n c e m e n t of the irradiation. T h e actual figures o b t a i n e d are s h o w n in Table I for the two groups of cases, a n d t h e average following each t r e a t m e n t is f o u n d to v a r y b e t w e e n 3"3 hr. a n d lO'5 hr. for t h e cortisone a n d 1"8 hr. a n d 5'1 hr. for the control. T h e overall average figures (Table H ) are f o u n d to be 6'9 hr. for the cortisone a n d 2"8 hr. for the control. T h e difference following each t r e a t m e n t is in fact f o u n d to b e statistically significant ( P > o ' o i ) only for the readings after t r e a t m e n t s I, 2, a n d 4, Table
Treatment
~L--LATENT PERIOD AFTER EACH TREATMENT (OVERALL AVERAGE FIGURES)
I
2
Control
5"1
3'4
Cortisone
9"7
lO"5
3 1.8 3"3
4
5
AVERAGE
2"0
i '8
2,8
8"5
2"25
6"9
a l t h o u g h the difference for t h e overall average figures, viz., 6"9 hr. a n d 2'8 hr., is in fact significant. I n C o u r t B r o w n ' s series, for single exposures of irradiation the l a t e n t p e r i o d was estimated at 2"7 hr. f r o m the c o m m e n c e m e n t of the irradiation. M o r e over the time was s h o r t e r in those patients w h o were generally m o r e easily upset, a n d the conclusion was r e a c h e d t h a t t h e m o r e sensitive an individual is to the effects of i r r a d i a t i o n t h e n the earlier are t h e s y m p t o m s likely to occur. I t will b e seen t h a t t h e figure o b t a i n e d f r o m the control g r o u p in this investigation is almost identical
70
JOURNAL
OF
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FACULTY
with that of Court Brown's for estimation of the latent period, viz., 2"8 and 2"7 hr. respectively. T h e r e is, ho,wever, a marked contrast with the latent period given by Ellis and Stoll (I952), whose figures Table IlL--RELATIONSHIP OF LATENT PERIOD TO SEVERITY OF SYMPTOMS CONTROL : SEVERITY
CORTISONE : SEVERITY
++
++
+
i
8"50
9"80 15"7o
5"80 5"00
2"00
2"80
2"50
+
i
x'8o
2"00
5"z5
6.00
5 'OO
12'oo
4'50
2"50
I "oo
1I'25
54"00
2"5 °
2-5 °
3"13
3'3 °
2"oo
31 " o o
z'4o
2"60
2"4 °
4"40
7"80
3"oo
Z'8o
3"5 °
26'00
3'5 o
1.7 o
1.6o
33 '30
8"40
2.00
5"OO
3"oo
8.00
lO'9O
2.oo
16"3o
2"25 4.7 ° Average
Average 8"5 °
[
I
9'20
3 "5 0
9"98
2"60
4"8o
8'7 o
range from 2 days to 24 d a y s - - v a s t l y different from the above. T h e s e authors were dealing with multitreatment cases as in the present series.
OF
RADIOLOGISTS
series there is found to be very little variation between the latent periods of the groups, with figures of 8"5, 9"2, and 9"98 for the + + , + , and =k groups respectively. I n the control series, however, the differences between the various groups appear to be in agreement with the above postulate that " the latent period is shorter in those cases who are more severely upset as compared with the less severely affected ". T h e inclusion of a single reading of 54"0 hr. in the third group makes the average i n this group appreciably higher, and statistically the difference between the varying •latent periods of this control group is not significant. O m i t t i n g this high figure, the average corrected latent period for the ~k group is found to be of the order of 4~8--identical with that of the moderately upset + group. T h e difference between the latent periods for the severely affected group in the control (2"6) and the moderately affected (4"8) is statistically not significant, although only just missing the borderline of probability. As is apparent, however, from the preceding tables, the overall period for the cortisone series remains appreciably longer in all groups. Conclusion.--The latent period for cases developing the s y m p t o m s of radiation sickness u n d e r cortisone cover IS increased by about 7 ° per cent over the control g r o u p - - a difference which statistically i s significant. SYMPTOM ANALYSIS (I) A qualitative as well as a quantitative analysis of the results shows appreciable differences between the two groups of cases. Fig. I indicates the numbers developing symptoms of any type during the duration of the course. It will be seen that in both series as
15. 14.
CORTISONE
I0-
4. ~5
[
Z. •
2
3
5
rmArMEur rio. 16-
CONTROL
141210-
6-
0
2 Fig.
I.--Symptom
4
3 rmArMeNr
NO
frequency during course.
F r o m the data obtained from this present investigation, the severity of each s y m p t o m has been grouped as either + + , + or -4-. T h e latent period for each s y m p t o m has been determined, and from this the average for each s y m p t o m group. T h e two are correlated as shown in Table I I I . In the cortisone
the course progresses the numbers developing symptoms decrease, but that the rate of this fall is far m o r e rapid in the cortisone group than in the control. T h e actual figures are, for the cortisone series, i i who developed symptoms after the initial treatment decreasing to 3 after the final exposure ;
CORTISONE
AND
THE
TREATMENT
compared w i t h 14, falling only to IO, in t h e control group. T h e actual severity of s y m p t o m a t i c u p s e t again contrasts o n analysis of the absolute figures .(Fig. 2). T h e degree of severity of each s y m p t o m was r e c o r d e d as outlined previously, covering + + for t h e m o s t
OF
RADIATION
71
SICKNESS
even after the fifth a n d final t r e a t m e n t . A m o r e detailed survey in relationship to s y m p t o m s developing after the initial t r e a t m e n t re-emphasizes t h e differences in severity b e t w e e n the two groups of cases (Fig. 3). T h e s e differences in s y m p t o m freq u e n c y are only significant statistically for the s e c o n d
CORTISONE /4-
io-
N 2-
mmmmmm~mmma~
2
I
3
4
5 hlIIIIIINIINIIIIIIIIIIIIIIIIIIIINIIIINI~
m~ArtdeA,rt¢o,
CONTROL
5
iill// a 0
2
I
3
4
INIIIIIIIIIIIIIIIIIllllllil m
TREATMEHT NO.
Fig.
2.--Syrnptomatic variation throughout course.
severely affected t o - - f o r c o m p l e t e absence of s y m p toms. T h u s it will b e seen t h a t u n d e r cortisone cover t h e r e were n o cases of t h e severe or m o d e r a t e l y severe u p s e t g r o u p ( + + or + ) r e c o r d e d after t h e time t h e t h i r d t r e a t m e n t h a d b e e n reached, w h e r e a s in the controls these degrees were n o t e d to b e p r e s e n t ,o-
CORTISONE
S-
@@6@ ®@6@
9-
- 5 =
It
Ta-
%
s-
~,t-
@@
o-
@@
@
a n d fifth t r e a t m e n t figures, b u t the general t r e n d in b o t h absolute n u m b e r s a n d degree of u p s e t is a p p a r e n t f r o m s u r v e y of t h e above histograms. A f t e r the final t r e a t m e n t of t h e course the n u m b e r of cases w h i c h d e v e l o p e d s y m p t o m s was only 3 (19 p e r cent) in t h e cortisone series, a n d these all to a m i n i m a l degree ~- as c o m p a r e d w i t h i o (63 p e r cent) in the controls; of w h i c h 7 (70 p e r cent) were of the severe or m o d e r a t e l y severe degrees. T h u s , following this final t r e a t m e n t i a of the p a t i e n t s receiving cortisone were completely a s y m p t o m a t i c as c o m p a r e d w i t h 5 of the o t h e r group. Conclusion.--In a m u l t i - t r e a t m e n t course of irradiation, s y m p t o m s are m u c h less f r e q u e n t a n d less severe u n d e r cortisone t h a n without, a n d f u r t h e r m o r e the rate of decrease of s y m p t o m freq u e n c y is appreciably m o r e r a p i d in the f o r m e r group.
SEVERITY OF S/MPTOMa I0-
CONTROL
9-
¢ ¢ [,~) - II ®®5® - 5
e71
o4-
I-
e~
O-
I
~
ee
e
SEVE,~'TY OF SYMPTOMS
Fig.
3 . - - S y m p t o m a t i c severity following initial exposure.
SYMPTOM
ANALYSIS
(2)
T h i s analysis deals w i t h t h e actual s y m p t o m s developing a n d t h e i r variation t h r o u g h o u t the course. I n those cases in w h i c h m o r e t h a n one s y m p t o m was f o u n d to occur s y n c h r o n o u s l y , t h e n each s y m p t o m was r e c o r d e d separately in t h e assessment. Fig. 6 shows the various s y m p t o m s n o t e d after the initial t r e a t m e n t a n d t h e i r relative frequency. I t will b e seen t h a t the c o m m o n e s t s y m p t o m s were malaise, headache, a n d n a u s e a in t h a t o r d e r of frequency. T h e incidence in t h e two series shows a r e m a r k a b l y similar p a t t e r n . A n o r e x i a is next in o r d e r of f r e q u e n c y a n d rigors the least c o m m o n of all.
72
JOURNAL
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FACULTY OF RADIOLOGISTS
Vomiting occurred as a presenting symptom in only one case, and that in a control. The presenting symptoms following the remainder
of the treatments is shown in F i g . 5. T h e same pattern is maintained with malaise, nausea, and headache predominant and anorexia, rigors, and
3 in the cortisone and 3 in the control series. A typical case was N o . . 26, a control. Following the first treatment, after a latent period of z½ hr. the patient developed headache of -t- severity, subsiding after 4 hr. T h e patient then remained asymptomatic until after the second treatment, w h e n after
/6-
CORTISON[
/4-
I MALAISE
NAUSEA
If
I HEADACHE
1
RIGORS
ANOREXIA
CONTROL 14/2l
o~ 4 o MALAISE
NAU.~EA
HEADACHE
F
RIGORS
ANOREXIA
1
Fig. 4 . - - I n i t i a l s y m p t o m index following first exposure.
vomiting less often manifest. Qualitatively the overall picture is essentially similar for the two series, but quantitatively the s y m p t o m frequency shows in the controls a marked increase. ~.
a latent period of 4 hr. malaise developed of -ldegree, subsiding after a further 4 hr. Finally the third and fourth t r e a t m e n t s ; after a latent period of 3 hr. the patient developed nausea and malaise CORTISONE
2o-
~a4-_ 12S
II
o MALAISE
NAUSEA
HEADACHE
ii
.ANOREXIA
34-
RIGORS
VOMITING
CONTROL
3228-
~a42O-
,eZ fez 4--
• ANOREXIA SYMPTOMS
Fig. 5 . ~ I n i t i a l
I R / GORS
II
YOM/T/NG
s y m p t o m analysis throughout course.
It was rare for the initial s y m p t o m presenting to vary once this had been established. T h u s if nausea occurred as an initial s y m p t o m following the first exposure to radiation, then the presenting s y m p t o m for the remaining exposures (if any symptom did occur) would also be this disturbance. A slight variation of initial s y m p t o m presentation did, however, appear in a small m i n o r i t y of patients:
synchronously. T h i s pattern was typical of the variable initial s y m p t o m picture and in the 6 cases recorded the only symptoms manifest were, as above, headache, malaise, and nausea and no other. A further finding in relation to this variation in presenting s y m p t o m is that in all but one of these 6 cases headache was the disturbance in question, a n d , after regressing within 5-6 hr., did not occur
CORTISONE
AND
THE
TREATMENT
again at any t i m e d u r i n g t h e course, e v e n t h o u g h other s y m p t o m s did appear. Fig. 6 shows t h e complete r e c o r d of all the symptoms developing at any t i m e d u r i n g t h e series. It will b e seen t h a t i n b o t h g r o u p s of cases a similar trend occurs, w i t h a similar p a t t e r n a p p e a r i n g after each exposure. T h e decreasing s y m p t o m f r e q u e n c y is also obvious as Well as the m o r e rapid fall in t h e 3~
OF
RADIATION
SICKNESS
73
o n the one h a n d , a n d n a u s e a a n d v o m i t i n g on t h e other. T h e i m p r e s s i o n g a i n e d f r o m this investigation was t h a t malaise a n d h e a d a c h e t e n d e d to be coupled t o g e t h e r a n d as a separate g r o u p anorexia, nausea, a n d vomiting. It is difficult to p r e s e n t u n e q u i v o c a l evidence to s u p p o r t this suggestion, b u t in an a t t e m p t to o b t a i n some guide the results were surveyed for t h e relative incidence of these CORTISONE
-
28
iiiiiiiiii~iiiiiiiii~iiiiEiiiiii~iiiiiiiiiiJiiiiiiii
"~'~-,~,,~'~
ii~i[iiilliii'iiiiiiiiiii}iiiiiiiii[iiii'iilliiiiiiiki
2
I
3
raEArMENrNO.
4
t6"~OACHe
5
/OMITING ~'~ ~ALA/SE ~
I
2
5 TREAMENT
Fig.
4
5
6.--Complete symptom index during course,
cortisone cases. A f t e r the fifth t r e a t m e n t those patients receiving cortisone developed only n a u s e a and malaise, whilst t h e controls show t h e p r e s e n c e of a complete s y m p t o m i n d e x excluding rigors. Again it will be n o t e d t h a t n a u s e a f r e q u e n c y shows little change in t h e c o n t r o l group, increasing after the second exposure a n d b e i n g m o r e p r e d o m i n a n t after the third, fourth, a n d fifth t r e a t m e n t s as compared w i t h the n u m b e r s following t h e first exposure. Malaise also shows only a slight decreasing f r e q u e n c y during t h e overall t i m e of t h e course, a n d it is only by the f o u r t h exposure t h a t a fall does occur. T h e remaining s y m p t o m s all show a very slight decrease as the course proceeds. U n d e r cortisone all s y m p toms a p p e a r to decrease in f r e q u e n c y in a gradual manner, b u t w i t h n a u s e a a n d malaise r e m a i n i n g t h e most recalcitrant. C o n c l u s i o n . - - T h e s y m p t o m a t i c picture o b t a i n e d by irradiation, b o t h w i t h a n d w i t h o u t cortisone cover, appears c o m p a r a b l e b u t w i t h a m a r k e d q u a n t i t a t i v e increase in s y m p t o m s in the control group. T h e decreasing s y m p t o m f r e q u e n c y is v e r y m u c h more a p p a r e n t w i t h cortisone, a n d in b o t h series nausea a n d malaise r e m a i n t h e m o s t lasting of t h e various disturbances.
S Y M P T O M A N A L Y S I S (3) C o u r t B r o w n in his s u r v e y suggests t h a t t h e r e may be two separate aetiological factors u n d e r l y i n g the d e v e l o p m e n t of t h e different disorders : malaise
6
NO
NAUSEA
two g r o u p s of s y m p t o m s w i t h special note as to any difference o c c u r r i n g w i t h or w i t h o u t cortisone. I n t h e control series t h e total c o m b i n e d s y m p t o m s , i.e., anorexia, nausea, v o m i t i n g , headache, a n d malaise, resulted o n exposure to i r r a d i a t i b n after 63 of t h e t r e a t m e n t s . Anorexia, nausea, a n d v o m i t i n g o c c u r r e d together without any other symptomatic disturbance o n i 6 occasions, a n d likewise h e a d a c h e and malaise p r e s e n t e d t o g e t h e r o n 7 occasions. U n d e r cortisone cover the full s y m p t o m i n d e x was n o t e d on 12 occasions. T h e n a u s e a c o m p l e x o c c u r r e d on 6 exposures, whilst t h e h e a d a c h e c o m p l e x resulted on n o less t h a n 13 occasions. Whilst, therefore, t h e r e is a n appreciable difference in the n u m b e r s b e t w e e n the two g r o u p s of cases, t h e r e is also a reversal in t h e relative frequencies of t h e two complexes. T a k i n g into c o n s i d e r a t i o n t h e o c c u r r e n c e of the initial s y m p t o m variation n o t e d above, in w h i c h h e a d a c h e once h a v i n g p r e s e n t e d was n o longer in evidence, plus this a p p a r e n t selective action of cortisone in controlling the n a u s e a g r o u p as distinct f r o m the h e a d ache group, t h e r e do a p p e a r to be two separate factors p r e s e n t u n d e r l y i n g the two s y m p t o m groups. It is therefore suggested t h a t in fact t h e r e m a y b e one aetiological factor u n d e r l y i n g anorexia, nausea, a n d v o m i t i n g on the one h a n d , a n d h e a d a c h e and malaise o n the other. I t is also i n t e r e s t i n g to c o n t r a s t the n u m b e r of times in w h i c h the s y m p t o m s o c c u r r i n g are a solitary m a n i f e s t a t i o n only, i.e., a m o n o s y m p t o m . T h i s took place in t h e controls o n I6
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occasions following t h e total of 80 t r e a t m e n t s given, i.e., a p e r c e n t a g e of 2o, a n d b e i n g e q u i v a l e n t to less t h a n o n e - q u a r t e r of all s y m p t o m s recorded. U n d e r cortisone cover m o n o - s y m p t o m a t i c upsets r e s u l t e d
OF
RADIOLOGISTS
3. A C T H p r o d u c e s hyperplasia a n d h y p e r t r o p h y of t h e adrenal cortex w i t h c o n t i n u a n c e even after A C T H is d i s c o n t i n u e d , c o n t r a s t i n g w i t h cortisone w h i c h has t h e opposite effect.
CORTISONE /6-
tO-
=i[[N[NN[[ii[[~,[N[!i[ii[i[[i[~
IHmmmHN[i[[iil[i[ii[i[[N i[iN[[i[i[i[[i[ii[ii[i[[i[~N[[[i
,.[~[![[![~i[i[[i[N[N[i~[!~i[~[[i[!![i[HL
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0 COMPLETE
VOMITING
HEAOACHE
!i!!!!N!i[NiN!!N!N!ii! N!NNN!i[!i[i!N![N[', E[~[l[[~lIN[[~[ININli[ii[ii[i[l[[Nl[[~
'[[[[i[i[iiii[[[[i[[i[ii[ii[ii[i[[[iiii[i[ii[i[ii[[[[~
NAUSEA
ANOREXIA
KE_Y
CONTROL ,~ e
,z
i[iiiii[i[iii[[iii[[iii[![[i[!![!![i!!!![[lii[ii
SYMPTOMS
~iN[lJlNN[¢[[i[ii[ii[iiNi[i[i[ ~diNi[iii*[[i[iiitii*[iiiiiiiiiiiiiN[i[ N!qf¢f!ffffffff!ffNNffffNf[ i
li[
!iii[i[ii[i[[
~ iii[iiiiN[[N[[i[[iiii[i[i![i[[i[i[[f[![]
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i COMPLETE
tNii [NN!!!N!!i iiii~,, i i[.......
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' fi¢{f[iNNNgigtg s [iig[[[ii[i[iNi[i[[i[ii[i[[i[ °~ 6 [[i[Ni[[i[iNNii[i
c
MALAISE
VOMITING
HEADACHE
ANORCXIA
NAUSEA
MALAISE
Fig. 7 . - - S y r n p t o m relief incidence.
o n 20 occasions f r o m t h e 76 total t r e a t m e n t s given, i.e., a p e r c e n t a g e of 27, a n d r e p r e s e n t i n g almost o n e - h a l f of all the total n u m b e r of s y m p t o m s recorded. C o n c l u s l o n . - - I r r a d i a t i o n u n d e r cortisone cover results in a single d i s t u r b a n c e m o r e f r e q u e n t l y t h a n w i t h o u t t h e h o r m o n e . S o m e evidence suggests a dual aetiology u n d e r l y i n g t h e d e v e l o p m e n t of h e a d ache a n d malaise o n t h e one h a n d , a n d anorexia, nausea, a n d v o m i t i n g o n t h e other.
TREATMENT T h e t r e a t m e n t of r a d i a t i o n sickness has r e m a i n e d largely empirical, w i t h a variety of d r u g s b e i n g used. Pyridoxine, v i t a m i n C, h y d r o c h l o r i c acid, benadryl, largactil, d r a m a m i n e , b e n z e d r i n e , are some of t h e c o m m o n e r w h i c h have b e e n employed, w i t h pyridoxine still p r o b a b l y b e i n g t h e m o s t popular. M a n y drugs have b e e n f o u n d successful i n o t h e r forms of vomiting, s u c h as h y p e r e m e s i s g r a v i d a r u m a n d m o t i o n sickness, a n d owe t h e i r use i n the t r e a t m e n t of radiation sickness solely to this factor, i g n o r i n g t h e p r o b a b l e differences in aetiology. Various A m e r i c a n authorities have e m p l o y e d A C T H in o r d e r to p r e v e n t or relieve radiation sickness. J e n k i n s o n a n d B r o w n (1944) r e p o r t e d relief of r a d i a t i o n sickness in 45-5 ° p e r cent of cases. T a b e r (1951) states t h a t " m o s t " of his cases were relieved of radiation sickness w i t h doses of Io i.u. daily. T h e o r e t i c a l l y t h e y state t h a t A C T H w o u l d a p p e a r to be b e t t e r t h a n cortisone as : - 1. A m o r e c o n s t a n t p r o d u c t i o n of cortisone w o u l d result. 2. All h o r m o n e s of the adrenal cortex w o u l d be produced.
A n essential factor for t h e relief of radiation sickness b y A C T H , as has b e e n p o i n t e d out, is an adrenal cortex w h i c h c a n r e s p o n d to its h o r m o n a l stimulation. T h u s , cases w h i c h h a d a d i m i n i s h e d Table IV.--SYMPTOM
RELIEF
CORTISONE
CONTROL
ELLIS A N D
per cent 81 "3
per cent
per cent
43 "75
64"0
~ausea
56"3
I2' 5
44"0
omiting
87"5
56"25
7i.o
[eadache
68.8
31.8
SYMPTOM
~norexia
lalaise
31 "3
i2"5
igors
[
87"5
87"5
Relief
37"5
I2"5
75"0
50'0
STOLL
46"0
i
artial relief
',± or
)
28 47 38-55
or a b s e n t cortical reserve w o u l d of necessity fail to r e s p o n d to A C T H therapy. Ellis a n d Stoll (1952) in a c o m p r e h e n s i v e survey reviewed t h e efficiency of a n u m b e r of these drugs e m p l o y e d in t h e t r e a t m e n t of irradiation s y m p t o m s . T h e i r conclusions were : - a. V o m i t i n g was t h e easiest of all r a d i a t i o n sickness s y m p t o m s to relieve a n d anorexia a n d nausea t h e m o s t difficult. b. T h a t i n e r t tablets gave a surprisingly high p r o p o r t i o n of relief of s y m p t o m s - - 2 o - 3 o p e r cent
CORTISONE
AND
THE
TREATMENT
obtaining c o m p l e t e relief. T h i s c o m p a r e s w i t h Court B r o w n ' s series in w h i c h z3"5 per cent developed s y m p t o m s as a result of s h a m irradiation. c. Pyridoxine a n d h y d r o c h l o r i c acid t o g e t h e r proved the m o s t efficacious c o m b i n a t i o n s of drugs, with complete relief of s y m p t o m s in j u s t over
OF
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75
50 per cent of cases. T h i s compares w i t h 19 p e r cent c o m p l e t e relief w h e n i n e r t tablets were used. C o m p l e t e relief of the ' difficult ' s y m p t o m s - anorexia and m a l a i s e - - o c c u r r e d in 57 per cent of cases w i t h the above d r u g c o m b i n a t i o n and in zI per cent e m p l o y i n g inert tablets.
CORTISONE Fig. 8. A, Black and white; B, Infra-red.
A
SICKNESS
CONTROL Fig. 9.--A, Black and white ; B, Infra-red.
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appears to b e t h e easiest s y m p t o m to c o m b a t a n d malaise t h e m o s t difficult in b o t h groups. Anorexia, headache, a n d n a u s e a follow in t h a t o r d e r in ease of relief. Table I V gives t h e overall absolute figures for this survey, i n c l u d i n g t h e results o b t a i n e d b y Ellis a n d Stoll for c o m p a r i s o n . Vorniting.--Agreeing w i t h Ellis a n d Stoll, t h e easiest s y m p t o m to relieve appears to b e t h a t of vomiting, w i t h over 5 ° p e r cent of p a t i e n t s o b t a i n i n g relief w i t h ' d u m m y ' tablets.
S y m p t o m R e l i e f . - - T h e varieties of s y m p t o m relief is given i n Fig. 7, w h i c h shows t h e n u m b e r s of patients in t h e cortisone series w h o o b t a i n e d relief f r o m t h e various s y m p t o m s c o m p a r e d w i t h those of t h e control group. I t will b e seen f r o m these diagrams t h a t once again a m a r k e d parallelism occurs b e t w e e n t h e two g r o u p s of cases. I t is also a p p a r e n t t h a t s y m p t o m a t i c relief results i n a far greater n u m b e r of cases i n p a t i e n t s u n d e r cortisone t h a n w i t h o u t . V o m i t i n g 14000 ~3ooo
12OOO "~.~•~
I 1000
I0000
";~
KEY --
OBSERVED
MEANS LINES PARALLEL REGRESSION LINES
_,_._ RECRESSION
"~ ~'~
- -
- -
- -
9000
Iz
8000
0
'
CORTISONE
u
700 O 6000
5000 ~
~
CONTROL
4000 3000
2OOO TREATMENT
NUMBER
Fig. io.--Total white-cell count.
KEY OES ES D MEERAVN , R.EGRESSION i LINES PARALLEL REGRE ION LISNSES
12000 I I
•
I000~ I
IooOO i i 9000i t-
i 8000 i
z
D 0
7000
CORTISONE
u
6000 5000 400C 3000 2000
CONTROL I I
I 2
I 3
TREATMENT NUMBER Fig. I I.--Polymorphonuclear count.
r 4
I 5
CORTISONE
AND
THE
TREATMENT
T h e difference b e t w e e n t h e s e figures is n o t significant (P of a b o u t I i n 5 (0"20)). Anorexia.--Next in o r d e r of ease of relief is anorexia i n b o t h series. T h e difference b e t w e e n the two w i t h P of a b o u t z i n 139 (o'oo7) is significant at o'oi.
T h i s contrasts w i t h Ellis a n d StoWs o b s e r v a t i o n s t h a t anorexia is one of t h e m o s t difficult s y m p t o m s to relieve.
OF
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SICKNESS
77
in t h e reactions s u s t a i n e d b e t w e e n the two sets of cover, a l t h o u g h 5 cases in t h e cortisone series were assessed as m i n i m a l as c o m p a r e d w i t h 3 in t h e control. P h o t o g r a p h i c r e c o r d i n g s of t h e reactions were t a k e n at t h e t i m e of inspection. R e p r e s e n t a t i v e b l a c k - a n d w h i t e a n d i n f r a - r e d p h o t o g r a p h s are s h o w n f r o m each group, verifying t h a t cortisone appears to exert n o appreciable m o d i f y i n g effect on the m i l d reactions r e s u l t i n g f r o m low dosage of irradiation (Figs. 8, 9).
IOO
-CORTISONE
80 FZ
O U
CONTROL
60
W
<
FZ
4C
20 J
O
I
!
t
2
3
4
TREATMENT NUMBER
Fig. :c2.--Mean percentage values polyrnorphonuclear count.
Headache.--Approximately twice t h e n u m b e r of cases o b t a i n e d relief u n d e r cortisone t h a n w i t h ' d u m m y ' tablets. T h e difference w i t h a p r o b a b i l i t y of a b o u t I in 2 6 (o'04) is significant at t h e o'o 5 level. Malaise.--The o t h e r ' d i f f i c u l t s y m p t o m ' of Ellis a n d StoWs s h o w e d relief to a m i n i m a l degree in t h e control g r o u p b u t over 3 ° p e r cent o b t a i n e d relief in the cortisone series. T h i s difference is n o t significant statistically. Nausea.--This s h o w e d relief in a low p e r c e n t a g e of cases in t h e control series b u t over 50 p e r cent with cortisone. T h e difference w i t h P of a b o u t i in 86 ( o ' o i ) is significant at t h e o ' o i level. A n additional s y m p t o m n o t e d in t h e series was the loss of taste for cigarettes w h i c h lasted t h r o u g h o u t the t r e a t m e n t , o c c u r r i n g in 2 cases in t h e cortisone g r o u p a n d in 5 cases in t h e control group. Reaction.--The work of H o u g h t o n , Walker, and J o n e s (1954) has s h o w n t h a t u n d e r cortisone cover t h e skin r e a c t i o n following exposure to irradiation is m a r k e d l y modified. I n this series t h e dosage .employed was a p p r e c i a b l y less t h a n t h a t e m p l o y e d In t h e above series, 15oo r as c o m p a r e d w i t h 6ooo r. E a c h case was i n s p e c t e d one week after c o m p l e t i o n of t r e a t m e n t a n d t h e degree of reaction assessed. I n b o t h series t h e reaction was n e v e r greater t h a n first degree (i.e., a n e r y t h e m a only), with, however, variations n o t e d r a n g i n g f r o m m i n i m a l to fully established. T h e r e a p p e a r e d to b e little difference
Conclusion.--Apart f r o m a significantly increased relief of anorexia u n d e r cortisone, t h e figures show a striking similarity to Ell,is a n d Stoll's series. BLOOD
PICTURE
I. W h i t e Blood-count.--The average p r e irradiation c o u n t s for t h e two series were : cortisone 1036o ; control 991o. T h e scatter a b o u t these values was considerable ( s t a n d a r d deviation 326), a n d the difference of 450 b e t w e e n the m e a n s was n o t significant. t (29 d . f . ) = o ' 3 8 0'8 p 0' 7 A f t e r the first i r r a d i a t i o n (see Fig. IO) the average w h i t e b l o o d - c o u n t for t h e c o r t i s o n e - t r e a t e d p a t i e n t s increased, a n d t h a t for t h e controls decreased slightly. T h e r e a f t e r , a s t e a d y decrease o c c u r r e d in each series. L i n e a r regression analysis shows t h a t this decrease could b e d e s c r i b e d as a decrease of 165o in t h e w h i t e b l o o d - c o u n t s p e r t r e a t m e n t in the cortisone group, a n d iOlO p e r t r e a t m e n t in t h e controls. O w i n g to t h e wide scatter of t h e ,individual white b l o o d - c o u n t s , however, this difference is n o t significant, a n d it is a d e q u a t e to r e p r e s e n t b o t h series b y parallel lines, each giving a decrease of 13o 5 p e r t r e a t m e n t . T h e s e parallel lines are s h o w n d o t t e d in Fig. IO. T h e distance b e t w e e n the two lines is 422o ± 4 9 o , w h i c h is h i g h l y significantly different f r o m zero (p>~o.ooI). T h i s result is n o t appreciably influenced
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b y the initial (non-significant) a d v a n t a g e of 450 in t h e m e a n w h i t e b l o o d - c o u n t for t h e cortisone group. Briefly, t h e n , if two g r o u p s of p a t i e n t s w i t h t h e same initial w h i t e b l o o d - c o u n t , one treated w i t h cortisone a n d t h e o t h e r not, are irradiated, t h e
OF
RADIOLOGISTS
above analysis of total w h i t e b l o o d - c o u n t (see also
Fig. i i ) . T h e initial m e a n - c o u n t s do n o t differ significantly. Difference b e t w e e n m e a n s -- 530, t = 0'56, o'7>p>o'6.
3000 /
2000
Z D O U COFLTI$ONE CONTROL
I000
o
i
i TREATMENT
~__
.I
NUMBER
Fig. i3.--Mean values of lymphocyte counts.
300000
Z
200000 CONTROL
0 L)
CORTISONE
IOOOOO
I 1
I 2
I .3
TREATMENT
NUMBER
I 4
I 5
Fig. I4.--Mean values of platelet counts. cortisone ,patients will h a v e a n a d v a n t a g e of some 4o0o in w h i t e b l o o d - c o u n t after t h e first irradiation, w h i c h will persist t h r o u g h o u t f u r t h e r t r e a t m e n t s u p to the fifth, d u r i n g w h i c h t i m e t h e w h i t e b l o o d c o u n t s of b o t h g r o u p s will decrease b y a b o u t 13oo per treatment. It s h o u l d be n o t e d t h a t this is n o t necessarily t r u e of i n d i v i d u a l patients, b u t only applies to t h e average w h i t e b l o o d - c o u n t s . 2. P o l y m o r p h s . - - T h e analysis of t h e absolute p o l y m o r p h - c o u n t s follows exactly t h e p a t t e r n of t h e
T h e m e a n p o l y m o r p h - c o u n t of t h e cortisone g r o u p is f o u n d to increase at the first t r e a t m e n t ; t h a t of t h e controls decreases and, thereafter, the cortisone g r o u p has a loss of I2ZO p e r t r e a t m e n t and t h e controls a loss of 72o p e r t r e a t m e n t . Again these do n o t differ significantly, a n d can b e repres e n t e d b y a m e a n of 950 p e r t r e a t m e n t in each group. T h e distance b e t w e e n the two regression lines is 375o-t-44o w h i c h is h i g h l y significant ( p < o ' o o I ) . T h e above result could be due solely to t h e lower total w h i t e b l o o d - c o u n t i n the control g r o u p after
CORTISONE
AND
THE
TREATMENT
each irradiation. It is of interest to see whether the difference in polymorph-counts can be attributed to this alone, or whether the composition of the white blood-cells is also affected by the administration of cortisone. T h e percentage of polymorphs has accordingly been analysed, and the mean values before irradiation and after the first five treatments for the two series are shown in Fig. 12. It will be noticed that the two series are relatively much closer together, and although Student's t e s t ' shows the m e a n values to differ significantly after the second, third and fifth treatments, the differences cease to be significant for the second and third treatments w h e n the initial small difference in percentage of polymorphs (pre-irradiation) is taken into account. We may conclude, then, that the effect of cortisone is to increase the total white blood-count initially, and the difference in polymorphs is largely due to this general increase and n o t to a differential effect on the components of the white blood-cells. 3. L y m p h o c y t e s . - - M e a n values of the absolute lymphocyte counts are shown in Fig. 13. In view of the wide scatter of individual counts, the differences between the two series d0 not reach significance, but the broad picture is similar to that of the polymorphs. 4. P l a t e l e t s . - - M e a n values of the platelet-counts are given in Fig. I4. T h e y show no evidence of a cortisone effect.
CONCLUSION T h e findings which are significant in this survey are as follows :-= a. An increase in the latent period following irradiation under cortisone cover by a factor of approximately 2'5. b. A decrease in symptoms, both qualitative and quantitative, u n d e r cortisone, with a further more rapid lessening of these s y m p t o m s a s the course progresses. c. A greater prevalence for symptoms to be of a solitary manifestation in the cortisone series. d. Relief of all symptoms in a higher percentage of cases with cortisone as compared with the controls, but only in the case of anorexia, headache, and nausea is the difference statistically significant. e. A ' p r o t e c t o r ' effect of cortisone on the .peripheral blood-count as evidenced by a lesser fall in the total white-cells during the course. f. Absence of any effect of cortisone on the mild first-degree erythema resulting from this quantity and quality of irradiation. If one postulates, as Porter (1952) has done, that the natural response to irradiation is a hyperactivity of the adrenal cortex, then failure to respond m a y be due to one of two causes--either absence of cortical tissue or the presence of cortical tissue with a markedly diminished or absent reserve. If, therefore, the lack of cortisone was the immediate cause of the radiation syndrome as has been suggested, adequate coverage as has been employed in this series should prevent all s y m p t o m s
OF
RADIATION
SICKNESS
79
developing in approximately 70-80 per cent of cases - - t h e remainder being those who would exhibit symptoms even after sham irradiation. T h e actual figure obtained in the cortisone series for the complete relief of symptoms is only 37"5 per cent and therefore one must conclude that lack of cortisone does not appear to be the immediate cause of radiation sickness, although undoubtedly significant modifying changes do occur after its administration. Aeknowledgements.--I would like to thank the Medical Research Council for their assistance and advice and for the donation of the cortisone and ' d u m m y ' t a b l e t s ; to Dr. J. A. C. Fleming and Professor F. T. G. Prunty, of St. T h o m a s ' s Hospital, for their help and encouragement in planning and undertaking the s u r v e y ; and to Mr. C. J. L. T h u r g a r , Director of the N o r t h East Cancer Organizations for his continued help in completion of the series. I also wish to thank Dr. D. D. Reid, of the D e p a r t m e n t of Epidemiology and Medical Statistics of the University of London, and Mr. D. J. Newall, of the D e p a r t m e n t of Industrial Health of the University of D u r h a m , for their most helpful advice in relation to the statistical aspects. Thanks also to Mr. N. H a m m e r s l e y and Mr. D. Jewers for their part in presenting the tables, etc., and the D e p a r t m e n t of Photography of St. T b o m a s ' s Hospital for the photographic undertaking. Finally to the departments of Pathology of St. T h o m a s ' s Hospital and the Newcastle General Hospital for their helpful cooperation in undertaking blood-count investigations. BIBLIOGRAPHY BACQ, Z. M., and ALEXANDER,P. (I955), Fundamentals of Radiobiology. London : Butterworth. BsowN, W. M. COURT (I953), Brit. reed. ft., I, 8o2. - - - - and MAHLER, R. F. (1953, a), Science, 118, 27i. (1953, b), Proc. R. Soc. Med., 46, 245. (I954), J. Fac. Radiol. Lond., $, 2oo. CSONKITE, E, P. (I953) , Atomic Medicine, I79-218. Baltimore i Williams & Wilkins. ELLINOER, F. ( i 9 4 i ) , Biologic Fundamentals of Radiation
Therapy. New York : Elsevier. - - - - (i945), Radiology, 44, 241. ELLIS, F., and STOLL, B. A. (1952), J. Fac. Radiol. Lond., 3, 207. HOtlCHTON, L. E., WALKER,J. B., and JoNEs, D. E. (I954), Brit. me&ft., 2, I313. JENKINSON, E. L., and BROWN, W. H. (I944), Amer. ft. Roentgenol., $ I, 496. KOHN, H. I. (1951), Amer. ff. Physiol., 165, 43. LANCENDOSFF, H., KOCH, R., and SAUES, H. (I954), Strahlentherapie, 93, 37, 44, 38L LASSES, E. C., and STENSTSOM, K. W. (I954), Amer. ft. Roentgenol., 72, 474. LEBLOND, C. P., and SEGAL, G. (I949), 1bid., 62, 547. POSTER, E. (I952), Radiology, 58, 246. SELYE, H. (195o, a), Brit, me&ft., 2, 1383 . --(i95o, b), " T h e Physiology and Pathology of Exposure to Stress ", Acta Inc., Montreal, Supp. 1951, 1952. TABES, K. W. (I95I), Radiology, 57, 7o2. WEICHEST, l.J. (I942), Strahlentherapie, 71, 127.
JOURNAL
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THE
FACULTY
OF
RADIOLOGISTS
Cortisone and the Treatment of Radiation Sickness R. FINNEY, M.B., B.S., F.R.C.S. (Edin.), D.M.R.T. Radiotherapist, Newcastle General Hospital THE t e r m ' r a d i a t i o n s i c k n e s s ' is applied to a general constitutional upset following irradiation. Characteristically, s y m p t o m s are gastro-intestinal, varying from nausea to prolonged vomiting and often associated with headache, lassitude, and mental depression. T h i s s y m p t o m - c o m p l e x is allied to the general radiation syndrome found to follow exposure to radiation produced by nuclear fission, as exemplified by the populations of H i r o s h i m a and Nagasaki. I n both, a fairly well-defined pattern of events occurs and we are indebted to Court Brown (1953) and Court Brown and M a h l e r (1953, a, b, 1954) for a great deal of important work in relation to the analysis of these symptomatic disturbances and the correlation of the related syndromes. T h e constitutional symptoms following irradiation have been recognized by therapists for years, and indeed m a y be of such severity as to be a limiting factor in radiotherapy treatment. M u c h has been written on the subject both in regard to the aetiology and to treatment, and the literature is filled with a mass of confused and often equivocal data dealing with various clinical and pathological findings in humans and animals. T h e r e is still no complete answer to either the aetiology or the treatment. In recent years interest has been focused on the role played by the adrenal cortex in this syndrome. In 1941 Ellinger emphasized the importance of adrenal cortical insufficiency i n radiation sickness. His results were based on metabolic phenomena, but in the light of more recent knowledge it has become difficult to interpret these results f r o m the specific action of radiation alone. Langendorff, Koch, and Sauer (1954) have demonstrated a small but definite protective effect in mice with D O C A or total extracts from the adrenal, but only if sublethal' doses of irradiation are given. 'Weichert (1942) noted the striking similarity between A d d i s o n ' s disease and severe radiation sickness and suggested that the toxic products of protein breakdown resulting from irradiation produces a relative adrenal insufficiency. L e b l o n d and Segal (1949) showed that heavy irradiation of lymphatic tissue with adequate shielding of the rest of the body p r o d u c e d hypertrophy of the adrenal cortex and involution of distant lymphatic organs. T h i s failed to occur in adrenalectomized animals. T h e s e findings a r e in keeping with the observations of therapists who have noted that irradiation of lymphatic tissue m a y produce decrease in the size of distant nodes.' It is also a c o m m o n clinical finding that irradiation of the u p p e r a b d o m e n with large fields results in radiation sickness in a high percentage of cases. I n this site lymphatic tissue occurs in large quantities and coupled with the known sensitivity of this tissue would appear to give further support to Weichert's suggestion that the breakdown products of irradiation are released into the circulation; resulting in the syndrome of radiation sickness.
Porter (1952), in a series of cases, estimated adrenal functions by means of 17 keto-steroid urinary excretion and total eosinophil counts, specifying that at least a 50 per cent fall in count m u s t occur to represent adrenal cortical response. T h e results f r o m this investigation were : - a. A fall in total eosinophil count or rise in 17 keto-steroid excretion is evident only following the onset of radiation sickness. b. Sickness occurred more readily if t h e initial eosinophil count was low. c. W h e n adrenal cortical activity became present, sickness s y m p t o m s abated. Porter concluded that those patients undergoing irradiation fitted in with the Selye adaptation theory (195o a, b) in that the radiation acted as stress, producing sickness as an alarm reaction and an adrenal response as a 'counter shock ' phase. In those cases in which there was evidence of cortical response during the remainder of the therapy course, it was assumed that the patient was ' in a stage of resistance ' and in those cases with a lowered adrenal reserve there was a greater susceptibility to alarm stimuli. It was assumed that the natural response to irradiation stress is a h y p e r t r o p h y of the adrenal cortex following a chain of e v e n t s - - t h e initial one being a release into the circulation of tissue breakdown products. Lasser and S t e n s t r o m (1954), in a controlled series employing a modification of the T h o r n A C T H eosinophil response as an indication of adrenal cortical function, came to the conclusion that the adrenal cortex undergoes changes in the course of irradiation but doubt the relationship to radiation sickness. Cronkite (I953) and K o h n (I95I) go so far as to state that it is impossible to f o r m a clear picture of the participation of the pituitary and adrenals in radiation sickness, and Bacq and Alexander (1955), in a comprehensive review of the whole subject, came to the conclusion that it is difficult to interpret all aspects of radiation sickness in the light of the adaptation syndrome in spite of a large amount of data on the subject. T h e y point out that one of the drawbacks of the adaptation theory is its very versatility, and that if a series of symptoms cannot be explained by adrenal insufficiency then they are fitted to be explained by adrenal hyperactivity. T h e m a i n difficulties therefore in deciding the relationship of adrenal cortical function and the syndrome of radiation sickness would appear to be : - a. T h e relative crudeness of the tests as yet to hand in estimating adrenal function. Bacq and Alexander have emphasized that all biochemical as well as biological findings should be surveyed before drawing any conclusions and not accept two or even one sign as evidence of pituitary-adrenal reaction. b. T h e difficulties in correlating the findings in experimental animals with those in man.
CORTISONE
AND
THE
TREATMENT
It was felt, however,, t h a t in spite of t h e i n c o m plete evidence for a n d against t h e p a r t p l a y e d b y the adrenal cortex in relation to t h e r a d i a t i o n syndrome, t h a t a series of cases s h o u l d b e i n v e s t i g a t e d employing cortisone in t h e t r e a t m e n t . F r o m this it was h o p e d i n f o r m a t i o n w o u l d b e g a i n e d w h i c h might help in clarifying a n d possibly v e r i f y i n g some of the data already obtained. INVESTIGATION
PROCEDURE
T h e original investigation was to have dealt w i t h the effect of cortisone in .treating r a d i a t i o n sickness developing after irradiation of the b r e a s t area following m a s t e c t o m y for c a r c i n o m a of t h e breast. T h e suggestion was made, however, t h a t t h e lytic properties of cortisone m i g h t exert a n u n f a v o u r a b l e effect o n t h e m a l i g n a n t processes b y allowing metastases to occur far m o r e readily in t h e absence of a protective fibrous m e s h w o r k . I t was t h e r e f o r e decided to deal only w i t h n o n - m a l i g n a n t c o n d i t i o n s and 32 cases were i n c l u d e d i n the series, all of w h i c h were of spinal a r t h r i t i s - - a n k y l o s i n g spondylitis or o s t e o - a r t h r i t i s - - n e c e s s i t a t i n g t r e a t m e n t to t h e w h o l e spine a n d sacro-iliac joints. T h e series was r a n d o m ized b y Dr. D. D. R e i d of t h e D e p a r t m e n t of M e d i c a l Statistics a n d E p i d e m i o l o g y in t h e U n i v e r s i t y of London, 16 cases b e i n g t r e a t e d b y cortisone a n d 16 by identical ' d u m m y ' tablets. T h e dosage of cortisone e m p l o y e d was 15o mg. daily in divided dosage, c o m m e n c i n g 48 h o u r s before the course of irradiation. T h i s dosage c o n t i n u e d t h r o u g h o u t the 14 days of the course of t r e a t m e n t , after w h i c h 75 rag. in divided dosage was given for 3 days, t h e n 25 mg. for a f u r t h e r 3 d a y s . T h i s gradual decrease in dosage reduced the possibility of cortisone w i t h d r a w a l effects. Some p a t i e n t s were t r e a t e d in the R a d i o t h e r a p y D e p a r t m e n t of St. T h o m a s ' s Hospital a n d some at the D e p a r t m e n t of t h e Newcastle G e n e r a l Hospital. In b o t h places a similar X - r a y m a c h i n e was u s e d at a kilovoltage of 220 kV., a half-value layer of 1'75 m m . Cu, a n d an o u t p u t of a b o u t 30 r p e r minute. A total dosage of 15oo r was g i v e n to t h e whole spine a n d sacro-iliac joints, g i v e n i n five t r e a t m e n t s over 14 days' overall time. T h e integral volume dose for t h e series as calculated b y t h e M a y n e o r d f o r m u l a was 2-2"9 m e g a g r a m m e r o e n t g e n s per t r e a t m e n t , the dosage v a r y i n g w i t h the thickness of the patient. E a c h case was t r e a t e d at t h e same time of day a n d o n t h e same days of t h e w e e k a n d detailed b l o o d - c o u n t s were carried o u t o n all cases t h r o u g h o u t t h e course. C o u n t s were t a k e n at t h e same time of day in each case to r e d u c e t h e effect of the diurnal variations in c o u n t a n d carried o u t b y one t e c h n i c i a n in each of t h e above hospitals. It was originally p l a n n e d for all cases to b e t r e a t e d for the first t r e a t m e n t as i n - p a t i e n t s to facilitate observation a n d enable c o m p a r i s o n w i t h C o u r t - B r o w n ' s series dealing w i t h single exposures to irradiation. Unfortunately, owing to difficulties in o b t a i n i n g beds, this p l a n was a b a n d o n e d a n d instead t h e p a t i e n t s were k e p t u n d e r o b s e r v a t i o n in a w a r d for t h e day of the first t r e a t m e n t - - u s u a l l y eight h o u r s following the initial irradiation t r e a t m e n t . S u b s e q u e n t l y each patient was i n t e r r o g a t e d daily t h r o u g h t h e t r e a t m e n t course. A detailed f o r m was filled in at each
OF
RADIATION
69
SICKNESS
i n t e r v i e w i n w h i c h the s y m p t o m s , if any, were noted, t h e t i m e of onset a n d cessation of each r e c o r d e d a n d t h e severity g r a d e d as f o l l o w s : + + Severe, + M o d e r a t e , ± M i n i m a l , -- Nil. I n all cases n o leading questions were asked a n d contact w i t h o t h e r r a d i o t h e r a p y cases was avoided. Latent P e r i o d . - - T h e l a t e n t p e r i o d in each case i n w h i c h s y m p t o m s were r e c o r d e d was calculated Table
L--LATENT
PERIOD
AFTER EACH
CONTROL
CORTISONE (31 R e a d i n g s ) I
2
3
4-
I
5
TREATMENT
(54 Readings)
2
3
4
5
2
2
I
2
2
I½
3½
2
2
2
2
2
6
8½
4 28
21
2
i½
2
2
2½
I
2½
~½
i½
31 24
I4
48
2
28 3
5
4
4 26
8
~
4
2½
12
i 2
3
2
2½
2
2½
2~
2
2
2
4½
2
4-
3
2
2
3 i½
2 4
2
3
5
I
4
¼
~½ 2
3
I
½
3
½
½
f r o m t h e t i m e of c o m m e n c e m e n t of the irradiation. T h e actual figures o b t a i n e d are s h o w n in Table I for the two groups of cases, a n d t h e average following each t r e a t m e n t is f o u n d to v a r y b e t w e e n 3"3 hr. a n d lO'5 hr. for t h e cortisone a n d 1"8 hr. a n d 5'1 hr. for the control. T h e overall average figures (Table H ) are f o u n d to be 6'9 hr. for the cortisone a n d 2"8 hr. for the control. T h e difference following each t r e a t m e n t is in fact f o u n d to b e statistically significant ( P > o ' o i ) only for the readings after t r e a t m e n t s I, 2, a n d 4, Table
Treatment
~L--LATENT PERIOD AFTER EACH TREATMENT (OVERALL AVERAGE FIGURES)
I
2
Control
5"1
3'4
Cortisone
9"7
lO"5
3 1.8 3"3
4
5
AVERAGE
2"0
i '8
2,8
8"5
2"25
6"9
a l t h o u g h the difference for t h e overall average figures, viz., 6"9 hr. a n d 2'8 hr., is in fact significant. I n C o u r t B r o w n ' s series, for single exposures of irradiation the l a t e n t p e r i o d was estimated at 2"7 hr. f r o m the c o m m e n c e m e n t of the irradiation. M o r e over the time was s h o r t e r in those patients w h o were generally m o r e easily upset, a n d the conclusion was r e a c h e d t h a t t h e m o r e sensitive an individual is to the effects of i r r a d i a t i o n t h e n the earlier are t h e s y m p t o m s likely to occur. I t will b e seen t h a t t h e figure o b t a i n e d f r o m the control g r o u p in this investigation is almost identical
70
JOURNAL
OF
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FACULTY
with that of Court Brown's for estimation of the latent period, viz., 2"8 and 2"7 hr. respectively. T h e r e is, ho,wever, a marked contrast with the latent period given by Ellis and Stoll (I952), whose figures Table IlL--RELATIONSHIP OF LATENT PERIOD TO SEVERITY OF SYMPTOMS CONTROL : SEVERITY
CORTISONE : SEVERITY
++
++
+
i
8"50
9"80 15"7o
5"80 5"00
2"00
2"80
2"50
+
i
x'8o
2"00
5"z5
6.00
5 'OO
12'oo
4'50
2"50
I "oo
1I'25
54"00
2"5 °
2-5 °
3"13
3'3 °
2"oo
31 " o o
z'4o
2"60
2"4 °
4"40
7"80
3"oo
Z'8o
3"5 °
26'00
3'5 o
1.7 o
1.6o
33 '30
8"40
2.00
5"OO
3"oo
8.00
lO'9O
2.oo
16"3o
2"25 4.7 ° Average
Average 8"5 °
[
I
9'20
3 "5 0
9"98
2"60
4"8o
8'7 o
range from 2 days to 24 d a y s - - v a s t l y different from the above. T h e s e authors were dealing with multitreatment cases as in the present series.
OF
RADIOLOGISTS
series there is found to be very little variation between the latent periods of the groups, with figures of 8"5, 9"2, and 9"98 for the + + , + , and =k groups respectively. I n the control series, however, the differences between the various groups appear to be in agreement with the above postulate that " the latent period is shorter in those cases who are more severely upset as compared with the less severely affected ". T h e inclusion of a single reading of 54"0 hr. in the third group makes the average i n this group appreciably higher, and statistically the difference between the varying •latent periods of this control group is not significant. O m i t t i n g this high figure, the average corrected latent period for the ~k group is found to be of the order of 4~8--identical with that of the moderately upset + group. T h e difference between the latent periods for the severely affected group in the control (2"6) and the moderately affected (4"8) is statistically not significant, although only just missing the borderline of probability. As is apparent, however, from the preceding tables, the overall period for the cortisone series remains appreciably longer in all groups. Conclusion.--The latent period for cases developing the s y m p t o m s of radiation sickness u n d e r cortisone cover IS increased by about 7 ° per cent over the control g r o u p - - a difference which statistically i s significant. SYMPTOM ANALYSIS (I) A qualitative as well as a quantitative analysis of the results shows appreciable differences between the two groups of cases. Fig. I indicates the numbers developing symptoms of any type during the duration of the course. It will be seen that in both series as
15. 14.
CORTISONE
I0-
4. ~5
[
Z. •
2
3
5
rmArMEur rio. 16-
CONTROL
141210-
6-
0
2 Fig.
I.--Symptom
4
3 rmArMeNr
NO
frequency during course.
F r o m the data obtained from this present investigation, the severity of each s y m p t o m has been grouped as either + + , + or -4-. T h e latent period for each s y m p t o m has been determined, and from this the average for each s y m p t o m group. T h e two are correlated as shown in Table I I I . In the cortisone
the course progresses the numbers developing symptoms decrease, but that the rate of this fall is far m o r e rapid in the cortisone group than in the control. T h e actual figures are, for the cortisone series, i i who developed symptoms after the initial treatment decreasing to 3 after the final exposure ;
CORTISONE
AND
THE
TREATMENT
compared w i t h 14, falling only to IO, in t h e control group. T h e actual severity of s y m p t o m a t i c u p s e t again contrasts o n analysis of the absolute figures .(Fig. 2). T h e degree of severity of each s y m p t o m was r e c o r d e d as outlined previously, covering + + for t h e m o s t
OF
RADIATION
71
SICKNESS
even after the fifth a n d final t r e a t m e n t . A m o r e detailed survey in relationship to s y m p t o m s developing after the initial t r e a t m e n t re-emphasizes t h e differences in severity b e t w e e n the two groups of cases (Fig. 3). T h e s e differences in s y m p t o m freq u e n c y are only significant statistically for the s e c o n d
CORTISONE /4-
io-
N 2-
mmmmmm~mmma~
2
I
3
4
5 hlIIIIIINIINIIIIIIIIIIIIIIIIIIIINIIIINI~
m~ArtdeA,rt¢o,
CONTROL
5
iill// a 0
2
I
3
4
INIIIIIIIIIIIIIIIIIllllllil m
TREATMEHT NO.
Fig.
2.--Syrnptomatic variation throughout course.
severely affected t o - - f o r c o m p l e t e absence of s y m p toms. T h u s it will b e seen t h a t u n d e r cortisone cover t h e r e were n o cases of t h e severe or m o d e r a t e l y severe u p s e t g r o u p ( + + or + ) r e c o r d e d after t h e time t h e t h i r d t r e a t m e n t h a d b e e n reached, w h e r e a s in the controls these degrees were n o t e d to b e p r e s e n t ,o-
CORTISONE
S-
@@6@ ®@6@
9-
- 5 =
It
Ta-
%
s-
~,t-
@@
o-
@@
@
a n d fifth t r e a t m e n t figures, b u t the general t r e n d in b o t h absolute n u m b e r s a n d degree of u p s e t is a p p a r e n t f r o m s u r v e y of t h e above histograms. A f t e r the final t r e a t m e n t of t h e course the n u m b e r of cases w h i c h d e v e l o p e d s y m p t o m s was only 3 (19 p e r cent) in t h e cortisone series, a n d these all to a m i n i m a l degree ~- as c o m p a r e d w i t h i o (63 p e r cent) in the controls; of w h i c h 7 (70 p e r cent) were of the severe or m o d e r a t e l y severe degrees. T h u s , following this final t r e a t m e n t i a of the p a t i e n t s receiving cortisone were completely a s y m p t o m a t i c as c o m p a r e d w i t h 5 of the o t h e r group. Conclusion.--In a m u l t i - t r e a t m e n t course of irradiation, s y m p t o m s are m u c h less f r e q u e n t a n d less severe u n d e r cortisone t h a n without, a n d f u r t h e r m o r e the rate of decrease of s y m p t o m freq u e n c y is appreciably m o r e r a p i d in the f o r m e r group.
SEVERITY OF S/MPTOMa I0-
CONTROL
9-
¢ ¢ [,~) - II ®®5® - 5
e71
o4-
I-
e~
O-
I
~
ee
e
SEVE,~'TY OF SYMPTOMS
Fig.
3 . - - S y m p t o m a t i c severity following initial exposure.
SYMPTOM
ANALYSIS
(2)
T h i s analysis deals w i t h t h e actual s y m p t o m s developing a n d t h e i r variation t h r o u g h o u t the course. I n those cases in w h i c h m o r e t h a n one s y m p t o m was f o u n d to occur s y n c h r o n o u s l y , t h e n each s y m p t o m was r e c o r d e d separately in t h e assessment. Fig. 6 shows the various s y m p t o m s n o t e d after the initial t r e a t m e n t a n d t h e i r relative frequency. I t will b e seen t h a t the c o m m o n e s t s y m p t o m s were malaise, headache, a n d n a u s e a in t h a t o r d e r of frequency. T h e incidence in t h e two series shows a r e m a r k a b l y similar p a t t e r n . A n o r e x i a is next in o r d e r of f r e q u e n c y a n d rigors the least c o m m o n of all.
72
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Vomiting occurred as a presenting symptom in only one case, and that in a control. The presenting symptoms following the remainder
of the treatments is shown in F i g . 5. T h e same pattern is maintained with malaise, nausea, and headache predominant and anorexia, rigors, and
3 in the cortisone and 3 in the control series. A typical case was N o . . 26, a control. Following the first treatment, after a latent period of z½ hr. the patient developed headache of -t- severity, subsiding after 4 hr. T h e patient then remained asymptomatic until after the second treatment, w h e n after
/6-
CORTISON[
/4-
I MALAISE
NAUSEA
If
I HEADACHE
1
RIGORS
ANOREXIA
CONTROL 14/2l
o~ 4 o MALAISE
NAU.~EA
HEADACHE
F
RIGORS
ANOREXIA
1
Fig. 4 . - - I n i t i a l s y m p t o m index following first exposure.
vomiting less often manifest. Qualitatively the overall picture is essentially similar for the two series, but quantitatively the s y m p t o m frequency shows in the controls a marked increase. ~.
a latent period of 4 hr. malaise developed of -ldegree, subsiding after a further 4 hr. Finally the third and fourth t r e a t m e n t s ; after a latent period of 3 hr. the patient developed nausea and malaise CORTISONE
2o-
~a4-_ 12S
II
o MALAISE
NAUSEA
HEADACHE
ii
.ANOREXIA
34-
RIGORS
VOMITING
CONTROL
3228-
~a42O-
,eZ fez 4--
• ANOREXIA SYMPTOMS
Fig. 5 . ~ I n i t i a l
I R / GORS
II
YOM/T/NG
s y m p t o m analysis throughout course.
It was rare for the initial s y m p t o m presenting to vary once this had been established. T h u s if nausea occurred as an initial s y m p t o m following the first exposure to radiation, then the presenting s y m p t o m for the remaining exposures (if any symptom did occur) would also be this disturbance. A slight variation of initial s y m p t o m presentation did, however, appear in a small m i n o r i t y of patients:
synchronously. T h i s pattern was typical of the variable initial s y m p t o m picture and in the 6 cases recorded the only symptoms manifest were, as above, headache, malaise, and nausea and no other. A further finding in relation to this variation in presenting s y m p t o m is that in all but one of these 6 cases headache was the disturbance in question, a n d , after regressing within 5-6 hr., did not occur
CORTISONE
AND
THE
TREATMENT
again at any t i m e d u r i n g t h e course, e v e n t h o u g h other s y m p t o m s did appear. Fig. 6 shows t h e complete r e c o r d of all the symptoms developing at any t i m e d u r i n g t h e series. It will b e seen t h a t i n b o t h g r o u p s of cases a similar trend occurs, w i t h a similar p a t t e r n a p p e a r i n g after each exposure. T h e decreasing s y m p t o m f r e q u e n c y is also obvious as Well as the m o r e rapid fall in t h e 3~
OF
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73
o n the one h a n d , a n d n a u s e a a n d v o m i t i n g on t h e other. T h e i m p r e s s i o n g a i n e d f r o m this investigation was t h a t malaise a n d h e a d a c h e t e n d e d to be coupled t o g e t h e r a n d as a separate g r o u p anorexia, nausea, a n d vomiting. It is difficult to p r e s e n t u n e q u i v o c a l evidence to s u p p o r t this suggestion, b u t in an a t t e m p t to o b t a i n some guide the results were surveyed for t h e relative incidence of these CORTISONE
-
28
iiiiiiiiii~iiiiiiiii~iiiiEiiiiii~iiiiiiiiiiJiiiiiiii
"~'~-,~,,~'~
ii~i[iiilliii'iiiiiiiiiii}iiiiiiiii[iiii'iilliiiiiiiki
2
I
3
raEArMENrNO.
4
t6"~OACHe
5
/OMITING ~'~ ~ALA/SE ~
I
2
5 TREAMENT
Fig.
4
5
6.--Complete symptom index during course,
cortisone cases. A f t e r the fifth t r e a t m e n t those patients receiving cortisone developed only n a u s e a and malaise, whilst t h e controls show t h e p r e s e n c e of a complete s y m p t o m i n d e x excluding rigors. Again it will be n o t e d t h a t n a u s e a f r e q u e n c y shows little change in t h e c o n t r o l group, increasing after the second exposure a n d b e i n g m o r e p r e d o m i n a n t after the third, fourth, a n d fifth t r e a t m e n t s as compared w i t h the n u m b e r s following t h e first exposure. Malaise also shows only a slight decreasing f r e q u e n c y during t h e overall t i m e of t h e course, a n d it is only by the f o u r t h exposure t h a t a fall does occur. T h e remaining s y m p t o m s all show a very slight decrease as the course proceeds. U n d e r cortisone all s y m p toms a p p e a r to decrease in f r e q u e n c y in a gradual manner, b u t w i t h n a u s e a a n d malaise r e m a i n i n g t h e most recalcitrant. C o n c l u s i o n . - - T h e s y m p t o m a t i c picture o b t a i n e d by irradiation, b o t h w i t h a n d w i t h o u t cortisone cover, appears c o m p a r a b l e b u t w i t h a m a r k e d q u a n t i t a t i v e increase in s y m p t o m s in the control group. T h e decreasing s y m p t o m f r e q u e n c y is v e r y m u c h more a p p a r e n t w i t h cortisone, a n d in b o t h series nausea a n d malaise r e m a i n t h e m o s t lasting of t h e various disturbances.
S Y M P T O M A N A L Y S I S (3) C o u r t B r o w n in his s u r v e y suggests t h a t t h e r e may be two separate aetiological factors u n d e r l y i n g the d e v e l o p m e n t of t h e different disorders : malaise
6
NO
NAUSEA
two g r o u p s of s y m p t o m s w i t h special note as to any difference o c c u r r i n g w i t h or w i t h o u t cortisone. I n t h e control series t h e total c o m b i n e d s y m p t o m s , i.e., anorexia, nausea, v o m i t i n g , headache, a n d malaise, resulted o n exposure to i r r a d i a t i b n after 63 of t h e t r e a t m e n t s . Anorexia, nausea, a n d v o m i t i n g o c c u r r e d together without any other symptomatic disturbance o n i 6 occasions, a n d likewise h e a d a c h e and malaise p r e s e n t e d t o g e t h e r o n 7 occasions. U n d e r cortisone cover the full s y m p t o m i n d e x was n o t e d on 12 occasions. T h e n a u s e a c o m p l e x o c c u r r e d on 6 exposures, whilst t h e h e a d a c h e c o m p l e x resulted on n o less t h a n 13 occasions. Whilst, therefore, t h e r e is a n appreciable difference in the n u m b e r s b e t w e e n the two g r o u p s of cases, t h e r e is also a reversal in t h e relative frequencies of t h e two complexes. T a k i n g into c o n s i d e r a t i o n t h e o c c u r r e n c e of the initial s y m p t o m variation n o t e d above, in w h i c h h e a d a c h e once h a v i n g p r e s e n t e d was n o longer in evidence, plus this a p p a r e n t selective action of cortisone in controlling the n a u s e a g r o u p as distinct f r o m the h e a d ache group, t h e r e do a p p e a r to be two separate factors p r e s e n t u n d e r l y i n g the two s y m p t o m groups. It is therefore suggested t h a t in fact t h e r e m a y b e one aetiological factor u n d e r l y i n g anorexia, nausea, a n d v o m i t i n g on the one h a n d , a n d h e a d a c h e and malaise o n the other. I t is also i n t e r e s t i n g to c o n t r a s t the n u m b e r of times in w h i c h the s y m p t o m s o c c u r r i n g are a solitary m a n i f e s t a t i o n only, i.e., a m o n o s y m p t o m . T h i s took place in t h e controls o n I6
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occasions following t h e total of 80 t r e a t m e n t s given, i.e., a p e r c e n t a g e of 2o, a n d b e i n g e q u i v a l e n t to less t h a n o n e - q u a r t e r of all s y m p t o m s recorded. U n d e r cortisone cover m o n o - s y m p t o m a t i c upsets r e s u l t e d
OF
RADIOLOGISTS
3. A C T H p r o d u c e s hyperplasia a n d h y p e r t r o p h y of t h e adrenal cortex w i t h c o n t i n u a n c e even after A C T H is d i s c o n t i n u e d , c o n t r a s t i n g w i t h cortisone w h i c h has t h e opposite effect.
CORTISONE /6-
tO-
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NAUSEA
ANOREXIA
KE_Y
CONTROL ,~ e
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c
MALAISE
VOMITING
HEADACHE
ANORCXIA
NAUSEA
MALAISE
Fig. 7 . - - S y r n p t o m relief incidence.
o n 20 occasions f r o m t h e 76 total t r e a t m e n t s given, i.e., a p e r c e n t a g e of 27, a n d r e p r e s e n t i n g almost o n e - h a l f of all the total n u m b e r of s y m p t o m s recorded. C o n c l u s l o n . - - I r r a d i a t i o n u n d e r cortisone cover results in a single d i s t u r b a n c e m o r e f r e q u e n t l y t h a n w i t h o u t t h e h o r m o n e . S o m e evidence suggests a dual aetiology u n d e r l y i n g t h e d e v e l o p m e n t of h e a d ache a n d malaise o n t h e one h a n d , a n d anorexia, nausea, a n d v o m i t i n g o n t h e other.
TREATMENT T h e t r e a t m e n t of r a d i a t i o n sickness has r e m a i n e d largely empirical, w i t h a variety of d r u g s b e i n g used. Pyridoxine, v i t a m i n C, h y d r o c h l o r i c acid, benadryl, largactil, d r a m a m i n e , b e n z e d r i n e , are some of t h e c o m m o n e r w h i c h have b e e n employed, w i t h pyridoxine still p r o b a b l y b e i n g t h e m o s t popular. M a n y drugs have b e e n f o u n d successful i n o t h e r forms of vomiting, s u c h as h y p e r e m e s i s g r a v i d a r u m a n d m o t i o n sickness, a n d owe t h e i r use i n the t r e a t m e n t of radiation sickness solely to this factor, i g n o r i n g t h e p r o b a b l e differences in aetiology. Various A m e r i c a n authorities have e m p l o y e d A C T H in o r d e r to p r e v e n t or relieve radiation sickness. J e n k i n s o n a n d B r o w n (1944) r e p o r t e d relief of r a d i a t i o n sickness in 45-5 ° p e r cent of cases. T a b e r (1951) states t h a t " m o s t " of his cases were relieved of radiation sickness w i t h doses of Io i.u. daily. T h e o r e t i c a l l y t h e y state t h a t A C T H w o u l d a p p e a r to be b e t t e r t h a n cortisone as : - 1. A m o r e c o n s t a n t p r o d u c t i o n of cortisone w o u l d result. 2. All h o r m o n e s of the adrenal cortex w o u l d be produced.
A n essential factor for t h e relief of radiation sickness b y A C T H , as has b e e n p o i n t e d out, is an adrenal cortex w h i c h c a n r e s p o n d to its h o r m o n a l stimulation. T h u s , cases w h i c h h a d a d i m i n i s h e d Table IV.--SYMPTOM
RELIEF
CORTISONE
CONTROL
ELLIS A N D
per cent 81 "3
per cent
per cent
43 "75
64"0
~ausea
56"3
I2' 5
44"0
omiting
87"5
56"25
7i.o
[eadache
68.8
31.8
SYMPTOM
~norexia
lalaise
31 "3
i2"5
igors
[
87"5
87"5
Relief
37"5
I2"5
75"0
50'0
STOLL
46"0
i
artial relief
',± or
)
28 47 38-55
or a b s e n t cortical reserve w o u l d of necessity fail to r e s p o n d to A C T H therapy. Ellis a n d Stoll (1952) in a c o m p r e h e n s i v e survey reviewed t h e efficiency of a n u m b e r of these drugs e m p l o y e d in t h e t r e a t m e n t of irradiation s y m p t o m s . T h e i r conclusions were : - a. V o m i t i n g was t h e easiest of all r a d i a t i o n sickness s y m p t o m s to relieve a n d anorexia a n d nausea t h e m o s t difficult. b. T h a t i n e r t tablets gave a surprisingly high p r o p o r t i o n of relief of s y m p t o m s - - 2 o - 3 o p e r cent
CORTISONE
AND
THE
TREATMENT
obtaining c o m p l e t e relief. T h i s c o m p a r e s w i t h Court B r o w n ' s series in w h i c h z3"5 per cent developed s y m p t o m s as a result of s h a m irradiation. c. Pyridoxine a n d h y d r o c h l o r i c acid t o g e t h e r proved the m o s t efficacious c o m b i n a t i o n s of drugs, with complete relief of s y m p t o m s in j u s t over
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50 per cent of cases. T h i s compares w i t h 19 p e r cent c o m p l e t e relief w h e n i n e r t tablets were used. C o m p l e t e relief of the ' difficult ' s y m p t o m s - anorexia and m a l a i s e - - o c c u r r e d in 57 per cent of cases w i t h the above d r u g c o m b i n a t i o n and in zI per cent e m p l o y i n g inert tablets.
CORTISONE Fig. 8. A, Black and white; B, Infra-red.
A
SICKNESS
CONTROL Fig. 9.--A, Black and white ; B, Infra-red.
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appears to b e t h e easiest s y m p t o m to c o m b a t a n d malaise t h e m o s t difficult in b o t h groups. Anorexia, headache, a n d n a u s e a follow in t h a t o r d e r in ease of relief. Table I V gives t h e overall absolute figures for this survey, i n c l u d i n g t h e results o b t a i n e d b y Ellis a n d Stoll for c o m p a r i s o n . Vorniting.--Agreeing w i t h Ellis a n d Stoll, t h e easiest s y m p t o m to relieve appears to b e t h a t of vomiting, w i t h over 5 ° p e r cent of p a t i e n t s o b t a i n i n g relief w i t h ' d u m m y ' tablets.
S y m p t o m R e l i e f . - - T h e varieties of s y m p t o m relief is given i n Fig. 7, w h i c h shows t h e n u m b e r s of patients in t h e cortisone series w h o o b t a i n e d relief f r o m t h e various s y m p t o m s c o m p a r e d w i t h those of t h e control group. I t will b e seen f r o m these diagrams t h a t once again a m a r k e d parallelism occurs b e t w e e n t h e two g r o u p s of cases. I t is also a p p a r e n t t h a t s y m p t o m a t i c relief results i n a far greater n u m b e r of cases i n p a t i e n t s u n d e r cortisone t h a n w i t h o u t . V o m i t i n g 14000 ~3ooo
12OOO "~.~•~
I 1000
I0000
";~
KEY --
OBSERVED
MEANS LINES PARALLEL REGRESSION LINES
_,_._ RECRESSION
"~ ~'~
- -
- -
- -
9000
Iz
8000
0
'
CORTISONE
u
700 O 6000
5000 ~
~
CONTROL
4000 3000
2OOO TREATMENT
NUMBER
Fig. io.--Total white-cell count.
KEY OES ES D MEERAVN , R.EGRESSION i LINES PARALLEL REGRE ION LISNSES
12000 I I
•
I000~ I
IooOO i i 9000i t-
i 8000 i
z
D 0
7000
CORTISONE
u
6000 5000 400C 3000 2000
CONTROL I I
I 2
I 3
TREATMENT NUMBER Fig. I I.--Polymorphonuclear count.
r 4
I 5
CORTISONE
AND
THE
TREATMENT
T h e difference b e t w e e n t h e s e figures is n o t significant (P of a b o u t I i n 5 (0"20)). Anorexia.--Next in o r d e r of ease of relief is anorexia i n b o t h series. T h e difference b e t w e e n the two w i t h P of a b o u t z i n 139 (o'oo7) is significant at o'oi.
T h i s contrasts w i t h Ellis a n d StoWs o b s e r v a t i o n s t h a t anorexia is one of t h e m o s t difficult s y m p t o m s to relieve.
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77
in t h e reactions s u s t a i n e d b e t w e e n the two sets of cover, a l t h o u g h 5 cases in t h e cortisone series were assessed as m i n i m a l as c o m p a r e d w i t h 3 in t h e control. P h o t o g r a p h i c r e c o r d i n g s of t h e reactions were t a k e n at t h e t i m e of inspection. R e p r e s e n t a t i v e b l a c k - a n d w h i t e a n d i n f r a - r e d p h o t o g r a p h s are s h o w n f r o m each group, verifying t h a t cortisone appears to exert n o appreciable m o d i f y i n g effect on the m i l d reactions r e s u l t i n g f r o m low dosage of irradiation (Figs. 8, 9).
IOO
-CORTISONE
80 FZ
O U
CONTROL
60
W
<
FZ
4C
20 J
O
I
!
t
2
3
4
TREATMENT NUMBER
Fig. :c2.--Mean percentage values polyrnorphonuclear count.
Headache.--Approximately twice t h e n u m b e r of cases o b t a i n e d relief u n d e r cortisone t h a n w i t h ' d u m m y ' tablets. T h e difference w i t h a p r o b a b i l i t y of a b o u t I in 2 6 (o'04) is significant at t h e o'o 5 level. Malaise.--The o t h e r ' d i f f i c u l t s y m p t o m ' of Ellis a n d StoWs s h o w e d relief to a m i n i m a l degree in t h e control g r o u p b u t over 3 ° p e r cent o b t a i n e d relief in the cortisone series. T h i s difference is n o t significant statistically. Nausea.--This s h o w e d relief in a low p e r c e n t a g e of cases in t h e control series b u t over 50 p e r cent with cortisone. T h e difference w i t h P of a b o u t i in 86 ( o ' o i ) is significant at t h e o ' o i level. A n additional s y m p t o m n o t e d in t h e series was the loss of taste for cigarettes w h i c h lasted t h r o u g h o u t the t r e a t m e n t , o c c u r r i n g in 2 cases in t h e cortisone g r o u p a n d in 5 cases in t h e control group. Reaction.--The work of H o u g h t o n , Walker, and J o n e s (1954) has s h o w n t h a t u n d e r cortisone cover t h e skin r e a c t i o n following exposure to irradiation is m a r k e d l y modified. I n this series t h e dosage .employed was a p p r e c i a b l y less t h a n t h a t e m p l o y e d In t h e above series, 15oo r as c o m p a r e d w i t h 6ooo r. E a c h case was i n s p e c t e d one week after c o m p l e t i o n of t r e a t m e n t a n d t h e degree of reaction assessed. I n b o t h series t h e reaction was n e v e r greater t h a n first degree (i.e., a n e r y t h e m a only), with, however, variations n o t e d r a n g i n g f r o m m i n i m a l to fully established. T h e r e a p p e a r e d to b e little difference
Conclusion.--Apart f r o m a significantly increased relief of anorexia u n d e r cortisone, t h e figures show a striking similarity to Ell,is a n d Stoll's series. BLOOD
PICTURE
I. W h i t e Blood-count.--The average p r e irradiation c o u n t s for t h e two series were : cortisone 1036o ; control 991o. T h e scatter a b o u t these values was considerable ( s t a n d a r d deviation 326), a n d the difference of 450 b e t w e e n the m e a n s was n o t significant. t (29 d . f . ) = o ' 3 8 0'8 p 0' 7 A f t e r the first i r r a d i a t i o n (see Fig. IO) the average w h i t e b l o o d - c o u n t for t h e c o r t i s o n e - t r e a t e d p a t i e n t s increased, a n d t h a t for t h e controls decreased slightly. T h e r e a f t e r , a s t e a d y decrease o c c u r r e d in each series. L i n e a r regression analysis shows t h a t this decrease could b e d e s c r i b e d as a decrease of 165o in t h e w h i t e b l o o d - c o u n t s p e r t r e a t m e n t in the cortisone group, a n d iOlO p e r t r e a t m e n t in t h e controls. O w i n g to t h e wide scatter of t h e ,individual white b l o o d - c o u n t s , however, this difference is n o t significant, a n d it is a d e q u a t e to r e p r e s e n t b o t h series b y parallel lines, each giving a decrease of 13o 5 p e r t r e a t m e n t . T h e s e parallel lines are s h o w n d o t t e d in Fig. IO. T h e distance b e t w e e n the two lines is 422o ± 4 9 o , w h i c h is h i g h l y significantly different f r o m zero (p>~o.ooI). T h i s result is n o t appreciably influenced
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b y the initial (non-significant) a d v a n t a g e of 450 in t h e m e a n w h i t e b l o o d - c o u n t for t h e cortisone group. Briefly, t h e n , if two g r o u p s of p a t i e n t s w i t h t h e same initial w h i t e b l o o d - c o u n t , one treated w i t h cortisone a n d t h e o t h e r not, are irradiated, t h e
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above analysis of total w h i t e b l o o d - c o u n t (see also
Fig. i i ) . T h e initial m e a n - c o u n t s do n o t differ significantly. Difference b e t w e e n m e a n s -- 530, t = 0'56, o'7>p>o'6.
3000 /
2000
Z D O U COFLTI$ONE CONTROL
I000
o
i
i TREATMENT
~__
.I
NUMBER
Fig. i3.--Mean values of lymphocyte counts.
300000
Z
200000 CONTROL
0 L)
CORTISONE
IOOOOO
I 1
I 2
I .3
TREATMENT
NUMBER
I 4
I 5
Fig. I4.--Mean values of platelet counts. cortisone ,patients will h a v e a n a d v a n t a g e of some 4o0o in w h i t e b l o o d - c o u n t after t h e first irradiation, w h i c h will persist t h r o u g h o u t f u r t h e r t r e a t m e n t s u p to the fifth, d u r i n g w h i c h t i m e t h e w h i t e b l o o d c o u n t s of b o t h g r o u p s will decrease b y a b o u t 13oo per treatment. It s h o u l d be n o t e d t h a t this is n o t necessarily t r u e of i n d i v i d u a l patients, b u t only applies to t h e average w h i t e b l o o d - c o u n t s . 2. P o l y m o r p h s . - - T h e analysis of t h e absolute p o l y m o r p h - c o u n t s follows exactly t h e p a t t e r n of t h e
T h e m e a n p o l y m o r p h - c o u n t of t h e cortisone g r o u p is f o u n d to increase at the first t r e a t m e n t ; t h a t of t h e controls decreases and, thereafter, the cortisone g r o u p has a loss of I2ZO p e r t r e a t m e n t and t h e controls a loss of 72o p e r t r e a t m e n t . Again these do n o t differ significantly, a n d can b e repres e n t e d b y a m e a n of 950 p e r t r e a t m e n t in each group. T h e distance b e t w e e n the two regression lines is 375o-t-44o w h i c h is h i g h l y significant ( p < o ' o o I ) . T h e above result could be due solely to t h e lower total w h i t e b l o o d - c o u n t i n the control g r o u p after
CORTISONE
AND
THE
TREATMENT
each irradiation. It is of interest to see whether the difference in polymorph-counts can be attributed to this alone, or whether the composition of the white blood-cells is also affected by the administration of cortisone. T h e percentage of polymorphs has accordingly been analysed, and the mean values before irradiation and after the first five treatments for the two series are shown in Fig. 12. It will be noticed that the two series are relatively much closer together, and although Student's t e s t ' shows the m e a n values to differ significantly after the second, third and fifth treatments, the differences cease to be significant for the second and third treatments w h e n the initial small difference in percentage of polymorphs (pre-irradiation) is taken into account. We may conclude, then, that the effect of cortisone is to increase the total white blood-count initially, and the difference in polymorphs is largely due to this general increase and n o t to a differential effect on the components of the white blood-cells. 3. L y m p h o c y t e s . - - M e a n values of the absolute lymphocyte counts are shown in Fig. 13. In view of the wide scatter of individual counts, the differences between the two series d0 not reach significance, but the broad picture is similar to that of the polymorphs. 4. P l a t e l e t s . - - M e a n values of the platelet-counts are given in Fig. I4. T h e y show no evidence of a cortisone effect.
CONCLUSION T h e findings which are significant in this survey are as follows :-= a. An increase in the latent period following irradiation under cortisone cover by a factor of approximately 2'5. b. A decrease in symptoms, both qualitative and quantitative, u n d e r cortisone, with a further more rapid lessening of these s y m p t o m s a s the course progresses. c. A greater prevalence for symptoms to be of a solitary manifestation in the cortisone series. d. Relief of all symptoms in a higher percentage of cases with cortisone as compared with the controls, but only in the case of anorexia, headache, and nausea is the difference statistically significant. e. A ' p r o t e c t o r ' effect of cortisone on the .peripheral blood-count as evidenced by a lesser fall in the total white-cells during the course. f. Absence of any effect of cortisone on the mild first-degree erythema resulting from this quantity and quality of irradiation. If one postulates, as Porter (1952) has done, that the natural response to irradiation is a hyperactivity of the adrenal cortex, then failure to respond m a y be due to one of two causes--either absence of cortical tissue or the presence of cortical tissue with a markedly diminished or absent reserve. If, therefore, the lack of cortisone was the immediate cause of the radiation syndrome as has been suggested, adequate coverage as has been employed in this series should prevent all s y m p t o m s
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79
developing in approximately 70-80 per cent of cases - - t h e remainder being those who would exhibit symptoms even after sham irradiation. T h e actual figure obtained in the cortisone series for the complete relief of symptoms is only 37"5 per cent and therefore one must conclude that lack of cortisone does not appear to be the immediate cause of radiation sickness, although undoubtedly significant modifying changes do occur after its administration. Aeknowledgements.--I would like to thank the Medical Research Council for their assistance and advice and for the donation of the cortisone and ' d u m m y ' t a b l e t s ; to Dr. J. A. C. Fleming and Professor F. T. G. Prunty, of St. T h o m a s ' s Hospital, for their help and encouragement in planning and undertaking the s u r v e y ; and to Mr. C. J. L. T h u r g a r , Director of the N o r t h East Cancer Organizations for his continued help in completion of the series. I also wish to thank Dr. D. D. Reid, of the D e p a r t m e n t of Epidemiology and Medical Statistics of the University of London, and Mr. D. J. Newall, of the D e p a r t m e n t of Industrial Health of the University of D u r h a m , for their most helpful advice in relation to the statistical aspects. Thanks also to Mr. N. H a m m e r s l e y and Mr. D. Jewers for their part in presenting the tables, etc., and the D e p a r t m e n t of Photography of St. T b o m a s ' s Hospital for the photographic undertaking. Finally to the departments of Pathology of St. T h o m a s ' s Hospital and the Newcastle General Hospital for their helpful cooperation in undertaking blood-count investigations. BIBLIOGRAPHY BACQ, Z. M., and ALEXANDER,P. (I955), Fundamentals of Radiobiology. London : Butterworth. BsowN, W. M. COURT (I953), Brit. reed. ft., I, 8o2. - - - - and MAHLER, R. F. (1953, a), Science, 118, 27i. (1953, b), Proc. R. Soc. Med., 46, 245. (I954), J. Fac. Radiol. Lond., $, 2oo. CSONKITE, E, P. (I953) , Atomic Medicine, I79-218. Baltimore i Williams & Wilkins. ELLINOER, F. ( i 9 4 i ) , Biologic Fundamentals of Radiation
Therapy. New York : Elsevier. - - - - (i945), Radiology, 44, 241. ELLIS, F., and STOLL, B. A. (1952), J. Fac. Radiol. Lond., 3, 207. HOtlCHTON, L. E., WALKER,J. B., and JoNEs, D. E. (I954), Brit. me&ft., 2, I313. JENKINSON, E. L., and BROWN, W. H. (I944), Amer. ft. Roentgenol., $ I, 496. KOHN, H. I. (1951), Amer. ff. Physiol., 165, 43. LANCENDOSFF, H., KOCH, R., and SAUES, H. (I954), Strahlentherapie, 93, 37, 44, 38L LASSES, E. C., and STENSTSOM, K. W. (I954), Amer. ft. Roentgenol., 72, 474. LEBLOND, C. P., and SEGAL, G. (I949), 1bid., 62, 547. POSTER, E. (I952), Radiology, 58, 246. SELYE, H. (195o, a), Brit, me&ft., 2, 1383 . --(i95o, b), " T h e Physiology and Pathology of Exposure to Stress ", Acta Inc., Montreal, Supp. 1951, 1952. TABES, K. W. (I95I), Radiology, 57, 7o2. WEICHEST, l.J. (I942), Strahlentherapie, 71, 127.