Background: Radiation pneumonitis is an interstitial pulmonary inflammation that can develop in as many as 5-15% of patients with thoracic irradiation, most often due to lung cancer, breast cancer, lymphoma, or thymoma. Acute radiation pneumonitis occurs within 1-6 months following treatment. Symptoms can include low-grade fever, cough, and fullness in the chest.
Severe reactions can result in dyspnea, pleuritic chest pain, hemoptysis, acute respiratory distress, and death. Fibrosis can occur without previous pneumonitis but once pneumonitis occurs, fibrosis is almost certain to take place. The radiographic hallmark of radiation pneumonitis is a diffuse infiltrate corresponding to a previous radiation treatment field.
Pathophysiology: Two separate and distinct mechanisms are involved in the pathogenesis of acute radiation pneumonitis.
The first, classical radiation pneumonitis, involves direct toxic injury to endothelial and epithelial cells from the radiation, resulting initially in an acute alveolitis. This process leads to an accumulation of inflammatory and immune effector cells within the alveolar walls and spaces. The accumulation of leukocytes distorts the normal alveolar structures and results in the release of lymphokines and monokines. The alveolar macrophage is thought to play a central role in the subsequent development of chronic inflammation (fibrosis).
The second mechanism, sporadic radiation pneumonitis, results in an "out-of-field" response. This is thought to be an immunologically mediated process resulting in bilateral lymphocytic alveolitis.
In contrast to acute radiation pneumonitis, permanent changes of radiation fibrosis can take months to years to evolve but normally stabilize within 1-2 years. Pulmonary fibrosis is the repair process that follows the acute inflammatory response and is characterized by progressive fibrosis of the alveolar septa thickened by bundles of elastic fibers. The process is not fully understood but believed to be a function of activation on cells to produce cytokines and growth factors, which orchestrate most aspects of the inflammatory response.
Current research focuses on chemotactic factors for fibroblasts, including transforming growth factor-beta (TGF-B, a cytokine known to promote connective tissue formation), fibronectin, and platelet-derived growth factor (PDGF). The most important stimulator of collagen synthesis is believed to be TGF-B, for which the alveolar macrophage is the main source.
Frequency:
- In the US: Asymptomatic radiologic findings are
observed in as many as 50% of treated patients.
Clinical radiation pneumonitis can develop in 5-15% of patients undergoing radiation treatment to the thorax. The clinical pathologic course is biphasic and is dependent upon the dose and volume of lung exposed and the use of chemotherapy agents.
Mortality/Morbidity: Morbidity and mortality vary greatly based on the volume of lung irradiated, dose per fraction of radiation delivered, use of concomitant chemotherapy, total dose of radiation delivered, and performance status of the patient.
Predisposing factors such as smoking history, collagen vascular disease, and steroid withdrawal also affect the frequency of symptoms.
Moderate-to-severe radiation pneumonitis occurs in an estimated 2-9% of patients treated for lung cancer with combination chemotherapy and irradiation. This represents the high-risk group. Even in this high-risk group, mortality is estimated to be 1-2%.
Race: No race predilection exists.
Sex: Women tend to have higher rates of moderate-to-severe radiation pneumonitis. This may reflect that most women have smaller lung volumes and smaller forced expiratory volume in 1 second (FEV1) values. Thus, given similar radiation field sizes, a greater proportion of lung may be at risk.
This also may represent an autoimmune predisposition to injury. Many autoimmune diseases, such as systemic lupus erythematosus, are more common in women than in men and are a known risk factor for increasing the chance of subsequent radiation-induced lung damage.
Age: No direct link to age exists. However, rates do increase as performance status decreases, which is indirectly related to age.
Clinical Details: Classic radiation pneumonitis has 3 main phases.
Early phase (first month): This represents a latent period of pneumonitis. During this phase, loss of both type I and type II pneumonocytes occurs. Type II pneumonocytes produce surfactant, and decreased amounts result in transudation of serum proteins into the alveoli. This leads to edema of the intersitial spaces.
Intermediate phase (1-6 months): This is characterized by dose-dependent leakage of proteins into the alveolar space, thickening of the alveolar septa, and development of clinical symptoms. Common clinical symptoms include nonproductive cough, low-grade fever, tachycardia, and dyspnea.
Late phase (6 months and later): This is characterized by a loss of capillaries and increased collagen deposition. This results in restrictive changes within the lung characterized by reductions in vital capacity, lung volumes, diffusing capacity of lung for carbon monoxide (DLCO), and total lung capacity.
Preferred Examination: Chest radiography is the preferred initial examination. Further imaging can be performed with CT scans, which are more sensitive.
Nuclear medicine imaging with ventilation/perfusion scans and, more recently, fluorine 18 fluorodeoxyglucose-positron emission tomography (FDG-PET) may provide additional information in clinically and radiographically equivocal cases.
Limitations of Techniques: Chest radiography
- Low sensitivity in detecting small volumes
- Cannot quantitate the volume of affected lung versus the total lung
volume
- Low sensitivity in detecting small areas close to the chest wall, as is the case in tangential field irradiation for breast cancer
DIFFERENTIALS
Idiopathic Pulmonary Fibrosis
Lung, Drug-induced Disease
Scleroderma, Thoracic
Other Problems to be Considered:
Recurrent cancer
X-RAY
Findings: Chest radiographic findings vary from normal or subtle hazy ground glass density to marked patchy or homogenous consolidation. Air bronchograms are commonly present and volume loss of the affected portion of the lung may be observed. There is usually a sharp boundary crossing the normal anatomic structures without segmental or lobar distribution. Rarely, an entire lung or both lungs are involved (adult respiratory distress syndrome [ARDS]).
Degree of Confidence: Chest radiographs occasionally are normal.
False Positives/Negatives: False positives include recurrent disease, infection/pneumonia, cardiac disease, and lymphangitic carcinomatosis.
CAT SCAN
Findings: Acute radiation pneumonitis changes, especially the subtle ground glass opacity (GGO), are seen earlier on CT than on radiographs. Different patterns of radiation-induced damage observed on chest radiographs are seen to better advantage with CT and vary from early homogenous, slight increase in radiodensity (GGO), to patchy or homogenous consolidation. Small pleural and pericardial effusions are not uncommon.
CT is useful in detecting recurrent tumor in an irradiated area. This is suggested by the presence of a masslike lesion or development of focal air space opacity without air bronchogram.
CT scans can be used to detect and calculate volumes of lung affected as a percentage of the total lung volume.
Degree of Confidence: CT scans are more sensitive that chest radiographs and detect abnormalities in as many as 50% of patients.
NUCLEAR MEDICINE
Findings: Nuclear medicine ventilation/perfusion scans are frequently abnormal following radiation treatment for lung cancer, breast cancer, or lymphoma involving the mediastinum. Perfusion defects are more common than ventilation defects. This process is thought to be the result of abnormal shunts occurring after radiation treatment, with some irradiated areas remaining ventilated but not adequately perfused. During the acute phase of radiation pneumonitis, perfusion defects begin approximately 25 days following the radiation exposure and reach a maximum within 150 days.
Three-dimensional single photon emission computed tomography (3-D SPECT) perfusion scans more recently have been shown to provide a 3-D map of functioning vascular/alveolar subunits within the lung.
Pulmonary perfusion is often not uniformly distributed. Pretreatment SPECT scans can be useful in designing treatment beams that minimize the physiologic impact of thoracic irradiation.
More recently, researchers have demonstrated that the acute phase of radiation pneumonitis results in increased uptake of FDG in regions of lung affected by radiation pneumonitis. FDG imaging with either a dedicated PET or dual-head coincidence gamma camera system can be used. This may become useful in the setting of clinically and radiographically equivocal cases.
INTERVENTION
Intervention: Corticosteroids remain the treatment of choice for radiation pneumonitis.
Prophylactically administered corticosteroids have been shown to decrease the physiologic effects of radiation in mice. However, in human studies, this approach has failed to prevent the development of clinical pneumonitis.
TGF-B has been the target of more recent studies. Angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease the expression of TGF-B1 in animals and recently have been tested in human trials. Researchers at Duke University recently reviewed the records of 213 patients receiving thoracic irradiation for lung cancer with curative intent. Of these patients, 12% were on ACE inhibitors for hypertension. Initial results revealed that at the dose used for the treatment of hypertension, ACE inhibitors had no protective effect. Future trials will evaluate larger doses.
The recommended treatment is to begin prednisone at 1 mg/kg as soon as the diagnosis is reasonably certain. The initial dose is maintained for several weeks and then reduced slowly. If steroids are tapered too soon or too quickly, exacerbation of symptoms has been reported, requiring higher doses and longer treatment with steroids.
Antibiotics and anticoagulants have been evaluated as treatment options but neither has been found to be clinically beneficial. Pentoxifylline has been shown to decrease late effects from radiation damage but clinical trials in humans have shown no benefit.
Special Concerns:
- Differentiating radiation pneumonitis from recurrent cancer is important.
PICTURES
| Caption: Picture 1. Radiation pneumonitis. Patient had received radiation treatment to left upper lobe. There is a focal linear area of soft tissue density in the left upper lobe with volume loss. | |
 |
|
| Picture Type: X-RAY | |
| Caption: Picture 2. Radiation pneumonitis. CT (same patient as Image 1) demonstrating localized area of peripheral fibrosis in the left upper lobe with a sharp edge corresponding to prior anteroposterior/posteroanterior treatment fields. | |
 |
|
| Picture Type: CT | |