Radiation-Induced Lung Injury: Assessment and Management

Abstract

Radiation-induced lung injury (RILI) encompasses any lung toxicity induced by radiation therapy (RT) and manifests acutely as radiation pneumonitis and chronically as radiation pulmonary fibrosis. Because most patients with thoracic and breast malignancies are expected to undergo RT in their lifetime, many with curative intent, the population at risk is significant. Furthermore, indications for thoracic RT are expanding given the advent of stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SABR) for early-stage lung cancer in nonsurgical candidates as well as oligometastatic pulmonary disease from any solid tumor. Fortunately, the incidence of serious pulmonary complications from RT has decreased secondary to advances in radiation delivery techniques. Understanding the temporal relationship between RT and injury as well as the patient, disease, and radiation factors that help distinguish RILI from other etiologies is necessary to prevent misdiagnosis. Although treatment of acute pneumonitis is dependent on clinical severity and typically responds completely to corticosteroids, accurately diagnosing and identifying patients who may progress to fibrosis is challenging. Current research advances include high-precision radiation techniques, an improved understanding of the molecular basis of RILI, the development of small and large animal models, and the identification of candidate drugs for prevention and treatment.

Keywords: cancer; fibrosis; lung injury; pneumonitis; radiation; thoracic.

Figure 1

The pathobiology of radiation pneumonitis and radiation-induced lung injury. Ionizing radiation induces free radicals and DNA damage to promote oxidative stress, vascular damage, and inflammation that manifest during radiation pneumonitis. Persistent inflammation sustains alveolar epithelial and vascular endothelial cell damage and contributes to pathologic changes, including immune cell infiltration, capillary permeability, and pulmonary edema. Prolonged alveolar and vascular damage leads to EMT and/or EndoMT and eventually culminates in fibrotic changes. α-SMA = alpha smooth muscle actin; CTGF = connective tissue growth factor; ECM = extracellular matrix; EMT = epithelial-to-mesenchymal transition; EndoMT = endothelial-to-mesenchymal transition; FGF = fibroblast growth factor; ILs = interleukins; ROS = reactive oxygen species; RNS = reactive nitrogen species; TGF-β = transforming growth factor beta; TNF-α = tumor necrosis factor alpha; VEGF = vascular endothelial growth factor.

Figure 2

Stereotactic body radiation therapy (SBRT) for a mediastinal lymph node. SBRT allows for high doses of radiation to small volumes of disease. The example presented demonstrates the use of SBRT to treat a site of oligometastatic disease in the mediastinum of a patient with otherwise controlled metastatic lung cancer. A dose-volume histogram (DVH) is also presented that shows the volume by dose of the target and organ at risk (in this case, the lungs). When radiation oncologists evaluate a DVH, the target should span to the upper right corner. Ideally, organs at risk will be to the bottom left corner. A pulmonologist can request the DVH or treatment plan for any patient from the radiation oncologist. SBRT is often used for early-stage lung cancer in patients medically ineligible for surgery and can spare normal tissue by distributing dose to numerous individual beamlets, which converge to an ablative dose at a specified target. The most common mode of delivery is volumetric modulated arc therapy, in which there exists a coplanar arc-beam arrangement. Essentially, as the gantry head rotates around the patient, beams from a complete spectrum of angles and with varying intensity deliver highly conformal dose to the target.

Figure 3

Conformal radiation techniques (3DCRT vs IMRT vs PSPT). Three cases are demonstrated with respective dose (color wash) utilizing the differing techniques. 3DCRT was the initial form of conformal radiotherapy, which requires beams to be manually arranged with custom blocks using multileaf collimators. IMRT is currently the most utilized technique for modern treatment planning. IMRT allows for an inverse planning computer optimization algorithm to select the optimum configuration of beam arrangements and multileaf collimator positions to produce ideal target dose and organ-sparing based on preset dosimetric goals. PSPT represents the most commonly used form of proton therapy and takes advantage of the lack of exit dose in a proton beam. Of note, IMRT tends to limit higher doses of radiation to normal structures vs 3DCRT, although it can increase low-dose spillage to a high volume of lung if V5 (percent lung volume receiving ≥ 5 Gy) constraint is not accounted for. PSPT in certain cases can completely spare contralateral lung. 3DCRT = three-dimensional conformal radiotherapy; IMRT = intensity-modulated radiation therapy; PSPT = passively scattered proton therapy. (Reprinted from Roelofs et al. Copyright [2012], with permission from Elsevier.)

Figure 4

Clinical algorithm outlining the assessment and management of RILI. Suspicion of RILI should be initiated when a patient’s physical examination findings correlate temporally (typically within 3 months) with completion of thoracic radiation. RILI = radiation-induced lung injury.

Figure 5

Locally advanced lung cancer treated with definitive chemoradiation. We present a case of locally advanced non-small cell lung cancer in a patient who underwent chemoradiation. The patient had node-positive disease as illustrated by staging PET/CT scan. He received 60 Gy/30 Fx utilizing VMAT/IMRT with daily image guidance. The RT plan with isodose lines (IDLs) is displayed. IDLs are generated to describe where the radiation dose is distributed. The bolded, red IDL represents the prescription line (6,000 cGy). The patient’s DVH is also displayed, which identifies organs-at-risk by displaying dose vs organ volume. In this patient’s case, the lung V20 or volume of lung receiving ≥ 20 Gy is above the 30% constraint. DVH = dose volume histogram; RT = radiation therapy; VMAT = volumetric modulated arc therapy. See Figure 3 legend for expansion of other abbreviation.

Figure 6

Radiographic appearance of RILI. The previously described patient (Fig 5) developed clinically significant radiation pneumonitis in the form of cough and required a short course of steroids at 6 weeks from the end of radiation (Grade 2). The radiographic findings of radiation pneumonitis at 6 weeks are illustrated on CT imaging (homogeneous ground-glass attenuation) and chest radiograph (linear, reticular stranding). The patient improved clinically following initiation of steroids, with stable radiographic findings. On follow-up, the patient’s mass initially decreased in size (24 months); however, at 48 months, there was significant concern for local recurrence given enlarging soft tissue density arising from the nodule on CT imaging. Results of biopsy and PET/CT imaging were negative for pathologic or metabolic evidence of malignancy. Ultimately, following continued observation, the lung findings improved, and the patient remains without evidence of disease at 5 years. Radiographic findings of progressive fibrosis are displayed over time on CT imaging (right upper lobe traction bronchiectasis, volume loss, and thickened interstitium). A chest radiograph represents radiographic fibrosis (linear fibrosis, scarring, and volume loss). Of note, the radiographic findings in this patient correspond anatomically to the original radiation fields, which is a key finding when making a diagnosis of RILI in the clinically symptomatic patient. At last follow-up, this patient was doing well and has no clinically significant fibrosis. See Figure 4 legend for expansion of abbreviation.