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Pulmonary irradiation effects and their treatment with cortisone and acth
I2
JOURNAL PULMONARY
OF
THE
IRRADIATION WITH
FACULTY EFFECTS
CORTISONE
OF AND AND
RADIOLOGISTS THEIR
TREATMENT
ACTH
BY A. G. W. WHITFIELD, W. H. BOND, AND W. MELVILLE ARNOTT FROM THE DEPARTMENTS OF MEDICINE AND RADIOTHERAPY~ QUEEN ELIZABETH HOSPITALp UNIVERSITY OF BIRMINGHAM
THE fact that deep X-ray therapy may produce damage to lung tissue was first recognized by Groover, Christie, and Merritt (i922), who described cases of carcinoma of,the breast in which dry cough developed synchronously with skin reaction after irradiation. The chest radiographs, which had previously been normal, showed shadowing at or near the hilum which, over the course of three or four weeks, spread to involve most of the lung. Coincident with these radiological changes dyspnea developed. In one case serial radiographs showed that after reaching a maximum the lung changes regressed and assumed a more fibrotic character. In the same year Hines (1922) published details of two cases in which post-mortem examination of the lungs revealed fibrosis and decrease in alveolar size wtlich appeared to result from irradiation, but the presence of lung metastases confused the issue. However, a large number of authentic cases of radiation pneumonitis have since been recorded, most of which have followed radiotherapy for carcinoma of the breast, but in a few the primary lesion was a reticulosis, an (esophageal or bronchial carcinoma, or some other form of malignant disease (Wintz, 1923 ; Groover, Christie, and Merritt, 1923 ; Evans and Leucutia, 1925 ; Fike, 1932 ; Mclntosh, 1934 ; Downs, 1936 ; Schairer and Krombach, 1939 ; Mclntosh and Spitz, i939 ; Fried and Goldberg, 194o ; Warren and Spencer, 194o ; Engelstad, 194o ; Jacobsen, 194o ; Widmann, 1942 ; Leach, Farrow, Foote, and Wawro, 1942 ; Bergmann and Graham, 1951) . Two fatal cases due to the occupational inhalation of radio-active dust have been reported (Belt, 1931 ; T6nges and Kalbfleisch, i937) , and a third in a radium plant worker (Rajewsky, 1939). Kaplan and Bell (1938) found no lung changes in 7 cases of carcinoma of the breast treated with massive doses of deep X rays and radium, thus suggesting that the condition is a rarity, but McIntosh and Spitz (1939) found radiological evidence of radiation damage in 36 of 60 cases of breast cancer, though only i i had symptoms. Engelstad (194o) reported an incidence of 5 per cent in cases of carcinoma of the breast and 20 per cent in ~sophageal carcinomata treated by irradiation, while Widmanu (1942) found 62 of 273 and Leach and others (1942) 77 of 347 cases of breast cancer with lung changes following X-ray treatment. Warren and Spencer (i94o), in a series of 234 autopsies on patients who had had radiotherapy during life, found histological evidence of radiation damage to the lungs in 28. Mclntosh (1934) and Mclntosh and Spitz (1939) have suggested that age and arteriosclerosis predispose to the development of radiation damage to the lungs, while thinness and the absence of the amputated breast have also been thought to play a part. It will of course be realized that there ar e many possible fallacies in these suppositions and the autopsy studies of Warren and Spencer (194o) indicate that such factors are unimportant and the animal experiments of Engelstad (194o) and the work of Evans and Leucutia (1925) show that the quantity of radiation given is the dominant influence. Excellent reviews of the condition have been published by Evans and Leucutia (I925) , Groover, Christie, Merritt, and Coe (I927) , Desjardins (I932), Mclntosh and Spitz (i939) , Engelstad (i94o), Warren (i942), and Bergmann and Graham (1951). The clinical and radiological features are very c0nstanL Within two or three weeks of the conclusion of radiotherapy, and at the same time as skin reaction develops, a dry irritating cough appears, exercise tolerance diminishes, and the chest radiograph Shows shadowing spreading from the hilum. During subsequent weeks the cough becomes increasingly troublesome, dyspnoea limits activity more and more and may become evident
CORTISONE
AND
ACTH
IN
X-RAY
LUNG
DAMAGE
I3
at rest, and the radiological changes become more widespread and intense. After reaching a maximum the symptoms and X-ray abnormalities regress and often disappear within a year, but in the more severe cases permanent fibrotic changes are left. In milder cases there may be transient radiological changes without symptoms (Evans and Leucutia, 1925; Mclntosh, 1934; and McIntosh and Spitz, 1939). Pleural effusion sometimes occurs (Desjardins, 1932 ; Warren, 1942 ; Bergmann and Graham, i951 ) and spontaneous rib fracture has been reported (Fike, 1932 ; Fried and Goldberg, 194° ; Leach and others, 1942). The victims of pulmonary fibrosis, whatever its origin, are notoriously prone to lung infection, and many instances of death from pneumonia have been reported (McIntosh, 1934; McIntosh and Spitz, 1939 ; Jacobsen, 194° ; and Fried and Goldberg, I94O), while others have died from cot pulmonale (Fried and Goldberg, 194o ). In some death appears to have been solely due to the uncomplicated effects of X-radiation on the lungs (Evans and Leucutia, 1925 ; Belt, 1931 ; T6nges and Kalbfleisch, 1937; Rajewsky, 1939; Schairer and Krombach, 1939; Warren and Spencer, 194o ; Engelstad, I94o). Several writers have commented on the difficulty of differentiating metastases, and infiltration by reticuloses from radiation effects during life (Mclntosh and Spitz, 1939 ; Warren, i942), and many instances are on record where further radiotherapy has been given--in the belief that radiation changes were metastatic--with resultant increase in lung damage leading to death and an autopsy where no histological evidence of malignant disease could be found (Mclntosh, 1934; Warren and Spencer, 194o ; Fried and Goldberg, 194o). The complexities of this crucial problem may be increased by the simultaneous presence of metastases and radiation fibrosis in the lungs. The pathology of irradiation changes in the lung has been widely explored by animal experiment (Ludin and Werthemann, 193o ; Engelstad, i94o ; and Warren and Gates, I94O), and the morbid anatomical and histological features of numerous fatal human cases have been recorded (Evans and Leucutia, 1925; Groover and others, 1927; Mclntosh, 1934; McIntosh and Spitz, 1939; Warren and Spencer, 194o ; Fried and Goldberg, i94o), while Bergmann and Graham (1951) have described the findings in two cases of unilateral radiation fibrosis treated by pneumonectomy. The changes are of course largely dependent on the time that has elapsed between irradiation and death. Broadly speaking the pathological process is a sequence of cellular injury and death, inflammatory reaction and repair. In early cases Gedema and congestion have been the striking features, but when the condition is of long standing fibrosis has been extreme. The majority, however, have shown diminished alveolar space owing partly to cellular proliferation producing thickening of the alveolar walls and partly to the filling of the alveoli with coagulum, macrophages, and desquamated cells. The bronchi have shown increased mucus secretion, destruction, and later regeneration of the bronchial epithelium and peribronchial fibrosis. A marked increase in connective tissue has also been evident around blood-vessels and throughout the lung. The pleura has usually shown thickening, adhesions, and fibrosis. Occasionally a pleural effusion has been found. Warren and Spencer (i94o), Warren and Gates (194o), and Warren (i94z) refer to the presence of an alveolar membrane, but Farber and Wilson (1932 , a, b) have shown that this is prone to develop in any dyspnceic state and is in no way peculiar to radiation lung damage. The abnormal pulmonary physiology in radiation fibrosis has been investigated in 17 cases by Leach (1943). He found a diminished vital capacity, complemental air and maximum breathing capacity, an increased respiratory rate, ventilation, and ventilation equivalent, and a normal oxygen absorption. He suggested that a multiplicity of factors are responsible for these abnormalities ; pleural changes, mediastinal and diaphragmatic fibrosis, and fixation and fibrosis of stdn, subcutaneous tissues and intercostal and accessory muscles all playing some part, in addition to the changes in the bronchi and lung parenchyma. Similar changes in pulmonary physiology were found in two cases reported by Baldwin, Cournand, and Richards (1949).
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U p to t h e p r e s e n t t h e r e h a s b e e n n o satisfactory t r e a t m e n t for r a d i a t i o n p n e u m o n i t i s , t h o u g h m o d e r n r a d i o t h e r a p e u t i c t e c h n i q u e has g o n e far to r e d u c e l u n g d a m a g e b y t a n g e n t i a l i r r a d i a t i o n of t h e superficial s t r u c t u r e s , a n d o n l y i n t h e t r e a t m e n t of i n t r a t h o r a c i c disease is severe p n e u m o n i t i s likely to occur. B e r g m a n n a n d G r a h a m ( i 9 5 i ) p e r f o r m e d p n e u m o n e c t o m y i n t w o severe cases of u n i l a t e r a l disease, b u t o t h e r w i s e t h e r a p y has b e e n c o n f i n e d to t h e c o n t r o l of s u p e r a d d e d i n f e c t i o n w i t h antibiotics, t h e a d m i n i s t r a t i o n of o x y g e n w h e n dyspnGea is severe or cyanosis is p r e s e n t , a n d t h e t r e a t m e n t of p u l m o n a r y h e a r t failure w h e n it ensues. Boys a n d H a r r i s (1943) s h o w e d t h a t in r a b b i t s t h e a d m i n i s t r a t i o n of h e p a r i n d u r i n g r a d i o t h e r a p y a p p e a r e d to r e d u c e p u l m o n a r y r a d i a t i o n effects, b u t s u c h p r o p h y l a c t i c m e a s u r e s are clearly i m p r a c t i c a b l e i n r o u t i n e h u m a n r a d i o t h e r a p e u t i c practice. W e h a v e r e c e n t l y h a d t h e o p p o r t u n i t y of t r e a t i n g f o u r cases of r a d i a t i o n p n e u m o n i t i s w i t h c o r t i s o n e a n d A C T H , a n d it was t h o u g h t t h a t it w o u l d b e of s o m e v a l u e to r e c o r d t h e results of such therapy.
CASE REPORTS Case I .--A male farm worker, aged zI, was awaiting admission to hospital for tonsillectomy, which had been
advised on account of recurrent attacks of tonsillitis, when he developed swollen glands on the left side of his neck. This was thought to be due to tonsiliar sepsis, but after his tonsils had been removed the glands increased in size. Six months after they had first appeared the glands were excmed and the histological report was Table I.--Case I.
RESPIRATORY FUNCTION
PREDICTED
OBSERVED DEC. 22, 1951. BEFORE CORTISONE THERAPY
OBSERVED JAN. 23, I952AFTER CORTISONE THERAPY
Total capacity
litres 5'53
litres 2"16
litres 2"47
Vital capacity
4'42
I'Z6
1"47
Inspiratory capacity
0"58
o"71
Expiratory reserve volume
o'68
o'76
1"58
1"76
I-II
0'90
I'OO
118"4 (per rain.)
63'5 (per rain.)
i i o (per rain.)
~ in.
2~ in.
Functional residual capacity Residual volume Maximum breathing capacity ~hest expansion
' lymphosarcoma '. Within six weeks the lymphadenopathy recurred in the left supraclavicular fossa and he was therefore admitted to the Queen Elizabeth Hospital, Birmingham, on July 30, 1951, for radiotherapy. At this time he was afebrile, no glandular enlargement was present elsewhere, the liver and spleen were impalpable, the chest radiograph was normal, and the peripheral blood, sternal marrow, and liver function tests showed no abnormality. Re-examination of the slides from the glands previously excised suggested a diagnosis of Hodgkin's disease rather than lymphosarcoma. He was given wide-field cervico-thoracic baths from the base of the skull to the diaphragm. After z45o r anteriorly and posteriorly he developed some oral mucosal reaction and dry desquamation of the skin of the chest wall, and further treatment was therefore confined to the left cervical gland fields and supraclavicular fossa, where over five days IOOO r was given to a 20 × io cm. field. He left hospital on Sept. i i , 1951 , but within a week or so he developed dry cough and exertional dYspnma, which increased and necessitated his re-admission three months later. At this time he was afebrile, no enlarged lymph-glands were present, the spleen and liver were impalpable, and his blood-count was normal.
CORTISONE
AND
ACTH
IN
X-RAY
LUNG
DAMAGE
I5
His chest was clear on physical examination, b u t expansion was limited to ~ in. and there was a very obvious ' catch ' whenever he attempted to take a full inspiration. His chest radiograph (Fig. I i A) showed fan-shaped shadowing t h r o u g h o u t both lung fields and marked ' tenting ' of the diaphragm and pericardium on the left side. Respiratory function tests (Table I) showed gross lung volume changes of the type seen in ' p u l m o n a r y fibrosis' and a m u c h reduced m a x i m u m breathing capacity. T h e arterial blood showed a normal oxygen saturation and carbon dioxide content at rest, b u t on exercise definite oxygen desaturation was evident, the
A
B
Fig. a.--Case I, A, After radiotherapy. Fan-shaped shadowing throughout both lung fields. Diaphragmatic and pericardial tenting on the left side_ B, After cortisone therapy. Diminution in lung shadowing and in diaphragmatic and pericardial tenting on the left side. C, Three months later. Increase in lung shadowing. Right pneumothorax and dinphragmatic tenting on right side.
carbon dioxide content remaining normal. Cardiac catheterization showed a normal cardiac output, but the p u l m o n a r y artery pressure rose to an abnormally high level on exercise (Table 1I). T h e electrocardiogram was normal. At this time supplies of cortisone and A C T I t were very limited. H e was given 1"5 g. cortisone intramuscularly over a period of thirteen days and thereafter a very small maintenance dose of 25 rag. was given daily for two weeks. At the end of this course of treatment there was a marked i m p r o v e m e n t in his exercise tolerance and reduction of cough, and his chest expanC sion was 23 in., while his respiratory function tests (Table I) showed some i m p r o v e m e n t and his arterial blood less desaturation on exercise (Table II). His chest radiograph (Fig. I i I~) showed appreciable clearing of the lung fields, and diaphragmatic and pericardial ' tenting ' was less evident. H e was discharged to a convalescent home on Feb. i, 1952, but had to be readmitted two weeks later on account of a respiratory tract infection which had p r o d u c e d considerable aggravation of his cough and dyspneea and profuse p u r u l e n t s p u t u m . A leucocytosis of 19,7oo was present but there was no anmmia, lymphadenopathy, or enlargement of the liver or spleen. He was treated with systemic penicillin and discharged to his home symptom-free apart from some exertional dyspnma on M a r c h 22. Subsequently his d y s p n e a became progressively m o r e disabling, and chest radiographs on April 25 (Fig. i i C) showed tenting
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JOURNAL
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of the right diaphragm and a right p n e u m o t h o r a x in addition to shadowing t h r o u g h o u t bbth lung fields. N o anmmia, lymphadenopathy, splenomegaly, or hepatomegaly developed, and he died on A u g . 4 , f r o m respiratory failure. N o autopsy was obtained. Table I I . - - C a s e I. BEFORE CORTISONE THERAPY (DEC. 22, 1951)
AFTER CORTISONE THERAPY (JAN. 30, 1952)
Arterial oxygen saturation : At rest After exercise
92"7 per cent 83. 3 per cent
92"3 per cent 87" 5 per cent
Arterial carbon dioxide c o n t e n t : At r e s t After exercise
46'35 per cent 44"55 per cent
---
Cardiac o u t p u t : Supine Sitting
4"8I 1. 5-4 ° 1.
P u l m o n a r y artery pressure : At rest After exercise
m
36/16 m m . H g 46/7 m m . H g
m
RADIOTHERAPEUTIC DETAILS.--Simple anterlor and posterior thoraco-cervical baths from base of skull to xiphisternum, with bolus in axillm and cervical region to give flat treatment planes. Separation between planes i 9 . o c m . ; kv. 25 ° ; H . V . L . i . o m m . Cu ; F.S.D. i o o c m . Incident dosez45o r in twenty treatments over twenty eight days. M a x i m u m skin r e a c t i o n - - d r y desquamation ; lowest platelet count--I3O,OOO per c.mm. Case 2 . - - A female secretary first attended the United Birmingham Hospitals in 1942 at the age of 18 complaining of a painless swelling on the right side of her neck which had been present for six weeks. It was Table I l L - - C a s e 2. BEFORE ACTH
THERAPY
RESPIRATORY FUNCTION AFTER FIRST COURSE
AFTER SECOND COURSE
255 Mo. ACTH
25o rio. ACTH
Total capacity
Iitres " 3"17
litres 3"55
litres 3-61
Vital capacity
2"o5
2"32
2'63
Inspiratory capacity
x "31
i "53
i "77
Expiratory reserve volume
0"74
0"79
0.86
Functional residual capacity ,
1"86
2'o2
1"84
Residual volume
1.12
1"13
0"98
47 (per min.)
7I (per min.)
119 (per min.)
1~ in.
I a in.
2~ in.
M a x i m u m breathing capacity Chest expansion
t h o u g h t at first to be a tuberculous adenitis, but s u b s e q u e n t biopsy revealed the typical pattern of l y m p h adenoma and she was given 3ooo r to the right side of her neck. She remained well until four years later, w h e n enlarged glands appeared in the left supraclavicular fossa. A further 3ooo r were given to this area and there was no further evidence of disease for five years, w h e n another gland appeared in the right supraclavicular fossa and the chest radiograph showed a small glandular mass on the right side of the mediastinum (Fig. 12 A).
CORTISONE
AND
ACTH
She was given f u r t h e r deep X - r a d i a t i o n to t h e right and posteriorly to t h e m e d i a s t i n u m over a period developed and b e c a m e m u c h m o r e m a r k e d following radiotherapy f u r t h e r hospitalization was necessary.
IN
X-RAY
LUNG
DAMAGE
I7
supraclavicular fossa a n d 3000 r were also given anteriorly of fourteen days. O n e m o n t h later exertional dyspnoea a cold, so t h a t four a n d a half m o n t h s after h e r mediastinal At this time there was no l y m p h a d e n o p a t h y , t h e spleen
A
B
Fig. I2.--Case 2. A, Before mediastinal radiotherapy. Small glandular mass present on right side of mediastinum. B, After mediastinal radiotherapy. Lung shadowing coi3fined to area of irradiation. C, After ACTH therapy. Little change in lung shadowing. :and liver were impalpable, and t h e b l o o d - c o u n t and liver f u n c t i o n tests were normal. T h e h e a r t a n d lungs were n o r m a l on clinical e x a m i n a t i o n a n d t h e electrocardiogram was physiological, b u t c h e s t expansion was reduced to 12 in- C h e s t radiographs (Fig. i z B) s h o w e d s h a d o w i n g confined to t h e precise area of irradiation as indicated by skin changes. L u n g v o l u m e and m a x i m u m b r e a t h i n g capacity estimations (Table 111) showed .changes of t h e type seen in m o d e r a t e p u l m o n a r y fibrosis. She was given A C T H by slow i n t r a v e n o u s drip .over two periods, t h e first of n i n e days (255 rag. total •dosage) a n d t h e second of eight days (250 rag. total .dosage.) H e r exercise tolerance r e t u r n e d to normal, h e r ,chest expansion increased to 2~ in. and h e r respiratory f u n c t i o n tests s h o w e d m a r k e d i m p r o v e m e n t , particularly t h e m a x i m u m b r e a t h i n g capacity, b u t chest radiographs :showed little change (Fig. IZ C). Follow-up has s h o w n s o m e slight r e t u r n of exertional dyspncea, b u t she C h a s been working a n d leading a n o r m a l life. T h e chest expansion is 2½ in., t h e chest radiograph s h o w s no change, a n d no l y m p h a d e n o p a t h y , splenomegaly, or h e p a t o m e g a l y has developed. RADIOTHERAPEUTIC D~TAILs.--Anterior a n d posterior opposed I5 × I5 era. fields at 17"o cm. separation ; kv. 2 3 0 ; H . V . L . 2"4 m m . C u ; F . S . D . 5o'o cm. I n c i d e n t dose 3000 r in io t r e a t m e n t s over thirteen .days.
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Case 3 . - - A housewife, aged 38, was admitted to the Queen Elizabeth Hospital, Birmingham, on June 3o~ x952, with a firm mobile gland in the right supraclavicular fossa and another m the right axilla. T h e r e was irregular pyrexia up to Iox ° and chest radiographs (Fig. I3 A) showed a mass projecting from the right superior
Fig. z3.--Case 3- A, Before radiotherapy, showing right superior mediastinal mass. B, After radiotherapy, showing marked reduction in size of right superior mediastinal mass and fan-shaped shadowing throughout both lung fields. C, After ACTH therapy. The lung shadowing l~as assumed a more fibrotic appearance and marked tenting of the diaphragm and pericardium has developed. mediastinum. T h e hver and spleen were impalpable and liver function tests were normal apart f r o m some hyperglobulin~emia (3'8 g. per cent). T h e blood-count showed anaemia, with 3-zz million red cells, 43 per cent hmmoglobin, and i i , i o o white cells, 82 per cent o f which were polymorphs. Bronchoscopy revealed s o m e compression of the right main bronchus and biopsy of the right supraclavicular gland Showed the histological appearances of Hodgkin's disease. She was given blood transfusions and intravenous iron together with eervico-thoracic deep X - r a y baths, a total of 2750 r being given anteriorly and posteriorly over twenty-eight days. H e r pyrexia rapidly subsided and w h e n she left hospital on Aug. 9, she was subjectively well, no glands were palpable, and her blood-count showed 4"81 million red cells and 84 per cent hmmoglobin. Six weeks later she had to be re-admitted because for fourteen days she had been increasingly dyspnceic on exertion and felt that there was some obstruction in her chest which prevented her f r o m taking a full inspiration. T h e r e C was no cough or s p u t u m and since the conclusion of her course of radiotherapy she had p u t on 2 st. in weight. She was afebrile, no l y m p h a d e n o p a t h y was evident, and the liver and spleen remained impalpable while her blood-count showed 5-41 million red cells and lO8 per cent hmmoglobin. She was dyspnceic and cyanosed at rest, b u t the chest was clear on physical examination t h o u g h there was a marked ' catch ' whenever she
CORTISONE
AND
ACTH
IN
X-RAY
LUNG
DAMAGE
19
attempted to take a full breath, a n d chest e x p a n s i o n was limited to 2 in. C h e s t radiographs (Fig. I3 B) s h o w e d that the superior mediastinal m a s s was r e d u c e d in size b u t f a n - s h a p e d m o t t l i n g h a d developed in b o t h lung fields. T h e d i a p h r a g m m o v e d poorly. T h e h e a r t was clinically n o r m a l and t h e electrocardiogram physiological. T h e m a x i m u m b r e a t h i n g capacity was only 36"6 litres p e r m i n u t e a n d the vital capacity z'o5 litres. It was u n c e r t a i n w h e t h e r h e r l u n g condition was a radiation effect or d u e to l y m p h a d e n o m a t o u s infiltration, b u t t h e f o r m e r was t h o u g h t m o r e likely so she was given 2o rag. A C T H daily by slow intravenous drip for ten days, at t h e conclusion of w h i c h t h e r e was no material change in h e r clinical state b u t h e r m a x i m u m breathing capacity h a d fallen to 32 litres p e r m i n u t e a n d h e r vital capacity to 1} litres, while chest radiographs (Fig. 13 C) showed that t h e l u n g s h a d o w i n g h a d a s s u m e d a m o r e fibrotic appearance and m a r k e d diaphragmatic a n d pericardial t e n t i n g h a d developed. I n view of the lack of response to A C T H t h e r a p y a n d our uncertainty regarding t h e precise n a t u r e of t h e changes in h e r lungs, s h e was given a course of triethylene melamine by m o u t h . H e r condition did n o t alter except p e r h a p s for s o m e increase in h e r d y s p n e a and eyanosis, a n d on Nov. I she was discharged to h e r h o m e , w h e r e s h e died four weeks later f r o m respiratory failure, there h a v i n g been no f u r t h e r evidence of extrathoracic t t o d g k i n ' s disease; N o a u t o p s y was obtained. RADIOTHERAPEUTIC DETAILS.--Technique a n d factors as for Case I . Separation b e t w e e n planes 17'o cm. Incident dose 275o r in t w e n t y - o n e t r e a t m e n t s over t w e n t y - n i n e days. M a x i m u m skin r e a c t i o n - - f i r s t degree erythema ; lowest platelet count--IOO,OOO p e r c . m m .
Case 4 . - - A male e n g i n e e r i n g apprentice, aged i8, was a d m i t t e d t o t h e Q u e e n Elizabeth Hospital, B i r m i n g h a m , on J u l y 19, I952, with a t w o - a n d - a - h a l f - y e a r s ' history o f progressive painless e n l a r g e m e n t of the l y m p h - n o d e s on t h e left side of his neck. T h e r e were no other s y m p t o m s a n d physical examination was Table I V . - - C a s e 4.
RESPIRATORY FUNCTION
FIVE WEEKS AFTER RADIOTHERAPY
AFTER FIRST COWRSE OF 665 MO. A C T H
FOUR WEEKS LATER
AFTER SECOND COURSE OF 2z5 Mo. ACTH
litres
litres
litres
litres
Total capacity
3"39
3"63
3-37
3"98
Vital capacity
1 '30
3'02
2'32
2"88
Inspiratory capacity
0"92
I'59
0"99
I'66
Expiratory reserve v o l u m e
0.38
1 '43
I'33
I "22
Functional residual capacity
2-47
•o 4
2,-38
2"32
Residual v o l u m e
2-09
o'6I
I 'o5
1"1o
71"4 (per rain.)
161.o 4 (per min.)
I43"7 (per m i n . )
I85-46 (per m i n . )
I} in.
3} in.
3} in.
3} in.
M a x i m u m b r e a t h i n g capacity Chest expansion
otherwise negative. H i s chest radiograph was n o r m a l a n d his b l o o d - c o u n t s h o w e d 4"74 million red cells, 94 p e r cent haemoglobin, 9,600 w h i t e ceils, a n d a n o r m a l differential count. Cervical l y m p h - g l a n d biopsy showed the histological appearances of l y m p h o s a r c o m a . Over a period of four a n d a half weeks he was given 291o r anteriorly a n d posteriorly f r o m t h e c h i n to the d i a p h r a g m . T h r e e weeks after t h e conclusion of his course of radiotherapy he d e v e l o p e d a dry c o u g h and increasing exertional dyspnma, and w h e n r e - a d m i t t e d on this account a fortnight later he was dyspnceic at rest and cyanose d on t h e slightest exertion. G e t t i n g o u t of bed and walking across t h e r o o m was t h e m a x i m u m possible physical effort a n d p r o d u c e d a state of respiratory distress d e m a n d i n g oxygen. T h o u g h his c h e s t was clear on p h y s i c a l examination, chest expansion was limited to i } in_, a n d t h e patient's complaint t h a t " his chest stuck w h e n he took a full b r e a t h " was a graphic description of his a t t e m p t s at m a x i m a l inspiration. Post-radiation skin effects Were a p p a r e n t a n d t h e p u l m o n a r y second s o u n d was accentuated, b u t there were no other physical abnormalities, no l y m p h a d e n o p a t h y was present, t h e spleen a n d liver were impalpable, and t h e b l o o d - c o u n t r e m a i n e d normal. T h e chest radiograph s h o w e d f a n - s h a p e d s h a d o w i n g t h r o u g h o u t b o t h l u n g fields and m a r k e d t e n t i n g of t h e left d i a p h r a g m (Fig. 14 A).
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Respiratory f u n c t i o n tests (Table IV) showed a m a r k e d reduction in t h e m a x i m u m b r e a t h i n g capacity a n d vital capacity a n d a h i g h residual volume. H e was given 665 m g . A C T H b y slow intravenous drip over three periods totalling twenty-six days, a n d at t h e conclusion of t h e r a p y he could go u p four flights of stairs w i t h o u t dyspncea, his c o u g h h a d disappeared,
A
g
Fig. I4.--Case 4- A, Chest radiographs 5 weeks after radiotherapy, showing shadowing throughout both lung fields and tenting of the left diaphragm. B, Chest radiograph after 665 rag. of ACTH by slow intravenous drip over 26 days, showing marked clearing of lung fields. C, Chest radiograph after a further z25 rag. ACTH by slow intravenous drip over 9 days, showing further improvement. his chest expansion was 3~ in., his m a x i m u m b r e a t h i n g capacity was n o r m a l (Table IV), while his l u n g v o l u m e (Table IV) and his chest radiograph (Fig. 14 B) s h o w e d m a r k e d i m p r o v e m e n t . W i t h i n a few days of d i s c h a r g e f r o m hospital he noticed a r e t u r n of his dry c o u g h a n d a reduction in his exercise tolerance, c o u g h rather t h a n dyspneea b e i n g t h e factor limiting exertion. H e was r e - a d m i t t e d four weeks later. N o l y m p h a d e n o p a t h y , hepatomegaly, or s p l e n o m e g a l y was apparent, t h e bloodc o u n t was normal, chest expansion was 31 in., t h e chest radiograph was u n c h a n g e d , and respiratory f u n c tion tests (Table IV) s h o w e d only slight deterioration. H e was given a f u r t h e r 225 mg. A C T H by slow intravenous drip over n i n e days, at the conclusion of w h i c h •C exercise tolerance was n o r m a l and t h e chest radiograph showed f u r t h e r clearing (Fig. 14 C). RADIOTHERAPEUTIC D E T A I L s . - - T e e h n i q u e as for Case i. Separation b e t w e e n planes 18"o cm. ; kv. 18o ; H . V . L . o'5 ram. C u ; F . S . D . 80"0 cm. I n c i d e n t dose z9oo r in t w e n t y - t w o t r e a t m e n t s over thirty-two days. L o w e s t platelet c o u n t - - 9 o , o o o per c . m m .
DISCUSSION T h e t e n d e n c y f o r p u l m o n a r y r a d i a t i o n c h a n g e s to r e g r e s s s p o n t a n e o u s l y w i t h i n 6 - 2 4 m o n t h s has been pointed out above, but the improvement that occurred in Cases 2 and 4 during ACTH therapy seemed quicker and greater than could have been expected without treatment. However,
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normality was not restored in either case, both patients still having a subnormal exercise tolerance and radiological evidence of fibrosis at the conclusion of therapy and during subsequent observation. It appears therefore that A C T H may hasten the regression of pulmonary radiation damage. The dosage given in each of these two cases was large and the period of therapy long. Both were treated by slow intravenous drip, Case 4 being given 890 mg. over thirty-five days and Case 2 505 mg. over seventeen days. The failure of A C T H therapy in Case 3 and the relatively slight and unsustained improvement which resulted from cortisone in Case i may have been due to dosage being too small and too short, but it is of course possible that the degree of radiation damage was more severe in these patients. Clinically, however, Case 4 appeared to be the most severe of the group studied. The difficulty of differentiating pulmonary radiation effects from secondary malignant infiltration and lung involvement by reticulosis has been referred to above. Case 3 exemplifies the difficulties and complexities of management in such cases and it is a problem with which workers in this field will not infrequently be faced. It might very reasonably be argued that if the lung changes are metastatic or due to involvement by a reticulosis, no treatment will avert a rapidly fatal issue, while if they result from irradiation they may be reduced by A C T H therapy so that such treatment cannot be in any way harmful. This attitude is further supported by the experience of Pearson, Eliel, Rawson, Dobriner, and Rhoads (1949) , and Spies, Lopez, Milanes, Toca, Reboredo, and Aramburu (195o), who found that A C T H therapy produced some improvement in reticuloses, and Spies, Stone, Lopez, Milanes, Toca, and Reboredo (195o), who noted a similar response in three patients with inoperable carcinoma. Nevertheless it is in every way desirable to differentiate radiation effects from malignant disease, as far as possible, as the latter diagnosis, if incorrect, may lead to further radiotherapy which by increasing lung damage may put the patient's life in unnecessary hazard. Sheinmel, Roswit, and Lawrence (195o) and Walpaw, Higley, and Hauser (1944) have described exactly similar radiological changes in the lung parenchyma in Hodgkin's disease as are seen in radiation pneumonitis, and the capacity of lymphangitic carcinomatous infiltration to produce such changes is well known. The main radiological differentiating factor is that in radiation pneumonitis diaphragmatic and pericardiN tenting is soon apparent, while it is rarely seen in malignant infiltration. More important, however, is the history of the case. Dyspnoea, cough, and radiological changes appearing within a few weeks of irradiation of the thorax are much more likely to be due to irradiation than they are to result from malignant spread, especially if the chest radiograph Was normal before radiation was commenced. A further diagnostic feature is the ' doorstop ' obstruction to full inspiration which was a feature of each of our four cases and is a phenomenon which we have observed only in pulmonary fibrosis. In retrospect, it seems clear that Case 3 was suffering from pulmonary radiation damage and that A C T H therapy in higher dosage and over a longer period might have prolonged life. SUMMARY i. The literature regarding pulmonary radiatio n damage is briefly reviewed and the clinical and radiological pattern of the condition is described. 2. Four cases are recorded in which treatment with A C T H or cortisone was given. 3- In two cases, remarkable improvement resulted, but in the other two therapy may have been inadequate and the patients died from respiratory failure. We are indebted to Drs. K. W. Donald, O. L. ,Wade, and D. G. B. Richards for help in the investigation of Case I ; t o Mr. T. F. Dee for reproduction of the radiographs and clinical photography; and to Imperial Chemical Industries Ltd., and the Endowment Fund of the United Birmingham Hospital, for financial assistance in this investigation.
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REFERENCES BALDWIN, E. de F., COURNAND, A., and RICHARDS, D. W. (I949), Medicine, 28, i. BELT, T. H. (I93I), Frankfurt. Z. Path., 42, 17o. BERGMANN, M., and GRAHAM, E. A. ( I 9 5 I ) , J . thorac. SurE., 22, 549. BoYs, F., and HARRIS, I. D. (I943), Amer, J. Roentgenol., 5o, I. DESJARDINS, A. U. (I932), Ibid., 28, 699. DOWNS, E. E. (I936), Ibid., 36, 61. ENGELSTAD, R. B. (194o), Ibid., 43, 676. EVANS, W. A., and LEUCUTIA, T. (I925), Ibid_, I3, 203FAREER, S., and WILSON, J. L. (i932 , a), Arch. Path. (Lab. Med.), 14, 437. (1932, b) Ibid., I4, 450. FIKE, R. H. (1932), Amer. J. Roentgenol., z7, 509 . FRIED, J. R., and GOLDBERG, H. (194o), Ibid., 43, 877. GROOVER, T. A., CHRISTIE, A. C_, and MEIH~ITT, E. A. (I922), Sth. reed. J., Nashville, I5, 44 o. (1923), Amer. J. Roentgenol., to, 471. and CoL, F. O. (1927), Sth. reed. J., Nashville, 2o, 153. HINES, L. E. (1922), J. Amer. reed. Ass., 79, 7zo. JACOBSEN, V. C. (194o), Amer. J. Roentgenol., 44, 235. KAPLAN, I. I., and BELL, D. (1938), Ibid_, 39, 387 • LEACH, J. E. (1943), Ibid., 5o, 772- - - - FARROW, J. H., FOOTE, F. W., and WAWRO, N. W. (1942), Ibid., 4% 74o. LUDIN, M., and WERTHEMANN, A. (193o), Strahlentherapie, 38, 684. MCINTOSH, H. C. (1934), Radiology, 23, 558- - and SPITZ, S. (I939), Amer. J. Roentgenol_, 41, 605. PEARSON, O. H., ELIEL, J. P-, RAWSON, R. W., DOBRINER, K., and RHOADS, C. P. (1949), Cancer, N. Y., 2, 943RAJEWSKY, B. (I939), Radiology., 32, 57. SCHAIREtt, E., and K~OMBACH, E. (I939), Strahlentherapie, 64, 267. SHEINMEL, A., ROSWlT, B., and LAWRENCE, L. R. (I95O), Radiology, 54, 165. SPIES, T. D., LoPEz, G. G., MILANES, F., TOCA, R. L., REBOREDO, A., and ARAMBURV,M. (195o), Sth. reed. J., Nashville, 43, 497. - - STONE, R. E., LOPEZ, G. G., MILANES, F., TOCA, R. L., and REBOREDO, A. (195o), Lancet, 2, 241. T6NGES, E., and KALEFLEISCH, H. H. (I937), Frankfurt. Z. Path., 5o, IOO. WALPAW, S. E., HmLEY, C. S., and HAUSER, H. (I944), Amer. J. Roentgenol., 52, 374. WARREN, S. (1942), Arch. Path. (Lab. Med.), 34, 917 . - - and GATES, O. (I940), Ibid., 3o, 44 o- - and SPENCER, J. (194o), Amer. J. Roentgenol., 43, 682. WIDMANN, B: P. (I942), Ibid., 47, 24. WINTZ, H. (1923), Ibid., IO, 14o. -
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BY A. G. W. WHITFIELD, W. H. BOND, AND W. MELVILLE ARNOTT FROM THE DEPARTMENTS OF MEDICINE AND RADIOTHERAPY~ QUEEN ELIZABETH HOSPITALp UNIVERSITY OF BIRMINGHAM
THE fact that deep X-ray therapy may produce damage to lung tissue was first recognized by Groover, Christie, and Merritt (i922), who described cases of carcinoma of,the breast in which dry cough developed synchronously with skin reaction after irradiation. The chest radiographs, which had previously been normal, showed shadowing at or near the hilum which, over the course of three or four weeks, spread to involve most of the lung. Coincident with these radiological changes dyspnea developed. In one case serial radiographs showed that after reaching a maximum the lung changes regressed and assumed a more fibrotic character. In the same year Hines (1922) published details of two cases in which post-mortem examination of the lungs revealed fibrosis and decrease in alveolar size wtlich appeared to result from irradiation, but the presence of lung metastases confused the issue. However, a large number of authentic cases of radiation pneumonitis have since been recorded, most of which have followed radiotherapy for carcinoma of the breast, but in a few the primary lesion was a reticulosis, an (esophageal or bronchial carcinoma, or some other form of malignant disease (Wintz, 1923 ; Groover, Christie, and Merritt, 1923 ; Evans and Leucutia, 1925 ; Fike, 1932 ; Mclntosh, 1934 ; Downs, 1936 ; Schairer and Krombach, 1939 ; Mclntosh and Spitz, i939 ; Fried and Goldberg, 194o ; Warren and Spencer, 194o ; Engelstad, 194o ; Jacobsen, 194o ; Widmann, 1942 ; Leach, Farrow, Foote, and Wawro, 1942 ; Bergmann and Graham, 1951) . Two fatal cases due to the occupational inhalation of radio-active dust have been reported (Belt, 1931 ; T6nges and Kalbfleisch, i937) , and a third in a radium plant worker (Rajewsky, 1939). Kaplan and Bell (1938) found no lung changes in 7 cases of carcinoma of the breast treated with massive doses of deep X rays and radium, thus suggesting that the condition is a rarity, but McIntosh and Spitz (1939) found radiological evidence of radiation damage in 36 of 60 cases of breast cancer, though only i i had symptoms. Engelstad (194o) reported an incidence of 5 per cent in cases of carcinoma of the breast and 20 per cent in ~sophageal carcinomata treated by irradiation, while Widmanu (1942) found 62 of 273 and Leach and others (1942) 77 of 347 cases of breast cancer with lung changes following X-ray treatment. Warren and Spencer (i94o), in a series of 234 autopsies on patients who had had radiotherapy during life, found histological evidence of radiation damage to the lungs in 28. Mclntosh (1934) and Mclntosh and Spitz (1939) have suggested that age and arteriosclerosis predispose to the development of radiation damage to the lungs, while thinness and the absence of the amputated breast have also been thought to play a part. It will of course be realized that there ar e many possible fallacies in these suppositions and the autopsy studies of Warren and Spencer (194o) indicate that such factors are unimportant and the animal experiments of Engelstad (194o) and the work of Evans and Leucutia (1925) show that the quantity of radiation given is the dominant influence. Excellent reviews of the condition have been published by Evans and Leucutia (I925) , Groover, Christie, Merritt, and Coe (I927) , Desjardins (I932), Mclntosh and Spitz (i939) , Engelstad (i94o), Warren (i942), and Bergmann and Graham (1951). The clinical and radiological features are very c0nstanL Within two or three weeks of the conclusion of radiotherapy, and at the same time as skin reaction develops, a dry irritating cough appears, exercise tolerance diminishes, and the chest radiograph Shows shadowing spreading from the hilum. During subsequent weeks the cough becomes increasingly troublesome, dyspnoea limits activity more and more and may become evident
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at rest, and the radiological changes become more widespread and intense. After reaching a maximum the symptoms and X-ray abnormalities regress and often disappear within a year, but in the more severe cases permanent fibrotic changes are left. In milder cases there may be transient radiological changes without symptoms (Evans and Leucutia, 1925; Mclntosh, 1934; and McIntosh and Spitz, 1939). Pleural effusion sometimes occurs (Desjardins, 1932 ; Warren, 1942 ; Bergmann and Graham, i951 ) and spontaneous rib fracture has been reported (Fike, 1932 ; Fried and Goldberg, 194° ; Leach and others, 1942). The victims of pulmonary fibrosis, whatever its origin, are notoriously prone to lung infection, and many instances of death from pneumonia have been reported (McIntosh, 1934; McIntosh and Spitz, 1939 ; Jacobsen, 194° ; and Fried and Goldberg, I94O), while others have died from cot pulmonale (Fried and Goldberg, 194o ). In some death appears to have been solely due to the uncomplicated effects of X-radiation on the lungs (Evans and Leucutia, 1925 ; Belt, 1931 ; T6nges and Kalbfleisch, 1937; Rajewsky, 1939; Schairer and Krombach, 1939; Warren and Spencer, 194o ; Engelstad, I94o). Several writers have commented on the difficulty of differentiating metastases, and infiltration by reticuloses from radiation effects during life (Mclntosh and Spitz, 1939 ; Warren, i942), and many instances are on record where further radiotherapy has been given--in the belief that radiation changes were metastatic--with resultant increase in lung damage leading to death and an autopsy where no histological evidence of malignant disease could be found (Mclntosh, 1934; Warren and Spencer, 194o ; Fried and Goldberg, 194o). The complexities of this crucial problem may be increased by the simultaneous presence of metastases and radiation fibrosis in the lungs. The pathology of irradiation changes in the lung has been widely explored by animal experiment (Ludin and Werthemann, 193o ; Engelstad, i94o ; and Warren and Gates, I94O), and the morbid anatomical and histological features of numerous fatal human cases have been recorded (Evans and Leucutia, 1925; Groover and others, 1927; Mclntosh, 1934; McIntosh and Spitz, 1939; Warren and Spencer, 194o ; Fried and Goldberg, i94o), while Bergmann and Graham (1951) have described the findings in two cases of unilateral radiation fibrosis treated by pneumonectomy. The changes are of course largely dependent on the time that has elapsed between irradiation and death. Broadly speaking the pathological process is a sequence of cellular injury and death, inflammatory reaction and repair. In early cases Gedema and congestion have been the striking features, but when the condition is of long standing fibrosis has been extreme. The majority, however, have shown diminished alveolar space owing partly to cellular proliferation producing thickening of the alveolar walls and partly to the filling of the alveoli with coagulum, macrophages, and desquamated cells. The bronchi have shown increased mucus secretion, destruction, and later regeneration of the bronchial epithelium and peribronchial fibrosis. A marked increase in connective tissue has also been evident around blood-vessels and throughout the lung. The pleura has usually shown thickening, adhesions, and fibrosis. Occasionally a pleural effusion has been found. Warren and Spencer (i94o), Warren and Gates (194o), and Warren (i94z) refer to the presence of an alveolar membrane, but Farber and Wilson (1932 , a, b) have shown that this is prone to develop in any dyspnceic state and is in no way peculiar to radiation lung damage. The abnormal pulmonary physiology in radiation fibrosis has been investigated in 17 cases by Leach (1943). He found a diminished vital capacity, complemental air and maximum breathing capacity, an increased respiratory rate, ventilation, and ventilation equivalent, and a normal oxygen absorption. He suggested that a multiplicity of factors are responsible for these abnormalities ; pleural changes, mediastinal and diaphragmatic fibrosis, and fixation and fibrosis of stdn, subcutaneous tissues and intercostal and accessory muscles all playing some part, in addition to the changes in the bronchi and lung parenchyma. Similar changes in pulmonary physiology were found in two cases reported by Baldwin, Cournand, and Richards (1949).
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U p to t h e p r e s e n t t h e r e h a s b e e n n o satisfactory t r e a t m e n t for r a d i a t i o n p n e u m o n i t i s , t h o u g h m o d e r n r a d i o t h e r a p e u t i c t e c h n i q u e has g o n e far to r e d u c e l u n g d a m a g e b y t a n g e n t i a l i r r a d i a t i o n of t h e superficial s t r u c t u r e s , a n d o n l y i n t h e t r e a t m e n t of i n t r a t h o r a c i c disease is severe p n e u m o n i t i s likely to occur. B e r g m a n n a n d G r a h a m ( i 9 5 i ) p e r f o r m e d p n e u m o n e c t o m y i n t w o severe cases of u n i l a t e r a l disease, b u t o t h e r w i s e t h e r a p y has b e e n c o n f i n e d to t h e c o n t r o l of s u p e r a d d e d i n f e c t i o n w i t h antibiotics, t h e a d m i n i s t r a t i o n of o x y g e n w h e n dyspnGea is severe or cyanosis is p r e s e n t , a n d t h e t r e a t m e n t of p u l m o n a r y h e a r t failure w h e n it ensues. Boys a n d H a r r i s (1943) s h o w e d t h a t in r a b b i t s t h e a d m i n i s t r a t i o n of h e p a r i n d u r i n g r a d i o t h e r a p y a p p e a r e d to r e d u c e p u l m o n a r y r a d i a t i o n effects, b u t s u c h p r o p h y l a c t i c m e a s u r e s are clearly i m p r a c t i c a b l e i n r o u t i n e h u m a n r a d i o t h e r a p e u t i c practice. W e h a v e r e c e n t l y h a d t h e o p p o r t u n i t y of t r e a t i n g f o u r cases of r a d i a t i o n p n e u m o n i t i s w i t h c o r t i s o n e a n d A C T H , a n d it was t h o u g h t t h a t it w o u l d b e of s o m e v a l u e to r e c o r d t h e results of such therapy.
CASE REPORTS Case I .--A male farm worker, aged zI, was awaiting admission to hospital for tonsillectomy, which had been
advised on account of recurrent attacks of tonsillitis, when he developed swollen glands on the left side of his neck. This was thought to be due to tonsiliar sepsis, but after his tonsils had been removed the glands increased in size. Six months after they had first appeared the glands were excmed and the histological report was Table I.--Case I.
RESPIRATORY FUNCTION
PREDICTED
OBSERVED DEC. 22, 1951. BEFORE CORTISONE THERAPY
OBSERVED JAN. 23, I952AFTER CORTISONE THERAPY
Total capacity
litres 5'53
litres 2"16
litres 2"47
Vital capacity
4'42
I'Z6
1"47
Inspiratory capacity
0"58
o"71
Expiratory reserve volume
o'68
o'76
1"58
1"76
I-II
0'90
I'OO
118"4 (per rain.)
63'5 (per rain.)
i i o (per rain.)
~ in.
2~ in.
Functional residual capacity Residual volume Maximum breathing capacity ~hest expansion
' lymphosarcoma '. Within six weeks the lymphadenopathy recurred in the left supraclavicular fossa and he was therefore admitted to the Queen Elizabeth Hospital, Birmingham, on July 30, 1951, for radiotherapy. At this time he was afebrile, no glandular enlargement was present elsewhere, the liver and spleen were impalpable, the chest radiograph was normal, and the peripheral blood, sternal marrow, and liver function tests showed no abnormality. Re-examination of the slides from the glands previously excised suggested a diagnosis of Hodgkin's disease rather than lymphosarcoma. He was given wide-field cervico-thoracic baths from the base of the skull to the diaphragm. After z45o r anteriorly and posteriorly he developed some oral mucosal reaction and dry desquamation of the skin of the chest wall, and further treatment was therefore confined to the left cervical gland fields and supraclavicular fossa, where over five days IOOO r was given to a 20 × io cm. field. He left hospital on Sept. i i , 1951 , but within a week or so he developed dry cough and exertional dYspnma, which increased and necessitated his re-admission three months later. At this time he was afebrile, no enlarged lymph-glands were present, the spleen and liver were impalpable, and his blood-count was normal.
CORTISONE
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His chest was clear on physical examination, b u t expansion was limited to ~ in. and there was a very obvious ' catch ' whenever he attempted to take a full inspiration. His chest radiograph (Fig. I i A) showed fan-shaped shadowing t h r o u g h o u t both lung fields and marked ' tenting ' of the diaphragm and pericardium on the left side. Respiratory function tests (Table I) showed gross lung volume changes of the type seen in ' p u l m o n a r y fibrosis' and a m u c h reduced m a x i m u m breathing capacity. T h e arterial blood showed a normal oxygen saturation and carbon dioxide content at rest, b u t on exercise definite oxygen desaturation was evident, the
A
B
Fig. a.--Case I, A, After radiotherapy. Fan-shaped shadowing throughout both lung fields. Diaphragmatic and pericardial tenting on the left side_ B, After cortisone therapy. Diminution in lung shadowing and in diaphragmatic and pericardial tenting on the left side. C, Three months later. Increase in lung shadowing. Right pneumothorax and dinphragmatic tenting on right side.
carbon dioxide content remaining normal. Cardiac catheterization showed a normal cardiac output, but the p u l m o n a r y artery pressure rose to an abnormally high level on exercise (Table 1I). T h e electrocardiogram was normal. At this time supplies of cortisone and A C T I t were very limited. H e was given 1"5 g. cortisone intramuscularly over a period of thirteen days and thereafter a very small maintenance dose of 25 rag. was given daily for two weeks. At the end of this course of treatment there was a marked i m p r o v e m e n t in his exercise tolerance and reduction of cough, and his chest expanC sion was 23 in., while his respiratory function tests (Table I) showed some i m p r o v e m e n t and his arterial blood less desaturation on exercise (Table II). His chest radiograph (Fig. I i I~) showed appreciable clearing of the lung fields, and diaphragmatic and pericardial ' tenting ' was less evident. H e was discharged to a convalescent home on Feb. i, 1952, but had to be readmitted two weeks later on account of a respiratory tract infection which had p r o d u c e d considerable aggravation of his cough and dyspneea and profuse p u r u l e n t s p u t u m . A leucocytosis of 19,7oo was present but there was no anmmia, lymphadenopathy, or enlargement of the liver or spleen. He was treated with systemic penicillin and discharged to his home symptom-free apart from some exertional dyspnma on M a r c h 22. Subsequently his d y s p n e a became progressively m o r e disabling, and chest radiographs on April 25 (Fig. i i C) showed tenting
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of the right diaphragm and a right p n e u m o t h o r a x in addition to shadowing t h r o u g h o u t bbth lung fields. N o anmmia, lymphadenopathy, splenomegaly, or hepatomegaly developed, and he died on A u g . 4 , f r o m respiratory failure. N o autopsy was obtained. Table I I . - - C a s e I. BEFORE CORTISONE THERAPY (DEC. 22, 1951)
AFTER CORTISONE THERAPY (JAN. 30, 1952)
Arterial oxygen saturation : At rest After exercise
92"7 per cent 83. 3 per cent
92"3 per cent 87" 5 per cent
Arterial carbon dioxide c o n t e n t : At r e s t After exercise
46'35 per cent 44"55 per cent
---
Cardiac o u t p u t : Supine Sitting
4"8I 1. 5-4 ° 1.
P u l m o n a r y artery pressure : At rest After exercise
m
36/16 m m . H g 46/7 m m . H g
m
RADIOTHERAPEUTIC DETAILS.--Simple anterlor and posterior thoraco-cervical baths from base of skull to xiphisternum, with bolus in axillm and cervical region to give flat treatment planes. Separation between planes i 9 . o c m . ; kv. 25 ° ; H . V . L . i . o m m . Cu ; F.S.D. i o o c m . Incident dosez45o r in twenty treatments over twenty eight days. M a x i m u m skin r e a c t i o n - - d r y desquamation ; lowest platelet count--I3O,OOO per c.mm. Case 2 . - - A female secretary first attended the United Birmingham Hospitals in 1942 at the age of 18 complaining of a painless swelling on the right side of her neck which had been present for six weeks. It was Table I l L - - C a s e 2. BEFORE ACTH
THERAPY
RESPIRATORY FUNCTION AFTER FIRST COURSE
AFTER SECOND COURSE
255 Mo. ACTH
25o rio. ACTH
Total capacity
Iitres " 3"17
litres 3"55
litres 3-61
Vital capacity
2"o5
2"32
2'63
Inspiratory capacity
x "31
i "53
i "77
Expiratory reserve volume
0"74
0"79
0.86
Functional residual capacity ,
1"86
2'o2
1"84
Residual volume
1.12
1"13
0"98
47 (per min.)
7I (per min.)
119 (per min.)
1~ in.
I a in.
2~ in.
M a x i m u m breathing capacity Chest expansion
t h o u g h t at first to be a tuberculous adenitis, but s u b s e q u e n t biopsy revealed the typical pattern of l y m p h adenoma and she was given 3ooo r to the right side of her neck. She remained well until four years later, w h e n enlarged glands appeared in the left supraclavicular fossa. A further 3ooo r were given to this area and there was no further evidence of disease for five years, w h e n another gland appeared in the right supraclavicular fossa and the chest radiograph showed a small glandular mass on the right side of the mediastinum (Fig. 12 A).
CORTISONE
AND
ACTH
She was given f u r t h e r deep X - r a d i a t i o n to t h e right and posteriorly to t h e m e d i a s t i n u m over a period developed and b e c a m e m u c h m o r e m a r k e d following radiotherapy f u r t h e r hospitalization was necessary.
IN
X-RAY
LUNG
DAMAGE
I7
supraclavicular fossa a n d 3000 r were also given anteriorly of fourteen days. O n e m o n t h later exertional dyspnoea a cold, so t h a t four a n d a half m o n t h s after h e r mediastinal At this time there was no l y m p h a d e n o p a t h y , t h e spleen
A
B
Fig. I2.--Case 2. A, Before mediastinal radiotherapy. Small glandular mass present on right side of mediastinum. B, After mediastinal radiotherapy. Lung shadowing coi3fined to area of irradiation. C, After ACTH therapy. Little change in lung shadowing. :and liver were impalpable, and t h e b l o o d - c o u n t and liver f u n c t i o n tests were normal. T h e h e a r t a n d lungs were n o r m a l on clinical e x a m i n a t i o n a n d t h e electrocardiogram was physiological, b u t c h e s t expansion was reduced to 12 in- C h e s t radiographs (Fig. i z B) s h o w e d s h a d o w i n g confined to t h e precise area of irradiation as indicated by skin changes. L u n g v o l u m e and m a x i m u m b r e a t h i n g capacity estimations (Table 111) showed .changes of t h e type seen in m o d e r a t e p u l m o n a r y fibrosis. She was given A C T H by slow i n t r a v e n o u s drip .over two periods, t h e first of n i n e days (255 rag. total •dosage) a n d t h e second of eight days (250 rag. total .dosage.) H e r exercise tolerance r e t u r n e d to normal, h e r ,chest expansion increased to 2~ in. and h e r respiratory f u n c t i o n tests s h o w e d m a r k e d i m p r o v e m e n t , particularly t h e m a x i m u m b r e a t h i n g capacity, b u t chest radiographs :showed little change (Fig. IZ C). Follow-up has s h o w n s o m e slight r e t u r n of exertional dyspncea, b u t she C h a s been working a n d leading a n o r m a l life. T h e chest expansion is 2½ in., t h e chest radiograph s h o w s no change, a n d no l y m p h a d e n o p a t h y , splenomegaly, or h e p a t o m e g a l y has developed. RADIOTHERAPEUTIC D~TAILs.--Anterior a n d posterior opposed I5 × I5 era. fields at 17"o cm. separation ; kv. 2 3 0 ; H . V . L . 2"4 m m . C u ; F . S . D . 5o'o cm. I n c i d e n t dose 3000 r in io t r e a t m e n t s over thirteen .days.
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Case 3 . - - A housewife, aged 38, was admitted to the Queen Elizabeth Hospital, Birmingham, on June 3o~ x952, with a firm mobile gland in the right supraclavicular fossa and another m the right axilla. T h e r e was irregular pyrexia up to Iox ° and chest radiographs (Fig. I3 A) showed a mass projecting from the right superior
Fig. z3.--Case 3- A, Before radiotherapy, showing right superior mediastinal mass. B, After radiotherapy, showing marked reduction in size of right superior mediastinal mass and fan-shaped shadowing throughout both lung fields. C, After ACTH therapy. The lung shadowing l~as assumed a more fibrotic appearance and marked tenting of the diaphragm and pericardium has developed. mediastinum. T h e hver and spleen were impalpable and liver function tests were normal apart f r o m some hyperglobulin~emia (3'8 g. per cent). T h e blood-count showed anaemia, with 3-zz million red cells, 43 per cent hmmoglobin, and i i , i o o white cells, 82 per cent o f which were polymorphs. Bronchoscopy revealed s o m e compression of the right main bronchus and biopsy of the right supraclavicular gland Showed the histological appearances of Hodgkin's disease. She was given blood transfusions and intravenous iron together with eervico-thoracic deep X - r a y baths, a total of 2750 r being given anteriorly and posteriorly over twenty-eight days. H e r pyrexia rapidly subsided and w h e n she left hospital on Aug. 9, she was subjectively well, no glands were palpable, and her blood-count showed 4"81 million red cells and 84 per cent hmmoglobin. Six weeks later she had to be re-admitted because for fourteen days she had been increasingly dyspnceic on exertion and felt that there was some obstruction in her chest which prevented her f r o m taking a full inspiration. T h e r e C was no cough or s p u t u m and since the conclusion of her course of radiotherapy she had p u t on 2 st. in weight. She was afebrile, no l y m p h a d e n o p a t h y was evident, and the liver and spleen remained impalpable while her blood-count showed 5-41 million red cells and lO8 per cent hmmoglobin. She was dyspnceic and cyanosed at rest, b u t the chest was clear on physical examination t h o u g h there was a marked ' catch ' whenever she
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AND
ACTH
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attempted to take a full breath, a n d chest e x p a n s i o n was limited to 2 in. C h e s t radiographs (Fig. I3 B) s h o w e d that the superior mediastinal m a s s was r e d u c e d in size b u t f a n - s h a p e d m o t t l i n g h a d developed in b o t h lung fields. T h e d i a p h r a g m m o v e d poorly. T h e h e a r t was clinically n o r m a l and t h e electrocardiogram physiological. T h e m a x i m u m b r e a t h i n g capacity was only 36"6 litres p e r m i n u t e a n d the vital capacity z'o5 litres. It was u n c e r t a i n w h e t h e r h e r l u n g condition was a radiation effect or d u e to l y m p h a d e n o m a t o u s infiltration, b u t t h e f o r m e r was t h o u g h t m o r e likely so she was given 2o rag. A C T H daily by slow intravenous drip for ten days, at t h e conclusion of w h i c h t h e r e was no material change in h e r clinical state b u t h e r m a x i m u m breathing capacity h a d fallen to 32 litres p e r m i n u t e a n d h e r vital capacity to 1} litres, while chest radiographs (Fig. 13 C) showed that t h e l u n g s h a d o w i n g h a d a s s u m e d a m o r e fibrotic appearance and m a r k e d diaphragmatic a n d pericardial t e n t i n g h a d developed. I n view of the lack of response to A C T H t h e r a p y a n d our uncertainty regarding t h e precise n a t u r e of t h e changes in h e r lungs, s h e was given a course of triethylene melamine by m o u t h . H e r condition did n o t alter except p e r h a p s for s o m e increase in h e r d y s p n e a and eyanosis, a n d on Nov. I she was discharged to h e r h o m e , w h e r e s h e died four weeks later f r o m respiratory failure, there h a v i n g been no f u r t h e r evidence of extrathoracic t t o d g k i n ' s disease; N o a u t o p s y was obtained. RADIOTHERAPEUTIC DETAILS.--Technique a n d factors as for Case I . Separation b e t w e e n planes 17'o cm. Incident dose 275o r in t w e n t y - o n e t r e a t m e n t s over t w e n t y - n i n e days. M a x i m u m skin r e a c t i o n - - f i r s t degree erythema ; lowest platelet count--IOO,OOO p e r c . m m .
Case 4 . - - A male e n g i n e e r i n g apprentice, aged i8, was a d m i t t e d t o t h e Q u e e n Elizabeth Hospital, B i r m i n g h a m , on J u l y 19, I952, with a t w o - a n d - a - h a l f - y e a r s ' history o f progressive painless e n l a r g e m e n t of the l y m p h - n o d e s on t h e left side of his neck. T h e r e were no other s y m p t o m s a n d physical examination was Table I V . - - C a s e 4.
RESPIRATORY FUNCTION
FIVE WEEKS AFTER RADIOTHERAPY
AFTER FIRST COWRSE OF 665 MO. A C T H
FOUR WEEKS LATER
AFTER SECOND COURSE OF 2z5 Mo. ACTH
litres
litres
litres
litres
Total capacity
3"39
3"63
3-37
3"98
Vital capacity
1 '30
3'02
2'32
2"88
Inspiratory capacity
0"92
I'59
0"99
I'66
Expiratory reserve v o l u m e
0.38
1 '43
I'33
I "22
Functional residual capacity
2-47
•o 4
2,-38
2"32
Residual v o l u m e
2-09
o'6I
I 'o5
1"1o
71"4 (per rain.)
161.o 4 (per min.)
I43"7 (per m i n . )
I85-46 (per m i n . )
I} in.
3} in.
3} in.
3} in.
M a x i m u m b r e a t h i n g capacity Chest expansion
otherwise negative. H i s chest radiograph was n o r m a l a n d his b l o o d - c o u n t s h o w e d 4"74 million red cells, 94 p e r cent haemoglobin, 9,600 w h i t e ceils, a n d a n o r m a l differential count. Cervical l y m p h - g l a n d biopsy showed the histological appearances of l y m p h o s a r c o m a . Over a period of four a n d a half weeks he was given 291o r anteriorly a n d posteriorly f r o m t h e c h i n to the d i a p h r a g m . T h r e e weeks after t h e conclusion of his course of radiotherapy he d e v e l o p e d a dry c o u g h and increasing exertional dyspnma, and w h e n r e - a d m i t t e d on this account a fortnight later he was dyspnceic at rest and cyanose d on t h e slightest exertion. G e t t i n g o u t of bed and walking across t h e r o o m was t h e m a x i m u m possible physical effort a n d p r o d u c e d a state of respiratory distress d e m a n d i n g oxygen. T h o u g h his c h e s t was clear on p h y s i c a l examination, chest expansion was limited to i } in_, a n d t h e patient's complaint t h a t " his chest stuck w h e n he took a full b r e a t h " was a graphic description of his a t t e m p t s at m a x i m a l inspiration. Post-radiation skin effects Were a p p a r e n t a n d t h e p u l m o n a r y second s o u n d was accentuated, b u t there were no other physical abnormalities, no l y m p h a d e n o p a t h y was present, t h e spleen a n d liver were impalpable, and t h e b l o o d - c o u n t r e m a i n e d normal. T h e chest radiograph s h o w e d f a n - s h a p e d s h a d o w i n g t h r o u g h o u t b o t h l u n g fields and m a r k e d t e n t i n g of t h e left d i a p h r a g m (Fig. 14 A).
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Respiratory f u n c t i o n tests (Table IV) showed a m a r k e d reduction in t h e m a x i m u m b r e a t h i n g capacity a n d vital capacity a n d a h i g h residual volume. H e was given 665 m g . A C T H b y slow intravenous drip over three periods totalling twenty-six days, a n d at t h e conclusion of t h e r a p y he could go u p four flights of stairs w i t h o u t dyspncea, his c o u g h h a d disappeared,
A
g
Fig. I4.--Case 4- A, Chest radiographs 5 weeks after radiotherapy, showing shadowing throughout both lung fields and tenting of the left diaphragm. B, Chest radiograph after 665 rag. of ACTH by slow intravenous drip over 26 days, showing marked clearing of lung fields. C, Chest radiograph after a further z25 rag. ACTH by slow intravenous drip over 9 days, showing further improvement. his chest expansion was 3~ in., his m a x i m u m b r e a t h i n g capacity was n o r m a l (Table IV), while his l u n g v o l u m e (Table IV) and his chest radiograph (Fig. 14 B) s h o w e d m a r k e d i m p r o v e m e n t . W i t h i n a few days of d i s c h a r g e f r o m hospital he noticed a r e t u r n of his dry c o u g h a n d a reduction in his exercise tolerance, c o u g h rather t h a n dyspneea b e i n g t h e factor limiting exertion. H e was r e - a d m i t t e d four weeks later. N o l y m p h a d e n o p a t h y , hepatomegaly, or s p l e n o m e g a l y was apparent, t h e bloodc o u n t was normal, chest expansion was 31 in., t h e chest radiograph was u n c h a n g e d , and respiratory f u n c tion tests (Table IV) s h o w e d only slight deterioration. H e was given a f u r t h e r 225 mg. A C T H by slow intravenous drip over n i n e days, at the conclusion of w h i c h •C exercise tolerance was n o r m a l and t h e chest radiograph showed f u r t h e r clearing (Fig. 14 C). RADIOTHERAPEUTIC D E T A I L s . - - T e e h n i q u e as for Case i. Separation b e t w e e n planes 18"o cm. ; kv. 18o ; H . V . L . o'5 ram. C u ; F . S . D . 80"0 cm. I n c i d e n t dose z9oo r in t w e n t y - t w o t r e a t m e n t s over thirty-two days. L o w e s t platelet c o u n t - - 9 o , o o o per c . m m .
DISCUSSION T h e t e n d e n c y f o r p u l m o n a r y r a d i a t i o n c h a n g e s to r e g r e s s s p o n t a n e o u s l y w i t h i n 6 - 2 4 m o n t h s has been pointed out above, but the improvement that occurred in Cases 2 and 4 during ACTH therapy seemed quicker and greater than could have been expected without treatment. However,
CORTISONE
AND
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D A M A G E
21
normality was not restored in either case, both patients still having a subnormal exercise tolerance and radiological evidence of fibrosis at the conclusion of therapy and during subsequent observation. It appears therefore that A C T H may hasten the regression of pulmonary radiation damage. The dosage given in each of these two cases was large and the period of therapy long. Both were treated by slow intravenous drip, Case 4 being given 890 mg. over thirty-five days and Case 2 505 mg. over seventeen days. The failure of A C T H therapy in Case 3 and the relatively slight and unsustained improvement which resulted from cortisone in Case i may have been due to dosage being too small and too short, but it is of course possible that the degree of radiation damage was more severe in these patients. Clinically, however, Case 4 appeared to be the most severe of the group studied. The difficulty of differentiating pulmonary radiation effects from secondary malignant infiltration and lung involvement by reticulosis has been referred to above. Case 3 exemplifies the difficulties and complexities of management in such cases and it is a problem with which workers in this field will not infrequently be faced. It might very reasonably be argued that if the lung changes are metastatic or due to involvement by a reticulosis, no treatment will avert a rapidly fatal issue, while if they result from irradiation they may be reduced by A C T H therapy so that such treatment cannot be in any way harmful. This attitude is further supported by the experience of Pearson, Eliel, Rawson, Dobriner, and Rhoads (1949) , and Spies, Lopez, Milanes, Toca, Reboredo, and Aramburu (195o), who found that A C T H therapy produced some improvement in reticuloses, and Spies, Stone, Lopez, Milanes, Toca, and Reboredo (195o), who noted a similar response in three patients with inoperable carcinoma. Nevertheless it is in every way desirable to differentiate radiation effects from malignant disease, as far as possible, as the latter diagnosis, if incorrect, may lead to further radiotherapy which by increasing lung damage may put the patient's life in unnecessary hazard. Sheinmel, Roswit, and Lawrence (195o) and Walpaw, Higley, and Hauser (1944) have described exactly similar radiological changes in the lung parenchyma in Hodgkin's disease as are seen in radiation pneumonitis, and the capacity of lymphangitic carcinomatous infiltration to produce such changes is well known. The main radiological differentiating factor is that in radiation pneumonitis diaphragmatic and pericardiN tenting is soon apparent, while it is rarely seen in malignant infiltration. More important, however, is the history of the case. Dyspnoea, cough, and radiological changes appearing within a few weeks of irradiation of the thorax are much more likely to be due to irradiation than they are to result from malignant spread, especially if the chest radiograph Was normal before radiation was commenced. A further diagnostic feature is the ' doorstop ' obstruction to full inspiration which was a feature of each of our four cases and is a phenomenon which we have observed only in pulmonary fibrosis. In retrospect, it seems clear that Case 3 was suffering from pulmonary radiation damage and that A C T H therapy in higher dosage and over a longer period might have prolonged life. SUMMARY i. The literature regarding pulmonary radiatio n damage is briefly reviewed and the clinical and radiological pattern of the condition is described. 2. Four cases are recorded in which treatment with A C T H or cortisone was given. 3- In two cases, remarkable improvement resulted, but in the other two therapy may have been inadequate and the patients died from respiratory failure. We are indebted to Drs. K. W. Donald, O. L. ,Wade, and D. G. B. Richards for help in the investigation of Case I ; t o Mr. T. F. Dee for reproduction of the radiographs and clinical photography; and to Imperial Chemical Industries Ltd., and the Endowment Fund of the United Birmingham Hospital, for financial assistance in this investigation.
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REFERENCES BALDWIN, E. de F., COURNAND, A., and RICHARDS, D. W. (I949), Medicine, 28, i. BELT, T. H. (I93I), Frankfurt. Z. Path., 42, 17o. BERGMANN, M., and GRAHAM, E. A. ( I 9 5 I ) , J . thorac. SurE., 22, 549. BoYs, F., and HARRIS, I. D. (I943), Amer, J. Roentgenol., 5o, I. DESJARDINS, A. U. (I932), Ibid., 28, 699. DOWNS, E. E. (I936), Ibid., 36, 61. ENGELSTAD, R. B. (194o), Ibid., 43, 676. EVANS, W. A., and LEUCUTIA, T. (I925), Ibid_, I3, 203FAREER, S., and WILSON, J. L. (i932 , a), Arch. Path. (Lab. Med.), 14, 437. (1932, b) Ibid., I4, 450. FIKE, R. H. (1932), Amer. J. Roentgenol., z7, 509 . FRIED, J. R., and GOLDBERG, H. (194o), Ibid., 43, 877. GROOVER, T. A., CHRISTIE, A. C_, and MEIH~ITT, E. A. (I922), Sth. reed. J., Nashville, I5, 44 o. (1923), Amer. J. Roentgenol., to, 471. and CoL, F. O. (1927), Sth. reed. J., Nashville, 2o, 153. HINES, L. E. (1922), J. Amer. reed. Ass., 79, 7zo. JACOBSEN, V. C. (194o), Amer. J. Roentgenol., 44, 235. KAPLAN, I. I., and BELL, D. (1938), Ibid_, 39, 387 • LEACH, J. E. (1943), Ibid., 5o, 772- - - - FARROW, J. H., FOOTE, F. W., and WAWRO, N. W. (1942), Ibid., 4% 74o. LUDIN, M., and WERTHEMANN, A. (193o), Strahlentherapie, 38, 684. MCINTOSH, H. C. (1934), Radiology, 23, 558- - and SPITZ, S. (I939), Amer. J. Roentgenol_, 41, 605. PEARSON, O. H., ELIEL, J. P-, RAWSON, R. W., DOBRINER, K., and RHOADS, C. P. (1949), Cancer, N. Y., 2, 943RAJEWSKY, B. (I939), Radiology., 32, 57. SCHAIREtt, E., and K~OMBACH, E. (I939), Strahlentherapie, 64, 267. SHEINMEL, A., ROSWlT, B., and LAWRENCE, L. R. (I95O), Radiology, 54, 165. SPIES, T. D., LoPEz, G. G., MILANES, F., TOCA, R. L., REBOREDO, A., and ARAMBURV,M. (195o), Sth. reed. J., Nashville, 43, 497. - - STONE, R. E., LOPEZ, G. G., MILANES, F., TOCA, R. L., and REBOREDO, A. (195o), Lancet, 2, 241. T6NGES, E., and KALEFLEISCH, H. H. (I937), Frankfurt. Z. Path., 5o, IOO. WALPAW, S. E., HmLEY, C. S., and HAUSER, H. (I944), Amer. J. Roentgenol., 52, 374. WARREN, S. (1942), Arch. Path. (Lab. Med.), 34, 917 . - - and GATES, O. (I940), Ibid., 3o, 44 o- - and SPENCER, J. (194o), Amer. J. Roentgenol., 43, 682. WIDMANN, B: P. (I942), Ibid., 47, 24. WINTZ, H. (1923), Ibid., IO, 14o. -
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