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The effects of radiation on the lungs in the treatment of carcinoma of the bronchus
THE EFFECTS OF RADIATION ON THE LUNGS IN THE T R E A T M E N T OF C A R C I N O M A O F T H E B R O N C H U S T H O M A S J. DEELEY, M.B., CH.B., F.F.R., D.M.R.T.
M.R.C. Radiotherapeutie Research Unit and Radiotherapy Department, Hammersmith Hospital, London THE changes occurring in the lung~ of patients treated for carcinoma of the bronchus by deep x-ray therapy may be due either to the effects of the radiation on the tumour or to the effects on the normal lung tissue. The interpretation of these changes may be made difficult by the presence of residual or recurrent growth and by infection in the chest. The radiological, physiological and pathological changes occurring in the lungs have been investigated in a group of sixty-one patients treated by the M.R.C, 8 MeV linear accelerator. Each patient in
tinal contents have been included in the treatment fields. A mean tumour dose of 4,500 rads was given in four weeks, except where a field size of over 200 sq. cm. was required when the dose was reduced to 3,600 rads. Whenever possible, two non-opposed fields were used, so arranged that the spinal cord and the opposite lung received only a small dose of radiation (Fig. 1). In very large lesions, however, it was not possible to use this technique, and two large opposed fields were applied to the front and back of the chest. R A D I O G R A P H I C CHANGES
7E?gg?OF
, ,O,SC "M°VLA
Chest radiographs taken at follow-up attendances have been compared with preliminary films taken before treatment and the changes noted. It is possible to distinguish two radiological pictures :--1. An increase in the size of the opacity in the treated lung; 2. Evidence of lung fibrosis and shrinkage. In this group of sixty-one patients there was an increase after treatment in the size of the opacity in twenty-seven patients [44 per cent). The opaque area is frequently hazy in appearance but there may be patchy areas of consolidation which often coalesce to form a dense shadow. This change is usually seen at about three to eight months after treatment, and the opacity is subsequently reduced in size by fibrosis and shrinkage. In no cases has the lung returned completely to normal. It is thought that this change is similar to that produced after radiation of the normal lung since it corresponds in size and position to the x-ray fields (Fig. 2). The majority of cases show evidence of lung shrinkage without an initial increase in the opacity. Lung shrinkage is shown by movement of the heart, the trachea and the hilum of the lung, tenting or elevation of the diaphragm, and contraction of the ribs on the affected side as compared with the film taken before treatment. At the same time as fibrosis occurs in one lung, there is evidence of emphysematous changes in the unaffected lung (Figs. 3 and 4). An attempt has been made to trace the development of the fibrosis by finding the proportion of
3d/ /
P"I O X B G M ~ Fro. I Two non-opposed fields technique using wedge filters for treatment of carcinoma of the bronchus with 8 MeV x-rays.
the group had a proved, inoperable carcinoma of the bronchus confined to the chest and each received a radical course of x-ray therapy. To reduce the number of radiographs where the lung changes may be due to carcinoma, only those patients who have survived for more than one year from the beginning of treatment have been included. The radiation techniques employed at this voltage have been described by Morrison and Deeley (1957). The opaque area as shown on the x-ray film and a surrounding area of 2 cm. of apparently normal lung, together with the medias33
34
CLINICAL
FiG. 2A
RADIOLOGY
FIG. 2B
Chest radiograph of patient with carcinoma of left upper lobe (a) before treatment and (b) one month after starting x-ray therapy showing an increase in the size of the opacity in the left lung.
FIG. 3A
FIG. 3n
Chest radiograph of patient with peripheral squamous carcinoma of left upper lobe (a) before treatment and (b) eleven months after treatment, showing dense opacity left upper lobe with deviation of the trachea and contraction of the ribs on the left side.
EFFECTS
OF
RADIATION
ON
THE
0
i~2 3 4 ~
Fro. 4 R a d i o g r a p h o f the c h e s t fifteen m o n t h s after t r e a t m e n t f o r s q u a m o u s cell c a r c i n o m a o f t h e r i g h t u p p e r l o b e s h o w i n g m a r k e d elevation a n d t e n t i n g o f the d i a p h r a g m a n d d e v i a t i o n o f the t r a c h e a .
radiographs each month after treatment showing evidence of lung shrinkage. When a radiograph has shown evidence of shrinkage and a subsequent film taken a few months later has revealed a similar picture, it has been assumed that shrinkage has persisted during the intervening months. I f a radiograph taken a few months after starting treatment showed no evidence of shrinkage, it has been assumed that none has occurred up to that time. Where one film showed no evidence of shrinkage and the next film has shown evidence of shrinkage, no attempt has been made to guess what has occurred in the intervening time. Figure 5 shows the percentage of radiographs with evidence of lung shrinkage for each month up to one year after treatment. The graph shows that there is a rapid increase in the development of lung shrinkage in the months immediately after treatment and that the majority of films showed some evidence of shrinkage at the end of the first year. Figure 6 shows the incidence and development of lung shrinkage in the radiographs of twentythree patients in the group analysed who survived for two or more years after treatment. It will be seen that the radiographs of all patients showed some evidence of lung shrinkage at the fourteenth month from the beginning of treatment. There is very little difference in the incidence and development of lung shrinkage up to twelve months after
35
LUNGS
s 67
s 9 to i t l 2 Months
FIG. 5 P e r c e n t a g e o f r a d i o g r a p h s s h o w i n g a n y evidence o f lung s h r i n k a g e for e a c h m o n t h u p to o n e y e a r after t r e a t m e n t m sixty-one p a t i e n t s t r e a t e d b y 8 M e V x-rays.
FIG. 6 P e r c e n t a g e o f r a d i o g r a p h s s h o w i n g a n y evidence o f l u n g s h r i n k a g e f o r e a c h m o n t h u p to t w o y e a r s after t r e a t m e n t m twentyt h r e e p a t i e n t s t r e a t e d b y 8 M e V x-rays.
Fro. 7 M o v e m e n t o f e a c h s t r u c t u r e r e c o r d e d every m o n t h in t w e n t y t h r e e p a t i e n t s s u r v i v i n g at least t w o years.
36
CLINICAL
RADIOLOGY
treatment, for the one and two year survivors. In the cases reviewed once shrinkage has occurred in the irradiated lung the process is irreversible. The movement of each structure in those patients who have survived for two years or more is shown in Figure 7. As would be expected, the more mobile structures--the trachea, the hilum and the diaphragm--are those chiefly affected. SYMPTOMS After treatment there is immediate palliation of' most of the original symptoms (Morrison and Deeley 1957). Some patients do not complain of further symptoms even though there is radiological evidence of fibrosis. Symptoms occurring after treatment may be due to recurrence of the carcinoma, to the effects of the fibrosis in the lung, or to subsequent infection of the diseased lung. The patient may complain of a cough, usually irritable and non-productive, dyspnoea which is often progressive, or recurring attacks of chest infection. In the group of sixty-one patients reviewed, ten had a history of chronic bronchitis with acute infective attacks; these attacks continued after treatment. Of the remaining fifty-one patients thirteen developed recurrent attacks of infection in the chest with pyrexia, dyspnoea and productive cough. These attacks frequently occurred in the winter months. The symptoms increased in severity with each attack, and the patient developed increasing dyspnoea between the acute episodes. It is thought that these acute attacks are due to infection of the lung already damaged by fibrosis. The damage caused by subsequent infection can only be repaired by further fibrosis in the lung. After several recurrent attacks o f acute infection in the chest one patient developed symptoms of right sided heart failure. At post mortem there was the picture of cor pulmonale, marked fibrosis at the site of the primary tumour and no evidence of recurrence of the growth. L U N G F U N C T I O N TESTS In the last few years all patients have had investigations of the lung physiology before treatment, and at monthly follow-up visits. Measurements of the vital capacity and the indirect maximum breathing capacity are available for twenty-eight patients who have survived for at least twelve months after treatment. All patients had radiological evidence of lung fibrosis in this time. The results of the lung function tests are shown in Figure 8. This is a composite graph for the twenty-eight patients showing the vital capacity
FIG. 8 L u n g f u n c t i o n tests t a k e n e a c h m o n t h f o r t w e n t y - e i g b t p a t i e n t s w h o s u r v i v e d m o r e t h a n o n e year.
and indirect maximum breathing capacity for each month after treatment expressed as a percentage of the reading taken before treatment. The graph shows that initially there is a slight increase in the vital Capacity over the first four to five months, but that after this there is a steady fall until at the end of the first year the capacity is only about 75 per cent of that taken before starting treatment. A similar pattern is seen with the indirect maximum breathing capacity, but the reduction is not so great, being about 95 per cent at twelve months. The initial improvement in vital capacity is probably due to the effect of the radiation on the tumour, reducing the amount of bronchial obstruction and increasing the amount of functioning lung tissue. A reduction in vital capacity occurs late and may be due to fibrosis or to an increase in the size of the growth. At about the same time there is an increase in the incidence of lung shrinkage as shown by chest radiographs (see Fig. 5). The increased thickening of the walls of the alveoli and the infiltration of the interstitial tissues causes increased resistance to distension and a reduction in the capacity. The maximum breathing capacity is not reduced to such an extent, as the airways are not obstructed. These changes are not specific to radiation fibrosis, and similar changes have been reported in other conditions causing fibrosis such as pulmonary sarcoidosis, silicosis, scleroderma and beryllium inhalation (Arnott i955). PATHOLOGY Several of these patients have died in hospital, and post mortem examinations have been possible. Pleural effusions were often present on the affected
EFFECTS
OF R A D I A T I O N
ON T H E L U N G S
37
FIG. 9 Section of lung taken at site of primary tumour showing dense fibrosis. ( x 160.)
side. Thickening of the pleura was seen in some cases and sometimes up to ½ cm. thick in places. The affected lung or lobe was collapsed and there was often evidence of emphysema of the remaining lung. Macroscopically the lung showed extensive fibrosis at the site of the primary tumour, and outside this region areas of patchy collapse and oedema. On histological examination, sections taken at the site of the primary lesion showed extensive fibrosis, the normal lung parenchyma being almost completely replaced by dense fibrous tissue (Fig. 9). Outside the area of the primary tumour but within the area of lung which had been irradiated there was filling of the alveolar spaces with macrophages and exudate. This reaction was more marked than in the non-irradiated lung. The alveolar walls were thickened and there was lymphocytic infiltration of the interstitial tissues (Fig. 10). Elastic staining showed fragmentation and thickening of the fibres (Fig. 11). These findings are not specific for radiation damage, and have been described in other conditions causing damage to the lung. Similar changes
have been reported in cases of oil pneumonias by Hutchison (1953). Fragmentation and thickening of the elastic tissues may be found in healed apical scars and infarcts and in cases of chronic pneumonias.
FIG- 10 Section of irradiated lung outside the area of primary tumour. (x72)
38
CLINICAL
FIG. 11 Section of irradiated lung outside the area of the primary turnout--elastic staining. (x72.)
Differential diagnosis.--The differential diagnosis of the radiation effects in the normal lung is between pulmonary tuberculosis, infection and secondary deposits. When cancer is present in the lung, it is difficult to differentiate between the effects of radiation on the lung, recurrence of the tumour and infection. Recurrent growth in the chest is usually associated with increasing dyspnoea and cough, often with haemoptysis. The chest radiographs show a steady increase in the size of the lung opacity. Collapse of a lobe may occur from pressure by the tumour, but this is of more sudden onset than the slow contraction seen in fibrosis. In advanced cases the tumour may cause a mediastinal shift to the opposite side. Sputum examination may show the presence of malignant cells. Infection in the lung is usually of acute onset, similar to the acute exacerbations of chronic bronchitis or pneumonia, with pyrexia, dyspnoea and a productive cough. Radiographs show an increase in the size and density of the opacity and often there are patchy areas of consolidation. There is seldom an increase in the degree of the mediastinal shift. Treatment.--Damage to the lung either by carcinoma or by radiation is repaired by fibrous tissue. In the uncomplicated case, there is some impairment in the respiratory function, but the patient learns to adapt himself to his restricted activity. The fibrosed lung, however, is very prone to infection which must be treated at once to prevent further damage to the lung parenchyma. I f there is evidence of infection in the chest every effort should be made to identify the organisms concerned so that the appropriate antibiotic can be used. This is not always possible and an anti-
RADIOLOGY
biotic with a b r o a d spectrum has to be given. It is important that the patient's family doctor is informed of the risk of infection and for the need of antibiotics as much valuable time may be wasted before the condition is recognised. Every effort should be made to establish the presence of recurrence in the lung before giving further x-ray therapy because this will cause an increase in the fibrosis. I f there is any doubt about the diagnosis the condition should be treated as infective and a course of antibiotics given. In a small number of patients respiratory embarrassment m a y lead to right sided heart failure, which requires treatment. In severe cases of radiation fibrosis the possibility of a pneumonectomy should be considered. Bergman and G r a h a m (1951) suggested that this should be done even if residual growth was present. There are possible dangers in performing operations on a site where there is such severe fibrosis. Healing may be delayed and bronchial fistulae m a y develop because of the limited blood supply. C O M P A R I S O N OF T H E R A D I O G R A P H I C FINDINGS IN PATIENTS TREATED-BY 8 MeV X-RAYS A N D 240 KV X-RAYS The chest x-rays of twenty-seven patients who had a proved carcinoma of the bronchus and who have survived one year after a radical course of
FIG. 12 Percentage of radiographs showing any evidence of lung shrinkage for each month up to one year after treatment in twentyseven patients treated by 240 kV x-rays.
EFFECTS OF R A D I A T I O N ON THE L U N G S
treatment with 240 kV x-rays have been reviewed in exactly the same way as that described above for those patients treated by 8 MeV x-rays. With the lower voltage, multiple fields were required to give an adequate tumour dose to the bronchus, In most patients eight or nine fields, each measuring 15 by 5 cm., were applied to one hemithorax and angled towards the mediastinum. A tumour dose of 4,500 r was given in four weeks. The graph (Fig. 12) shows the proportion of patients with any radiological evidence of lung shrinkage for each month after treatment. Comparing this with the graph in Figure 4 it will be seen that the d e v e l o p m e n t of lung shrinkage is almost the same for the two methods of treatment. CONCLUSIONS The reactions occurring in the lungs after x-ray therapy for carcinoma of the bronchus are similar to those found when cancer is treated elsewhere in the body. At the site of the primary tumour there is dense fibrosis. In the normal tissues there is at first a reaction shown on the radiograph as an increased opacity in the lung fields and microscopically as oedema of the tissues with lymphocytic infiltration and exudate into the alveoli. This reaction corresponds to that seen on the mucous membrane in the mouth or in the rectum and to the moist desquamation found in the skin. The reaction may resolve, as it sometimes does, at the other sites mentioned, but with the doses normally given in the treatment of carcinoma the damage is usually too severe for complete resolution to take place and fibrosis occurs. Evidence of lung shrinkage is found in all patients who survive for fourteen months. This may be due to the fibrosis at the site of the primary turnout or to fibrosis occurring in the normal lung which was damaged by the radiation. The resultant fibrosis and lung shrinkage cause some reduction in
39
the respiratory reserve but most patients are able to adapt themselves to this. In some patients the fibrosed lung becomes infected and recurrent attacks of chest infection occur with further damage to the diseased lung. Infection developing at any time, in the lungs of a patient treated by radiotherapy to the chest, must be treated with antibiotics as soon as symptoms develop because of the risk of further damage. SUMMARY A description is given of the radiological, physiological and pathological changes occurring in the lungs of sixty-one patients treated for carcinoma of the bronchus by megavoltage x-ray therapy. The changes in the lung are similar to the changes caused by radiation in other tissues, there is a stage of reaction to the treatment followed by fibrosis and repair of damage. Radiological evidence of lung shrinkage was found in all patients who survived for fifteen months. As a result of this shrinkage there is a reduction in the physiological function of the lungs. The fibrosed lung is prone to infection and the need for immediate antibiotic therapy is stressed. The incidence and development of lung shrinkage was similar for patients treated by 8 MeV x-rays and 240 kV x-rays when a radical tumour dose was given. Acknowledgements.--[wish to thank Dr I. Doniach for his help in interpreting the pathological changes, Drs C. A. P. Wood, R. Morrison and P. B. Woodyatt under whose care the patients were treated and Drs J. G, Kenney and M. Sutton who estimated the lung functions.
REFERENCES ARNOTT, W. (1955). Brit. reed. J. 2, 279. BERGMAN,D., &; GRAHAM,E. A. (1951). J. thorae. Surg. 22, 549. HUTCHISON, H . E . (1953). Glasg. reed. J. 34, 299. MORRISON, R., & DEELEY, T. J. (1957). Lancet, 2"73, 907.
M.R.C. Radiotherapeutie Research Unit and Radiotherapy Department, Hammersmith Hospital, London THE changes occurring in the lung~ of patients treated for carcinoma of the bronchus by deep x-ray therapy may be due either to the effects of the radiation on the tumour or to the effects on the normal lung tissue. The interpretation of these changes may be made difficult by the presence of residual or recurrent growth and by infection in the chest. The radiological, physiological and pathological changes occurring in the lungs have been investigated in a group of sixty-one patients treated by the M.R.C, 8 MeV linear accelerator. Each patient in
tinal contents have been included in the treatment fields. A mean tumour dose of 4,500 rads was given in four weeks, except where a field size of over 200 sq. cm. was required when the dose was reduced to 3,600 rads. Whenever possible, two non-opposed fields were used, so arranged that the spinal cord and the opposite lung received only a small dose of radiation (Fig. 1). In very large lesions, however, it was not possible to use this technique, and two large opposed fields were applied to the front and back of the chest. R A D I O G R A P H I C CHANGES
7E?gg?OF
, ,O,SC "M°VLA
Chest radiographs taken at follow-up attendances have been compared with preliminary films taken before treatment and the changes noted. It is possible to distinguish two radiological pictures :--1. An increase in the size of the opacity in the treated lung; 2. Evidence of lung fibrosis and shrinkage. In this group of sixty-one patients there was an increase after treatment in the size of the opacity in twenty-seven patients [44 per cent). The opaque area is frequently hazy in appearance but there may be patchy areas of consolidation which often coalesce to form a dense shadow. This change is usually seen at about three to eight months after treatment, and the opacity is subsequently reduced in size by fibrosis and shrinkage. In no cases has the lung returned completely to normal. It is thought that this change is similar to that produced after radiation of the normal lung since it corresponds in size and position to the x-ray fields (Fig. 2). The majority of cases show evidence of lung shrinkage without an initial increase in the opacity. Lung shrinkage is shown by movement of the heart, the trachea and the hilum of the lung, tenting or elevation of the diaphragm, and contraction of the ribs on the affected side as compared with the film taken before treatment. At the same time as fibrosis occurs in one lung, there is evidence of emphysematous changes in the unaffected lung (Figs. 3 and 4). An attempt has been made to trace the development of the fibrosis by finding the proportion of
3d/ /
P"I O X B G M ~ Fro. I Two non-opposed fields technique using wedge filters for treatment of carcinoma of the bronchus with 8 MeV x-rays.
the group had a proved, inoperable carcinoma of the bronchus confined to the chest and each received a radical course of x-ray therapy. To reduce the number of radiographs where the lung changes may be due to carcinoma, only those patients who have survived for more than one year from the beginning of treatment have been included. The radiation techniques employed at this voltage have been described by Morrison and Deeley (1957). The opaque area as shown on the x-ray film and a surrounding area of 2 cm. of apparently normal lung, together with the medias33
34
CLINICAL
FiG. 2A
RADIOLOGY
FIG. 2B
Chest radiograph of patient with carcinoma of left upper lobe (a) before treatment and (b) one month after starting x-ray therapy showing an increase in the size of the opacity in the left lung.
FIG. 3A
FIG. 3n
Chest radiograph of patient with peripheral squamous carcinoma of left upper lobe (a) before treatment and (b) eleven months after treatment, showing dense opacity left upper lobe with deviation of the trachea and contraction of the ribs on the left side.
EFFECTS
OF
RADIATION
ON
THE
0
i~2 3 4 ~
Fro. 4 R a d i o g r a p h o f the c h e s t fifteen m o n t h s after t r e a t m e n t f o r s q u a m o u s cell c a r c i n o m a o f t h e r i g h t u p p e r l o b e s h o w i n g m a r k e d elevation a n d t e n t i n g o f the d i a p h r a g m a n d d e v i a t i o n o f the t r a c h e a .
radiographs each month after treatment showing evidence of lung shrinkage. When a radiograph has shown evidence of shrinkage and a subsequent film taken a few months later has revealed a similar picture, it has been assumed that shrinkage has persisted during the intervening months. I f a radiograph taken a few months after starting treatment showed no evidence of shrinkage, it has been assumed that none has occurred up to that time. Where one film showed no evidence of shrinkage and the next film has shown evidence of shrinkage, no attempt has been made to guess what has occurred in the intervening time. Figure 5 shows the percentage of radiographs with evidence of lung shrinkage for each month up to one year after treatment. The graph shows that there is a rapid increase in the development of lung shrinkage in the months immediately after treatment and that the majority of films showed some evidence of shrinkage at the end of the first year. Figure 6 shows the incidence and development of lung shrinkage in the radiographs of twentythree patients in the group analysed who survived for two or more years after treatment. It will be seen that the radiographs of all patients showed some evidence of lung shrinkage at the fourteenth month from the beginning of treatment. There is very little difference in the incidence and development of lung shrinkage up to twelve months after
35
LUNGS
s 67
s 9 to i t l 2 Months
FIG. 5 P e r c e n t a g e o f r a d i o g r a p h s s h o w i n g a n y evidence o f lung s h r i n k a g e for e a c h m o n t h u p to o n e y e a r after t r e a t m e n t m sixty-one p a t i e n t s t r e a t e d b y 8 M e V x-rays.
FIG. 6 P e r c e n t a g e o f r a d i o g r a p h s s h o w i n g a n y evidence o f l u n g s h r i n k a g e f o r e a c h m o n t h u p to t w o y e a r s after t r e a t m e n t m twentyt h r e e p a t i e n t s t r e a t e d b y 8 M e V x-rays.
Fro. 7 M o v e m e n t o f e a c h s t r u c t u r e r e c o r d e d every m o n t h in t w e n t y t h r e e p a t i e n t s s u r v i v i n g at least t w o years.
36
CLINICAL
RADIOLOGY
treatment, for the one and two year survivors. In the cases reviewed once shrinkage has occurred in the irradiated lung the process is irreversible. The movement of each structure in those patients who have survived for two years or more is shown in Figure 7. As would be expected, the more mobile structures--the trachea, the hilum and the diaphragm--are those chiefly affected. SYMPTOMS After treatment there is immediate palliation of' most of the original symptoms (Morrison and Deeley 1957). Some patients do not complain of further symptoms even though there is radiological evidence of fibrosis. Symptoms occurring after treatment may be due to recurrence of the carcinoma, to the effects of the fibrosis in the lung, or to subsequent infection of the diseased lung. The patient may complain of a cough, usually irritable and non-productive, dyspnoea which is often progressive, or recurring attacks of chest infection. In the group of sixty-one patients reviewed, ten had a history of chronic bronchitis with acute infective attacks; these attacks continued after treatment. Of the remaining fifty-one patients thirteen developed recurrent attacks of infection in the chest with pyrexia, dyspnoea and productive cough. These attacks frequently occurred in the winter months. The symptoms increased in severity with each attack, and the patient developed increasing dyspnoea between the acute episodes. It is thought that these acute attacks are due to infection of the lung already damaged by fibrosis. The damage caused by subsequent infection can only be repaired by further fibrosis in the lung. After several recurrent attacks o f acute infection in the chest one patient developed symptoms of right sided heart failure. At post mortem there was the picture of cor pulmonale, marked fibrosis at the site of the primary tumour and no evidence of recurrence of the growth. L U N G F U N C T I O N TESTS In the last few years all patients have had investigations of the lung physiology before treatment, and at monthly follow-up visits. Measurements of the vital capacity and the indirect maximum breathing capacity are available for twenty-eight patients who have survived for at least twelve months after treatment. All patients had radiological evidence of lung fibrosis in this time. The results of the lung function tests are shown in Figure 8. This is a composite graph for the twenty-eight patients showing the vital capacity
FIG. 8 L u n g f u n c t i o n tests t a k e n e a c h m o n t h f o r t w e n t y - e i g b t p a t i e n t s w h o s u r v i v e d m o r e t h a n o n e year.
and indirect maximum breathing capacity for each month after treatment expressed as a percentage of the reading taken before treatment. The graph shows that initially there is a slight increase in the vital Capacity over the first four to five months, but that after this there is a steady fall until at the end of the first year the capacity is only about 75 per cent of that taken before starting treatment. A similar pattern is seen with the indirect maximum breathing capacity, but the reduction is not so great, being about 95 per cent at twelve months. The initial improvement in vital capacity is probably due to the effect of the radiation on the tumour, reducing the amount of bronchial obstruction and increasing the amount of functioning lung tissue. A reduction in vital capacity occurs late and may be due to fibrosis or to an increase in the size of the growth. At about the same time there is an increase in the incidence of lung shrinkage as shown by chest radiographs (see Fig. 5). The increased thickening of the walls of the alveoli and the infiltration of the interstitial tissues causes increased resistance to distension and a reduction in the capacity. The maximum breathing capacity is not reduced to such an extent, as the airways are not obstructed. These changes are not specific to radiation fibrosis, and similar changes have been reported in other conditions causing fibrosis such as pulmonary sarcoidosis, silicosis, scleroderma and beryllium inhalation (Arnott i955). PATHOLOGY Several of these patients have died in hospital, and post mortem examinations have been possible. Pleural effusions were often present on the affected
EFFECTS
OF R A D I A T I O N
ON T H E L U N G S
37
FIG. 9 Section of lung taken at site of primary tumour showing dense fibrosis. ( x 160.)
side. Thickening of the pleura was seen in some cases and sometimes up to ½ cm. thick in places. The affected lung or lobe was collapsed and there was often evidence of emphysema of the remaining lung. Macroscopically the lung showed extensive fibrosis at the site of the primary tumour, and outside this region areas of patchy collapse and oedema. On histological examination, sections taken at the site of the primary lesion showed extensive fibrosis, the normal lung parenchyma being almost completely replaced by dense fibrous tissue (Fig. 9). Outside the area of the primary tumour but within the area of lung which had been irradiated there was filling of the alveolar spaces with macrophages and exudate. This reaction was more marked than in the non-irradiated lung. The alveolar walls were thickened and there was lymphocytic infiltration of the interstitial tissues (Fig. 10). Elastic staining showed fragmentation and thickening of the fibres (Fig. 11). These findings are not specific for radiation damage, and have been described in other conditions causing damage to the lung. Similar changes
have been reported in cases of oil pneumonias by Hutchison (1953). Fragmentation and thickening of the elastic tissues may be found in healed apical scars and infarcts and in cases of chronic pneumonias.
FIG- 10 Section of irradiated lung outside the area of primary tumour. (x72)
38
CLINICAL
FIG. 11 Section of irradiated lung outside the area of the primary turnout--elastic staining. (x72.)
Differential diagnosis.--The differential diagnosis of the radiation effects in the normal lung is between pulmonary tuberculosis, infection and secondary deposits. When cancer is present in the lung, it is difficult to differentiate between the effects of radiation on the lung, recurrence of the tumour and infection. Recurrent growth in the chest is usually associated with increasing dyspnoea and cough, often with haemoptysis. The chest radiographs show a steady increase in the size of the lung opacity. Collapse of a lobe may occur from pressure by the tumour, but this is of more sudden onset than the slow contraction seen in fibrosis. In advanced cases the tumour may cause a mediastinal shift to the opposite side. Sputum examination may show the presence of malignant cells. Infection in the lung is usually of acute onset, similar to the acute exacerbations of chronic bronchitis or pneumonia, with pyrexia, dyspnoea and a productive cough. Radiographs show an increase in the size and density of the opacity and often there are patchy areas of consolidation. There is seldom an increase in the degree of the mediastinal shift. Treatment.--Damage to the lung either by carcinoma or by radiation is repaired by fibrous tissue. In the uncomplicated case, there is some impairment in the respiratory function, but the patient learns to adapt himself to his restricted activity. The fibrosed lung, however, is very prone to infection which must be treated at once to prevent further damage to the lung parenchyma. I f there is evidence of infection in the chest every effort should be made to identify the organisms concerned so that the appropriate antibiotic can be used. This is not always possible and an anti-
RADIOLOGY
biotic with a b r o a d spectrum has to be given. It is important that the patient's family doctor is informed of the risk of infection and for the need of antibiotics as much valuable time may be wasted before the condition is recognised. Every effort should be made to establish the presence of recurrence in the lung before giving further x-ray therapy because this will cause an increase in the fibrosis. I f there is any doubt about the diagnosis the condition should be treated as infective and a course of antibiotics given. In a small number of patients respiratory embarrassment m a y lead to right sided heart failure, which requires treatment. In severe cases of radiation fibrosis the possibility of a pneumonectomy should be considered. Bergman and G r a h a m (1951) suggested that this should be done even if residual growth was present. There are possible dangers in performing operations on a site where there is such severe fibrosis. Healing may be delayed and bronchial fistulae m a y develop because of the limited blood supply. C O M P A R I S O N OF T H E R A D I O G R A P H I C FINDINGS IN PATIENTS TREATED-BY 8 MeV X-RAYS A N D 240 KV X-RAYS The chest x-rays of twenty-seven patients who had a proved carcinoma of the bronchus and who have survived one year after a radical course of
FIG. 12 Percentage of radiographs showing any evidence of lung shrinkage for each month up to one year after treatment in twentyseven patients treated by 240 kV x-rays.
EFFECTS OF R A D I A T I O N ON THE L U N G S
treatment with 240 kV x-rays have been reviewed in exactly the same way as that described above for those patients treated by 8 MeV x-rays. With the lower voltage, multiple fields were required to give an adequate tumour dose to the bronchus, In most patients eight or nine fields, each measuring 15 by 5 cm., were applied to one hemithorax and angled towards the mediastinum. A tumour dose of 4,500 r was given in four weeks. The graph (Fig. 12) shows the proportion of patients with any radiological evidence of lung shrinkage for each month after treatment. Comparing this with the graph in Figure 4 it will be seen that the d e v e l o p m e n t of lung shrinkage is almost the same for the two methods of treatment. CONCLUSIONS The reactions occurring in the lungs after x-ray therapy for carcinoma of the bronchus are similar to those found when cancer is treated elsewhere in the body. At the site of the primary tumour there is dense fibrosis. In the normal tissues there is at first a reaction shown on the radiograph as an increased opacity in the lung fields and microscopically as oedema of the tissues with lymphocytic infiltration and exudate into the alveoli. This reaction corresponds to that seen on the mucous membrane in the mouth or in the rectum and to the moist desquamation found in the skin. The reaction may resolve, as it sometimes does, at the other sites mentioned, but with the doses normally given in the treatment of carcinoma the damage is usually too severe for complete resolution to take place and fibrosis occurs. Evidence of lung shrinkage is found in all patients who survive for fourteen months. This may be due to the fibrosis at the site of the primary turnout or to fibrosis occurring in the normal lung which was damaged by the radiation. The resultant fibrosis and lung shrinkage cause some reduction in
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the respiratory reserve but most patients are able to adapt themselves to this. In some patients the fibrosed lung becomes infected and recurrent attacks of chest infection occur with further damage to the diseased lung. Infection developing at any time, in the lungs of a patient treated by radiotherapy to the chest, must be treated with antibiotics as soon as symptoms develop because of the risk of further damage. SUMMARY A description is given of the radiological, physiological and pathological changes occurring in the lungs of sixty-one patients treated for carcinoma of the bronchus by megavoltage x-ray therapy. The changes in the lung are similar to the changes caused by radiation in other tissues, there is a stage of reaction to the treatment followed by fibrosis and repair of damage. Radiological evidence of lung shrinkage was found in all patients who survived for fifteen months. As a result of this shrinkage there is a reduction in the physiological function of the lungs. The fibrosed lung is prone to infection and the need for immediate antibiotic therapy is stressed. The incidence and development of lung shrinkage was similar for patients treated by 8 MeV x-rays and 240 kV x-rays when a radical tumour dose was given. Acknowledgements.--[wish to thank Dr I. Doniach for his help in interpreting the pathological changes, Drs C. A. P. Wood, R. Morrison and P. B. Woodyatt under whose care the patients were treated and Drs J. G, Kenney and M. Sutton who estimated the lung functions.
REFERENCES ARNOTT, W. (1955). Brit. reed. J. 2, 279. BERGMAN,D., &; GRAHAM,E. A. (1951). J. thorae. Surg. 22, 549. HUTCHISON, H . E . (1953). Glasg. reed. J. 34, 299. MORRISON, R., & DEELEY, T. J. (1957). Lancet, 2"73, 907.