Pulmunary Toxicity

Mechanism of Lung Injury

  • Most susceptible cells
    • Capillary endothelial cells
    • Type I cells (epithelial lining cells)

What Radiation does in lung?

  • Specific signal transduction pathways are activated by radiation, including sphingomyelin hydrolysis, which generates ceramide as a second messenger and leads to apoptotic DNA degradation.
  • Nonlethal Rt
    • —> Activates a stress response in cells
      • ==> up-regulation of specific nuclear transcription factors
        • ==> Initiates a repair process that involves cytokines and growth factors
          • Basic fibroblast growth factor
          • Vascular endothelial growth factor
          • Platelet-derived growth factor
          • Tumor necrosis factor-α
          • Interleukin-1
          • Transforming growth factor-β (TGF-β).
  • Up-regulation of prostaglandin synthesis
  • Regenration of capillaries
  • Repopulation of alveolar epithelium is repopulated by type II cells (surfactant-producing cells)
    • because type I pneumocytes do not regenerate
    • Some type II cells redifferentiate into type I cells
  • Damage to extracellular matrix components of the lung
    • Basement membrane glycoproteins & proteoglycans
  • Stimulates production of matrix metalloproteinase
    • Enzyme capable of degrading the type IV basement membrane collagen
      • ==> impede reconstruction of the delicate three-dimensional structure of the alveolar-capillary unit
        • ==> functional derangement and scar formation
  • Loss of integrity of pulunary capillaries
  • Exudation of fluid into alveoli
  • Leakage of plasma protein into the alveolar space
  • Loss of compliance
  • Abnormal gas exchange
  • respiratory failure
  • This type of genetic damage may also explain why pneumonitis can happen so late after radiation. One might speculate that some endothelial cells initially remain normal but that in the course of the next four cell divisions, chromosomal aberrations prevent further reduplication, which leads to loss of integrity of the capillary. Alternatively or concurrently, a cellular infiltrate is observed in bronchoalveolar lavage fluid and lung tissue, which is interpreted as an inflammatory response to the radiation injury. In experimental animal models, systemic administration of corticosteroids can suppress this inflammatory response, yet does not abrogate the subsequent development of chronic fibrosis. Based on these pathophysiologic considerations, animal studies suggest that lung gene transfer of constructs encoding several superoxide dismutase genes confers protection against radiation pneumonitis. Similar protective effects have been observed with systemic administration of competitive inhibitors of nitric oxide synthase. Inhibition of endothelial cell apoptosis by therapeutic administration of basic fibroblast growth factor or vascular endothelial growth factor has been beneficial in some animal models, but no human trials have been attempted.

Certain factors are critical to the development of classic radiation pneumonitis. In general, damage to the lung increases as the volume of lung tissue irradiated increases. A threshold effect also appears to occur, such that irradiation of at least 10% of the lung is required to produce significant pulmonary toxicity. This threshold may be reached in the treatment of some patients with breast cancer, depending on the specifics of their individualized treatment program. Also, the toxic effects of radiation as measured by symptoms and signs, radiographic changes, and physiologic tests are proportionate to the total amount delivered to the lung. Radiation pneumonitis seldom occurs with fractionated total doses of less than 20 Gy but is more likely when doses exceed 60 Gy. Because local control of lung cancer is greater when higher doses are delivered to the tumor, methods have been devised to give high doses to the target tissue while sparing normal surrounding lung. One such technique is called stereotactic body radiotherapy, which is a noninvasive treatment that delivers small highly focused radiation beams in potent doses of one to five treatments to tumor targets. Studies have suggested that local control with this modality is comparable to surgery with minimal morbidity.3,4

Besides the total radiation dose, the number of fractions into which it is divided, and, to a lesser extent, the time span over which it is delivered are important factors. The greater the number of fractions in which the radiation is given, the lower is the damaging effect. However, the incidence of radiation pneumonitis still exhibits a threshold effect and a steep sigmoidal dose-response curve. Fractionation is different from dose rate, which refers to output of the machine during radiation therapy. Dose rate certainly has an effect on lung tolerance: radiation delivered as 0.05 Gy/min is less damaging than radiation delivered at 0.3 Gy/min, which in turn is less damaging than radiation delivered at 2 to 3 Gy/min. The incidence and severity of radiation damage to the lungs are thus related principally to the volume of lung tissue irradiated, the total dose, the fractions into which the total dose is divided, and the quality of the radiation.

Taking all of these considerations into account, stereotactic body radiotherapy offers the best strategy to reduce the risk of radiation pneumonitis while improving local control of the cancer.5 Advances in the technology of positron emission tomography scanning have improved its usefulness for diagnosis and staging of lung cancer. Combined positron emission tomography/computed tomography (CT) imaging offers some advantages in designing the radiation port and in detecting metastases not evident on CT, thus changing the intent of the radiotherapy from curative to palliative.6,7 Genetic factors also influence the severity of response to lung irradiation in animals and presumably may do so in humans as well, although there is no current method to evaluate this clinically.

A new technology for the curative treatment of early-stage medically inoperable lung cancer and palliation of small pulmonary metastases called radiofrequency ablation is emerging. Radiofrequency ablation is a minimally invasive technique that is performed percutaneously, under conscious sedation and as an outpatient or with a short hospital stay. The complication rates are low and early outcomes are acceptable compared with more aggressive procedures. Pneumothorax and pleural effusions are the major complications; radiation pneumonitis has not been reported with this technique. Other technologies such as protein beam therapy are being evaluated.

Histopathology
The histopathologic changes of radiation-induced pulmonary toxicity can be divided into early, intermediate, and late stages based on the time course and intensity of the radiation injury. Early radiation damage (0 to 2 months after radiation) is characterized by injury to small vessels and capillaries, with the development of vascular congestion and increased capillary permeability. At this stage, a fibrin-rich exudate is present in the alveolar spaces. Hyaline membranes form on the alveoli, probably from condensation of the intra-alveolar fibrin. After 1 month, there is also an inflammatory infiltrate, which may lead to a second course of increased permeability. Abnormalities in the intermediate stage (2 to 9 months after radiation) are characterized by obstruction of pulmonary capillaries by platelets, fibrin, and collagen. Alveolar-lining cells (primarily type II pneumonocytes) become hyperplastic, and the alveolar walls become infiltrated with fibroblasts and mast cells. If the radiation injury is mild, these changes may subside entirely; however, when the injury is severe, a chronic phase (9 months or more after radiation) ensues that may persist or progress for months or years. In animal models, there is marked activation of genes that encode fibrillar collagens. The histopathologic appearance is then dominated by dense fibrosis, thickening of the alveolar walls, vascular subintimal fibrosis, and luminal narrowing. In some instances, the lung may shrink to less than half its original size, with a thickened adherent pleura and scarred hilar structures.

In addition to this classic pattern of radiation pneumonitis, another syndrome of out-of-field pneumonitis, characterized by a hypersensitivity pneumonitis in areas of lung not directly radiated, has been described. This syndrome, which occurs in a minority of patients, is characterized by a bilateral lymphocytic alveolitis of activated CD4+ T lymphocytes 4 to 6 weeks after strictly unilateral lung irradiation.

Clinical Features
Signs and Symptoms
The clinical syndrome of radiation pneumonitis develops in 5% to 15% of patients receiving high-dose external-beam radiation for treatment of lung cancer. Factors that can add to the development of radiation pneumonitis include concomitant chemotherapy, previous irradiation, and withdrawal of steroids. No significant difference is seen in the incidence of radiation pneumonitis between the young and elderly, but the pneumonitis is inclined to be more severe in the latter. Underlying chronic obstructive pulmonary disease does not appear to potentiate radiation damage.

Symptoms of acute radiation pneumonitis usually become evident 2 to 3 months after the completion of therapy; rarely, they occur within the first month and occasionally as late as 6 months after irradiation.8 In general, the early onset of symptoms implies a more serious and more protracted clinical course. The cardinal symptom of radiation pneumonitis is dyspnea. It may be self-limited or may progress to severe respiratory distress depending on the extent and intensity of the injury. Patients may also have a nonproductive cough or a cough productive of small amounts of pinkish sputum. Frank hemoptysis early in the clinical course is distinctly uncommon; however, massive hemoptysis has been reported as a late complication of therapeutic pulmonary irradiation. Fever is unusual but can be high and spiking; in severe cases, other constitutional symptoms may occur. Chest pain, which is rarely a prominent feature, may be the result of fractured ribs, pleural changes, or coughing. Symptoms of airway obstruction can occur in the first few days of radiation therapy and are usually associated with swelling of a central bronchogenic carcinoma. Severe respiratory distress can result and may be prevented by the administration of steroids the day before and several days after the initiation of radiation therapy. Hemoptysis and other manifestations of radiation pneumonitis may also occur in patients given palliative endobronchial brachytherapy or after surgical implantation of radioactive seeds.

On physical examination, signs of pulmonary involvement are minimal. Occasionally, moist rales, a pleural friction rub, or evidence of pleural fluid may be heard over the area of irradiation. In severe cases, tachypnea and cyanosis may be present, and occasionally evidence of acute cor pulmonale appears, usually predicting a fatal outcome. Finger clubbing due to radiation is distinctly unusual and, if present, is most likely caused by the underlying malignancy. Skin changes corresponding to the ports of irradiation are often present but provide no clue as to the presence or severity of the pulmonary reaction beneath.

Although patients with acute pneumonitis may show complete resolution of signs and symptoms, most develop gradual progressive fibrosis. In some cases, patients present with radiation fibrosis without a previous history of acute pneumonitis. The permanent changes of fibrosis take 6 to 24 months to evolve but usually remain stable after 2 years. Patients with fibrosis can be asymptomatic or can have varying degrees of dyspnea. The major complications of radiation pneumonitis occur late in the disease and are secondary to persistent fibrosis of a large volume of lung. These include cor pulmonale and respiratory failure.

Diagnostic Imaging
Although radiographic abnormalities are invariably found at the time clinical radiation pneumonitis is present, these changes may be seen in asymptomatic patients as well. Early radiographic changes include a ground-glass opacification, diffuse haziness, or indistinctness of the normal pulmonary markings over the irradiated area. Later, the chest radiograph may show alveolar infiltrates or dense consolidation with or without air bronchograms. As the pneumonitis progresses to fibrosis, the radiographic appearance changes to that of linear streaks radiating from the area of pneumonitis and of contraction toward the hilar, the perimediastinal, or the apical areas. Pleural effusions, if present, are usually small and always coincident with the pneumonitis. They can persist for long periods but often disappear spontaneously and never increase during a period of stability unless secondary complications occur, such as radiation-induced pericarditis. Mediastinal or hilar adenopathy and cavitation are almost always due to causes other than radiation pneumonitis. Pneumothorax is occasionally associated with radiation fibrosis but not with acute pneumonitis.

One of the most characteristic features of radiation pneumonitis and fibrosis is that the radiologic changes are confined to the outlines of the field of radiation. In a few cases, extensive changes outside the field, even in the contralateral lung, have been observed. This syndrome of out-of-field pneumonitis is thought to represent a hypersensitivity response to the radiation. Other possible explanations for this phenomenon include obstruction of lymphatic flow from radiation-induced mediastinal fibrosis and absorption of x-rays by regions outside the irradiated ports.

Some data suggest that CT scans of the chest and gallium-67 citrate imaging are more sensitive than chest radiography in the detection of radiation changes. Correlation of abnormalities seen in these tests with the development of physiologic dysfunction and clinical toxicity needs clarification.

Pulmonary Function Tests
Prediction of changes in pulmonary function after high-dose irradiation to the lung has proven to be problematic.9 No gross physiologic changes occur in the lung until 4 to 8 weeks after completion of irradiation, usually coincident with the period of clinical pneumonitis. Then one sees a decrease in lung volumes, which can progress. These changes persist indefinitely, with little evidence of recovery. Gas exchange abnormalities, which include a decrease in diffusing capacity and arterial hypoxemia, especially with exercise, occur at approximately the same time but show some tendency toward recovery after 6 to 12 months. A fall in compliance coincident with the clinical pneumonitis is seen in most subjects. Accordingly, the elastic work of breathing is increased, and dyspnea, resulting from the increased workload, ensues. Air-flow parameters remain close to normal in most studies.

Diagnosis
The diagnosis of radiation pneumonitis can sometimes be made clinically based on the timing of irradiation in relation to symptoms and the typical chest radiographic appearance (i.e., infiltrates corresponding to the margins of the irradiated portal).9 Differentiation from recurrent malignancy or infection often poses a problem, and then lung biopsy is necessary. Although histopathologic changes are nonspecific for radiation pneumonitis, when elements of the acute stages (fibrin exudate in the alveoli) are seen adjacent to the more chronic stages (alveolar fibrosis and subintimal sclerosis), this entity can be diagnosed with reasonable certainty.Biochemical markers that indicate radiation lung injury before the onset of clinical pathologic events would be valuable in the early diagnosis and management of patients with radiation toxicity. In irradiated animals, studies demonstrate that alveolar epithelial cell proteins such as KL-6 or surfactant apoproteins in addition to endothelial soluble intercellular adhesion molecule-1 or TGF-β found in the serum may be markers for later radiation pneumonitis.

Treatment
Corticosteroid administration during irradiation in mice markedly improves the physiologic abnormalities and decreases mortality without an effect on late pulmonary fibrosis. No controlled clinical trials in humans are available on the efficacy of steroid therapy in radiation pneumonitis. Rubin and Casarett10 collected data from eight studies on humans and categorized them according to whether corticosteroids were used prophylactically or therapeutically. Corticosteroids given prophylactically failed to prevent radiation pneumonitis, but when they were administered as clinical pneumonitis occurred, an objective response was seen. In other reports, steroid therapy failed to ameliorate severe pneumonitis. Nonetheless, it is the authors’ practice to begin prednisone, 1 mg/kg, as soon as the diagnosis is reasonably certain. The initial dose is maintained for several weeks and then reduced cautiously and slowly. It has been the authors’ experience that symptoms can be exacerbated if steroids are tapered too rapidly, necessitating higher doses for longer periods. Similarly, if corticosteroids are part of a recent chemotherapeutic regimen, stopping them abruptly can precipitate clinically evident radiation pneumonitis. What parameters, if any, to follow during the tapering schedule are not known, and no studies are available. Generally, the authors follow symptoms. Most authors agree that corticosteroids have no place in the treatment of radiation fibrosis.

Pentoxifylline has been found to have some beneficial effects on radiation pneumonitis by inhibiting platelet aggregation and tumor necrosis factor. In a recent randomized trial, pentoxifylline, given prophylactically to breast and lung cancer patients receiving irradiation, showed a significant protective effect on both the early and late lung radiotoxicity.11

Radiation-Related Bronchiolitis Obliterans with Organizing Pneumonia
Although bronchiolitis obliterans with organizing pneumonia (BOOP) is an unusual histopathologic pattern for cancer therapy–related lung injury, radiation damage resulting in BOOP has been reported.12 Patients with lung cancer usually receive the highest doses of radiation to the largest volume of lung tissue, which makes them more susceptible to radiation pulmonary injury compared with other irradiated patients. Most of the cases of radiation-related BOOP, however, have occurred in patients receiving radiation treatment to the breast. Whether the low dose or indirect radiation that these patients receive makes them more susceptible to this type of lung injury is not known. Besides the unusual pathologic pattern in these patients, there are clinical and radiologic differences, compared with conventional radiation pneumonitis. Whereas dyspnea is the hallmark of radiation-induced pneumonitis, fever and cough are the predominant features of radiation-related BOOP. Radiographically, the pulmonary infiltrates can begin in radiated areas as with radiation pneumonitis, but they always progress outside the portal, and in approximately 40% of cases, infiltrates were observed on the side contralateral to the irradiated breast. Although patients respond dramatically to corticosteroid therapy with no obvious evidence of residual damage, there is a 67% relapse rate when the drug is tapered or discontinued. Similar to conventional radiation-induced pneumonitis, there are no studies available on the minimal effective dose or duration of therapy, but in view of the high relapse rate, it seems prudent to taper corticosteroid therapy very slowly, with meticulous vigilance for clinical signs of relapse.