Radiation-Induced LungDisease

Lindsay G. Jensen, Mark M. Fuster, and Ajay P. Sandhu

BACKGROUND

Radiotherapy for thoracic neoplasms often includes normal lung tissue within the field, creating a risk of radiation-induced lung injury. Reports on the frequency of radiation-induced lung injury after radiotherapy for lung cancer, breast cancer, esophageal cancer, and Hodgkin disease vary widely depending upon whether the study assesses radiographic or clinical features. Post radiation changes are common and occur in the majority of patients in some studies; however, clinical symptoms occur in a much smaller proportion of patients. Although the increasing use of conformal radiation therapy (RT) techniques can limit normal-tissue exposure, radiation-induced lung injury is an important consideration during radiotherapy planning and treatment.

PATHOPHYSIOLOGY

Radiation creates reactive oxygen and nitrogen species which damage cell proteins, membranes, and DNA. The exact pathophysiology of radiation injury is incompletely understood, but involves damage to endothelial cells as well as type I and II pneumocytes.

The acute phase of radiation pneumonitis is characterized by endothelial cell changes, swelling of the basement membrane, interstitial edema, variable capillary occlusion, and presence of inflammatory cells. There is an initial increase in surfactant due to release of surfactant-containing lamellar bodies from type II pneumocytes, followed by decreased surfactant and hyaline membrane change. Sloughing endothelial cells and increased capillary permeability result in capillary obstruction and accumulation of proteinaceous exudate in alveoli, impairing gas exchange.

Inflammatory cells in the acute phase of radiation pneumonitis induce a cytokine cascade, which ultimately mediates a host response characterized by fibrosis. Cytokines including transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1 play an important role, and their serum levels have been studied as potential predictors of radiation pneumonitis. Late injury, occurring 6 months or more after RT, is characterized by fibrosis and thickening of vessel walls and alveolar septa. TGF-β in particular is thought to be involved in the development of chronic fibrosis by increasing synthesis of collagen and fibronectin.

The likelihood of developing radiation-induced lung injury depends on total dose, dose per fraction, concurrent chemotherapy, total lung volume irradiated, location of tumor, history of chest irradiation, and pre-existing lung disease. Older age and large gross tumor volume (GTV) may increase risk. Smokers may have a decreased risk of developing radiation pneumonitis. Studies have shown conflicting results on whether abnormal pulmonary function tests (PFTs) at baseline can predict for radiation pneumonitis. Dose per fraction and total lung dose have been shown to be particularly important, and higher total doses can be delivered without inducing lung injury when smaller fraction sizes are used. In large single doses, the frequency of radiation pneumonitis increases rapidly with fraction size above 7.5 Gy. Using smaller fraction sizes of 1.8 to 2 Gy, the estimated whole lung doses resulting in a 5% and 50% probability of a complication within 5 years are approximately 17.5 and 24.5 Gy, respectively. Several studies evaluating dose–volume parameters have sought to establish the relationship between radiation pneumonitis and V_DOSE, which is defined as the percent of lung volume (V) receiving greater than or equal to a specified dose in Gray (DOSE). No single dose parameter can reliably predict for lung damage, but mean lung dose (MLD) above 20 Gy and V₁₃, V₂₀, and V₃₀ above 40%, 25% to 30%, and 10% to 15%, respectively, appear to increase probability of symptomatic radiation pneumonitis.

Predicting radiation pneumonitis as a function of dose is an area of active research. A review of studies reporting dose–volume parameters, normal-tissue complication probability (NTCP) models, and MLD found that most models had only fair to poor accuracy in predicting likelihood of radiation pneumonitis. Predictive models to determine risk for radiation-induced lung injury based on large patient datasets have also not proven to be effective when applied to other datasets.

Chemotherapy with drugs that are toxic to the lung can exacerbate the effects of radiation pneumonitis. Bleomycin is the most well-known of these compounds, but Adriamycin (doxorubicin), busulfan, paclitaxel, cisplatin, dactinomycin, vincristine, cyclophosphamide, mitomycin, gemcitabine, and other chemotherapeutic agents may also contribute to radiation-induced lung injury. Sequential, rather than concurrent, administration of chemotherapy drugs may decrease lung injury. Certain chemotherapeutic agents have also been reported to cause a “recall pneumonitis,” where signs and symptoms of radiation pneumonitis occur in the previously irradiated field within hours of receiving the chemotherapeutic drug. This response can occur months after the completion of radiotherapy.

CLINICAL PRESENTATION

Radiation-induced lung disease can be divided into two stages: acute radiation pneumonitis and chronic radiation fibrosis.

Acute Radiation Pneumonitis

Damage to lung tissue begins within days of radiation exposure, but radiation pneumonitis usually becomes symptomatic after 1 to 3 months. Early onset is associated with a worse clinical course. The most common symptom of radiation pneumonitis is dyspnea, but cough, fever, and chest pain can also occur. Cough is typically minimally productive, occasionally with streaky hemoptysis. Chest pain may be vague or pleuritic in nature. Physical exam is usually normal, but crackles, pleural, or pericardial rub may be heard. Signs of consolidation may also be noted in the affected lung area. Acute radiation pneumonitis can rarely progress to fulminant respiratory failure and death.

Chronic Radiation Fibrosis

Chronic fibrosis usually develops 6 months or more after radiotherapy and stabilizes by 2 years. Fibrosis likely occurs to some degree in all patients receiving radiation to the lung, but it is often asymptomatic. Dyspnea is the most common symptom. In severe cases of fibrosis, pulmonary hypertension and cor pulmonale may develop. Physical findings may include inspiratory crackles, elevated hemidiaphragms, cyanosis, clubbing, and elevated venous pressure.

Radiographic Changes

Radiographic changes for both early and late pulmonary injury are more common than clinical symptoms. Acute radiation pneumonitis typically presents as hazy opacity on chest radiography. Radiation changes can have a sharp edge corresponding to the shape of the radiation port, but this may be less pronounced as more patients are treated with conformal radiotherapy fields. Later findings include septal thickening and air bronchograms. Radiation fibrosis appears within the irradiated area as a linear interstitial pattern, dense fibrotic strands with occasional dense consolidation, volume loss, and traction bronchiectasis. Pleural thickening may also be seen. CT is more sensitive than plain radiography in assessing structural lung changes, which include (in order of severity) increased density, patchy consolidation, and solid consolidation. MRI may be particularly useful in differentiating radiation pneumonitis from recurrent disease.

While radiographic findings are confined to the irradiated area, a bilateral lymphocytic alveolitis has been described outside of the radiation field. Bronchoalveolar lavage in patients undergoing unilateral breast irradiation shows increased lymphocytes and neutrophils compared to controls, with no difference in number between the irradiated and nonirradiated sides. It is unclear if the degree of lymphocytosis correlates with symptoms of radiation pneumonitis.

Functional imaging studies can also aid in the diagnosis and quantification of lung injury. Increasing fludeoxyglucose positron emission tomography (FDG-PET) uptake following radiotherapy appears to correlate with maximum degree of clinical radiation pneumonitis. FDG-PET uptake following radiotherapy also increases with radiation dose, but there is a significant variation in the magnitude of increase, indicating possible differences in the underlying biologic response between patients. Single photon emission computed tomography (SPECT) shows decreased ventilation and perfusion 3 to 4 months after RT with some studies reporting partial recovery of function occurring at 18 months.

PFTs are variable in radiation-induced lung injury and are particularly difficult to evaluate in lung cancer patients who may have abnormal PFTs at baseline. The diffusion capacity of carbon monoxide is more consistently decreased than other parameters. Decreased forced expiratory volume in 1 second (FEV₁) is also fairly common. Total lung capacity and vital capacity may decrease as a result of fibrosis. In some cases, PFTs may improve when tumor shrinkage decreases obstruction. The most common laboratory findings associated with radiation pneumonitis are polymorphonuclear leukocytosis and elevated erythrocyte sedimentation rate.

Differential diagnosis for radiation-induced lung injury includes infection, pericarditis, drug toxicity, pulmonary emboli, exacerbation of baseline lung disease, recurrent tumor, or lymphangitic tumor spread. Radiation-induced lung injury is usually scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, Radiation Therapy Oncology Group (RTOG) scale, or Southwest Oncology Group (SWOG) scale. All are 5-point scales where 1 is minimal or asymptomatic and 5 is death, but reported grade of toxicity has been shown to vary depending on which scale is used.

COMPLICATIONS

Pleural effusion, pneumothorax, bronchial stenosis, and tracheoesophageal fistula are uncommon complications of thoracic radiation. Pleural effusions are typically small and occur in the same time frame as other radiographic findings of acute pneumonitis. Bronchial stenosis has been reported mainly in patients receiving endobronchial brachytherapy, but can occur after high-dose external beam radiotherapy.

Bronchiolitis obliterans organizing pneumonia (BOOP) is an inflammatory reaction that can occur after thoracic radiotherapy. Symptoms are similar to those of radiation pneumonitis, including cough and dyspnea, but BOOP can be differentiated from radiation pneumonitis by the presence of affected lung tissue outside of the radiotherapy field and migratory infiltrates on chest radiograph or CT. BOOP is uncommon, occurring in 2.5% of patients in breast cancer series, and can present months to years after the completion of radiotherapy. Symptoms of BOOP are typically responsive to corticosteroids, but recur more frequently than classic radiation pneumonitis symptoms when corticosteroids are withdrawn.

PREVENTION AND TREATMENT

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