Effects of Therapeutic Irradiation Delivered in Early Childhood Upon Subsequent Lung Function

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Effects

of Therapeutic

Irradiation

Delivered

in Early

Childhood

Upon

Subsequent

Lung

Function

Mary Ellen B. Wohl, M.D., N. Thorne Griscom, M.D., Demetrius G. Traggis, M.D.

and

Norman Jaffe,

M.D.

Frarn the Departments ofMedicine, Radiology, and Cardiology (Pulmonary Laboratory). Ghildren ‘s Hospital MedicalCenter; the Department ofPediatrics, Harvard.%IedicalSchool; tile Department ofPhysiology, Harrard School of Public Health; and the Children s Cancer Research Foundation, Boston, Massachusetts

ABSTRACT. To determine the long-term effects of

thera-peutic pulmonary irradiation and treatment with actino-mycin D during a period of lung growth, 12 patients

treat-ed for \Vilms’ tumor metastatic to the lung and 8 patients treated for Wilms’ tumor with no evidence of pulmonary metastases were studied 7 to 14 years after their initial tumor therapy. All patients had received irradiation to the tumor bed and treatment with actinomycin D. Group 1 had received a single course of bilateral pulmonary irradiation; group 2 had received additional pulmonary irradiation and/or thoracic surgery; group 3 had received no

therapeu-tic irradiation directed primarily to the chest. Total lung

capacity (TLC) averaged 71% of predicted value in group 1, 58% in group 2, and 94% in group 3. Diffusing capacity in groups 1 and 2 was reduced to the same extent as lung volume. Quasi-static pressure-volume relationships, studied

115 three of six patients in group 1, were within the normal range when lung volume was expressed as percentage of ob-served TLC. Airway resistance, evaluated by spirometry, maximum expiratory flow-volume curves, and resistance of the total respiratory system, was normal or reduced. The data support the hypothesis that therapeutic irradiation during a period of lung growth primarily affects the lung parenchyma and produces a decrease in subsequent size of both the lung and chest wall. No effect of actinomycin D alone upon the lung could be denionstrated. Pediatrics, 55:507, 1975, WILMS TUMOR; LUNG, EFFECTS OF

IRRADIA-TION; ACTINOMYCIN D, EFFECT ON LUNGS; RADIOTHERAPY,

EFFECT ON LUN(;s.

alveolar lining cells, with subsequent desquama-tion and development of hyaline membranes and fibrosis.”2 Airway changes include partial desqua-mation of epithelium and excessive mucous secre-tion.1 The long-term effects of irradiation on lung function observed both in adult patients and ex-perimental animals have recently been summa-rized.3 In adult patients these include a loss of lung volume,’2 lung compliance,7 and diffusing capacity for carbon monoxide (D1CO).8

Since early childhood is a period of rapid lung growth, the effect of therapeutic irradiation to the lung of young children might depend on its inter-action with lung growth. Airways are formed early in gestational life13 and during childhood they increase in size but not in number. In con-trast, the number of alveoli increases rapidly dur-ing the first few years of life.” Therapeutic irra-diation to the lung could limit the development of new alveoli by limiting the ability of cells to pro-liferate or by interfering with vascular supply. Alternatively, the growing lung might

compen-Therapeutic irradiation to the lung can injure both alveoli and airways. Parenchymal changes include early edema, swelling, and distortion of

(Received April 23; revision accepted for publication June 13, 1974.)

Supported by Public Health Service research grants HDO 1392 and HL 10346.

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sate and produce additional or larger units as has been suggested by some15’8 but not alll9 reports on the long-term effects of pulmonary resection in childhood.

The purpose of this study is to characterize the physiological properties of the lungs in patients who received therapeutic bilateral pulmonary ir-radiation in early childhood. These patients were also treated with actinomycin D which enhances the effects of irradiation on normal tissue2#{176}and in-creases the incidence of radiation pneumonitis in patients who receive therapeutic pulmonary irra-diation.2’ Furthermore, they had received irradia-tion to the primary tumor bed and had developed skeletal abnormalities including short stature which were probably secondary to this irradia-tion.22

To

examine the possible effect on the lung of treatment with actinomycin D and irradiation of

the

primary tumor bed, eight patients who had no pulmonary metastases and received no irradiation directed primarily to the lung were included in the study.

PATiENTS AND METHODS

All

patients had undergone similar treatment of the primary Wilms’ tumor. Nephrectomy was fol-lowed by irradiation of the tumor bed, including

the affected

hemiabdomen and the entire width of the spine through opposed portals measuring from 9

x

10 to 15

x

16 cm. The fields generally extended up to the T9-T10 interspace. A 250-ky apparatus with a haff-value layer of 2.7 mm of copper or similar apparatus was used. Exposures at the midplane of the abdomen ranged from 900 roentgen? in 11 elapsed days to 3,100 R in 27 elapsed days (median was 2,730 R in 24 elapsed days). Treatments were given five days a week. The patients received one to nine courses of acti-nomycin D in doses of 70tg/kg per course at the time of treatment of the primary tumor bed or subsequently.

With respect to pulmonary status the patients

belonged

in three different groups. Patients in groups 1 and 2 developed pulmonary metastases. Group 1 (six children) received a single course of bilateral pulmonary irradiation undertaken with the same apparatus through opposed portals mea-swing from 14

x

1 1 to 16

x

16 cm to include both lung fields. Exposures at the midplane of the chest ranged from 850 to 1,240 R and were deliv-ered in an average of 11 days. They were 22 to 49 months old (average, 43 months) at the time of the

‘3,876 R is equal to 1 coulomb/kg in the New Interna-tional System of Units.

pulmonary irradiation and 7 to 13 years (average, 10 years) had elapsed between the pulmonary ir-radiation and the time of study.

Group 2 (six children) differed from group 1 in that these children had received additional put-monaiy radiotherapy or thoracic surgery or bQth (Table I). One patient (B.H.) who had had two courses of unilateral pulmonary irradiation at an-other hospital using anterior left lateral and poste-rior exposure to the hilum and who had under-gone a thoracotomy and rib resection was in-cluded. Initial radiotherapy to the lung was other-wise similar to group 1 and was delivered with the same or similar equipment. The children were 33 to 50 months of age (average, 43 months) at the time of the initial pulmonary irradiation and 2 to 6 years old at the time of additional radi-otherapy. At the time of study, 7 to 17 years (aver-age, 1 1 years) had elapsed since the initial pulmo-nary irradiation and 4 to 16 years had elapsed since surgery or the last course of radiotherapy.

Group 3 (eight children) did not develop put-monary metastases and therefore received no irra-diation directed primarily to the lung.

At the time of study the patients were 10 to 19 years of age and had no evidence of tumor recur-rence. The patients in groups 1 and 2 were select-ed on the basis of geographical proximity from the 16 patients with Wilms’ tumor metastatic to the lung, treated with bilateral pulmonary irradiation in early childhood, who survived to be 10 years or older.

Radiographs of the chest and spine were re-viewed without knowledge of current status of the patients. Radiographs obtained at the time of

mi-tial radiation to the lung were analyzed for tumor volume (assuming metastases to be spherical in shape) relative to lung volume.23 Recent radi-ographs were reviewed for estimation of paren-chymal change, pleural disease, chest volume, and bony changes. Scoliosis was measured by the method of Cobb on films obtained in the erect po-sition.

Lung volumes were measured in an air-condi-tioned volume displacement body plethysmo-graph.24 Measurements of thoracic gas volume were performed by the method of DuBois et al.25 at functional residual capacity (FRC) and were fot-lowed by a full inspiration to total lung capacity (TLC). Vital capacity (VC) was subtracted from TLC to determine residual volume (RV). At least five determinations of TLC were made for each subject and the results were averaged. Individual lung volumes were compared to the predicted

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TABLE I

CLINICAL INFORMATION

Patient Age at

Nephrec-tomy (mo)

Irradiation to Tumor Bed

Midplane

Exposure’ Age

(mo)

Bilateral Pulmonary Irradiation

Midplane Exposure’

Age (mo)

Additional Irradiation

Exposure’ Location

Ch Age

est Surgenj Operation

M.R. 20 2,730 23 22 1,190 23

Group 1

CS. 23 3,100 27 31 1,250 9

C.D.t 47 2,990 23 49 1,240 8

J.K. 19 2,370 33 24 1,210 9

1,090 9

N.M. 33 900 11 33 850 9

S.A. 28 2,290 25 41 1,230 12

D.S. 41 2,798 29* 513 1,200 8

Group 2

59mo Segmental resection RUL

R.T. 35 3,000 26 42 920 6 13 yr Granuloma RLL

K.S.t 29 2,400 37* 36 1,200 10 39 1,860 30 Chest RL 42 mo Lobectomy, R

D.R. 33 2,910 24 47

60

1,310 8

1,320 8

72 1,900 14 RL 6yr RLL wedge

resection

R.M. 32 2,970 3J$ 33

38

1,280 11

1,210 9

38 2,050 12 Abdomen

RL

B.H. 30 1,500 19

500 10

38 44

1,250 10

1,240 6

L lung R

lumbo-sacral gutter

5 yr Biopsy R lung; resection rib tumor

SB. 39 3,250 31

Group 3

J.H. 38 2,940 27

KS. 41 3,030 37

L.S. 7 1,790 31

2,840 20 (age 11 mo)

J.T. 6 1,400 23

J.W. 47 3,060 28

D.F. 46 2,910 26

J.K. 53 3,120 25

‘Exposure expressed in ;oentgens in elapsed days.

C.D. previously reported’; KS., DR., and R.M. previously reported.”

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values of Cook and Hamann26 which are based upon standing height. The diffusing capacity for carbon monoxide (DLCO) was measured by the single breath method of Ogilvie et 27 Forced ex-piratory volume in one second (FEV1) was calcu-lated from spirographic tracings and expressed in percent VC.

Static elastic properties of the lung were stud-ied with an esophageal balloon positioned at a point in the middle third of the esophagus free of tracheal artifact28 in three

(J.

K., N. M., and S. A.) of the six patients in group 1. Following three breaths to TLC the airway was obstructed at a number of points during deflation. The pressure difference between esophagus and airway mea-sured by a differential pressure transducer (San-born 268 B) and lung volume measured in the body plethysmograph were recorded on an oscil-lograph. Volume-pressure curves were drawn by eye through an X-Y plot of the data and compared to results obtained by the same technique in six normal children ranging in age from 1 1 to 15 years and in height from 146 to 172 cm.

Maximum expiratory flow-volume (MEFV)

curves were obtained after inspiration from FRC to TLC. Instantaneous flow rates, measured with a pneumotachograph (Fleisch *4) and a pres-sure transducer (Sanborn #270k), and lung volume, measured in the body plethysmograph, were displayed on a storage oscilloscope and photographed. For the three children in whom the static elastic properties of the lung were mea-sured, the conductance of the upstream segment of the airways29 was calculated by dividing the maximum expiratory flow by the transpulmonary pressure at the same lung volumes.

Resistance of the total respiratory system was measured by the technique of forced oscillation described by DuBois et al.3#{176}and modified by

Grim-by et al.31 Inspiratory and expiratory resistance

and Rexp) were calculated at midtidal vol-ume at an oscillatory frequency of 5 cycles/sec. Conductance of the respiratory system expressed as a function of the lung volume at which it was measured was compared to data on normal chil-dren studied in this laboratory.

RESULTS

In nine of the 12 patients from groups 1 and 2 the volume of lung metastases, as estimated from

*Sanborn Division, Hewlett Packard, Waltham,

Massa-chusetts.

Instrumentation Associates, New York, New York.

(ITektronix type 564, P.O. Box 500, Beaverton, Oregon.

radiographs taken at the beginning of pulmonary irradiation, represented less than 2% of lung volume. But tumor volume represented 25% of lung volume in one patient (R. M.) and 10% in an-other (C. D.). In one patient (K. S.) tumor volume could not be estimated because of a large pleural effusion.

Review of the current chest radiographs re-vealed that the patients in group 1 had either mm-imal or no pleural or pulmonary parenchymal ab-normalities. Most of the patients in group 2 had evidence of minor interstitial and pleural thicken-ing. The most severe radiographic changes were observed in D. R. who had had two courses of bilat-eral pulmonary irradiation, one additional course to the right lung, and a segmental resection. In this patient the lower part of the right lung field was fibrotic, the bronchi were distended with thickened walls suggestive of bronchiectasis, and there was moderate pleural thickening on the right. Recent chest radiographs were not avail-able on R. M., the other patient who received a second course of bilateral pulmonary irradiation. In group 3 one patient had blunting of one costo-phrenic sulcus; the others had no pleural or parenchymat changes.

Shortening and deformity of the lower thoracic and lumbar vertebrae within the abdominal treat-ment field22 were observed in all patients at-though in one third these changes were minimal. In groups 1 and 2 lateral spinal curvatures ranging from 5 to 35 degrees (mean, 13 degrees) were ob-served in all but one patient (N. M.). They were located between T10 and L5 except for one 12-de-gree curvature extending from T5 to T12 (S. A.). In group 3 spinal curvatures ranging from 5 to 42 degrees and located between T9 and L2 were oh-served in four children. The lower torsos were small and short in all patients. The lower ribs within the field of irradiation to the tumor bed were shorter and thinner and flared out less than the lower ribs on the unirradiated side and the lower chest and iliac bones on the treated side were small.

These changes probably influenced height. Only two patients were above the mean height for their age and three were below 2 SD (Table II). The average deviations from the predicted mean heights for age32 were -0.5 SD, -1.7 SD, and -0.6 SD for groups 1, 2 and 3, respectively.

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TABLE II

LuNG FUNCTION IN PATIENTS Wiio RECEIVED BILATERAL PULMONARY IRRADiATION (GROUP 1), ADDITIONAL PULMONARY

IRRAI)IATION OR THORACOTOMY (GROUP 2), AND No PULMONARY ImWIATI0N (GROUP 3)

Patient

Age

Sex (yr)

Ileight (cm)’

VCt (Liters)

TLC FRC

(Liters) (Liters)

D1 CO FEV, Resistance

R ‘1’ (ml CO/min/ (cm H20/liter/sec)

(Liters) mm Hg) (% of VC) Insp. Exp.

Group 1

MR. F 1 1.0 126(-2.4) 1.17 (71) 1.67 (78) 1.07 (78) 0.50 (94) 14.6 (86) 92 2.6 4.9

CS. F 13.8 150(-1.5) 1.76 (57) 2.53 (70) 1.38 (72) 0.64 (72) 14.4 (56) 98 5.9 8.1

CD. F 1 1.0 145(0) 2.12 (85) 2.54 (77) 1.32 (77) 0.42 (51) 20.9 (86) 93 6.4 6.5

J.K.t M 13.1 154(-0.2) 2.20 (67) 2.85 (67) 1.54 (75) 0.70 (70) 16.6 (58) 76 4.8 5.0

N.M.t NI 15.3 179(+1.1) 3.36 (66) 4.41 (62) 2.27 (67) 1.02 (64) 24.3 (61) 92 2.3 2.4

S.A. M 11.7 147(-0.2) 2.20 (79) 2.73 (74) 1.35 (77) 0.54 (62) 15.8 (61) 92 5.2 6.0

Mean ± SD 72±8 71±6 74±4 69±14 68±14 90±73 45±i.7 5.5± 1.9

D.S. M 10.2 150( + 1.8) 2.25 (76)

Group 2

3.01 (77) 1.81 (96) 0.71 (73;) 23.0 (85) 87 5.2 4.4

R.T. F 16.7 148(.-2.4) 2.48 (94) 2.74 (79) 1.04 (57) 0.26 (30) 16.2 (64) 79 4.8 4.9

KS. M 16.0 156(-2.1) 2.05 (61) 2.61 (60) 1.39 (65) 0.56 (54 16.4 (56) 89 5.0 6.3

DR. F 1 1.9 136(-1.8) 0.74 (36) 0.93 (34) 0.51 (36) 0.20 (30) 10.8 (50) 85 14.2 147(-1.9) 0.76 (30) 1.05 (31) OMJ (34) 0.28 (33)

R.M.* M 14.1 157(-0.6) 1.33 (42) 1.84 (43) 0.86 (38) 0.51 (49) 92

B.H.t F 19.6 140(-3.7) 1.26 (49) 1.91 (56) 1.06 (63) 0.65 (77) 12.0 (49) 94 2.5 3.0

Mean ± SD 60±22 58±18 59±22 52±20 61±16 88±5.3 4.5±1.1 4.8±1.2

SB. M 14.2 162(-0.1) 3.02 (80)

Group 3

4.11 (83) 2.05 (84) 1.08 (92) 28.9 (91) 80 3.6 3.6

J.H. F 15.9 151(-1.8) 2.90 (104) 4.12 (111) 2.07 (106) 1.22 (133) 24.8 (95) 89 4.4 3.9

KS. F 14.3 159(-0.2) 2.62 (81) 3.75 (90) 2.03 (90) 1.13 (108) 24.5 (85) 73 2.9 3.3

L.S. F 16.2 153(-1.5) 2.62 (90) 3.79 (99) 1.96 (97) 1.17 (124) 26.2 (98) 84 3.6 5.7

J.T. M 12.8 156(0) 3.10 (93) 4.27 (97) 2.17 (101) 1.17 (112) 35.5 (121) 78 4.0 4.9

J.W. D.F.

F 13.2 F 14.8

154(-0.3) 156(-0.9)

2.56 (85) 3.10 (101)

3.31 (85) 1.71 (83) 4.07 (98) 1.81 (84)

0.78 (81) 19.6 (72) 84 7.1 7.8

1.88 (88) 26.6 (91) 90 3.2 4.1

J.K. F 16.2 159(-0.6) 2.70 (83) 3.82 (89) 2.07 (90) 1.12 (106) 25.8 (89) 91 3.4 3.3

Mean ± SD 90±9 105±18 92±14 84±6.3 4.0±1.3 4.6± 1.5

0Number of SD from mean height for age in parentheses.

tNumbers in parentheses are percentages of predictions.

tJ.K. and N.M. studied with esophageal balloons; R.M. was studied elsewhere; B.H. had unilateral pulmonary irradiation.

volumes in this group but the dose range was nar-row and the reduction relatively uniform. TLC ranged from 62% to 78% of predicted value. The patients were asymptomatic except for two

(J. K.

and N. M.) who experienced slight exercise intol-erance. In group 2 (Table II) TLC and VC ex-pressed as percentage of predicted values aver-aged 58% and 60%, respectively. The two patients (D. S. and R. T.) whose only additional therapy consisted of resection of small amounts of lung tis-sue had reductions comparable to those observed in group 1. The two patients (D. R. and R. M.) who received two courses of bilateral pulmonar’ irradiation had reductions in TLC to 34% and 44% of predicted value. D. R. complained of exercise intolerance, had dyspnea on climbing one flight of stairs, and had a resting respiratory rate of 32 breaths per minute. Detailed clinical information is not available for R. M.

In group 3 (Table II) TLC and VC, expressed as

percentage of predicted values, averaged 94% and 90%, respectively.

DLCO was reduced to the same extent as lung volume in all patients who received pulmonary ir-radiation and was normal in group 3 (Fig. 1).

The

pressure-volume relationship of the lungs, obtained in three patients in group 1, showed de-creased compliance and increased elastic recoil when lung volume was plotted as percentage of predicted TLC (Fig. 2, A) but normal elastic properties when lung volume was expressed as

percentage of measured TLC (Fig. 2, B).

Transpulmonary pressure at TLC was not

in-creased. Transpulmonary pressure at FRC ranged from 5.4 to 6.2 cm H2O, showing no difference from the range of 4.3 to 7.9 cm H2O observed in normal children.

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50

40

I

30 DLco

C 20

E

10

. Irradiated Patients

Non-Irradiated

0 Patients

Mean for Normal

Children

1 2 3 4 5 6

Total Lung Capacity in Liters

FIG. 1. Relationship of single breath diffusing capacity (DLCO) to lung volume in patients treated with pulmonary irradiation and actinomycin D (groups 1 and 2; closed

circles) and patients treated with actinomycin D alone

(group 3; open circles). The solid line represents the rela-tionship between DLCO and TLC for normal children stud-ied in our laboratory and the dashed lines gives the 2 SD

intervals.

flows expressed in VC per second as great as those observed in normal children. Three patients in groups 1 and 2 had high maximum expiratory flows over most of the volume range.

Conductance

of the

respiratory

system

The

conductance

of the

upstream segment of the airways calculated for the three patients in group

1 whose

pressure-volume

curves

were

known

(Fig.

5)

was

increased

particularly

at low lung

volumes.

DISCUSSION

All patients who had received bilateral

pulmo-nary irradiation showed reduction in lung

volumes and commensurate reduction in diffusing capacity. The reduction was greatest in those pa-tients who received multiple courses of pulmo-nary irradiation. Surgical excision of lung tissue might account for a reduction in lung volume to 75% of predicted value’9 in K. S. but in the other four patients who underwent thoracotomy the amount

of lung

tissue

resected

was

small.

Normal lung volumes were predicted from

height.26

Irradiation to the lower spine probably

altered

subsequent

linear growth in our patients. However, the expected height-lung volume rela-tionship was preserved in patients in group 3 who

had received

no pulmonary irradiation but did re-ceive irradiation to the lower spine. Therefore,

the findings

in groups 1 and 2, whether compared

to predicted

values

or to the

results

of group

3,

represented

a true

reduction

in lung volume. The

magnitude

of

this reduction would be even great-er than the reported estimate if, because of short

stature,

the

predicted

values

were

too

low.

A

number

of possible

mechanisms

exist

to explain

this reduction.

First, space within the thorax could be reduced

as

a

result

of skeletal

abnormalities.

Most

of these

patients

had

scoliosis

secondary

to irradiation

of

the spine.22 But their curves of 36 degrees or less

were

not severe

enough

to produce

significant

re-duction in lung volumes even if they had been to-cated in the midthoracic spine33’34 and they were primarily lumbar or thoracolumbar. The rib deformities noted in all patients might be

expect-ed

to alter

thoracic

volume

and

the

pelvic

de-formity to displace abdominal contents into the chest. However, these skeletal changes, largely or entirely secondary to irradiation of the tumor bed,

were

common

to all patients

including

those

in

group

3 who

received

no pulmonary

irradiation

and had near-normal lung volumes. The possibili-ty exists that for all groups the predicted values for lung volumes were low and that the normal height-lung volume relationship in group 3 was the result of a small reduction in lung volume caused by the skeletal abnormalities.

Another possibility is that the primary cause of the reduced lung volume resided in the lung

pa-renchyma,

either

in alveoli or in very small air-ways. Areas of lung tissue which had been re-placed or infiltrated by tumor may have become scarred and fibrotic. If this mechanism (tumor re-placing lung)

had

led

to significant

loss

of lung

volume,

the

loss might

be expected

to be

com-mensurate with the initial tumor volume. Our ra-diographic estimates of tumor volume were less than the observed loss of lung volume in all in-stances. However, the possibility exists that

nu-merous

small

areas

of tumor

were

present

which

did

not

produce

recognizable

radiographic

den-sities.

Diffuse

radiation

fibrosis

is another

possible

cause for the reduced lung volumes. Increased transpulmonary pressures at TLC and FRC which

have

been

observed

in adults

with

pulmonary

fi-brosis35 were not observed in our three patients in

whom

measurements

were

made.

Because

the

chest wait of the growing child may accommodate to a reduced lung volume, as suggested by Cook

and

Bucci,’9

the

absence

of increased

pressures

cannot be taken as absolute evidence against dif-fuse fibrosis. Lack of radiographic evidence of fi-brosis in most patients in group 1 is also suggestive

evidence

against

fibrosis

although

radiographic

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B

100

10 20 30 40 50 0 10 20 30 40 50

Pressure , cm H2O

120

100

0

Q) ._J

E-0 260

>0

O)

.

40

20

0

80

-

Normal Children

Irradiated Patients

FIG. 2. The static elastic pressures on deflation in three patients in group 1(J. K., N. M., and

S. A.) are shown by solid lines and compared to the deflation curves of normal controls

repre-sented by dashed lines. In A volume is plotted as percentage of predicted TLC and in B as

percentage of measured TLC.

However, interference with lung growth must

be considered

and

cannot

be separated

from

loss

of lung parenchyma. Our data are consistent with the hypothesis that units had been destroyed or

failed

to develop

and that

subsequent

lung

growth

had not compensated for this. Injury to dividing cells in the region of the respiratory bronchioles and alveolar ducts may have prevented the forma-tion of new alveolar units. Alternatively,

injury

to cells at the level of terminal bronchioles with oh-struction of these airways might have produced atelectasis of the parenchyma distal to the oh-struction followed by scarring and effective “re-moval” of these terminal units and the alveoli which would have developed

within

them.

The

finding

of normal

transpulmonary

pres-sures suggests that the alterations in growth or size of the lung which we observed in these chit-dren were matched by alterations in growth of the chest wall. Mismatching of lung and chest-wall size would result in altered pressure-volume rela-tionships (Fig. 6). if the lung alone is small, either because of failure to grow or because of fibrosis, transoulmonary pressures would be elevated at

FRC

and

TLC

(Fig.

6,

B) compared to normal (Fig. 6, A).

Conversely,

if the

chest

wall

is small

and stiff at high lung volumes, transpulmonary pressure would be expected to be reduced at TLC and FRC (Fig. 6, C).

Our

observations

indicate

that

lung

and

chest-wall

size

were

both

reduced

proportionately and suggest either that radiation influenced the size and

mechanical

properties

of

the chest

wall

as well

as the volume

of the lung

or

that

reduced

lung

volume

during

a period

of lung

growth influenced the subsequent size and

mechanical

properties

of the

chest

wall.

Similar-ly, although the reduction in lung volume which

we observed

cannot

be accounted

for by the

skele-tal

abnormalities

secondary

to irradiation

of the

tumor

bed,

the

possibility

remains

that

the

put-monary

irradiation

influenced

chest-wall

growth

primarily and that reduced chest-wall volume

during

a period

of lung

growth

influenced

the

sub-sequent

size

and

mechanical

properties

of the

lung.

Airway resistance evaluated in several ways

and

judged

in relationship

to lung

volume

was

normal or reduced. if the long-term effects on the

lung

of irradiation

were

primarily

limited

to the

lung parenchyma and if the airways in which the

major

portion

of airway

resistance

resides

were

relatively

unaffected,

the

conductance

of the

res-piratory

system

would

be

expected

to be

high

when

plotted

against

lung

volume.

Small

in-creases in conductance might be obscured by the

great

variability

observed

in

normals

(Fig.

4).

However,

markedly

increased

conductance

was

(8)

0

Cl)

0

>

0

LL. 1

0

Normal Children

mean and range

Irradiated patients

70 50 30 10

Volume , % VC

Ii

ao

91

I

1.5

) 1.0

I-c5

C

0

( 0 20 40 60 80 100

3’oVital Capacity

FIG. 5. Conductance of the upstream segment of the air-ways in three patients treated with pulmonary irradiation (dashed lines) and in normal children with the mean value given by a solid line and the range shown by the brackets.

0.4

0.3

0.2

0.1

SUMMARY

S Irradiated Patients

0 Non-Irradiated Patients

- Mean for Normal

Children

FIG. 4. Relationship of conductance of the total respiratory system to lung volume in patients who received pulmonary irradiation (closed circles) and patients treated with actino-mycin D alone (open circles). The solid line represents the relationship between conductance and lung volume for normal children studied in our laboratory and dashed lines

give the 2 SD interval.

4 - Irradiated Patients

. Non-Irradiated

3 Patients

Mean for Normal

Children ±2SD

FiG. 3. Maximum expiratory How-volume relationships in patients who received pulmonary irradiation (groups 1 and

2; solid lines) and patients treated with actinomycin D

alone (group 3; dashed lines). Volume is represented as per-centage of VC and flow as VC/sec. The shaded area

repre-sents data on normal children ± 2 SD.

expiratory

flow expressed

in VC per second

would

be expected

to be high but again

the variability

in

normals is large (Fig. 3). Despite this variability,

high

flows

were

observed

in five children

above

50%

VC.

These

findings

support

the

concept

that

airway

size had

been

less influenced

by the

radia-tion than parenchymal size.

All patients

in

this study had been treated with

actinomycin

D, which

interferes

with

protein

syn-thesis and could thereby alter growth and cause a

reduction

in lung

size.

Our

data

cannot

support

or

. .-. 2SD

I

p.. , , , I

0 1 2 3 4 5

Absolute Lung Volume in Liters

clearly

refute

this possibility. In the discussion of

the

possible

influence

on lung

volumes

of the

rib

and

pelvic

abnormalities

it was pointed out that

the

predicted

values

of lung

volume,

based

on

height,

might

be low

in these

short

children

and that the normal height-lung volume relationship which we observed might in fact reflect a

reduc-tion

in lung

volume

to the

skeletal

abnor-malities.

Similarly,

if the

predicted

values

are

low, the normal height-lung volume relationship observed in group 3 might reflect some small

in-fluence

of actinomycin

D upon

the lung.

As in the

case of the skeletal abnormalities, the influence of actinomycin D upon lung volume, if present, is

small

indeed.

Lung function studies and chest radiographs were obtained in 12 patients 7 to 17 years after

they

received

pulmonary

irradiation

and

treat-ment with actinomycin D during early childhood,

a

period

of

alveolar

development

and

lung

growth.

Eight

patients

who

received

actinomycin

D in conjunction

with

treatment

of the

primary

tumor bed but no pulmonary irradiation were also

studied.

Chest

radiographs

in the

six patients

who

re-ceived

only

one course

of bilateral

pulmonary

ir-radiation

revealed

absent

or minimal

evidence

of

pleural

or

pulmonary

parenchymal

abnormali-ties. However, those patients who received

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A. NORMAL

100

TLC :100O,, predicted

r

RV

PLat TLC 40 cm H20

PLaIFRC: 5.5cm H20

80

TLC: 80#{176}/opredicted

RV :100/o predicted

PLatTLC 50cm H20

PLatFRC 8cmH2O

-20

C. CHEST WALL SMALL 100

80

6c

I

TLC: 82#{176}/opredicted

/

Rv =83O, predicted I PLatTLC: 22cmH20

,# 20 PLatFRCZ4.3cmH2O

20 40 -20 0 20 40

PRESSURE ,CM H20

80

5 .

I

0.

:; Jo

I

-. 20

B. LUNG SMALL 100 ,

-20 0 20 40

FIG. 6. Predictions for the hypothetical relationship between lung (solid line) and chest wall (dashed line). In A relationship is normal; in B the lung is small relative to the chest wall; and

in C the chest wall is small relative to the lung. Lung volume is expressed as percentage of predicted TLC. TLC is taken as the point where the pressure across the hypothetical total respiratory system equals 50 cm H2O and RV is determined by the characteristics of the chest

wall. In C the chest wall is assumed to be stiff at high lung volumes.

Lung volumes were modestly reduced in those who received one course of bilateral pulmonary irradiation and substantially reduced in those who received repeated courses of pulmonary irradia-tion. The reductions were particularly severe in the two children who received two courses of bi-lateral pulmonary irradiation.

The reductions in lung volume were associated with normal static elastic properties of the lung in the three patients in whom the measurements were made when lung volume was expressed as percentage of observed TLC. This and the obser-vation that transpulmonary pressures at TLC and FRC were normal suggest that the size and the mechanical properties of the chest wall had been affected either directly by the irradiation or in re-sponse to the presence of a small lung during a period of chest-wall growth.

The resistance of the airways evaluated by MEFV curves, the resistance of the total respira-tory system, and the conductance of the upstream

segment was low or normal when related to

volume. This suggests that the airways in which the major portion of airway resistance resides were relatively unaffected and that the long-term effects on the lung of pulmonary irradiation were limited to the lung parenchyma.

The height-lung volume relationship was nor-mat in those children who received only irradia-tion to the tumor bed and treatment with actino-mycin D. This does not completely exclude some small influence of actinomycin D and/or skeletal abnormalities secondary to irradiation of the

tumor bed upon lung volume since the predicted lung volumes, based on height, may have been low in these children of short stature.

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ACKNOWLEDGMENT

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1975;55;507

Pediatrics

Mary Ellen B. Wohl, N. Thorne Griscom, Demetrius G. Traggis and Norman Jaffe

Lung Function

Effects of Therapeutic Irradiation Delivered in Early Childhood Upon Subsequent

Services

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