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Treatment of radiation pneumonitis with prednisolone
Brit. o7. Dis. Chest (x959) 53, 346.
TREATMENT OF RADIATION PNEUMONITIS WITH PREDNISOLONE BY A. C. DOUGLAS From the Northern General Hospital and Department of Tuberculosis and Diseases of the Respiratory System, University of Edinburgh
ALTHOUGH radiation pneumonitis was first described as early as 1922 by Groover, Christie and Merritt, only in recent years have other than symptomatic measures been available in the treatment of this condition. The control of superadded infection, to which patients with established radiation damage a r e prone, became possible with the development of antibiotics but had little effect on the prognosis; a few patients with severe fibrosis mainly confined to one lung have undergone surgical resection (Bergmann and Graham, i95i), but this has not been applicable to the majority of cases. The use of corticosteroid therapy gave promise of a great advance in the treatment of radiation pneumonids. In i95i Cosgriff and Kligerman reported the use of A C T H and cortisone in a 68-year-old woman who developed radiation pneumonitis following therapy for a solitary lung metastasis from a carcinoma of colon. Treatment with A C T H was begun 7 weeks after completion of radiotherapy. A dramatic relief of symptoms occurred within 48 hours and improvement continued during the 3 ° days A C T H was given. Considerable improvement in the radiographic changes was also observed. During the week after A C T H was discontinued, however, there was progressive clinical deterioration with return of dyspnoea, though no change occurred in the chest radiograph. Cordcosteroid treatment was, therefore, resumed, this time using cortisone. Improvement was again noted, though this was slower and less marked than with ACTH. The total duration of cordcosteroid treatment was just under 2 months and no immediate symptomatic relapse followed its withdrawal. Two months later, however, the changes of fibrosis were evident ill the chest radiograph. In 1953 Bluestein and Roemer reported the treatment of radiation pneumonitis occurring in " a virgin lung which had not been affected by carcinoma, arteriosclerosis or infection." The patient was a 45-year-old female who suddenly developed dyspncea and cough following radiotherapy for carcinoma of the breast. The radiographic appearances were consistent with radiation pneumonitis. Treatment with cortisone was begun at once and continued for 3 weeks. Improvement was noted within 24 hours and after one week all symptoms had subsided. One month after treatment was discontinued cough recurred, but responded to a further course of cortisone. Three months after beginning treatment the chest radiograph was normal. From experience with this and other cases the authors stressed the importance of early treatment, maintenance of treatment with high dosage of cortisone for at least 4 weeks, with a total duration of treatment of at least 6 to 8 weeks. (Receivedfor publication June ~5, 1959.)
T R E A T M E N T OF R A D I A T I O N PNEUMONITIS W I T H PREDNISOLONE
347
Subsequent contributions have given conflicting views on the value of corticosteroids, both in the prevention of radiation pneumonitis and in its treatment. In i954 Freidenberg and Rubenfeld reported the use of cortisone in the prevention of radiation pneumonitis. Though admitting that a precise evaluation of the problem is not possible until the incidence of pulmonary fibrosis following irradiation is known, these writers felt that the results of their study of 9 patients suggested that cortisone may be of value in inhibiting postradiation pulmonary fibrosis. They also recorded a case with established pneumonitis treated with cortisone for 36 days which showed symptomatic improvement but no marked change in the radiographic appearances. Whitfield, Bond and Arnott (i 954) recorded the treatment of 4 patients with A C T H or cortisone. In two cases remarkable improvement resulted but the other two died from respiratory failure. Chu, Nickson and Uzel (i956), reporting the largest series so far (I 5 cases), were unable to find definite evidence of protection against the development of pneumonitis by A C T H or cortisone, and, though some patients with established pneumonitis benefited symptomatically from these drugs, no appreciable radiographic improvement was noted in the majority. With such diverse opinions expressed on the value of corticosteroids in the prevention and treatment of radiation pneumonitis, only a controlled clinical trial would give an early answer to the problem. Although this might be justifiable in attempting an assessment of the preventiveaction of corticosteroids it is difficult to justify a trial of corticosteroids in the treatment of developed pneumonitis. In a condition such as radiation pneumonitis which, if severe, can lead to crippling respiratory insufficiency or even death, the failure to use a form of treatment which carries with it no great hazard and which has shown clearly beneficial results in some cases amounts to a denial of treatment. It follows, therefore, that only from a studY of recorded experience will it be possible to determine the value of corticosteroids and the best way to use them. The present series of 4 cases is a small contribution to this experience. CAsE I. Mrs. H. M., rot. 27. This patient came under observation in discovery at routine mass radiography of a large mass in the upper mediastinum. A presumptive diagnosis of lymphadenoma was made and a radical course of wide field radiation was given to the thorax over a period of 7 weeks to a total dosage of 3,000 rads at 250 kV, over 33 treatments. At the end of treatment there was considerable reduction in size of the mediastinal mass. Three weeks after the last X-ray treatment she began to have a dry cough and slight exertional dyspncea, which over the next 6 weeks became progressively more severe and was finally present in a distressing degree at rest. She was admitted to hospital at this stage when she was severely breathless at rest with a respiratory rate of 38 per minute and obvious cyanosis. She demonstrated well the sudden arrest of full inspiration to which the name "door-stop" breathing has been applied (Fig. I). The chest radiograph showed extensive bilateral shadowing (Fig. 2*) and at first the possibility of a recurrence of reticulosis was
April I956following the
* The figures referred to, other than those in the text, appear on Plates XLVIII-XLIX.
DOUGLAS
3~8
considered. This was rejected in favour of radiation pneumonitis because of the rapid development of the radiographic changes so soon after completion of treatment, and it was decided to begin treatment with corticosteroids. Prednisolone was given initially in high dosage (50 mg. per day) and thereafter progressively reduced, treatment covering in all a period of 27 weeks. A C T H was given every 2 weeks to maintain adrenal function. Within 48 hours of the start of treatment there had been a striking improvement in the dyspnoea and cyanosis, and the respiratory rate had returned to normal. In Io days the patient was walking about the ward without distress.
A. BEFORE TREATMENT SHOWING "DOOP,--STOP*
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She was discharged from hospital after 6 weeks to continue treatment at home. Her ventilatory function steadily improved (Fig. 3) and 5 months after the start of treatment she had no residual disability. In fact she was able to take part in, and enjoy, country dancing. The chest radiograph became stable 20 weeks after beginning treatment and has remained unchanged since, showing minor residual fibrosis (Fig. 4)- The patient remains well 2½ years after withdrawal of prednisolone. Moderate facial mooning and a disturbing degree of acne were present during the earlier months of treatment, but these rapidly subsided when it was discontinued. C ~ . 2. J. H., aet. 28. In March i955 this patient had an orchidectomy for histologically proven seminoma. Routine post-operative irradiation was given to the abdominal glands. He remained weU until June I956 , when he
PLATE X L V I I I
FIa. 2.--Case 1 (H.M.) Chest radiograph at beginning of treatment,
Fm. 4.--Case i (H.M.) Chest radiograph after treatment, showing slight residual fibrosis.
]ha. 5.--Case 2 (J.H.) Chestradiograph at beginning of treatment.
FIa. 7.--Case 2 (J.H.) Normal chest radiograph after treatment. To face p. 348
PLATE X L I X
Fro. 8.--Case 3 (B.H.) Chest radiograph at beginning of treatment,
FIG. 9.--Case 3 (B.H.) Chest radiograph showing maximum degree of clearing achieved.
~'IO. IO.--Case 3 (B.H.) Chest radiograph showing diffuse infiltration with lymphadenoma,
FIG. I I.--Case 4 (P.T.) Chest radiograph at beginning of treatment.
TREATMENT
OF R A D I A T I O N PNEUMONITIS W I T H
PREDNISOLONE
349
developed rapidly progressive dyspnoea. The chest radiograph then showed massive mediastinal glandular metastases and collapse of the right middle and lower lobes. Over the next 7 weeks wide field radiation was given to the thorax, to a total dosage of 2,z5o fads at 250 kV over 34 treatments. At the end of treatment his exercise tolerance had virtually returned to normal, but 3 weeks later he began to be breathless again. Dyspncea became rapidly more severe and finally was present at rest. As a result he was confined to bed for the next 6 weeks. A chest radiograph 3 weeks after radiotherapy was IMPROVEMENT
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VITAL
IN VITAL CAPACITY ON PREDNISOLONE.
CAPACITY.
CASE H.M.
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Fzo. 3 completed, i.e. when dyspnoea began, showed no pulmonary abnormality such as could be ascribed to radiation, but diffuse bilateral changes of that type were present in a film taken a month later (Fig. 5). Treatment with cortisone was begun on the recommendation of the Radiotherapy Unit and he received zoo rag. of cortisone for 3 days, 75 rag. for 4 days and 50 mg. for z6 days, at which time he was referred to the Northern General Hospital. Even on these relatively small doses of cortisone the patient experienced considerable relief, which had been evident within a few days of beginning treatment, and the chest radiograph showed improvement. Nevertheless, when seen at the Northern General Hospital he still had considerable dyspnoea, although there was no cyanosis at rest. Breathing was of the classical " d o o r - s t o p " type and chest expansion was poor. The radiographic appearances VOL. LIII. 4
2
~5 0
DOUGLAS i
had improved but there was still well-marked evidence ofpneumonitis. He had obviously not achieved maximum benefit and it was therefore decided to resume corficosteroid therapy, this time in the form of prednisolone on an out-patient basis. Prednisolone was given in a dose of 40 mg. daily initially, with gradually reducing dosage thereafter, treatment extending over a period of I8 weeks. A C T H was given at fortnightly intervals throughout. Because of the rapid clinical response seen in Case i an attempt was made to demonstrate this by ventilatory function tests. These were performed at the beginning of treatment with prednisolone and again 3 days later, by which time clinical improvement IMPROVEMENT MLS.
VI'rAL
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CAPACITY ON
CAPACITY.
PREDNISOLONE, CASE J.H.
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FIG. 6 was evident. The vital capacity showed an increase from 1,65 ° ml. to 2,14 ° ml. over this period. Six weeks after beginning prednisolone the patient was entirely free of dyspncea, even on strenuous exertion. Corresponding improvement was seen in serial function tests (Fig. 6) and chest radiographs. Twentyeight days after beginning prednisolone and 51 days after beginning cortisone the chest radiograph was normal (Fig. 7). The only complications of treatment were a mild degree :of facial mooning and acne during the first few months. The patient has remained well for 2½ years with no recurrence of dyspnoea and no radiographic deterioration. He now regularly takes part in week-end motor-cycle hill trials.
T R E A T M E N T 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
PREDNISOLONE
351
CASI~ 3" B. H., ~et. 44. This patient was admitted to another hospital in J u l y i957 with cough, swelling of the face and prominence of the veins over the upper chest, of 2 months' duration. A lymph node removed from the neck was reported as showing lymphadenoma. The chest radiograph showed an anterior mediastinal mass. She was therefore given wide field deep X-ray therapy to include the whole chest, supraclavicular regions and axillm, receiving an incident dose of 2,500 rads at 250 kV over 33 treatments. At the end of treatment the mediasfinal mass was much smaller and a node previously present in the right axilla was no longer palpable. Radiotherapy was given from 6.8.57 to 23.9.57 At the beginning of December she began to have a dry cough and to feel easily breathless on exertion. Over the next 3 weeks dyspncea became exceedingly severe even at rest and the patient felt as if her chest were circled by bands which would not let her take a deep breath. O n 2.1.58 the chest radiograph showed diffuse opacities of the type seen in radiation pneumonitis (Fig. 8). She was admitted to the Northern General Hospital on i5.I.58 , when physical examination revealed slight cyanosis and tachypncea at rest (respiratory rate 28 per minute) and an obvious abrupt halt to full inspiration. The vital capacity was markedly reduced to 850 ml. (predicted 3,17 ° ml.). Treatment was begun with prednisolone 40 mg. daily, on i6.I.58. Within 36 hours the patient volunteered improvement and with each successive day she felt progressively more capable of respiratory effort. Serial function tests showed progressive improvement in the vital capacity, which had doubled by the sixth day of treatment. At the same time chest radiographs showed progressive clearing of the diffuse pulmonary opacities. Prednisolone was given in a dose of 40 mg. daily from 16.1.58 to 5.2.58 and 30 rag. per day from 6.2.58 to I3.2.58. She was then discharged from hospital and continued treatment at home with 20 mg. prednisolone daily. Though considerably improved the chest radiograph still showed substantial shadowing (Fig. 9). Up to this time function tests had shown a steady increase in vital capacity, but thereafter a slow deterioration occurred. No further improvement was seen in the chest radiograph and 2 months after discharge the diffuse pulmonary opacities, particularly those on the left side, became more prominent and assumed a nodular character. Clinical evidence of resurgence of the original disease was discovered at this time in the form of enlarged glands in the left axilla. This was attended by pain in the arm, and a further course of radiotherapy was given to the left axilla and supraclavicular region with a satisfactory response. Nevertheless she remained reasonably well with little complaint of dyspncea until J u n e 1958, when an attempt was made to reduce the dose of prednisolone from 20 rag. to 15 mg. daily. This was followed by lassitude and slight dyspn~ea which abated when the dose was increased to 20 rag. daily. In July a respiratory infection necessitated temporary increase in the dosage of prednisolone to 4 ° mg. per day until the infection was controlled, and in September she developed a staphylococcal septica~mia which responded to antibiotics and increase in the dosage of prednisolone. Throughout this time the chest radiograph had shown slow deterioration with the development throughout both lungs of enlarging nodular opacities, and it was now considered likely that the appearances were due to infiltration w i t h lymphadenoma. In October the patient's general condition began to deteriorate with general
352
DOUGLAs
weakness and return of disabling dyspncea. Extra-thoracic progression of the primary disease had occurred with the development of further glandular swellings in the neck, axillm and groins, and though increase of the prednisolone dosage to 4 ° and finally 5° mg. per day had some subjective ameliorating effect, it was obvious that corticosteroid therapy was no longer influencing the deterioration in respiratory function. After several weeks of increasing dyspncea the patient died of respiratory insufficiency on 6.12.58. A final chest film on 4.12.58 had shown further deterioration in all zones (Fig. io). At autopsy there was widespread involvement with lymphadenoma of lymph nodes, bone marrow and both lungs. The lungs showed scattered nodules of pale, firm tumour up to 2 cm. in diameter which had no particular relation to hilum, bronchi or pleura. The microscopic sections of the lungs showed lymphadenoma together with "lipid pneumonitis" and a moderate amount of interstitial fibrosis. The pathologist commented that the latter may have represented a radiation pneumonitis component, but that the differentiation of two sclerosing lesions was not possible. CASE 4. P- T., ~et. 56. This patient, a coal miner all his working life, was well, apart from symptoms of mild chronic bronchitis, until September 1957, when he developed a sore throat and hoarseness and noticed for the first time a swelling in the neck. A clinical diagnosis of carcinoma of the thyroid was made and, following preliminary radiotherapy to the gland, a right hemithyroidectomy was performed. The pathological specimen proved to be a poorly differentiated adeno-carcinoma. Prophylactic wide field radiotherapy to the thorax was then given from 2.1o.57 to 8.i 1.57 to a total of 2,45o rads at 25o kV. At the end of this treatment the patient developed a cough with mucopuruIent sputum for which a 7-day course of tetracycline was given with little effect. The chest radiograph at this time, apart from showing early simple pneumoconiosis, was negative, but by 22.11.57 streaky shadowing had appeared in both upper lung zones and throughout the next few weeks the radiographic changes became more extensive, finally involving all lung zones (Fig. I I). With the development of the lung changes the patient experienced increasing exertional dyspncea, so that when referred to the Northern General Hospital on 7.1.58 he was breathless on the slightest exertion. The vital capacity was reduced to x,I6O ml. (predicted 3,17 ° ml.). A diagnosis of radiation pneumonitis was made and treatment was begun with prednisolone 4 ° mg. daily. The sputum was mucoid in character at this stage and no specific organism was isolated on culture. Nevertheless, because of the recent history of recurring pus in the sputum tetracycline was also given in 1½ G. daily dosage. On this r~gime the vital capacity had increased to 1,72o ml. by the fourth day, and by the twelfth day of treatment further increases in vital capacity had been recorded. The prednisolone dosage was thereafter reduced by 5 mg. daily over the next 4 days, 2o mg. being given from 23.i.58 onwards. Seven days after the start of treatment pus again appeared in the sputum and continued intermittently over the next few weeks. Radiographic improvement thus far had been disappointing in spite of the improvement in respiratory function. On 24.1.58 a routine radiograph showed the development of a shallow right upper pneumothorax, unexpected because of the early obliteration of the pleural space in most cases of radiation pneumonitis. By 12.2.58 the pneumothorax had spontaneously absorbed but recurred on 2o.2.58.
T R E A T M E N T OF R A D I A T I O N PNEUMONITIS W I T H PREDNISOLONE
353
With the development of frank pus in the sputum on 27.i.58 penicillin was begun (6 mega units daily) and continued until 20.2.58. This was effective initially in clearing the sputum of pus, but in spite of this the patient's general condition began to deteriorate and he again began to complain of exertional dyspnoea. Repeated vital capacity recordings confirmed the deterioration in respiratory function. On i5.2.58 pus again appeared in the sputum and on 20.2.58 chloramphenicol was substituted for penicillin following the repeated culture from the sputum of Staph. pyogenes sensitive to chloramphenicol and erythromycin only. In spite of this and increase in prednisolone dosage to 60 mg. daily from 13.2.58 onwards, dyspncea became progressively worse and on 2.3.58 the patient diett of respiratory insufficiency. A final chest radiograph on 26.2.58. had shown absorption of the pneumothorax. The initial slight improvement in the pulmonary opacities had not been maintained and the final film showed generalised slight deterioration compared with that at the start of treatment. At autopsy no evidence of malignancy was found in the thyroid or elsewhere in the body. Examination of the respiratory system was reported as follows: "Larynx, trachea and bronchi showed no abnormality beyond some mucosal congestion. There was slight excess of transudate in each pleural sac. There were no pleural adhesions. The right lung weighed 830 G. and the left 73° G. Sectioning revealed similar changes in both lungs. In each upper lobe there was diffuse fibrosis and blackening by carbon pigment. The middle and lower lobes showed evidence of diffuse pneumonitis without complete consolidation. Grey-brown areas were present on a red background. There appeared to be no tumour invasion of lung and the hilar lymph nodes were not enlarged. Changes were consistent with post-radiation pneumonitis and fibrosis. Microscopy. Lungs: The abnormalities in the lungs show considerable variation from one area to another. Comparatively little normal lung survives and such unconsolidated lung as there is tends to be emphysematous. Otherwise most inter-alveolar septa show some degree of thickening. Some of the alveoli are occupied by polymorphonuclear inflammatory exudate, others by fibrin and others by fibrous tissue which may extend from one alveolus to the next through gaps in the septa. Some small areas of lung show diffuse fibrosis heavily pigmented by carbon and it is possible that this fibrosis preceded radiotherapy or was only exaggerated by radiotherapy. Many of the bronchi are dilated and occupied by mucopus. The bronchiolar epithelium is often hyperplastic and the alveolar epithelium frequently shows cubical metaplasia. There is some calcification of small vessels but the large vessels show no gross damage or evidence of former thrombosis. These lungs show more evidence of pyogenic inflammation than is usually described in post-radiation fibrosis; without the history it might be difficult to distinguish the lesion from a primary infective pulmonary inflammation." Discussion Though improved radiotherapeutic technique has reduced the incidence of radiation pneumonitis, despite a trend toward higher radiation dosage, this condition is by no means uncommon, especially following wide field treatment to the thorax. In a severe form radiation pneumonitis is attended by dyspu~ca which may be extreme, and death from respiratory insufficiency has been
354
DOUGLAs
reported within a week of the onset of symptoms (Whitfield et al., i956 ). As congestion and cedema characterise the early stages it was logical that corticosteroids, because of their marked anti-inflammatory effects, should be tried in treatment. That these drugs can exert a profound beneficial influence, in at least some cases, has already been clearly demonstrated, and the early and dramatic response in Cases i and 2 in the present series cannot be interpreted otherwise than as a consequence of corticosteroid therapy. The response of the radiation changes in Case 3 was no less satisfactory than in Cases I and 2 and the deterioration in respiratory function was clearly related to the development of pulmonary infiltration with lymphadenoma. Nevertheless there is also on record substantial evidence of the failure of these drugs either to exert any influence at all on radiation pneumonitis or to effect more than temporary relief, in spite of adequate dosage (Chu et al., i956), and Case 4 is a further example of this. This elderly patient had a previous history of chronic bronchitis and long-continued dust exposure and it is interesting to speculate whether these factors, as well as predisposing to the development of radiation changes, may also have affected the response of these changes to corficosteroids. Moreover it is conceivable that in some cases, perhaps as a result of individual variation in tissue response, a degree of pulmonary damage may occur which precludes reversal of the inflammatory process by corticosteroids. There was, however, a further factor, out of the realm of conjecture, which undoubtedly played a significant part in this particular patient. Considerable evidence of associated infection was observed pathologically, of a degree much in excess of that normally seen in radiation pneumonitis, and it is important to note that the organism most frequently cultured from the sputum in the latter part of the illness was Staph. pyogenes. The early response to treatment with prednisolone indicated the presence of some reversible change, probably tissue oedema. It now seems fairly certain that the slow deterioration of respiratory function which followed, though perhaps due primarily to cellular response to radiation injury, was contributed to materially by a widespread suppurative pneumonia and that the latter was the immediate cause of death. The susceptibility of cases with radiation pneumonitis to develop secondary infection has long been appreciated. The danger of superinfection with the ubiquitous Staph. pyogenes is considerable when the patient is admitted to hospital and, in the absence of effective antibiotic control, such infection may be enhanced by the use of corticosteroids. Ideally, therefore, cases of radiation pneumonitis requiring hospitalisation should be nursed in isolation with all the precautions necessary for the prevention of cross-infection. In the absence of definite answers to the many questions which surround the treatment of radiation pneumonitis it is reasonable to assume that the best results will occur ff treatment with corticosteroids is begun early, dosage is reasonably high initially and treatment is sufficiently prolonged to allow the inflammatory reaction to subside completely. In this last respect it is of interest to note that in Cases I and 2 the improvement in respiratory function continued for a considerable time after stabilisation of the radiographic appear-
TREATMENT OF RADIATION PNEUMONITIS WITH PREDNISOLONE
355
ances. T h e latter should not therefore be r e g a r d e d as a n index to cessation o f t r e a t m e n t which, if p r e m a t u r e , m a y lead to " r e b o u n d " p h e n o m e n a (Cosgriff et al., i 9 5 i ; Bluestein et al., I953). T h e most satisfactory response in the present series was observed in a y o u n g subject with previously healthy lungs in w h o m the above conditions o f t r e a t m e n t were fulfilled. In this case complete clearing o f radiographic opacities a n d complete restoration o f respiratory function was achieved b y t r e a t m e n t extending over a period of 18 weeks.
Summary F o u r cases of radiation pneumonitis treated with prednisolone are described. T w o patients are alive a n d w i t h o u t respiratory symptoms 2½ years after treatment. O n e of these has a n o r m a l chest r a d i o g r a p h ; the o t h e r has only slight residual p u l m o n a r y fibrosis. T w o patients died of respiratory insufficiency. E a c h h a d shown a n initial response to t r e a t m e n t . D e t e r i o r a t i o n was due to infiltration of the lungs with l y m p h a d e n o m a in one patient, a n d in the o t h e r uncontrolled, widespread suppurative p n e u m o n i a was the i m m e d i a t e cause of death. I wish to thank Professor J. Crofton (Case 3) and Dr. I. W. B. Grant (Gases I, 2 and 4) for permission to publish the cases and for helpful advice and criticism; Dr. N. Maclean and Dr. A. Gordon for the pathological reports; Dr. J. G. Pearson, Dr. J. NewaU and Dr. K. A. Mackenzie of the Radiotherapy Department, Edinburgh, for providing details of the treatment given; Mrs. M. Beaton for performing the respiratory function tests; and Miss W. A. M. Tait for secretarial assistance. REFERENCES BEROMANN,M., and GaAHn_~, E. A. (I95I) : 07. thorac. Surg., 22, 549. BLUESTEIN, S. G., and ROEMER, J. (1953): ft. med. Soc. At.ft., 50, IO6. CHU, F. C. H., NmKSON,J. J., and UZEL, A. R. (x956) : Amer. ft. Roentgenol., 75, 53o. CosomFF, S. W., and KLIO~.I~AN, M. N. (x95x) : Radiology, 57, 536. FRSID~NBERQ,R. M., and RUBENFELD,S. (1954) : Amer. 07. Roentgenol., 72, ~7 I. WHITFIELD,A. G. W., BOND, W. H., and ARNOTT,W. M. (1954)1o7.gac. Radiol. (Lond.), 6, 12. (I956): Quart. 07. Med., Vol. XXV, 97, 67.
TREATMENT OF RADIATION PNEUMONITIS WITH PREDNISOLONE BY A. C. DOUGLAS From the Northern General Hospital and Department of Tuberculosis and Diseases of the Respiratory System, University of Edinburgh
ALTHOUGH radiation pneumonitis was first described as early as 1922 by Groover, Christie and Merritt, only in recent years have other than symptomatic measures been available in the treatment of this condition. The control of superadded infection, to which patients with established radiation damage a r e prone, became possible with the development of antibiotics but had little effect on the prognosis; a few patients with severe fibrosis mainly confined to one lung have undergone surgical resection (Bergmann and Graham, i95i), but this has not been applicable to the majority of cases. The use of corticosteroid therapy gave promise of a great advance in the treatment of radiation pneumonids. In i95i Cosgriff and Kligerman reported the use of A C T H and cortisone in a 68-year-old woman who developed radiation pneumonitis following therapy for a solitary lung metastasis from a carcinoma of colon. Treatment with A C T H was begun 7 weeks after completion of radiotherapy. A dramatic relief of symptoms occurred within 48 hours and improvement continued during the 3 ° days A C T H was given. Considerable improvement in the radiographic changes was also observed. During the week after A C T H was discontinued, however, there was progressive clinical deterioration with return of dyspnoea, though no change occurred in the chest radiograph. Cordcosteroid treatment was, therefore, resumed, this time using cortisone. Improvement was again noted, though this was slower and less marked than with ACTH. The total duration of cordcosteroid treatment was just under 2 months and no immediate symptomatic relapse followed its withdrawal. Two months later, however, the changes of fibrosis were evident ill the chest radiograph. In 1953 Bluestein and Roemer reported the treatment of radiation pneumonitis occurring in " a virgin lung which had not been affected by carcinoma, arteriosclerosis or infection." The patient was a 45-year-old female who suddenly developed dyspncea and cough following radiotherapy for carcinoma of the breast. The radiographic appearances were consistent with radiation pneumonitis. Treatment with cortisone was begun at once and continued for 3 weeks. Improvement was noted within 24 hours and after one week all symptoms had subsided. One month after treatment was discontinued cough recurred, but responded to a further course of cortisone. Three months after beginning treatment the chest radiograph was normal. From experience with this and other cases the authors stressed the importance of early treatment, maintenance of treatment with high dosage of cortisone for at least 4 weeks, with a total duration of treatment of at least 6 to 8 weeks. (Receivedfor publication June ~5, 1959.)
T R E A T M E N T OF R A D I A T I O N PNEUMONITIS W I T H PREDNISOLONE
347
Subsequent contributions have given conflicting views on the value of corticosteroids, both in the prevention of radiation pneumonitis and in its treatment. In i954 Freidenberg and Rubenfeld reported the use of cortisone in the prevention of radiation pneumonitis. Though admitting that a precise evaluation of the problem is not possible until the incidence of pulmonary fibrosis following irradiation is known, these writers felt that the results of their study of 9 patients suggested that cortisone may be of value in inhibiting postradiation pulmonary fibrosis. They also recorded a case with established pneumonitis treated with cortisone for 36 days which showed symptomatic improvement but no marked change in the radiographic appearances. Whitfield, Bond and Arnott (i 954) recorded the treatment of 4 patients with A C T H or cortisone. In two cases remarkable improvement resulted but the other two died from respiratory failure. Chu, Nickson and Uzel (i956), reporting the largest series so far (I 5 cases), were unable to find definite evidence of protection against the development of pneumonitis by A C T H or cortisone, and, though some patients with established pneumonitis benefited symptomatically from these drugs, no appreciable radiographic improvement was noted in the majority. With such diverse opinions expressed on the value of corticosteroids in the prevention and treatment of radiation pneumonitis, only a controlled clinical trial would give an early answer to the problem. Although this might be justifiable in attempting an assessment of the preventiveaction of corticosteroids it is difficult to justify a trial of corticosteroids in the treatment of developed pneumonitis. In a condition such as radiation pneumonitis which, if severe, can lead to crippling respiratory insufficiency or even death, the failure to use a form of treatment which carries with it no great hazard and which has shown clearly beneficial results in some cases amounts to a denial of treatment. It follows, therefore, that only from a studY of recorded experience will it be possible to determine the value of corticosteroids and the best way to use them. The present series of 4 cases is a small contribution to this experience. CAsE I. Mrs. H. M., rot. 27. This patient came under observation in discovery at routine mass radiography of a large mass in the upper mediastinum. A presumptive diagnosis of lymphadenoma was made and a radical course of wide field radiation was given to the thorax over a period of 7 weeks to a total dosage of 3,000 rads at 250 kV, over 33 treatments. At the end of treatment there was considerable reduction in size of the mediastinal mass. Three weeks after the last X-ray treatment she began to have a dry cough and slight exertional dyspncea, which over the next 6 weeks became progressively more severe and was finally present in a distressing degree at rest. She was admitted to hospital at this stage when she was severely breathless at rest with a respiratory rate of 38 per minute and obvious cyanosis. She demonstrated well the sudden arrest of full inspiration to which the name "door-stop" breathing has been applied (Fig. I). The chest radiograph showed extensive bilateral shadowing (Fig. 2*) and at first the possibility of a recurrence of reticulosis was
April I956following the
* The figures referred to, other than those in the text, appear on Plates XLVIII-XLIX.
DOUGLAS
3~8
considered. This was rejected in favour of radiation pneumonitis because of the rapid development of the radiographic changes so soon after completion of treatment, and it was decided to begin treatment with corticosteroids. Prednisolone was given initially in high dosage (50 mg. per day) and thereafter progressively reduced, treatment covering in all a period of 27 weeks. A C T H was given every 2 weeks to maintain adrenal function. Within 48 hours of the start of treatment there had been a striking improvement in the dyspnoea and cyanosis, and the respiratory rate had returned to normal. In Io days the patient was walking about the ward without distress.
A. BEFORE TREATMENT SHOWING "DOOP,--STOP*
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B. FOLLOWING PREDNISOLONE. TRF.ATMENT. •,
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She was discharged from hospital after 6 weeks to continue treatment at home. Her ventilatory function steadily improved (Fig. 3) and 5 months after the start of treatment she had no residual disability. In fact she was able to take part in, and enjoy, country dancing. The chest radiograph became stable 20 weeks after beginning treatment and has remained unchanged since, showing minor residual fibrosis (Fig. 4)- The patient remains well 2½ years after withdrawal of prednisolone. Moderate facial mooning and a disturbing degree of acne were present during the earlier months of treatment, but these rapidly subsided when it was discontinued. C ~ . 2. J. H., aet. 28. In March i955 this patient had an orchidectomy for histologically proven seminoma. Routine post-operative irradiation was given to the abdominal glands. He remained weU until June I956 , when he
PLATE X L V I I I
FIa. 2.--Case 1 (H.M.) Chest radiograph at beginning of treatment,
Fm. 4.--Case i (H.M.) Chest radiograph after treatment, showing slight residual fibrosis.
]ha. 5.--Case 2 (J.H.) Chestradiograph at beginning of treatment.
FIa. 7.--Case 2 (J.H.) Normal chest radiograph after treatment. To face p. 348
PLATE X L I X
Fro. 8.--Case 3 (B.H.) Chest radiograph at beginning of treatment,
FIG. 9.--Case 3 (B.H.) Chest radiograph showing maximum degree of clearing achieved.
~'IO. IO.--Case 3 (B.H.) Chest radiograph showing diffuse infiltration with lymphadenoma,
FIG. I I.--Case 4 (P.T.) Chest radiograph at beginning of treatment.
TREATMENT
OF R A D I A T I O N PNEUMONITIS W I T H
PREDNISOLONE
349
developed rapidly progressive dyspnoea. The chest radiograph then showed massive mediastinal glandular metastases and collapse of the right middle and lower lobes. Over the next 7 weeks wide field radiation was given to the thorax, to a total dosage of 2,z5o fads at 250 kV over 34 treatments. At the end of treatment his exercise tolerance had virtually returned to normal, but 3 weeks later he began to be breathless again. Dyspncea became rapidly more severe and finally was present at rest. As a result he was confined to bed for the next 6 weeks. A chest radiograph 3 weeks after radiotherapy was IMPROVEMENT
Mt.S.
VITAL
IN VITAL CAPACITY ON PREDNISOLONE.
CAPACITY.
CASE H.M.
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2000 ISO0
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Fzo. 3 completed, i.e. when dyspnoea began, showed no pulmonary abnormality such as could be ascribed to radiation, but diffuse bilateral changes of that type were present in a film taken a month later (Fig. 5). Treatment with cortisone was begun on the recommendation of the Radiotherapy Unit and he received zoo rag. of cortisone for 3 days, 75 rag. for 4 days and 50 mg. for z6 days, at which time he was referred to the Northern General Hospital. Even on these relatively small doses of cortisone the patient experienced considerable relief, which had been evident within a few days of beginning treatment, and the chest radiograph showed improvement. Nevertheless, when seen at the Northern General Hospital he still had considerable dyspnoea, although there was no cyanosis at rest. Breathing was of the classical " d o o r - s t o p " type and chest expansion was poor. The radiographic appearances VOL. LIII. 4
2
~5 0
DOUGLAS i
had improved but there was still well-marked evidence ofpneumonitis. He had obviously not achieved maximum benefit and it was therefore decided to resume corficosteroid therapy, this time in the form of prednisolone on an out-patient basis. Prednisolone was given in a dose of 40 mg. daily initially, with gradually reducing dosage thereafter, treatment extending over a period of I8 weeks. A C T H was given at fortnightly intervals throughout. Because of the rapid clinical response seen in Case i an attempt was made to demonstrate this by ventilatory function tests. These were performed at the beginning of treatment with prednisolone and again 3 days later, by which time clinical improvement IMPROVEMENT MLS.
VI'rAL
IN
VITAL
CAPACITY ON
CAPACITY.
PREDNISOLONE, CASE J.H.
3500
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TIME IN DAYS
FIG. 6 was evident. The vital capacity showed an increase from 1,65 ° ml. to 2,14 ° ml. over this period. Six weeks after beginning prednisolone the patient was entirely free of dyspncea, even on strenuous exertion. Corresponding improvement was seen in serial function tests (Fig. 6) and chest radiographs. Twentyeight days after beginning prednisolone and 51 days after beginning cortisone the chest radiograph was normal (Fig. 7). The only complications of treatment were a mild degree :of facial mooning and acne during the first few months. The patient has remained well for 2½ years with no recurrence of dyspnoea and no radiographic deterioration. He now regularly takes part in week-end motor-cycle hill trials.
T R E A T M E N T 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
PREDNISOLONE
351
CASI~ 3" B. H., ~et. 44. This patient was admitted to another hospital in J u l y i957 with cough, swelling of the face and prominence of the veins over the upper chest, of 2 months' duration. A lymph node removed from the neck was reported as showing lymphadenoma. The chest radiograph showed an anterior mediastinal mass. She was therefore given wide field deep X-ray therapy to include the whole chest, supraclavicular regions and axillm, receiving an incident dose of 2,500 rads at 250 kV over 33 treatments. At the end of treatment the mediasfinal mass was much smaller and a node previously present in the right axilla was no longer palpable. Radiotherapy was given from 6.8.57 to 23.9.57 At the beginning of December she began to have a dry cough and to feel easily breathless on exertion. Over the next 3 weeks dyspncea became exceedingly severe even at rest and the patient felt as if her chest were circled by bands which would not let her take a deep breath. O n 2.1.58 the chest radiograph showed diffuse opacities of the type seen in radiation pneumonitis (Fig. 8). She was admitted to the Northern General Hospital on i5.I.58 , when physical examination revealed slight cyanosis and tachypncea at rest (respiratory rate 28 per minute) and an obvious abrupt halt to full inspiration. The vital capacity was markedly reduced to 850 ml. (predicted 3,17 ° ml.). Treatment was begun with prednisolone 40 mg. daily, on i6.I.58. Within 36 hours the patient volunteered improvement and with each successive day she felt progressively more capable of respiratory effort. Serial function tests showed progressive improvement in the vital capacity, which had doubled by the sixth day of treatment. At the same time chest radiographs showed progressive clearing of the diffuse pulmonary opacities. Prednisolone was given in a dose of 40 mg. daily from 16.1.58 to 5.2.58 and 30 rag. per day from 6.2.58 to I3.2.58. She was then discharged from hospital and continued treatment at home with 20 mg. prednisolone daily. Though considerably improved the chest radiograph still showed substantial shadowing (Fig. 9). Up to this time function tests had shown a steady increase in vital capacity, but thereafter a slow deterioration occurred. No further improvement was seen in the chest radiograph and 2 months after discharge the diffuse pulmonary opacities, particularly those on the left side, became more prominent and assumed a nodular character. Clinical evidence of resurgence of the original disease was discovered at this time in the form of enlarged glands in the left axilla. This was attended by pain in the arm, and a further course of radiotherapy was given to the left axilla and supraclavicular region with a satisfactory response. Nevertheless she remained reasonably well with little complaint of dyspncea until J u n e 1958, when an attempt was made to reduce the dose of prednisolone from 20 rag. to 15 mg. daily. This was followed by lassitude and slight dyspn~ea which abated when the dose was increased to 20 rag. daily. In July a respiratory infection necessitated temporary increase in the dosage of prednisolone to 4 ° mg. per day until the infection was controlled, and in September she developed a staphylococcal septica~mia which responded to antibiotics and increase in the dosage of prednisolone. Throughout this time the chest radiograph had shown slow deterioration with the development throughout both lungs of enlarging nodular opacities, and it was now considered likely that the appearances were due to infiltration w i t h lymphadenoma. In October the patient's general condition began to deteriorate with general
352
DOUGLAs
weakness and return of disabling dyspncea. Extra-thoracic progression of the primary disease had occurred with the development of further glandular swellings in the neck, axillm and groins, and though increase of the prednisolone dosage to 4 ° and finally 5° mg. per day had some subjective ameliorating effect, it was obvious that corticosteroid therapy was no longer influencing the deterioration in respiratory function. After several weeks of increasing dyspncea the patient died of respiratory insufficiency on 6.12.58. A final chest film on 4.12.58 had shown further deterioration in all zones (Fig. io). At autopsy there was widespread involvement with lymphadenoma of lymph nodes, bone marrow and both lungs. The lungs showed scattered nodules of pale, firm tumour up to 2 cm. in diameter which had no particular relation to hilum, bronchi or pleura. The microscopic sections of the lungs showed lymphadenoma together with "lipid pneumonitis" and a moderate amount of interstitial fibrosis. The pathologist commented that the latter may have represented a radiation pneumonitis component, but that the differentiation of two sclerosing lesions was not possible. CASE 4. P- T., ~et. 56. This patient, a coal miner all his working life, was well, apart from symptoms of mild chronic bronchitis, until September 1957, when he developed a sore throat and hoarseness and noticed for the first time a swelling in the neck. A clinical diagnosis of carcinoma of the thyroid was made and, following preliminary radiotherapy to the gland, a right hemithyroidectomy was performed. The pathological specimen proved to be a poorly differentiated adeno-carcinoma. Prophylactic wide field radiotherapy to the thorax was then given from 2.1o.57 to 8.i 1.57 to a total of 2,45o rads at 25o kV. At the end of this treatment the patient developed a cough with mucopuruIent sputum for which a 7-day course of tetracycline was given with little effect. The chest radiograph at this time, apart from showing early simple pneumoconiosis, was negative, but by 22.11.57 streaky shadowing had appeared in both upper lung zones and throughout the next few weeks the radiographic changes became more extensive, finally involving all lung zones (Fig. I I). With the development of the lung changes the patient experienced increasing exertional dyspncea, so that when referred to the Northern General Hospital on 7.1.58 he was breathless on the slightest exertion. The vital capacity was reduced to x,I6O ml. (predicted 3,17 ° ml.). A diagnosis of radiation pneumonitis was made and treatment was begun with prednisolone 4 ° mg. daily. The sputum was mucoid in character at this stage and no specific organism was isolated on culture. Nevertheless, because of the recent history of recurring pus in the sputum tetracycline was also given in 1½ G. daily dosage. On this r~gime the vital capacity had increased to 1,72o ml. by the fourth day, and by the twelfth day of treatment further increases in vital capacity had been recorded. The prednisolone dosage was thereafter reduced by 5 mg. daily over the next 4 days, 2o mg. being given from 23.i.58 onwards. Seven days after the start of treatment pus again appeared in the sputum and continued intermittently over the next few weeks. Radiographic improvement thus far had been disappointing in spite of the improvement in respiratory function. On 24.1.58 a routine radiograph showed the development of a shallow right upper pneumothorax, unexpected because of the early obliteration of the pleural space in most cases of radiation pneumonitis. By 12.2.58 the pneumothorax had spontaneously absorbed but recurred on 2o.2.58.
T R E A T M E N T OF R A D I A T I O N PNEUMONITIS W I T H PREDNISOLONE
353
With the development of frank pus in the sputum on 27.i.58 penicillin was begun (6 mega units daily) and continued until 20.2.58. This was effective initially in clearing the sputum of pus, but in spite of this the patient's general condition began to deteriorate and he again began to complain of exertional dyspnoea. Repeated vital capacity recordings confirmed the deterioration in respiratory function. On i5.2.58 pus again appeared in the sputum and on 20.2.58 chloramphenicol was substituted for penicillin following the repeated culture from the sputum of Staph. pyogenes sensitive to chloramphenicol and erythromycin only. In spite of this and increase in prednisolone dosage to 60 mg. daily from 13.2.58 onwards, dyspncea became progressively worse and on 2.3.58 the patient diett of respiratory insufficiency. A final chest radiograph on 26.2.58. had shown absorption of the pneumothorax. The initial slight improvement in the pulmonary opacities had not been maintained and the final film showed generalised slight deterioration compared with that at the start of treatment. At autopsy no evidence of malignancy was found in the thyroid or elsewhere in the body. Examination of the respiratory system was reported as follows: "Larynx, trachea and bronchi showed no abnormality beyond some mucosal congestion. There was slight excess of transudate in each pleural sac. There were no pleural adhesions. The right lung weighed 830 G. and the left 73° G. Sectioning revealed similar changes in both lungs. In each upper lobe there was diffuse fibrosis and blackening by carbon pigment. The middle and lower lobes showed evidence of diffuse pneumonitis without complete consolidation. Grey-brown areas were present on a red background. There appeared to be no tumour invasion of lung and the hilar lymph nodes were not enlarged. Changes were consistent with post-radiation pneumonitis and fibrosis. Microscopy. Lungs: The abnormalities in the lungs show considerable variation from one area to another. Comparatively little normal lung survives and such unconsolidated lung as there is tends to be emphysematous. Otherwise most inter-alveolar septa show some degree of thickening. Some of the alveoli are occupied by polymorphonuclear inflammatory exudate, others by fibrin and others by fibrous tissue which may extend from one alveolus to the next through gaps in the septa. Some small areas of lung show diffuse fibrosis heavily pigmented by carbon and it is possible that this fibrosis preceded radiotherapy or was only exaggerated by radiotherapy. Many of the bronchi are dilated and occupied by mucopus. The bronchiolar epithelium is often hyperplastic and the alveolar epithelium frequently shows cubical metaplasia. There is some calcification of small vessels but the large vessels show no gross damage or evidence of former thrombosis. These lungs show more evidence of pyogenic inflammation than is usually described in post-radiation fibrosis; without the history it might be difficult to distinguish the lesion from a primary infective pulmonary inflammation." Discussion Though improved radiotherapeutic technique has reduced the incidence of radiation pneumonitis, despite a trend toward higher radiation dosage, this condition is by no means uncommon, especially following wide field treatment to the thorax. In a severe form radiation pneumonitis is attended by dyspu~ca which may be extreme, and death from respiratory insufficiency has been
354
DOUGLAs
reported within a week of the onset of symptoms (Whitfield et al., i956 ). As congestion and cedema characterise the early stages it was logical that corticosteroids, because of their marked anti-inflammatory effects, should be tried in treatment. That these drugs can exert a profound beneficial influence, in at least some cases, has already been clearly demonstrated, and the early and dramatic response in Cases i and 2 in the present series cannot be interpreted otherwise than as a consequence of corticosteroid therapy. The response of the radiation changes in Case 3 was no less satisfactory than in Cases I and 2 and the deterioration in respiratory function was clearly related to the development of pulmonary infiltration with lymphadenoma. Nevertheless there is also on record substantial evidence of the failure of these drugs either to exert any influence at all on radiation pneumonitis or to effect more than temporary relief, in spite of adequate dosage (Chu et al., i956), and Case 4 is a further example of this. This elderly patient had a previous history of chronic bronchitis and long-continued dust exposure and it is interesting to speculate whether these factors, as well as predisposing to the development of radiation changes, may also have affected the response of these changes to corficosteroids. Moreover it is conceivable that in some cases, perhaps as a result of individual variation in tissue response, a degree of pulmonary damage may occur which precludes reversal of the inflammatory process by corticosteroids. There was, however, a further factor, out of the realm of conjecture, which undoubtedly played a significant part in this particular patient. Considerable evidence of associated infection was observed pathologically, of a degree much in excess of that normally seen in radiation pneumonitis, and it is important to note that the organism most frequently cultured from the sputum in the latter part of the illness was Staph. pyogenes. The early response to treatment with prednisolone indicated the presence of some reversible change, probably tissue oedema. It now seems fairly certain that the slow deterioration of respiratory function which followed, though perhaps due primarily to cellular response to radiation injury, was contributed to materially by a widespread suppurative pneumonia and that the latter was the immediate cause of death. The susceptibility of cases with radiation pneumonitis to develop secondary infection has long been appreciated. The danger of superinfection with the ubiquitous Staph. pyogenes is considerable when the patient is admitted to hospital and, in the absence of effective antibiotic control, such infection may be enhanced by the use of corticosteroids. Ideally, therefore, cases of radiation pneumonitis requiring hospitalisation should be nursed in isolation with all the precautions necessary for the prevention of cross-infection. In the absence of definite answers to the many questions which surround the treatment of radiation pneumonitis it is reasonable to assume that the best results will occur ff treatment with corticosteroids is begun early, dosage is reasonably high initially and treatment is sufficiently prolonged to allow the inflammatory reaction to subside completely. In this last respect it is of interest to note that in Cases I and 2 the improvement in respiratory function continued for a considerable time after stabilisation of the radiographic appear-
TREATMENT OF RADIATION PNEUMONITIS WITH PREDNISOLONE
355
ances. T h e latter should not therefore be r e g a r d e d as a n index to cessation o f t r e a t m e n t which, if p r e m a t u r e , m a y lead to " r e b o u n d " p h e n o m e n a (Cosgriff et al., i 9 5 i ; Bluestein et al., I953). T h e most satisfactory response in the present series was observed in a y o u n g subject with previously healthy lungs in w h o m the above conditions o f t r e a t m e n t were fulfilled. In this case complete clearing o f radiographic opacities a n d complete restoration o f respiratory function was achieved b y t r e a t m e n t extending over a period of 18 weeks.
Summary F o u r cases of radiation pneumonitis treated with prednisolone are described. T w o patients are alive a n d w i t h o u t respiratory symptoms 2½ years after treatment. O n e of these has a n o r m a l chest r a d i o g r a p h ; the o t h e r has only slight residual p u l m o n a r y fibrosis. T w o patients died of respiratory insufficiency. E a c h h a d shown a n initial response to t r e a t m e n t . D e t e r i o r a t i o n was due to infiltration of the lungs with l y m p h a d e n o m a in one patient, a n d in the o t h e r uncontrolled, widespread suppurative p n e u m o n i a was the i m m e d i a t e cause of death. I wish to thank Professor J. Crofton (Case 3) and Dr. I. W. B. Grant (Gases I, 2 and 4) for permission to publish the cases and for helpful advice and criticism; Dr. N. Maclean and Dr. A. Gordon for the pathological reports; Dr. J. G. Pearson, Dr. J. NewaU and Dr. K. A. Mackenzie of the Radiotherapy Department, Edinburgh, for providing details of the treatment given; Mrs. M. Beaton for performing the respiratory function tests; and Miss W. A. M. Tait for secretarial assistance. REFERENCES BEROMANN,M., and GaAHn_~, E. A. (I95I) : 07. thorac. Surg., 22, 549. BLUESTEIN, S. G., and ROEMER, J. (1953): ft. med. Soc. At.ft., 50, IO6. CHU, F. C. H., NmKSON,J. J., and UZEL, A. R. (x956) : Amer. ft. Roentgenol., 75, 53o. CosomFF, S. W., and KLIO~.I~AN, M. N. (x95x) : Radiology, 57, 536. FRSID~NBERQ,R. M., and RUBENFELD,S. (1954) : Amer. 07. Roentgenol., 72, ~7 I. WHITFIELD,A. G. W., BOND, W. H., and ARNOTT,W. M. (1954)1o7.gac. Radiol. (Lond.), 6, 12. (I956): Quart. 07. Med., Vol. XXV, 97, 67.