Pulmonary Radiation Injury

reviews Pulmonary Radiation Injury* Benjamin Movsas, MD; Thomas A Raffin, MD; Alan H. Epstein, MD; and Charles]. Link, Jr. , MD

(CHEST 1997; 111:1061-76) Key words: pulmonary fibrosis; radiation; radiation pneumonitis

Abbreviations: ACE=angiotensin-converting enzyme; PA= plasminogen activator; PTX=pentoxifylline; TGF=transforming growth factor; TGF-I)=transforming growth factor-beta; TNFu = tumor necrosis factor-a; 3-D=three-dimensional

fundamental ability to successfully treat any T heneoplasm ultimately depends on the therapeutic

ratio, ie, the ability to sterilize the tumor while sparing normal tissues. There are t:\vo strategies to improve the therapeutic ratio-one can either maximize the numerator, ie, tumor cell kill, or minimize the denominator, ie, the effect on normal structures. Sometimes the latter strategy is overlooked. Yet, normal tissue tolerance often requires treatment breaks or dose reductions that limit the success of therapy. In treating neoplasms of the thorax, an essential normal structure is the lung parenchyma itself. This review will summarize the clinical syndromes, histopathologic condition, underlying mechanisms, radiologic and physiologic effects, predisposing factors , differential diagnosis, treatment, and prevention for pulmonary radiation injury. Most analyses of radiation tolerance of normal human tissues are fraught with difficulty. Many of the studies, particularly regarding the mechanisms underlying radiation pulmonary injury, are based on animal data. Although these studies are important, the extrapolation of data from other mammals to humans is not always reliable. Human studies are limited for other reasons, such as the lack of stan*From the Department of Radiation Oncology (Dr. Movsas), Fox Chase Cancer Center, Philadelphia; the Department of Medicine (Dr. RafHn) , Stanford University School of Medicine, Stanford, Calif; the Department of Radiology and Nuclear Medicine (Dr. Epstein), Uniformed Services University of the Health Sciences, Bethesda, Md; and the Human Gene Therapy Research Institute (Dr. Link), Central Iowa Health Systems, Des Moines. Manuscript received April 24, 1996; revision accepted July 25. Reprint requests: Dr. Raffin, Professor and Chief, Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center-Room H3151 , Stanford, CA 94305-5236

dardized end points , limited follow-up for late effects due to patient attrition, and patient and observer variability within an analysis. To start, what is the incidence of radiation pneumonitis? At first glance, this appears to be a relatively simple question. Yet, Table 1, which reports the incidence from a variety of studies, 1- 18 shows that the answer is far from well defined. The rate of symptomatic pneumonitis ranges from 1 to 34%, whereas the rate of radiologic changes ranges from 13 to 100%. Differences between institutions make direct data comparisons difficult. Some studies use radiographic criteria to make the diagnosis of pulmonary radiation damage, while others use clinical features. The frequency and timing of follow-up visits vary between institutions and this may alter the reported incidence. Patients who die soon after therapy before sufficient time to express radiation-induced syn1ptoms are often included in the number of patients at risk, thereby underestimating the incidence of pulmonary complications. The volume of lung irradiated can be significantly different in patients with different diseases (eg, lung cancer vs mesothelioma), also making comparisons difficult. Some investigators take into account the effect of inhomogeneous tissues (such as the lung) on dosimetric calculations, while others do not. Moreover, radiotherapy techniques and technology are constantly being revised and improved. As expected, new treatment approaches (eg, combined chemotherapy and radiotherapy) can alter the host susceptibility to pulmonary radiation damage. Nevertheless, this table provides a clinically useful guide. When one combines all patients in these studies, the percentage of symptomatic radiation pneumonitis is approximately 7%. This corresponds closely to a recent review of almost 2,000 patients in whom the incidence of symptomatic pneumonitis was 8%.1 9 Of note, the percent of patients who manifest radiologic changes is significantly higher, averaging approximately 43% . As the radiologic abnormalities are significantly more frequent than the clinical symptoms, a careful distinction should be CHEST I 111 I 4 I APRIL, 1997

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Table l-lncidence of Radiation Pneumonitis and Radiation Fibrosis * Cancer Type

No. of Patients

Various Breast Breast Breast Breast Breast Breast Lung Lung Lung Lung Lung Hodgkin's Hodgkin's Hodgkin's Hodgkin 's Hodgkin's Hodgkin's Hodgkin's Mesothelioma

545 749 140 50 135 29 1,624 109 82 365 316 391 248 41 20 28 25 590 13 34

RT Technique Various Direct portal Tangential En face + tangential Various Various Various

RP by CXR,% 19 62 13 70 56 48

18 Various Various Direct portal Single dose mediastinum Course to mediastinum Extended field Upper mantle Mantle Mantle :':: whole lung Mantl e High-dose hemithorax

65 25

RP by Symptoms,% 21 6 14 13 34 1

RF by CXR,%

RF by Symptoms,%

19 21 1 57

14

65

4

10 2 3 5 6 15

3 <1

80 25 60

0

62

0

5.9 100

Study Year

Reference No.

1963 1955 1955 1957 1961 1990 1991 1964 1964 1980 1985 1987 1973 1973 1974 1979 1985 1990 1990 1991

1 2 2 3 4 5 6 7 8 9 10 ll

12 12 13 14 15 16 17 18

*RT = radiation therapy; RP=radiation pneumonitis; CXR=chest radiograph; RF = radiation fibrosis.

made between the clinical syndrome and its radiologic sequelae, which are typically asymptomatic.

CLINICAL SYNDROMES

There are two well-recognized syndrom es associated v.-ith pulmonary radiation damage: radiation pneumonitis and radiation fib rosis.

A k ey point to remember is that acute pulmonary radiation damage, radiation pneumonitis, can present anywhere in a spectrum of pathologic conditions. On the one extreme, the symptoms of acute radiation pneumonitis may be absent if the involved area of the lung is small. On the other extreme, the course can be fulminant with severe respiratory insufficiency and cyanosis progressing to acute cor pulmonale in a matter of days. In gene ral, the early onset of symptoms implies a more serious and more protracted clinical course.

Radiation Pneumonitis

Radiation Fibrosis

There is typically a latent period between radiation exposure and the development of acute pulmonary reactions, due to the low mitotic index of the pulmonaty parenchym al cells. This petiod usually ranges from l to 3 months following completion of a course of radiothe rapy. Symptoms may develop before radiographs c hange.20 Dyspnea, the most common symptom, can vary from mild to seve re. 2 Cough , which i s typically prominent, can become severe and hacking. 1 Although usually nonproductive, later it may produce a pink (blood-tinged ) sputum.2 1 Hemoptysis is rare. 1 F ever can be high and spiking but it is usually low grade and transient if it occurs at all. 2 ·20 ·2 1 The relative frequency of symptoms in 29 patients with radiation pne umonitis was dyspnea in 28 (93%), cough in 17 (58%), and fever in two (7%) 11 Some patients report a sense of fullness in the c hest. 22 Weakness may be present proportionate to the degree of dyspnea. 1 Physical findin gs on routine c hest examination are usually absent. Occasionally, moist rales, a pleural friction rub , or evidence of consolidation may be present over the area of irradiation. 1 ·21 · 23 Skin changes secondary to radiation exposure can be present, but do not correlate well with the extent of pulmonary radiation damage. 24 Res ults of laboratory tests in the acute period are nonspecific. A polymorphonuclear leukocytosis (usually moderate) is common , as is an elevated erythrocyte sedimentation rate.

Radiation fibrosis, however, is the term applied to the clinical syndrome that results from chronic pulmonaty lung damage. The perm anent changes of fibrosis take 6 to 24 months to evolve, but usually remilln stable after 2 years. Patients may present with radiation fibrosis without a history of acute pneumonitis. Patients with radiographic fibrosi s can be asymptomatic or have varying degrees of dyspnea. In patients in whom a large volume of lung has been irradiated, chronic pulmonary insuffici ency may develop. This may progress to chronic cor pulmonale from the resultant pulmonary hypertension.25 •2 fi Heart filllure will cause the usual symptoms of shortness of breath, dyspnea on exertion, and orthopnea. The patient may have chest pilln, abdominal discomfort from liver enlargement, or suffer from recurrent upper r espiratory tract infections. 20 Physical findings in the mildly symptomatic patient with chronic pulmonary radiation damage are sparse. Areas of the lung fi eld with extensive damage may have altered breath sounds or dullness to percussion. 27 Chronic cor pulmonale may cause cyanosis, hepatomegaly, or liver tenderness. 20 ·21 Extensive fibrosis may cause findings of mediastin al shift and curvature of the spine toward the side of damage. 2 1•27 Howeve r, with modern techniques, most patients do not develop such severe consequences .

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Reviews

HISTOPATHOLOGY

The histopathologic changes following pulmonary irradiation can be divided into early, intermediate, and late stages. 23 Early radiation damage (seen at 0 to 2 months after radiation) is typically characterized by injury to small vessels and capillaries with the development of vascular congestion and increased capillary permeability. Pathologists reported the histologic features of the acute changes of pulmonmy radiation damage in 1939: "alveolar walls were generally thickened, and alveolar epithelium desquamated into the air vesicles. D efinite increase in perivascular and peribronchial connective tissue was present."28 An autopsy study of 398 cases developed three criteria for acute pulmonary radiation damage: hyaline membranes (fibrin-like material in alveoli), swelling and destruction of alveolar lining cells with hyperplasia and atypia, and marked edema. Autopsies of patients who had received thoracic radiotherapy demonstrated hyaline membranes as the most characteristic early finding in 88 of 215 patients (41 %). 29 However, these membranes are nonspecific and may occur in acute viral or bacterial pneumonias, chemical pneumonitis, postimmersion syndrome, lung transplant rejection, and uremia. 3 0 .3 1 Abnormalities in the intermediate stage (at 2 to 9

FIGURE l.

months after radiation) are characterized by obstruction of pulmonary capillaries by platelets, fibrin, and collagen. Figure 1 shows changes of endothelial hyperplasia 4 months following treatment with a radiation dose of 62 Gy. Alveolar-lining cells become hyperplastic, and the alveolar walls become infiltrated with fibroblasts. The septae are more hypercellular and exhibit interstitial fibrosis with bands of collagen. If the radiation injury is mild, these changes may subside. However, when injury is severe, a chronic phase (typically 2:9 months after radiation) ensues. This histopathologic appearance is dominated by progressive alveolar septal thickening and progressive vascular sclerosis. 22 Underlying Mechanisms There are approximately 40 different cell types in the lung. 23 As the cornerstone of radiation injury is secondary to mitotic cell death, one would predict that the radiation-induced lung damage will be secondary to effects on the cell types with the highest mitotic index. This essentially rules out the type I pneumocyte, which is a fixed postmitotic cell. However, the type II (or granular) pneumocyte has a turnover rate of 20 to 35 days in mice. 23 These cells, which are the principal source of surfactant, are

Changes of endothelial hype1plasia 4 months following treatment with 62 Gy of radiation. CHEST I 111 I 4 I APRIL, 1997

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reverting postmitotic cells that are capable of rapid division into type I cells in response to injury. Of note, capillary endothelial cells have a similar mitotic activity to the type II pneumocyte. These two cell types, the type II pneumocyte and the endothelial cell, are most closely linked to the mechanistic theories underlying radiation pneumonitis. Pathophysiologically, the first occurrence after lung irradiation is the immediate injury to the alveolar type II cell as detected by electron microscopy and the early release of surfactant. 32 The ultrastructure of radiation injury to the lung was first presented in 1966. 33 Within l h of radiation exposure, there is a decrease of lamellar bodies in type II pneumocytes. The lamellar bodies of type II pneumocytes secrete surfactant by exocytosis. Surfactant exists in several different forms and irradiation increases the proportion of high buoyant subtypes. The decreased conversion to low buoyancy surfactant results from a proteinase inhibitor present in the alveolar space after irradiation. 34 ·35 Other material present in the alveoli probably impairs their surface activity. 34 As we will see, investigators have attempted to take advantage of this early release of surfactant to develop a marker for radiation pneumonitis. By 24 h, subendothelial and perivascular edema with proteinaceous material appears and type II pneumocytes are devoid oflamellar inclusions. 36 The next phase, a proliferative one for the type II pneumocytes, occurs between l and 3 months, and there is compensatory hypertrophy of the lamellar bodies.37 Alveolar septae are more hypercellular (with mast cells, plasma cells, fibroblasts, macrophages, and polymorphonuclear cells) and exhibit interstitial fibrosis with bands of collagen fibrils. 38 Type II pneumocytes are abnormal, exhibiting organellar degeneration, and some have bizarre shapes. 39 After 6 months, there is obliteration of capillaries by fibrosis , extensive collagen deposits, and more numerous type II pneumocytes and arterial smooth muscle cells. 38 After 9 or more months, inflammatory cells have disappeared; type II pneumocytes have returned to their normal number and some capillaries have regenerated. According to this model, radiation pneumonitis is an alveolitis resulting from damage to the alveolar type II pneumocytes that maintain alveolar patency. Damage to the endothelial cell, rather than the type II pneumocyte, has also been implicated in the development of radiation pneumonitis or fibrosis. Within days after radiation exposure, endothelial cells show ultrastructural changes and increased permeability occurs 40 as evidenced by perivascular edema and congestion. 41 By l week postirradiation, some endothelial cells separate from the basement 1064

membrane and many capillaries swell and obstruct.42 Late vascular changes in mice that manifest little or no fibrosis following thoracic irradiation appear to be important. 43 Measures of capillmy perfusion by infusion of colloidal carbon have demonstrated that almost 50% of the lung acini were nonfunctional as a result of lost perfusion. 43 Three products of the endothelial cells include the following: angiotensin-converting enzyme (ACE), prostacyclin, and plasminogen activator (PA). ACE occurs on the luminal surface of the lung's vascular endothelium. ACE activity steadily decreases to 20% of control values starting about 30 days postirradiation.41 Endothelial cells synthesize prostacyclin, a potent vasodilator and platelet inhibitor, and its level initially declines with radiation exposure, but then climbs to !:\vice normal by 6 months. 40 ·41 PA, an enzyme that cleaves plasminogen in the fibrinolysis cascade, has reduced activity l month postirradiation.40 This decreased activity correlates vvith decreased fibrinolysis in the irradiated lung vs control. Murine strains prone to radiation-induced pulmonary fibrosis exhibit significantly lower inhinsic PA and ACE activity than do strains not prone to radiation fibrosis. 44 This association between intrinsic lung endothelial enzyme activity and development of fibrosis is consistent with the hypothesis that vascular damage contributes to radiation pneumatoxicity. Rubin and colleagues45 developed an intriguing hypothesis of a "cascade of cytokines" beginning immediately at the time of irradiation and persisting up to the appearance of late injury that underlies the development of pulmonary fibrosis. They first measured specific factors known to be produced by the alveolar macrophage. 45 The studies were based on lavaging the lungs of rabbits after thoracic irradiation. Compared with macrophages obtained from the normal lungs, they found enhanced production and release of transforming growth factor (TGF), and particularly TGF-beta (TGF-~) in the radiated lungs. TGF is known to stimulate fibroblast proliferation and TGF -~ induces synthesis and secretion of extracellular matrix components, including collagen and fibronectin. 45 The increased level of cytokines, such as TGF-~, is not a unique response to radiation and is well recognized following different types of injury that also lead to pulmonary fibrosis, such as bleomycin. 46 A7 Similarly, in patients undergoing bone marrow transplantation, serum TGF -~ levels were found to be significantly higher in patients in whom idiopathic interstitial pneumonitis developed.4S,49 In a subsequent report, using RNA probes and in situ hybridization techniques, Rubin and colleagues50 found confirmatory evidence of dramatic Reviews

alterations in TGF -13 gene expression as early as one day after irradiation. They also demonstrated early changes in the fibroblast gene expression of collagens 1, 3, and 4, and fibronectin. These observations support an early molecular "afferent-efferent" intercellular radiation response paradigm. 49 In the afferent limb, the macrophage or type II pneumocyte (ie, the injured cell) manifests immediate cellular damage following irradiation. The cellular injury leads to altered genetic expression and prompt release of growth factors, such as TGF -13. In the efferent limb, growth factor receptors are activated, leading to signal transduction. The stimulated fibroblasts respond by turning on collagen genes, leading to the production of extracellular matrix proteins. These early alterations, within days to weeks of the irradiation, may play a major role in the subsequent development of chronic fibrosis 5 to 6 months later. In a recent report, these investigators provide evidence of the long-term persistence of the molecular events predicted by this model.5o Complex scenarios of intercellular communication have been proposed. However, the exact mechanism of how these cells and cytokines interact has not been elucidated. Which cytokines play the dominant role in which process? Some investigators have suggested that tumor necrosis factor is a key cytokine involved in mediating pulmonary damage. 51 This particular cytokine, though, does not appear to play a major role in the model of Rubin et al. 50 Nevertheless, the end results of these molecular events are clinical effects on the patient. These pathologic events next lead to radiologic and physiologic changes from pulmonary radiation injury.

DIAGNOSTIC IMAGING

Radiologic Findings

Radiographs are an essential part of the diagnosis and follow-up of pulmonary radiation damage. The first typical finding is a diffuse haziness or fuzziness in areas of the irradiated lung, especially around the hilus.3. 20·24 Slight indistinctness of the pulmonary vasculature at this stage also occursJ3 Next the areas of haziness become more patchy or flocculent. These areas of increased density then coalesce to form a relatively sharp edge that does not follow the pattern of the lung's anatomic borders, but rather follows the shape and size of the treatment portsJ3.22 Air bronchograms are sometimes visible in these areas of increased density. 3 If mild, the radiograph changes completely resolve in a few weeks. 2 If severe, adhesions may form between the pleura and the pericardium or between the diaphragm or the pericardium

or pleura. 20 More severe changes, if they remit, can resolve over a matter of months. 2 Extensive unilateral areas of pneumonitis can cause a shift of the mediastinum toward the damage and elevation of the ipsilateral diaphragm .2 Pleural, pericardia!, or intralobar fluid may accumulate within the areas of infiltrate. 20·24 In an area of radiation pneumonitis, pulmonary fibrosis almost universally follows. 3·52 Radiation fibrosis is a more difficult radiographic diagnosis to make, since the fibrosis distorts the outline of the radiotherapy ports, which is so characteristic for radiation pneumonitis. The late changes of fibrosis usually begin 6 to 9 months after the course of radiotherapy and become stable after 2 years. 2 Serial radiographs can be very useful to follow the transition from acute to chronic lung damage. 3 If the fibrosis is mild, a variety of subtle changes are possible: elevation of the hemidiaphragms, elevation of the minor fissure, apical thickening, or para-mediastinal fibrosis with widening of the mediastinum. 3·12 More usually, a linear or patchy density in the lung fields with contraction and compensatory emphysema appears. 2·2 Chronic fibrous contraction can cause atelectasis, mediastinal shifting, pleuro-pericardial adhesions, and tenting of the diaphragm. 22 ·27 The fibrosis can be severe enough to shift the trachea and cause stenosis. 20 Later, the diaphragm can scar and become immobile. 21 Encapsulated pleural fluid and calcified plaques can appear in areas of pulmonary radiation damage years later. 3 There are occasional reports of radiologic changes outside the radiation field, and rarely in the contralateral lung. Many unsubstantiated theories have been developed to explain this phenomenon, such as obstruction of lymphatic flow from mediastinal radiation or changes secondary to stray radiation. One intriguing possibility revolves around an autoimmune mediated mechanism. To study this phenomenon, one group designed a prospective study to investigate the bilateral pulmonary effects of strictly unilateral radiotherapy for breast carcinoma.53 They found that, after radiation, the number of lavaged lymphocytes increased significantly. This was most dramatic in those patients who developed clinical pneumonitis and were found to have an increase in the gallium index. Interestingly, there was no statistical difference between the irradiated and the unirradiated sides of the chest in either lavage or gallium scan studies. These findings raise the possibility of an immunologically mediated mechanism such as a hypersensitivity pneumonitis and may explain why steroids can be an effective treatment for radiation pneumonitis.

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Computed Tomography In addition to chest radiographs, CT of radiationinduced lung damage has also been studied. CT can visualize radiation-induced lung damage.5 4 A CT scan can document acute and chronic pulmonary radiation damage in detail, including increased areas of attenuation in radiation pneumonitis and chronic soft-tissue density changes consistent with radiation fibrosis. 55 The CT scans can demonstrate serial changes in lung density and these may be useful in predicting the prognosis for a patient suffering pulmonary radiation damage. 56 The group at Princess Margaret Hospital was able to demonstrate a doseresponse relationship between the frequency of finding CT evidence of lung injury and the estimated single dose from the nominal standard dose modeJ.57

Nuclear Medicine Scans Technetium- (99 mTc) labeled macroalbumin aggregates have shown decreased perfusion in lung areas after irradiation. 38 ·58 A 99 mTc pyrophosphate bone scan revealed increased uptake in an area of pulmonary radiation damage. 59 In the relatively early stages of radiation pneumonitis, 99 mTc-diethylene triaminepenta-acetic acid (99 mTc-DTPA), a diffusable hydrophilic solute that can quantify vascular permeability, shows increased uptake in areas of radiation pneumonitis in experimental models.6o Gallium-67 (67 Ga) citrate scintigraphy is indicative of radiation pneumonitis in 57% of symptomatic individuals and can manifest changes before chest radiography; however, the sensitivity and specificity are still rather low. 61 Similarly, the changes in MRI signals following irradiation are difficult to interpret due to artifacts related to the air-tissue interface. Recently, physicians have used three-dimensional (3-D), single-photon emission CT lung perfusion scans to provide a quantitative 3-D map of the distribution of functioning pulmonary vascular and alveolar subunits.62 With doses in excess of 40 Gy, they found a reduction in regional function not necessarily accompanied by a reduction in pulmonary function test results. 62 By delineating regions of nonfunctioning pulmonary parenchyma prior to radiation, this technique may also be useful in designing radiotherapy fields to spare as much functioning lung as possible. Physiologic Studies Pulmonary Function Tests: Many studies of pulmonary function are from work vvith Hodgkin's disease patients who had received mantle irradiation either for prophylaxis or for intrathoracic disease.14·63-66 Lung function changes from radiation damage can be severe and prolonged, but are usually 1066

mild and transient. 14 Measurable changes start 2 to 3 months after irradiation, are maximal at 4 to 6 months and return to normal (or nearly so) by 8 months. 65 Patients vvith intrathoracic disease demonstrate more improvement in lung function, but start out with greater deficits. Those without intrathoracic disease show a greater compromise of function from normal pretreatment values. 65 In lung cancer patients, vital capacity can show a slight increase 4 weeks posttherapy. 67 In Hodgkin's disease patients, vital capacity decreases between 1 to 4 months, then normalizes by 12 months with only a slight deficit.63·65 In otherwise healthy patients, this small loss in vital capacity is probably significant only if they participate in competitive sports. 63 Total lung capacity and inspiratory capacity also show small deficits at 12 months. 63 These losses probably represent the physiologic effects of mild pulmonary fibrosis. Forced expiratory volume reduces at 5 months, but increases back to pretreatment levels by 8 months.64 .The most predictive test of pulmonary function after radiotherapy is the measurement of carbon monoxide diffusion capacity, which may prognosticate the risk of pulmonary radiation damage.68 The diffusion capacity falls 20 to 60% during the first 3 to 5 months after irradiation, and then usually returns to normal at 12 months and beyond.64,66 The change in diffusion capacity correlates with the volume loss of tissue for gas transfer. 67 This test reflects the alveolar-capillary block in affected tissues, which can be severe. 26 Peak oxygen consumption significantly decreases in some patients. In long-term follow-up (> 12 months) , 12 of 50 patients (24%), mostly with intrathoracic disease, showed a greater peak oxygen consumption deficit. 66 The compliance in the lung changes in a dose- and time-related fashion.69 Rat models show a 50 to 75% fall in compliance from preirradiation levels independent of changes in the thoracic wall. 70 Arterial Blood Gases: In lethally irradiated rats, arterial blood gas values deteriorate 15 weeks after exposure, but no relationship between dose and arterial blood gas measurements was noted since the animals compensated by increasing their breathing effort. 71 Although fulminant cases appeared in the past,26 hypoxemia in humans has not been noted, even with moderate exercise, in more recent studies.63·72 Hypercarbia likewise was either slight or has not occurred.63,67,72

PREDISPOSING FACTORS

There are many factors that can alter the risk of developing pulmonary radiation damage. These include the following: (1) radiation treatment factors; Reviews

(2) prior irradiation; (3) use of chemotherapy; (4) steroid therapy withdrawal; and (5) preexisting lung disease. (1) Radiation Treatment Factors

The chief radiotherapy treatment factors that influence whether a particular patient develops radiation damage of the lung include total dose, fractionation/dose rate, and lung volume. Total Dose: Total dose of irradiation absorbed is an important factor contributing to pulmonary damage. The effect of the total radiation dose is dramatically altered by the daily fraction size, as reviewed next. Total radiotherapy dose correlates best with late changes, such as radiation fibrosis , as opposed to radiation pneumonitis. 21 Nevertheless, an increased incidence of symptomatic radiation pneumonitis does correlate roughly with increasing dose. Pulmonary damage is rare using total doses (to part of the lung) <25 to 30 Gy, sometimes seen with 30 to 35 Gy, common with 35 to 40 Gy, and essentially universally seen with doses >40 Gy.13 In upper half-body therapy, an actuarial risk for symptomatic radiation pneumonitis occurs in 2.7% of patients with doses <6.0 Gy, 17.5% with 6.0 Gy, 35.6% with 8.0 Gy, and 83.5% with 10.0 Gy.73 These data show that the relationship between dose and incidence is not linear, but increases significantly after achieving a threshold dose, a phenomenon that also occurs experimentally in mice. 74 This concept of a threshold dose is important in radiation treatment planning of thoracic malignancies as lung tissue receiving "subcritical" radiation doses may never develop clinical or radiographic signs of radiation injury. Fractionation and Dose Rate: Fractionation greatly reduces the biological impact of radiation and is the dominant factor in determining the late effects of radiation. Data show that the respiratory frequency 76 weeks following bilateral whole lung irradiation in mice is clearly a function of fractionation.75 The sparing effect of fractionation has similarly been observed by decreasing the dose rate or the output of the machine. Although low-dose rate irradiation is protective when administering totalbody irradiation, it shifts the lung dose-response curve by only 2 to 3 Gy to the right. 76 A recent large retrospective study, including almost 2,000 patients in 24 series, has analyzed factors associated with radiation pneumonitis resulting from combined modality therapy for lung cancer.l 9 In a multivariate analysis, only daily fraction size, number of daily fractions, and total dose were significantly associated with the risk of radiation pneumonitis. In particular,

the use of a daily fraction size greater than 2.67 Gy was the most significant factor associated with an increased risk of radiation pneumonitis. Interestingly, twice-daily radiation seemed to reduce the risk compared to the same total daily dose given as a single fraction. This retrospective analysis is limited in that field size information was not reported, such that the effect of the treatment volume could not be assessed. Nevertheless, this study emphasizes the importance of the daily fraction size. Lung Volume: Physicians have long recognized that lung volume irradiated is an important contributing factor to radiation pneumonitis. Rubin and Casarett21 suggested that irradiating 25% of the lung results in minimal expectation of symptoms developing, although pathology reports on tissues from such areas might show evidence of damage. If patients receive high doses (::=::50 Gy) in small fields, especially in the lower lung (more functional areas and higher volumes), symptoms can occur. With 50% or more of the lung irradiated, a higher incidence of symptomatic radiation pneumonitis occurs, particularly if therapy is to both lungs. Of 69 patients with Hodgkin's disease requiring one or both lungs irradiated, 23 (33%) developed symptoms, eight (11.5%) were severe, and four (5.8%) were fataP 2 As patients in this study were treated with older techniques, the incidence of pneumonitis is likely lower using modern treatment planning. Irradiation of the entirety of both lungs with :::::30 Gy is uniformly fatal.2 1 Some authors consider total doses of >25 Gy to have unacceptable risk of pulmonary insufficiency and death. 21 A case of fatal radiation pneumonitis occurred with a dose of I3 Gy given to a moderate part of both lung fields. 77 Half-body x-ray therapy, used for treating patients with advanced cancer, provides insight into the lung's tolerance for irradiation. At the University of Toronto, 245 patients received upper half body x-ray therapy. 73 Forty-four patients ( 17.5%) developed pul~onary symptoms and 37 (15.1 %) died. The influence of field size on pulmonary toxicity has been evaluated in patients treated on a Radiation Therapy Oncology Group protocoP8 The protocol required that the irradiation field margins extend 2 em beyond the primary tumor and involved nodes . When the treatment field margins exceeded the protocol specifications, there was a significant increase in the degree of lung toxicity. Based on this analysis, individualized irradiation treatment p01tals must be designed using customized blocking in the modern radiotherapeutic management of lung cancer patients. CHEST I 111 I 4 I APRIL, 1997

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(2) Prior Irradiation Prior irradiation to the lung, even if unaccompanied with symptoms or signs of damage, can increase the risk for further pulmonary radiation damage. 20 If symptoms were present with the initial course of radiotherapy, a severe case of radiation pneumonitis will probably occur with the second course. 2 Clinicians recognized this warning sign decades ago. 23 Experimental evidence supports the importance of this risk factor.7 9 Hodgkin's disease patients demonstrate a difference with and without prior irradiation of 15% vs 6.4%, respectively, in the incidence of radiation pneumonitis. 12 The pathologic condition of the pulmonary radiation damage is also more severe in patients who were reirradiated. 29

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(3) Chemotherapy Many chemotherapy agents may produce pulmonary injury. Of more relevance, many antineoplastic agents have been found to potentiate the damaging effects of radiation on the lung. The best characterized, bleomycin, given with lung irradiation, produces lung toxicity that is greater than when either agent is administered alone. Of 115 patients treated simultaneously with thoracic irradiation and bleomycin, 19% suffered pulmonary damage and 10% died.6S Dactinomycin administration also increases the incidence of radiation pneumonitis. 80 An extensive review on the effect of dactinomycin on lung radiosensitivity found moderate to severe enhancement of pulmonary lethality in mice and an increase (sometimes lethal) in severity of radiation pneumonitis in man.s1 Cyclophosphamide, and to a lesser extent, vincristine also enhanced the toxicity of thoracic irradiation. 81 The effects of radiation are also potentiated by doxorubicin hydrochloride (Adriamycin). Investigators from the Princess Margaret Hospital have studied the quantitative effect of combined chemotherapy and fractionated radiotherapy on the incidence of radiation-induced lung damage as defined by CT changes.s2 They found that when doxorubicin-containing regimens were employed in addition to radiation the incidence of CT-detected radiation changes increased significantly more than with other chemotherapy regimens. Also well described is the presence of a "recall" pneumonitis following treatment with doxorubicin or dactinomycin. 83 Although a full discussion of the effects of chemotherapy in predisposing to radiation pneumonopathy is beyond the scope of this review, many chemotherapeutic agents significantly increase the risk of developing radiation pulmonary injury. This is especially true when the chemotherapy and radiation are administered concurrently. Breast cancer patients 1068

treated concurrently with radiation and chemotherapy had an 8.8% incidence of radiation pneumonitis, compared to a 1.3% incidence for patients treated sequentially. 6 In the current era of combined modality therapy, often a more appropriate term than "radiation" pneumonitis may be "combined modality" pneumonitis. (4) Steroid Therapy Withdrawal The conversion of occult radiation injury in the lungs to symptomatic radiation pneumonitis after steroid therapy withdrawal has been documented by several investigators. 21 ·25 In one study, the symptoms of radiation pneumonitis developed shortly after completion of either cycle 1 or cycle 4 of MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), the only cycles in which high doses of prednisone were given. 25 The authors postulated that the rapid withdrawal of high-dose steroid therapy may have activated the subclinical radiation injmy. (5) Preexisting Lung Disease Preexisting lung disease might be an important factor with regard to lung radiation damage in two ways. First, "the status of the patient's lung may be of significance relative to preexisting disease to which the radiation effect would be additive." 21 Specifically, the authors refer to chronic pulmonary emphysema, pneumoconiosis, and old pulmonary tuberculosis and their significance relative to the development of pulmonary fibrosis. Second, processes in the lung that increase tissue density, such as consolidated pneumonia or asbestos exposure, may play a role. In seven cases of fatal bilateral radiation pneumonitis, five patients had consolidation secondary to persistent lung infection at the time of treatment. 20 Consolidation from infection was believed to have caused an increase in the total radiation dose absorbed in the lung tissue, which might explain why the patients developed such fulminant radiation pneumonitis. 20 Other reports, however, show some forms of preexisting lung disease, such as chronic bronchitis, to be unimportant. One hundred sixtyone patients with chronic bronchitis who underwent radiotherapy for bronchogenic carcinoma had no change in survival, severity of bronchitis, and incidence of radiation pneumonitis or fibrosis. 8

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of pulmonary radiation damage can be a confusing one, as can be seen in Table 2. In particular, clinicians must distinguish the Reviews

Table 2-Differential Diagnosis of Radiation Lung Injury Chronic

Acute

Recurrent neoplasm Infection Bacterial Viral Fungal Exposure-induced chronic fibrosis Inhalation exposures Chemotherapy induced

Recurrent neoplasm Lymphangitic spread of neoplasm Infection Bacterial Viral Fungal Pneurrwcystis carinii

Chemical pneumonitis Secondary to aspiration Inhalation exposures Chemotherapy induced

acute damage, radiation pneumonitis, from recurrence of neoplasm . Criteria that indicate that the diagnosis is more likely to be neoplasm include the following: interval between radiotherapy and diagnosis >4 months; presence of metastatic disease; steady progression of radiographic abnormalities and symptoms; changes outside the radiation field; anemia; associated hemoptysis; and prior documentation of tumor growth. 3·27 Lymphatic spread of neoplasm usually has more prominent changes at the lung base associated with septal lines on the radiograph, symptoms that are more severe than the radiograph indicates, and sequential radiographs showing significant interval changes. 13 Infection is typically associated with positive cultures, lobar or anatomic distribution on radiograph, and persistent or high fever. In the immunocompromised host, Pneurrwcystis carinii pneumonia should be considered, particularly if the patient fails to respond to therapy for radiation pneumonitis or develops symptoms either too early or at an unusually low dose of radiation.s4 Acute pericarditis is a possibility with an enlarged cardiac silhouette. It usually accompanies pleural effusions and does not have the pulmonary density seen in radiation pneumonitis. Similarly, clinicians must differentiate chronic radiation damage resulting in pulmonary fibrosis from numerous other diagnoses with a similar appearance.85 To make the diagnosis of pulmonary radiation damage requires a combination of clinical and radiographic findings.

TREATMENT

An important point regarding the treatment of radiation pneumonitis is that most cases are subclinical or mild and do not require therapy. Mild abnormalities on chest radiography that correspond to treatment ports need only expectant management.

Minor symptoms need only be addressed to ensure that they do not portend the development of a more severe clinical syndrome. Pharrnacologic Therapy

Corticosteroids are the mainstay of treatment for radiation pneumonitis. Experimental models and clinical experience have suggested their utility. Mice treated with methylprednisolone after thoracic irradiation could tolerate a higher dose of radiation than control mice, and the withdrawal of steroid therapy during the period of pneumonitis resulted in an increased mortality that was equivalent to untreated control animals. 86 Data from large human studies of corticosteroid treatment are not available, but the long clinical history of steroid usage supports their efficacy for treating radiation pneumonitis and approximately 80% of patients respond. 21 Using corticosteroids as prophylaxis, however, is not of substantial, if any, benefit. 21 Gross 23 suggests a dose range of 60 to 100 mg daily of prednisone once the diagnosis is reasonably certain, and then a gradual taper (after several weeks) while observing for signs of radiation pneumonitis flare. When steroids are effective, the reversal of symptoms can be dramatic, 1·73 but severe or well-established cases may be refractory to even very high doses of steroid therapy.l,21,26 Analysis of nonsteroidal anti-inflammatory drugs' effects on radiation pneumonitis suggests that the benefit of steroids may be secondary to their antiinflammatory effect. 87 This experimental work suggested that nonsteroidal anti-inflammatory drugs , especially those that inhibit lipoxygenase, may be of benefit for the treatment of radiation pneumonitis.s7 Antibiotics provide little benefit in this setting unless an infection is present, although pulmonary radiation damage can predispose to infection.2l-23,88 Anticoagulants are also not effective.21 No intervention in humans is of proven benefit for the treatment of pulmonary fibrosis. For such patients, appropriate therapy is supportive with 0 2, bronchodilators, and expectorants . In experimental models, penicillamine, a collagen antagonist, has shown some promise, but the compound is slow acting and poorly tolerated.41 Preventive Strategies

As our ability to treat radiation lung damage is limited, preventive strategies are particularly important. These include modifying standard radiotherapy techniques, as well as developing innovative radiotherapy approaches, markers for radiation pulmonary injury, and new biological modifiers. Changes in radiotherapy technique may be useful in decreasing the frequency or severity of pulmonary radiation CHEST /111 /4/ APRIL, 1997

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damage. Strategies include "thin lung blocks" to shield the area of the lung that only needs prophylaxis, a "shrinking field" that exposes a tumor field to a modest dose of radiation and then decreases the field size as the tumor shrinks, and "full lung blocks" used to shield the lung completely.l 2 .89 Thin lung shielding for patients receiving total body irradiation reduced the rate of radiation pneumonitis to 0% compared to 26% without shielding. 90 The following case visually and quantitatively demonstrates the simplest, yet effective, method for limiting the sequelae of radiation pneumonitis, via the proper use of lung blocks. A 44-year-old white woman had a history of stage IliA (TlN2MO) poorly differentiated adenocarcinoma of the left upper lobe. The patient underwent left upper lobectomy and then received chemotherapy (cisplatin and etoposide). One year later, the patient developed a prominent right paratracheal recurrence. The patient received hyperfractionated radiation therapy and iododeoxyuridine (radiosensitizer) to a total dose of 61.5 Gy (at 1.5 Gy twice daily) administered 36.0 Gy anteroposterior-posteroanterior (using the field in Fig 2) and 25.5 Gy right posterior oblique/left anterior oblique (using the field in Fig 3). Three months after radiotherapy, the patient de-

veloped low-grade fevers, nonproductive cough, and mild-to-moderate dyspnea on exertion. Chest radiograph revealed an infiltrate in the right midlung (Fig 4), not present prior to radiotherapy. A presumptive diagnosis of radiation pneumonitis was based on the following factors: (l) normal findings from workup for an infectious etiology; (2) the timing of the patient's symptoms 3 months after radiotherapy; (3) the relative sharp edge of the infiltrate that did not correspond to an anatomic boundary of the lung; and (4) the location of the infiltrate within the margins of the radiation port. The entire infiltrate on chest CT corresponded to the region encompassed by the 85% isodose line on the cumulative dosimetric plan (Fig 5). What, though, was the effect of the small blocks at the field edges? To answer this question, another cumulative dosimetric plan was calculated without the blocks in place (Fig 6). The 85% isodose line now included a significantly increased volume of lung, a region that would presumably have manifested the radiographic changes of radiation pneumonitis if it had not been blocked. These plans emphasize the importance of even relatively small blocks in limiting the radiographic sequelae of radiation pneumonitis, and thereby, possibly its clinical manifestations. The

2. Simulation radiograph of anteroposterior-posteroanterior field to treat area of tumor recurrence and mediastinum. (The white rectangle delineates the radiation port, slightlymodified after the initial simulation. The black cross-hatched areas at the field edges correspond to the custom-made blocks. ) FIGURE

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radiation pneumonitis in this case was self-limited and resolved within a few weeks without the need for steroid therapy. Recently, innovative radiotherapeutic techniques have been developed that may be useful in reducing radiation pulmonary injury. Three-dimensional conformal radiotherapy is external-beam radiotherapy in which the prescribed dose volume (treatment volume ) is made to conform closely to the target volume. With this technique, precise anatomic data are accumulated from high-resolution CT scans to build a computerized 3-D image of a patient's normal structures and the tumor. The optimal radiation beam parameters and orientation are selected by comparing plans using calculations and visual displays. This approach enables one to escalate the dose to the target volume while reducing the exposure of normal structures. Armstrong and colleagues91 compared the use of conventional and 3-D planning for locally advanced lung cancer and demonstrated that delivery of high-dose radiation to the target volume was significantly better witl1 the 3-D system. They also found that the average volume of lung receiving 2::25 Gy was reduced by 11% in tl1e ipsilateral lung and 51% in the contralateral lung. The group at tl1e University of Michigan quantitatively related the 3-D radiation dose distribution within tl1e lungs of 63 patients to the development of clinical pneumonitis. 92 The results suggest that it may be possible to calculate realistic estimates of the

FIGURE 4. Infiltrate in right midlung that developed 3 months after radiotherapy.

risk of normal tissue injury based on the 3-D dose distributions. As expected, they found that when volumes of irradiated lung were small, few serious pneumonitis occurrences were seen at even high doses (2::67 Gy). Such analyses allow for the design of dose escalation protocols as a function of volume utilizing 3-D conformal techniques. Another novel approach is computer-controlled radiation therapy, a technique for delivering radiation treatments in which a machine parameter, such as gantry angle, field shape, or dose rate is adjusted during the actual treatment. The changes in machine parameter settings are designed to maximize the dose to the target volume while sparing adjacent normal tissues. One group has explored a technique of varying field shape using a multileaf collimator and va1ying tl1e angle of beam entry using the machine gantry.93 Compa1ing computer-controlled plans with standard ones, they have shown tl1at under tl1e same spinal cord and lung tolerance restrictions, a higher minimum target dose can be delivered with the computer-controlled technique . The wider availability of multileaf collimators makes this approach even more appealing.

Potential Markers of Pulmonary Radiation Injury The application of preventive strategies will be enhanced by the development of useful markers for pulmona1y radiation injury. The potential use of alveolar surfactant lavage to detect late radiation pneumonitis has been suggested in experimental CHEST/111 /4/ APRIL, 1997

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FIGURE 5. CT after radioth erapy s howing th e pneumonitis infiltrate. Cumulative isodose cmves (with blocks in place) have been superimposed.

work on mice.94 Utilizing single-dose radiation exposure to the whole thorax in mice, Rubin et al 94 found steep dose-response curves for lavaged alveolar surfactant 7 to 28 days after exposure. There was no

significant change in the level of alveolar surfactant until 13 Gy, when it dramatically climbed and plateaued at 16 to 17 Gy. Correspondingly, the lethality of the m ice at 200 days followed a similar dose-

FIGURE 6. Same CT slice as Figure 5except th e superimposed isodose c urves were calculated without the blocks in place. 1072

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response curve. This study suggests that alveolar surfactant may be an early biochemical marker that predicts for subsequent radiation pneumonitis injury. Interestingly, a Chinese herb (764-1 ) administered daily after unilateral lung irradiation in rats was found to inhibit the level of alveolar surfactant detected following radiotherapy.95 Histopathologic correlation also suggested a decrease in the severity of lung fibrosis in the treated group. Although the study regarding lavaged surfactant levels has merit, lung lavage profiles are dependent on relative increases, which vary with alveolar surface areas lavaged, and a constant baseline value is difficult to establish. BAL is also an invasive procedure and as such is typically not suitable for clinical situations. In the rabbit model, a series of experiments has indicated a correlation between surfactant released in bronchoalveolar fluid and surfactant detected in serum. 96 The detection of serum antigens released as byproducts of radiation-induced cell injury would be a much simpler assay for radiation pneumonitis. A current Radiation Therapy Oncology Group protocol (No. 91-03) is studying this issue. In another study, 97 plasma TGF -13 levels were obtained before, during, and at each follow-up evaluation after definitive radiotherapy for eight patients with lung cancer. In the three patients who did not develop pneumonitis, plasma TGF-13 levels had normalized by the end of radiotherapy. In contrast, four of the five patients who suffered pneumonitis had persistently elevated plasma TGF -13 levels by the end of therapy. These results suggest that plasma TGF-13 levels during treatment may predict which patients are at higher risk of developing symptomatic pneumonitis. Future Directions As discussed, recent research implicates the involvement of cytokines in the pathogenesis of lung injury. The ability to modify these cytokines may provide a promising preventive strategy. Investigators at Stanford have shown that the administration of tumor necrosis factor-alpha (TNF-a) to guinea pigs induces a syndrome similar to Gram-negative bacteria-related septic shock, which includes capillary permeability lung injury.51 TNF-a has been shown to increase neutrophil phagocytosis and increase oxygen-free radical formation . Since pentoxifylline (PTX) has been shown to decrease phagocytic activity and superoxide anion formation , they raised the hypothesis that PTX may have aprotective effect on lung damage caused by TNF administration.5l Pulmonary edema was assessed by measuring lung wet-to-dry weight. They found that the TNF-atreated group had a significantly increased wet-to-

dry lung ratio compared to the PTX!TNF group. The extrapolation of these results of animal studies to the clinic should be approached with caution. Nevertheless, recent cytokine research unravels molecular events that may lead to future preventive strategies and thereby further open up the therapeutic window. If, for example, TGF-13, TNF-a, or other cytokines are causal of radiation lung damage, monoclonal antibodies or other biological modifiers of these factors could potentially prevent radiation pulmonary injury. Another exciting strategy on the horizon is the potential to protect lung from irradiation damage by gene therapy. Recently, a method has been developed to transiently elevate bronchoalveolar cell levels of manganese superoxide dismutase, an enzyme involved in the reduction of oxygen-free radicals.98 Mice received liposomes containing a plasmidencoded human manganese superoxide dismutase transgene. They demonstrated detectable messenger RNA levels and a decrease in acute pulmonary changes. Such plasmid vectors, which can be eliminated by the immune system, may transiently provide high levels of transgene expression that may be sufficient to protect the lung. These novel strategies and others provide for new avenues to prevent pulmonary radiation injury. ACKNOWLEDGMENTS: The authors wish to thank Louise Marcewicz and Virginia Austin for their secretarial assistance in the preparation of this article.

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