Radiation-Induced Lung Injury: Assessment, Management, and Prevention

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.[1] As this complication continues to be clinically relevant and remains an area of active investigation, we herein provide an updated review.

Molecular Mechanisms

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.

FIGURE 1

Molecular/Cellular Effects of 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 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)[8] and endobronchial brachytherapy.[9] Similarly, fatal hemoptysis is an established risk of endobronchial brachytherapy, occurring in 5% to 30% of patients.[10]

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.[11] 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.[12]

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[9] 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.

Clinical Endpoints

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.[16] 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,[17] 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.

Imaging

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.

TABLE 1

Frequency of Radiologic Changes Following Thoracic RT

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.[18]

• 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.[20] 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.

FIGURE 2

SPECT and CT Density

• 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.[21] 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).[22]

Dose-dependent reductions in perfusion are seen as early as 1.5 months after RT[24,25] and peak by approximately 6 months.[25] 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.[24] 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.[25]

Pulmonary Function Tests

FIGURE 3

Effects of RT on Lung Function

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.

TABLE 2

Prospective Studies Evaluating PFTs in Patients With Lung Cancer

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,[26] 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).[27]

Lung Tolerance and Predicting Injury

Whole-Lung Irradiation

Irradiation of both lungs occurs in multiple clinical contexts including total-body irradiation (TBI) as part of the preparative regimen for stem cell transplants, hemibody irradiation in the setting of diffuse symptomatic metastatic disease, and whole-lung irradiation for pulmonary metastases from various malignancies. Clinical experience in these settings has permitted the tolerance of whole-lung irradiation to be estimated.

FIGURE 4

Pneumonitis, Chemotherapy, and RT Fractionation

• Single Fraction-With single-fraction whole-lung irradiation, the risk of pneumonitis is dependent on dose-rate and whether chemotherapy is also prescribed. The risk of pneumonitis is decreased with low dose-rate schedules (eg, 5–25 cGy/min, typical of TBI) compared with higher dose-rate schedules (400 cGy/min, typical of hemibody irradiation and whole-lung irradiation).[28] Furthermore, the addition of chemotherapy shifts the dose-response curve to the left (Figure 4). The dose-response curve for whole-lung irradiation is steep, such that a difference of only 1 to 2 Gy increases the risk of pneumonitis substantially. The development of pneumonitis after TBI is an ominous sign, proving fatal in up to 80% of patients.[29]

• Multiple Fractions-Two randomized studies of prophylactic, fractionated whole-lung irradiation-one with chemotherapy[30] and the other without[31]-utilized doses of 15 to 17.5 Gy. Lung density corrections were not utilized in either study; thus, the true total physical doses delivered were likely in the neighborhood of 17 to 20 Gy. No cases of pneumonitis were reported in either trial. A retrospective study of whole-lung irradiation for a variety of tumor histologies, mostly pediatric malignancies, reported no cases of pneumonitis after doses ranging from 15 to 25 Gy.[32] Furthermore, in several retrospective studies in which TBI was utilized in the preparative regimen prior to stem cell transplant, the risk of pneumonitis appeared to be lower with fractionation.[33-35]

These studies suggest that fractionated RT is better tolerated by the lungs. In two randomized studies comparing single-fraction TBI with fractionated TBI, the investigators found no difference in the risk of pneumonitis (viral plus idiopathic), but there were fewer cases of idiopathic pneumonitis with fractionation.[36,37] Most TBI regimens are now fractionated and are associated with low rates of pneumonitis.

Partial-Lung Irradiation

FIGURE 5

Pneumonitis and Dosimetric Parameters

• Conventional Fractionation-Most patients receiving partial-lung irradiation undergo fractionated regimens. Determining tolerance doses and accurately predicting the risk of RT-associated pulmonary toxicity after partial-lung irradiation is challenging. Multiple parameters have been associated with an increased risk of developing symptomatic pneumonitis, including underlying lung disease,[19,38] decreased baseline pulmonary function,[19,39] low performance status,[19,39] female gender,[39] lower lobe tumors,[40,41] and history of smoking.[19] However, these findings have been inconsistent across studies, and none of these parameters have been found to be a robust and reliable risk factor for the development of RT-induced lung injury. Similarly, biochemical markers such as TGF-β have not been consistently predictive and are not currently utilized in routine clinical practice.

TABLE 3

Incidence of Pneumonitis Based on Dosimetric Parameters

Conversely, multiple dosimetric parameters have consistently been correlated with an increased risk of acute pneumonitis, including mean lung dose[38,40,42-47] and the percentage of lung receiving a specified amount of radiation (Table 3, Figures 5 and 6).[40,42,44,48,49] These parameters are readily extractable from either a dose-volume histogram (DVH) or treatment planning software.

Traditional DVHs assume that all regions of the lung contribute equally to pulmonary function, which is often an erroneous assumption since many patients have heterogeneous regional lung function (eg, from tumor or COPD). Furthermore, metrics such as the V20 or V30 (volume of lung receiving at least 20 or 30 Gy, respectively), consider only a single point on the cumulative DVH. Mean lung dose (MLD) might be a preferable metric because it considers the entire 3D dose distribution. In most series, however, the majority of patients are treated to MLDs in the lower aspect of the range shown. Thus, even though the incidence of pneumonitis is less when the MLD is lower, the absolute number of patients with pneumonitis derived from the low-MLD group is relatively high (Figure 6). In this regard, MLD is not particularly sensitive (ie, it does not predict a high fraction of pneumonitis cases).

FIGURE 6

Pneumonitis and Mean Lung Dose

In practice it is not practical to determine which parameter (MLD vs V20) is truly "optimal" since there tends to be a strong correlation between the different dosimetric parameters, at least with relatively uniform treatment techniques.[40,45,50] Kong et al concluded that the parameters predictive for acute pneumonitis and late fibrosis are largely similar.[45]

• Hypofractionation-There is increasing interest in the application of stereotactic body radiation therapy (SBRT) for medically inoperable stage I non–small-cell lung carcinoma (NSCLC) and oligometastases involving the lung. SBRT consists of only a few large (14–20 Gy) fractions given over 5 to 10 days. A representative fractionation scheme is 60 Gy in three fractions. Such biologically potent doses are feasible because only small volumes are treated with highly conformal fields, thereby creating steep dose gradients and minimizing high doses to surrounding critical structures.

Most patients develop increased tissue density on CT in the high-dose region after SBRT.[51,52] This finding can be difficult to differentiate from persistent or progressive tumor. Symptoms consistent with radiation pneumonitis have occurred in 4% to 25% of patients.[53-55] Serious, and sometimes lethal, pulmonary toxicity has been associated with the treatment of perihilar/central tumors.[56] Dose guidelines for SBRT are in a state of rapid flux as the number of clinical reports appears to be rapidly increasing. Currently used fractionation schemes of 20 Gy × 3,[55] 12 Gy × 4,[54] and 10 Gy × 5[57] appear to provide a reasonable therapeutic ratio for small lesions.

• Intensity-Modulated Radiation Therapy-Intensity-modulated radiation therapy (IMRT) facilitates conformal treatment of irregularly shaped and concave targets. This is especially useful for targets adjacent to critical structures. However, IMRT planning usually delivers lower doses of radiation to larger volumes of surrounding normal tissue. The impact of large-volume/low-dose lung irradiation in the context of curative treatment of lung cancer is not known.

The M.D. Anderson Cancer Center recently published the largest clinical experience using IMRT in 68 patients with lung cancer.[58] In this report, the incidence of grade ≥ 3 radiation pneumonitis was significantly lower in patients treated with IMRT vs a comparison group treated with conventional 3D-conformal RT (8% vs 32% at 12 months, P = .002). In the IMRT group, patients with V5 values (volume of lung receiving more than 5 Gy) greater than 70% appeared to be at higher risk of pneumonitis. Other dosimetric parameters (MLD, V20) were not assessed for their association with pneumonitis. Conversely, a smaller report from Memorial Sloan-Kettering Cancer Center noted a slightly higher rate of pneumonitis in 35 patients with inoperable stage III NSCLC treated with IMRT vs 3D-conformal RT (11% vs 5%, respectively, P = NS).[59] Additional experience is necessary to confirm the safety and efficacy of IMRT for lung cancer.

Another important application of IMRT is postoperative treatment of malignant mesothelioma after extrapleural pneumonectomy. An initial report from the M.D. Anderson Cancer Center reported a low rate of lethal radiation pneumonitis (1.6%, 1/62).[60] However, of 13 patients treated with IMRT at the Dana-Farber Cancer Institute, 6 experienced lethal radiation pneumonitis (46%, 6/13).[61] The mean lung dose was 15 Gy for patients who developed pneumonitis (all lethal) vs 13 Gy for those who did not (P = .07). Similarly, the V20 was 18% for patients who developed pneumonitis vs 11% for those who did not (P = .08). In a reanalysis of the same data, fatal pulmonary toxicities (whether previously ascribed to RT or not) were noted to have occurred in 10% of patients. These events were more common in patients with higher V20 values.[62] While IMRT may be particularly suited for the concave targets encountered with the postoperative treatment of mesothelioma, dose to the contralateral lung must be minimized.

Recommended Dose/Volume Constraints

TABLE 4

Recommended Dose-Volume Constraints

The lung is one of the most challenging organs for which to define strict dose/volume constraints, for several reasons. Coexisting diseases (eg, COPD) produce marked interpatient variation in pre-RT lung function, and this must be taken into account in the planning process. On the other hand, there is often tumor-related compromise of pulmonary function, especially with large central tumors, such that lung function may actually improve after treatment. Finally, in order to appropriately treat large tumors, it is sometimes necessary to utilize large RT fields irrespective of baseline function, with the understanding that pulmonary function may decline. Thus, patients need to be carefully counseled about the potential risks of lung injury and the uncertainty in defining individual risk. With these caveats in mind, there are nevertheless some broad guidelines that can be useful clinically (Table 4).

It is important to optimize a patient's medical condition by treating any reversible process (bronchospasm, infection, ischemic heart disease, pulmonary embolus, pleural effusion), particularly in those with poor baseline lung function. The use of elective nodal irradiation is controversial. While we do advocate rational elective nodal irradiation, this should be restricted in cases where lung function is significantly compromised. In patients with central lesions and PFTs of concern, assessment of regional perfusion/ventilation (eg, with SPECT) can be helpful to determine if regional tumor effect is contributing to poor lung function. The University of Michigan has developed a technique for prescribing RT dose based on the estimated risk of injury to the lung, such that a group of patients can be treated at a relatively uniform risk (by using nonuniform doses).[45]

Prevention

TABLE 5

Randomized Trials of Amifostine

Amifostine (Ethyol) is a thio-organic prodrug that is believed to scavenge harmful free radicals produced by the interaction of ionizing radiation and water molecules. The utility of amifostine in patients receiving RT for lung cancer has been assessed in multiple randomized studies and a meta-analysis (Table 5).[63] The largest study was performed by the Radiation Therapy Oncology Group.[64] The incidence of grade ≥ 3 pulmonary toxicity was not statistically different between patients receiving amifostine and those who did not. This study has been criticized because the drug was administered once daily (4 d/wk) and the RT was delivered twice daily (5 d/wk), and thus 60% of the RT fractions were delivered without the protector. Conversely, there are several single-institutional randomized trials suggesting a protective effect of amifostine.[65-68]

Such mixed results, combined with the acute toxicities of amifostine (eg, nausea/vomiting, hypotension, infection, rash), have dissuaded many from using the agent in routine practice. Another compound with potential is pentoxifylline, an immunomodulator that is used primarily for patients with intermittent claudication. One small randomized study demonstrated a smaller decline in DLCO as well as reduced perfusion defects and chest x-ray abnormalities in patients receiving pentoxifylline.[69] However, pentoxifylline is not currently used in routine clinical practice. Keratinocyte growth factor has been suggested in animal studies to protect against RT-induced lung injury.[70]

Chemotherapy

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Amifostine (Ethyol)
Bleomycin
Carboplatin
Cisplatin
Docetaxel (Taxotere)
Doxorubicin
Etoposide
Mitomycin
Paclitaxel
Pentoxifylline

Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.

Many chemotherapeutic agents have known pulmonary toxicities[71] and may exacerbate RT-induced alveolar/capillary injury. Combinations of RT and chemotherapeutic agents with known pulmonary toxicity have generally been associated with higher rates of radiation pneumonitis, including mitomycin,[38] bleomycin,[72] and docetaxel (Taxotere).[73] Interestingly, chemotherapeutic drugs that do not normally induce significant pulmonary toxicity may nonetheless potentiate the toxic effects of RT. For example, in a small series of 24 lung cancer patients treated with 40 Gy of RT concurrent with doxorubicin (10 mg/m²), 13 (54%) developed radiation pneumonitis. Fortunately, the chemotherapeutic agents most commonly used with RT for lung cancer, such as cisplatin, carboplatin, paclitaxel, and etoposide, have not consistently been shown to increase the risk of pneumonitis.[39,40,42,74]

Conclusions

RT-induced lung injury continues to be a relevant complication of thoracic RT. The molecular pathways culminating in clinically apparent injury continue to be elucidated and may reveal more effective therapeutic and prophylactic interventions. Our ability to predict an individual's risk of developing radiation pneumonitis is imperfect and relies largely on dosimetric parameters. More predictive methods are needed and are the subject of active research. Our clinical experience with newer RT techniques such as IMRT and SBRT is limited, and investigation of RT-induced lung injury using these modalities is ongoing.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

Acknowledgements:Special thanks to Jessica Hubbs and Lauren Jackson for their assistance in preparing the manuscript and figures.

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