ABSTRACT: Radiation therapy (RT) is an important treatment modality for multiple thoracic malignancies. Incidental irradiation of the lungs, which are particularly susceptible to injury, is unavoidable and often dose-limiting. The most radiosensitive subunit of the lung is the alveolar/capillary complex, and RT-induced lung injury is often described as diffuse alveolar damage. Reactive oxygen species generated by RT are directly toxic to parenchymal cells and initiate a cascade of molecular events that alter the cytokine milieu of the microenvironment, creating a self-sustaining cycle of inflammation and chronic oxidative stress. Replacement of normal lung parenchyma by fibrosis is the culminating event. Depending on the dose and volume of lung irradiated, acute radiation pneumonitis may develop, characterized by dry cough and dyspnea. Fibrosis of the lung, which can also cause dyspnea, is the late complication. Imaging studies and pulmonary function tests can be used to quantify the extent of lung injury. While strict dose-volume constraints to minimize the risk of injury are difficult to impose, substantial data support some general guidelines. New modalities such as intensity-modulated radiation therapy and stereotactic body radiation therapy provide new treatment options but also pose new challenges in safely delivering thoracic RT.
Radiation therapy (RT) is an important treatment modality for multiple thoracic malignancies. Incidental irradiation of the lungs, which are particularly susceptible to injury, is unavoidable and often dose-limiting. We presented a review of RT-induced lung injury in this journal in 1994. As this complication continues to be clinically relevant and remains an area of active investigation, we herein provide an updated review.
The complex molecular mechanisms underlying RT-induced lung injury are often not considered by the clinician. However, a basic understanding of these processes facilitates an understanding of the clinical and radiologic changes observed after RT.
Immediately after exposure to RT, a cascade of molecular and cellular events is initiated that proceeds during a clinically occult period. The inciting event is the production of free radicals by ionizing radiation (Figure 1). These reactive oxygen and nitrogen species, however, can only produce a limited amount of direct damage. Amplification and propagation of these species is necessary to create a sustained imbalance between oxygen-derived free radicals and cellular antioxidant capacity.[2,3] Chronic oxidative stress is the end result of this persistent imbalance, leading to endothelial dysfunction, increased vascular permeability and edema, monocyte migration, lipid peroxidation, inflammation, and fibrosis.[4-7]
A self-sustaining cycle of inflammation and fibroproliferation ensues, driven by tissue hypoxia, macrophage accumulation and activation, oxidative stress, and profibrogenic (transforming growth factor–beta [TGF-β]) and proangiogenic (hypoxia inducible factor 1-alpha [HIF-1α], vascular endothelial growth factor [VEGF]) cytokine activity.[4,7] These molecular and cellular events lead to cell death, collagen(Drug information on collagen) deposition, and fibrosis in irradiated tissues.
Anatomic Basis of Injury
The lungs are complex organs, consisting of the large central airways such as the trachea and mainstem bronchi, the smaller conducting airways, a complex vascular network, and the alveolar sacs where gas exchange occurs.
The trachea and proximal airways are lined with pseudostratified ciliated columnar epithelial cells with admixed mucus-producing goblet cells. While the mucosa of these structures can become acutely denuded during RT, causing mild dry cough and/or sore throat, the depleted mucosa is usually replenished promptly after completion of treatment and the associated symptoms prove transient. With conventional doses of RT, complications related to the larger airways, as well as the larger vascular structures, are uncommon. However, bronchial stenosis has been observed following high-dose external-beam RT (twice daily RT, 74–86 Gy) and endobronchial brachytherapy. Similarly, fatal hemoptysis is an established risk of endobronchial brachytherapy, occurring in 5% to 30% of patients.
The functional subunit of the lung is the alveolar/capillary complex, which is particularly sensitive to the effects of RT. The alveoli are lined by type I pneumocytes, which are flat epithelial cells with minimal cytoplasm and few organelles that form a complete, thin (0.2 μm) lining of the alveoli. Type II pneumocytes also reside in the alveolar lining and produce surfactant. The histopathologic changes observed in the lung after RT are broadly characterized as diffuse alveolar damage. Acutely, increased vascular permeability leads to edema of the interalveolar septa and extravasation of proteinaceous material into the alveoli. Type I pneumocytes are depleted and type II pneumocytes proliferate to restore the integrity of the alveolar epithelium. However, type II pneumocytes are also known to be damaged by RT, leading to the release of surfactant into the alveolar lumen. Increased levels of alveolar surfactant can be seen within hours of RT and can persist for 2 to 6 weeks.
Physiologic Effects of Injury
RT-induced lung injury can disrupt multiple aspects of normal pulmonary physiology, including efficient gas exchange, optimal matching of perfusion and ventilation, and adequate airflow. For example, the rate at which a gas diffuses between the alveoli and capillaries is proportional to the partial pressure gradient of the gas and the available surface area for exchange, but inversely proportional to the thickness of the intervening tissues. Deposition of scar tissue within the interalveolar septum will directly impede gas exchange and also decrease lung compliance (and therefore the partial pressure of oxygen), while destruction of alveoli decreases the surface area available for gas exchange.
In healthy individuals, alveolar ventilation and pulmonary capillary perfusion are closely matched for optimal efficiency. RT reduces both parameters, though perfusion is affected to a greater degree than ventilation.[13,14] This results in a reduction in the number of perfused alveoli and therefore increases alveolar dead-space (ie, ventilated alveoli with reduced or absent perfusion). Finally, resistance to airflow within the larger airways is almost entirely dependent on the radius of the airways. Poiseuille's law dictates that resistance is inversely proportional to the fourth power of the radius. Thus, even modest reductions may be sufficient to cause pulmonary symptoms. Symptomatic bronchial stenosis has been reported following brachytherapy and with higher-than-conventional doses of external-beam RT (≥ 70 Gy).[8,15] Whether narrowing of the bronchi occurs after conventional doses (60–70 Gy) is not known.
Symptoms and Management
Radiation pneumonitis manifests 1 to 6 months after RT as shortness of breath, dry cough, and occasionally fever. Auscultation of the chest is typically unremarkable, though a friction rub or rales are sometimes evident. Chest x-ray should be obtained but is often unrevealing. Differentiating radiation pneumonitis from other processes (eg, tumor progression, infection, pulmonary emboli, heart disease) can be challenging. Acute pneumonitis is therefore a clinical diagnosis (typically of exclusion) after considering other disorders that cause similar symptoms.
Treatment for symptomatic acute pneumonitis is typically oral corticosteroids. We recommend oral prednisone(Drug information on prednisone), 40 to 60 mg daily for 1 to 2 weeks followed by a slow taper (reducing ~10 mg every 1–2 weeks). The majority of patients with pneumonitis recover. Progressive symptoms requiring oxygen or hospitalization are uncommon.
Most patients who receive thoracic RT develop readily identifiable abnormalities on radiologic studies, often termed "fibrotic." The majority of such patients are asymptomatic, especially if the volume of involved lung is small. We do not treat asymptomatic patients with RT-induced abnormalities on imaging studies. However, symptomatic fibrosis of the lung can become a chronic and debilitating process, particularly in patients with poor baseline pulmonary reserve or extensive regions of fibrosis. Established radiation fibrosis is generally considered to be irreversible.
Chest x-ray and computed tomography (CT), which evaluate structure and tissue density, are the most commonly utilized imaging modalities for assessing RT-induced lung injury. Single-photon emission computed tomography (SPECT) scanning is a more specialized approach that has been used largely in research settings, and can assess the functional endpoints of ventilation and perfusion.
The incidence of lung injury as assessed with imaging is affected by the sensitivity of each modality. In general, perfusion SPECT is more sensitive than CT, which in turn is more sensitive than chest x-ray (Table 1). Comparisons between studies are challenging since the patient populations and RT doses vary. Nevertheless, these generalizations appear to be true in studies that have considered multiple imaging modalities.
• Chest X-ray—The most common finding on plain radiographs after thoracic RT is increased density (radiopacity), typically in a patchy distribution, developing shortly after completion of RT and peaking at approximately 6 months.[19,20] The changes are usually stable by 12 months. Early changes are likely a reflection of increased interstitial edema and/or alveolar consolidation from the influx of both proteinaceous material and released surfactant. Pulmonary fibrosis, typically seen at later time points, has a similar appearance, but often with more defined edges and associated tissue retraction. Other common findings are nonanatomic margination (corresponding to the RT field edge), volume loss with midline shift, and pleural thickening.
• Computed Tomography—The abnormalities noted with CT and chest x-ray are similar. CT appears to have higher sensitivity, in part because paramediastinal abnormalities may be obscured by the cardiac or aortic silhouette on chest x-ray. The findings on CT are often described as ground-glass opacities that progress to consolidation and volume loss. Traction bronchiectasis develops from tethering of the bronchial wall by RT-induced fibrosis. Differentiating mass-like fibrosis from persistent or recurrent tumor can be challenging. Comparing the CT scan obtained for RT planning (and hence the three-dimensional [3D] dose distribution) with post-RT scans demonstrates dose-dependent increases in tissue density, predominantly in regions receiving ≥ 40 Gy (Figure 2).[22,23]
• Single-Photon Emission Tomography—Nuclear medicine imaging of regional perfusion and/or ventilation can also be used to assess RT-induced lung injury. In perfusion SPECT, radiolabeled microspheres injected into the venous system are trapped in the small capillaries of the lung. The local concentration, in principle, is proportional to regional pulmonary blood flow. Regional perfusion defects are appreciated at doses lower than required to cause CT abnormalities, and therefore RT-induced changes in perfusion appear to be even more common than corresponding changes on CT (Figure 2).
Dose-dependent reductions in perfusion are seen as early as 1.5 months after RT[24,25] and peak by approximately 6 months. The extent of recovery is unknown. Following modest doses of RT for breast cancer and lymphoma, investigators at the Netherlands Cancer Institute report up to 50% recovery by 18 months. At our institution we have not seen such recovery, but our study population was predominantly patients with lung cancer receiving higher doses of thoracic RT.
Pulmonary Function Tests
Pulmonary function tests (PFTs) objectively assess multiple pulmonary parameters including lung volumes, the amount and rate of air flow (spirometry), and the ability of the lung to transfer gas at the alveolar level. Diffusing capacity of the lung for carbon monoxide (DLCO) is likely the best parameter to assess lung function after RT, since the ultimate role of the lungs is to facilitate gas exchange. Loss of alveolar surface area and thickening of the intra-alveolar septi are the primary causes for reductions in DLCO. Thus, both acute (edema, extravasation of material into the alveoli) and chronic (fibrosis, loss of alveoli) injury can affect DLCO. The forced expiratory volume in 1 second (FEV1) is another useful parameter, often interpreted in the context of the FEV1/forced vital capacity (FVC) ratio. Decreased FEV1 with a normal FEV1/FVC ratio is most consistent with a restrictive process, such as fibrosis.
Assessing the impact of RT on PFTs in patients with lung cancer is challenging because many patients have baseline pulmonary dysfunction from smoking (chronic obstructive pulmonary disease [COPD]), and some patients continue to smoke after RT with continued and accelerated diminutive effects on function. Conversely, pulmonary function may actually improve transiently if a large central tumor obstructing the conducting airways or vessels regresses.
Most studies show a decline in PFTs after thoracic RT (Table 2). Reductions in FEV1 are appreciated approximately 3 to 6 months post-RT, sometimes followed by partial or complete recovery at about 12 months. DLCO is typically reduced to a greater degree than FEV1 and appears to show less recovery at 12 months than FEV1. Most studies show a proportional decline in both FEV1 and FVC, such that the FEV1/FVC ratio remains in the normal range, consistent with a restrictive process. In the few patients systematically studied for long-term changes in PFTs, there appears to be continued diminution in PFTs 2 to 8 years post-RT (Figure 3).