INTRODUCTION — Radiation-induced lung injury (RILI) was first described in 1898, soon after the development of roentgenograms [1]. The distinction between two separate types of RILI, radiation pneumonitis and radiation fibrosis, was made in 1925 [2]. Both types of lung injury are observed today in patients who have undergone thoracic irradiation for the treatment of lung, breast, or hematologic malignancies. Radiation-induced damage to normal lung parenchyma remains a dose-limiting factor in chest radiotherapy, and can involve other structures within the thorax in addition to the lungs (table 1).
A large body of literature describes the histopathologic, biochemical, kinetic, physiologic, and molecular responses of lung cells to ionizing radiation [3-7]. However, the clinical diagnosis of RILI is often complicated by the presence of other conditions, including malignancy, infection, and cardiogenic pulmonary edema [8]. RILI will be reviewed here. The cardiac, esophageal, chest wall, and brachial plexus effects of therapeutic radiation to the chest are discussed separately. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies" and "Overview of gastrointestinal toxicity of radiation therapy" and "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse" and "Stereotactic body radiation therapy for lung tumors".)
PATHOGENESIS — Ionizing radiation causes the localized release of sufficient energy to break strong chemical bonds and generate highly reactive free radical species. Cellular molecules including peptides, lipids, and DNA (deoxyribonucleic acid) can be affected directly or indirectly via the interaction of the ionizing radiation with tissue water.
RILI results from the combination of direct cytotoxicity upon normal lung tissue and, perhaps more importantly, the development of fibrosis triggered by radiation-induced cellular signal transduction. The cytotoxic effect is largely a consequence of DNA damage that causes clonogenic death in normal lung epithelial cells, though apoptotic pathways are also induced by radiation. The development of fibrosis that can compromise lung function is mediated by a number of different cytokines, as discussed below.
●Genetic background – Animal and human studies suggest that there is a significant role for genetic susceptibility to irradiation injury [9-11]. Contemporary studies of patients receiving irradiation for breast cancer have shown suggestive associations between certain genetic factors and development of cutaneous telangiectasia [12] and/or fibrosis following irradiation [13,14]. Among 137 patients receiving irradiation for non-small cell or small cell lung cancer, presence of a single nucleotide polymorphism in the methylene tetrahydrofolate reductase gene (MTHFR; rs1801133) was associated with an increased risk of radiation pneumonitis [15]. In separate studies of lung cancer patients, polymorphisms of the ataxia telangiectasia mutated (ATM) gene were associated with an increased risk of radiation pneumonitis [16,17].
●Role of cytokines – Several cytokines are upregulated following lung irradiation and together are thought to mediate the pathologic changes described above.
•Clinically, the most extensively studied radiation-induced cytokine is transforming growth factor beta 1 (TGF-beta), which can induce fibroblast collagen deposition. The plasma TGF-beta level at the end of a clinical course of radiotherapy has been observed to be a predictor of the risk of pneumonitis [18]. This knowledge has been applied in a prospective trial in which patients with normal TGF-beta levels at the completion of a specified course of treatment were given additional boost treatment [19]. Subsequent trials have shown no predictable pattern of TGF-beta change in those with and without radiation lung injury [20].
•The proinflammatory cytokines, tumor necrosis factor-alpha (TNFa) and interleukin 1-alpha (IL-1a), are upregulated immediately following irradiation.
•IL-6 concentrations rise following irradiation, and elevated pretreatment plasma IL-6 concentrations correlate with an increased risk of developing RILI [21,22].
•Platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF), which are potent fibroblast mitogens are upregulated in animal models of lung irradiation injury prior to the development of histologically recognizable fibrosis along with TGF-beta 1 [23]. Investigators have been able to reduce RILI and apoptosis in mice by the intravenous administration of bFGF [24]. Basic fibroblast growth factor is thought to inhibit radiation-induced apoptosis in endothelial cells via activation of protein kinase C.
•Interferon-gamma has been shown to reduce the number of neutrophils and the protein concentration in bronchoalveolar lavage (BAL) fluid following irradiation in a rat model [25]. It has the potential to reduce RILI via inhibition of both neutrophil accumulation and fibroblast collagen synthesis.
•CD40 is displayed by antigen-presenting cells including B lymphocytes, macrophages, and dendritic cells. These cells are activated in the presence of CD40 ligand-bearing cells, such as T lymphocytes, mast cells, and eosinophils. The role of inflammation in the pathogenesis of RILI is supported by the observation that anti-CD40 ligand antibodies significantly reduce the influx of inflammatory cells, collagen deposition, and septal thickening in a murine model of RILI [26].
●Hypersensitivity reaction – A less common and unpredictable lung injury has also been described that may involve areas of the lung outside the radiation port. Investigators have described a CD4+ lymphocytic alveolitis and increased gallium uptake in both irradiated and nonirradiated lung, consistent with a hypersensitivity pneumonitis-like reaction. The early development of a bilateral hypersensitivity reaction (as assessed by bronchoalveolar lavage) appears to be a common phenomenon following unilateral chest radiotherapy, but does not predict progression to clinically significant radiation pneumonitis [27].
PATHOLOGY — The pathologic and clinical changes in the lung following irradiation may be understood as an evolution through five phases, although these phases may not be clinically apparent [28]:
●The immediate phase begins within hours to days following radiation exposure, and is generally asymptomatic. It is characterized by hyperemic, congested mucosa with leukocytic infiltration and increased capillary permeability, resulting in pulmonary edema. An exudative alveolitis follows, accompanied by tracheal bronchial hypersecretion and degenerative changes in the alveolar epithelium and endothelium. Type I alveolar epithelial cells (pneumocytes) are sloughed, and alveolar surfactant levels are increased [5].
●During the next phase (the latent phase), thick secretions accumulate due to an increase in the number of goblet cells combined with ciliary dysfunction.
●The third phase (acute exudative phase) is clinically referred to as radiation pneumonitis. It occurs 3 to 12 weeks following exposure and consists of sloughing of endothelial and epithelial cells, with narrowing of the pulmonary capillaries and microvascular thrombosis. Hyaline membranes form as a result of alveolar pneumocyte desquamation and leakage of a fibrin-rich exudate into the alveoli. Giant cells may be seen along the endothelium, and type II pneumocytes become hyperplastic with marked atypia.
●In the fourth phase (intermediate phase), there may be resolution of the alveolar exudate and dissolution of the hyaline membranes, or there may be collagen deposition by fibroblasts, which results in thickening of the interstitium. Fibroblasts, probably of bone marrow origin, migrate into and proliferate within the alveolar walls and spaces [29,30].
●A final phase consists of fibrosis. It may be evident as early as six months following irradiation, and can progress over years. There is an increase in the number of myofibroblasts within the interstitium and alveolar spaces, along with an increase in collagen. The anatomic narrowing of alveolar spaces results in diminishing lung volume; vascular subintimal fibrosis and distortion cause a loss of capillaries. Traction bronchiectasis, complicated by chronic infection, can develop. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)
A histopathologic appearance consistent with organizing pneumonia has also been reported approximately 3 to 17 months after radiotherapy [31-34]. Organizing pneumonia can be seen in areas outside the radiation port, including the contralateral lung. (See "Cryptogenic organizing pneumonia", section on 'Histopathologic diagnosis of organizing pneumonia'.)
RISK FACTORS — Many factors affect the development of radiation-induced lung disease. The volume of lung irradiated and the mean lung dose (MLD) are important risk factors, but do not completely explain differences in the risk of RILI across various tumors, radiation methods, and treatment schedules.
Volume of lung irradiated — The risk of radiation-induced injury is directly related to the volume of irradiated lung [35,36]. In patients with breast cancer, for example, the risk of transient lung inflammation following adjuvant chest wall irradiation is approximately 5 percent. The risk is higher with increasing lung volume in the tangential fields, treatment to the regional lymph nodes (supraclavicular, axillary apex, and internal mammary regions [37]), and the use of concurrent compared with sequential chemotherapy (8.8 versus 1.3 percent in one series) [38]. In one report, when tangential beam irradiation was utilized following breast-conserving surgery, pneumonitis was observed only when >10 percent of the lung was irradiated [39]. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)
Dose of radiation — The dose of radiation delivered to the lung is a critical factor in determining if injury will occur [35,40-44]. As noted above, MLD can be a predictor of the risk of radiation pneumonitis, as can the V20, defined as the volume of normal lung (total lung volume minus planning target volume for radiotherapy) that receives more than 20 Gy.
In 2010, a group of physicians and physicists analyzed more than 70 articles as part of the QUANTEC series to determine the radiation dose and lung volumes that predict a greater risk of pneumonitis [35]. They concluded that MLD and V20 were the best supported for routine clinical practice and recommended keeping the V20 to ≤30 to 35 percent and MLD ≤20 to 23 Gy to keep the risk of pneumonitis ≤20 percent.
Time-dose factor — In a systematic review, the use of twice daily fractionation appeared to reduce the risk of RILI compared with administration of the same total daily dose as a single fraction [45]. However, in a study of 37 patients receiving radiation for non-small cell lung cancer (NSCLC), 14 developed radiation pneumonitis, suggesting no benefit to the twice daily fractionation regimen [46]. Due to lack of clear benefit and the increase in logistical difficulties, twice daily dose fractionation is rarely used for NSCLC. By contrast, twice daily fractionation is frequently used for limited stage small cell lung cancer (SCLC). (See "Limited-stage small cell lung cancer: Initial management", section on 'Dose fractionation schedule'.)
Method of irradiation — Radiation oncologists continue to work to improve the targeting of radiation, increasing the dose given to diseased tissue while sparing normal tissue [47]. (See "Radiation therapy techniques in cancer treatment".)
This general approach of shaping the distribution of therapeutic radiation dose within the patient to match as well as possible to the intended target volume, while minimizing the dose to other tissues, is often referred to as conformal radiation therapy (CRT). More specialized techniques of CRT include intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT). (See "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques' and "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)
The impact of these technical changes on RILI has not been completely clarified. However, growing evidence supports IMRT for locally advanced NSCLC. (See "Management of stage III non-small cell lung cancer", section on 'Administration of radiation'.)
●In a secondary analysis of the NRG Oncology clinical trial (RTOG 0617) that included 482 patients with locally advanced NSCLC, IMRT was administered to 227 patients and 3D-CRT to 255 [48]. Two-year overall survival, progression-free survival, local failure, and distant metastasis-free survival were not different between the groups, but the rate of grade 3 pneumonitis was less with IMRT (7.9 versus 3.5 percent, p = 0.039).
●In a retrospective study of chemoradiation for NSCLC, rates of pneumonitis from two secular periods were compared [49]. In the earlier period, patients received 3D-CRT, while in the later period, 4D (includes lung movement with respiration) IMRT was used. Chemotherapeutic approach did not change. Patients in the later period had a significantly lower volume of lung receiving more than 20 Gy (V20) and a lower mean lung dose (MLD) and were less likely to develop pneumonitis than patients treated earlier.
Stereotactic body radiation therapy — Clinically significant radiation pneumonitis develops in fewer patients (5 to 15 percent) treated with SBRT compared with conventional radiation therapy [50-53]. This is likely attributable to lower irradiated lung volumes and a lower mean lung dose. The risk of RILI increases once the V20 exceeds 10 percent or the mean lung dose is higher than 6 Gy [54]. Thus, the increased accuracy of newer radiation models appears to reduce global measures of lung irradiation and radiation pneumonitis as well.
Proton beam therapy — The use of protons rather than photons may decrease the incidence of radiation pneumonitis by decreasing the volume of lung receiving a clinically significant dose. In a systematic review of proton beam therapy for breast cancer, 1 of 102 (<1 percent) patients across four studies developed radiation pneumonitis [55].
Initial data from an observational study of 16 patients suggest that proton beam therapy may be safer in high-risk patients with ILD/IPF who are undergoing radiation therapy for lung cancer [56]. In a phase 2 study of high dose proton therapy in combination with weekly carboplatin for unresectable NSCLC, 1 of 44 treated patients developed pneumonitis, suggesting that high-dose proton therapy administered concurrently with chemotherapy is well-tolerated [57].
Induction chemotherapy — The use of induction chemotherapy prior to chemoradiotherapy may increase the risk of radiation pneumonitis [58-60]. In a retrospective review of 96 patients treated for esophageal cancer, the incidence of moderate to severe pneumonitis at one year was higher among those who received induction chemotherapy prior to chemoradiotherapy, compared with those who did not (49 versus 14 percent) [60]. (See "Radiation therapy, chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized cancers of the esophagus".)
Concurrent chemotherapy — Several chemotherapeutic agents are known sensitizers to radiotherapy, including doxorubicin, taxanes, dactinomycin, bleomycin, cyclophosphamide, vincristine, mitomycin, gemcitabine, recombinant interferon-alpha, and bevacizumab [58,61-65]. Patients receiving these drugs are at a higher risk of developing RILI. In addition, several of the drugs themselves are associated with lung injury. By contrast, other drugs may sensitize tumor cells to the effects of radiation without an increase in lung injury [66]. (See "Bleomycin-induced lung injury" and "Cyclophosphamide pulmonary toxicity" and "Taxane-induced pulmonary toxicity".)
A 2012 meta-analysis of eight studies and 1607 patients demonstrated an increased odds ratio (OR) of 1.6 (1.11 to 2.32) of radiation pneumonitis in patients receiving concurrent compared with sequential chemotherapy. Other risk factors identified included older age, pulmonary comorbidities and mid- to lower lung tumor location [67]. Consequently, the relationship between the timing of irradiation and chemotherapy regarding the risk for radiation pneumonitis requires further clarification.
●Anthracyclines – Concurrent rather than sequential chemotherapy appears to increase the risk of radiation pneumonitis in women undergoing anthracycline-based adjuvant chemotherapy plus radiotherapy for breast cancer [38,58]. In one report, the risk of pneumonitis in women treated with a supraclavicular field and concurrent versus sequential chemotherapy was 9 versus 1.3 percent, respectively [38]. Because of this risk, concurrent anthracycline-based chemotherapy and radiation are generally avoided in the treatment of breast cancer.
●Paclitaxel – It is likely that sequential administration of paclitaxel and radiation therapy diminishes the risk of radiation pneumonitis as compared with concurrent treatment. However, women who receive taxanes as a component of their adjuvant therapy for breast cancer may also need to have a smaller volume of lung included in the radiation field. This topic is addressed in detail elsewhere. (See "Taxane-induced pulmonary toxicity", section on 'Concomitant radiotherapy' and "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Timing of chemotherapy and radiation'.)
●Gemcitabine – Gemcitabine is included in many lung cancer treatment protocols and is a potent radiation sensitizer. When given as concurrent therapy at standard doses, pulmonary toxicity is prohibitive [68]. Toxicity is prominent, even with reduced doses. In a series of 19 patients with NSCLC, induction chemotherapy with carboplatin and gemcitabine (800 mg/m2) followed by weekly gemcitabine (200 mg/m2) concurrent with radiation was associated with grade 3 to 5 (fatal) radiation pneumonitis in 32 percent [69]. However, radiation treatment planning in this report used a two-dimensional technique and the fields were large (including the primary lesion, grossly involved nodal sites, plus ipsilateral hilum, and mediastinum with a margin of 2 cm). Details about the dose to normal lung were not described. (See "Management of stage III non-small cell lung cancer", section on 'Preferred approach: Chemoradiotherapy'.)
Among patients receiving concurrent gemcitabine, toxicity appears less with conformal (three-dimensional) compared with two-dimensional treatment planning [70]. Toxicity is greater with regimens that include induction chemotherapy prior to chemoradiotherapy, combinations of gemcitabine with a taxane as opposed to a platinum-type drug, and more frequent dosing of gemcitabine (eg, 30 mg/m2 twice weekly) [59,70-72].
●Pemetrexed – The exact interaction of pemetrexed with irradiation is not known, although it appears to have some radiosensitizing and radiation recall effects [73-75]. In the PROCLAIM trial of 598 patients with unresectable nonsquamous NSCLC, thoracic radiation therapy was administered concurrently with either pemetrexed plus cisplatin or etoposide plus cisplatin [76]. The overall incidence of pneumonitis was higher with pemetrexed-cisplatin group than with etoposide-cisplatin, although the incidence of pneumonitis ≥grade 3 was not increased. (See "Management of stage III non-small cell lung cancer", section on 'Choice of chemotherapy'.)
●Immune checkpoint inhibitors – Immune checkpoint inhibitor (ICI) therapy is revolutionizing cancer therapy across most malignancies. For example, it is part of first- and second-line therapy for Stage III and IV patients with both NSCLC and small cell lung cancer. ICIs are associated with an inherent risk of ICI-associated pneumonitis of up to 19 percent [77] and possibly an increased risk of RILI. Given that ICI use will continue and likely expand, teams caring for patients receiving ICI and radiotherapy should remain vigilant for symptoms of RILI and counsel patients that there may be some increased risk, but the benefits will outweigh the risks for most patients. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Pneumonitis'.)
The PACIFIC study, which randomized patients to receiving the ICI, durvalumab, or placebo following definitive chemotherapy and radiation for stage III NSCLC, showed a significant survival advantage to ICI therapy for these patients, resulting in broad utilization [78]. While the overall risk of any pneumonitis was higher with durvalumab (33.9 versus 24.8 percent), the incidence of clinically important Grade 3 or 4 events was similar (3.4 versus 2.6 percent) suggesting the use of ICI following chemoradiotherapy was relatively safe. However, some retrospective studies have suggested an increased risk of RILI when radiotherapy and ICI are combined. A single center case series reported more frequent grade 2 and higher RILI among patients receiving adjuvant durvalumab versus only chemotherapy and radiation, 18 versus 9 percent [79]. In a large retrospective case series 7 of 10 patients treated with radiation and ICI (neoadjuvant, concurrent, and adjuvant) developed RILI within six months of radiation [80]. ICI may also increase the risk of RILI in patients with early stage NSCLC treated with SBRT and ICI, a combination therapy which is currently under investigation [81].
Radiation recall — Radiation recall pneumonitis can occur when certain antineoplastic agents (eg, doxorubicin, erlotinib, etoposide, gemcitabine, paclitaxel, pemetrexed, everolimus) and immune checkpoint inhibitors are administered to a patient who has received prior radiation therapy to the lung [73,82-91]. Patients typically develop symptoms such as cough and dyspnea, associated with radiographic opacities that conform to the prior radiation field.
Other factors — Prior thoracic irradiation, volume loss due to lung collapse, younger age, smoking history, poor pretreatment performance status, poor pretreatment lung function, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), female sex, endocrine therapy for breast cancer, and glucocorticoid withdrawal during radiotherapy have all been reported to influence the risk of radiation pneumonitis [61,65,67,82,92-94].
●Smoking – Smoking has been reported as a risk-modifying factor in some studies [92,93]. A small retrospective study compared the incidence of clinical radiation pneumonitis in active smokers and nonsmokers, among 405 women who underwent radiotherapy for treatment of breast or esophageal cancer [95]. The authors found that none of the subjects who were active cigarette smokers developed clinical pneumonitis following irradiation.
These findings are intriguing because other inflammatory lung diseases with a predominance of lymphocytes, such as hypersensitivity pneumonitis, are also uncommon in smokers. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis", section on 'Effect of cigarette smoking'.)
●COPD – Data are conflicting regarding the effect of COPD on the risk of radiation pneumonitis [82,96-99]. In a retrospective study, patients with more severe COPD were found to have less symptomatic radiation pneumonitis than those with more normal lungs [96]. While this could be confounded by the lack of randomization and difficulties with scoring of radiation pneumonitis due to the similarity of symptoms of COPD exacerbation and radiation pneumonitis, it is possible that the less diseased lungs tolerate radiation less well than those afflicted by COPD [97]. Among 80 patients with stage III NSCLC treated with cisplatin-based chemotherapy and irradiation, COPD was associated with an increased frequency of radiation pneumonitis and an increased risk of more severe pneumonitis [82].
●Endocrine therapy for breast cancer – Several studies suggest that concurrent, but not sequential use of tamoxifen increases the rate of pulmonary fibrosis in women treated for breast cancer; however, this has not been a consistent finding, and in general, higher rates of symptomatic pneumonitis have not been seen [100]. In contrast, the frequency of radiation-induced organizing pneumonia may be increased by concurrent endocrine therapy. In a retrospective series of 702 women with breast cancer who received breast conserving therapy, organizing pneumonia was associated with concurrent radiation and endocrine therapy (OR 3.05, 95% CI 1.09-8.54) [31].
●ILD – One of the most significant predictors of RILI is the presence of baseline ILD [101,102]. ILD has been associated with a significant risk of Grade 4 and 5 radiation pneumonitis [101,103]. Given that ILD is frequently associated with parenchymal lung inflammation, observations that pretreatment non-target lung 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) uptake may serve as a biomarker for baseline lung inflammation and predict the risk for radiation pneumonitis are not surprising [104]. In a large single center series 39 of 537 patients treated with SBRT had pre-existing ILD (13 UIP and 24 possible UIP). The rate of radiation pneumonitis, greater and equal to grade 2, was higher (20.5 versus 5.8 percent) in these patients and they accounted for two-thirds of grade 5 cases [105]. This high rate of mortality was confirmed in a multi-institutional Japanese study reporting 6.9 percent fatal cases of radiation pneumonitis among 242 patients with early stage lung cancer and pre-existing ILD treated with SBRT. A mean percentage normal lung volume receiving more than 20 Gy (V20) >10 percent constituted the biggest risk factor for fatal radiation pneumonitis [106].
Predicting radiation lung injury — Data from studies based upon various radiation therapy parameters have been used to predict the likelihood of RILI [107,108]. Although these efforts have yielded statistically significant results, the clinical prediction has been modest. Similarly, polymorphisms of the transforming growth factor (TGF)-beta 1 gene and serum levels of TGF-beta 1 obtained four weeks after the start of radiotherapy also are predictive of subsequent RILI [109,110]. Single nucleotide polymorphisms of the heat shock protein pathway member HSPB1 have been associated with lower rates of radiation pneumonitis in a retrospective study [49]. However, to date none of these methods is sufficiently reliable to be clinically useful, either in guiding dose modification or in suggesting the use of agents that might modify RILI.
EPIDEMIOLOGY — The incidence of radiation pneumonitis varies depending upon the particular regimen used and upon the radiation field. In addition, there is a discrepancy between the frequency of clinically apparent pneumonitis and radiographic evidence of lung disease.
●Among patients undergoing radiation therapy for lung cancer (conventional fractionation 1.8 to 2.0 Gy per day), symptomatic RILI developed in 7 percent of those in whom 22 to 31 percent of the lung volume received more than 20 Gy (V20) [111]. The incidence increased to 13 percent in those with a V20 of 32 to 40 percent. In a separate study of 251 patients receiving stereotactic body radiotherapy (median dose: 60 Gy delivered in three fractions to the 80 percent isodose line), symptomatic RILI occurred in 9 percent overall, but varied based on the radiation dose and volume of lung irradiated [112].
●In patients with breast cancer, radiation-associated organizing pneumonia occurs in 1 to 3 percent [31,34,113,114] and grade 2 or higher radiation pneumonitis occurs in approximately 1 to 9 percent depending on the extent of the radiation field and whether concurrent chemotherapy is administered [65].
●Among 110 patients with Hodgkin and non-Hodgkin lymphoma treated with intensity modulated radiation therapy (IMRT), 14 percent developed symptomatic RILI, of these 5 percent were grade 3 (cough and dyspnea at rest) and none were grade 4 or 5 [115].
CLINICAL MANIFESTATIONS — Symptoms caused by acute radiation pneumonitis usually develop approximately 4 to 12 weeks following irradiation, whereas symptoms of late or fibrotic radiation pneumonitis develop after 6 to 12 months. (See 'Pathology' above.)
The symptoms and signs of the two phases are similar, although fever is less likely to occur in the fibrotic phase. The following symptoms have been described [116,117]:
●A nonproductive cough, which may occur during therapy as a manifestation of bronchial mucosal injury or later as a manifestation of fibrosis.
●Dyspnea may only occur with exertion, or may be described as an inability to take a deep breath.
●Fever is usually low grade, but can be more pronounced in severe cases.
●Chest pain may be pleuritic or substernal and can represent pleuritis, esophageal pathology, or rib fracture.
●Malaise and weight loss may be observed.
Physical signs include the following:
●Crackles or a pleural rub may be heard; in some cases auscultation is normal.
●Dullness to percussion may be detected as a result of a small pleural effusion; this occurs in about 10 percent of patients. Effusions often cause no symptoms and may spontaneously remit. In contrast to malignant effusions, radiation-induced effusions do not increase in size after a period of observed stability. (See "Diagnostic evaluation of a pleural effusion in adults: Initial testing".)
●Skin erythema may outline the radiation port but is not predictive of the occurrence or the severity of radiation pneumonitis.
●Tachypnea, cyanosis, or signs of pulmonary hypertension may be seen in more advanced cases. (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
DIAGNOSTIC EVALUATION — RILI should be suspected when a patient who has undergone thoracic irradiation develops symptoms or signs, such as dyspnea, cough, fever, malaise, auscultatory crackles, or a pleural rub, in the weeks to months after radiation therapy. The evaluation is designed to assess the severity of respiratory impairment, determine the correspondence of radiographic changes with the radiation therapy portal to exclude other possible causes of the findings, such as infection, thromboembolic disease, drug-induced pneumonitis, spread of the underlying malignancy, tracheoesophageal fistula, or exacerbation of underlying chronic obstructive pulmonary disease (COPD), interstitial lung disease, or heart failure [8].
Laboratory studies — No commonly employed laboratory test identifies the development of radiation pneumonitis. A low-grade peripheral blood polymorphonuclear leukocytosis is often present, and the sedimentation rate, serum lactic dehydrogenase (LDH), and C-reactive protein may be modestly elevated and procalcitonin is typically low, but these findings are nonspecific [118].
Most patients are evaluated with a complete blood count and differential. Clotting studies, blood cultures, brain natriuretic peptide, and serologic tests for viral infection are obtained as appropriate to evaluate for infection, heart failure, and bleeding.
Serum KL-6, a sialylated carbohydrate epitope that is highly expressed in bronchial epithelial cells and type II pneumocytes, has been associated with interstitial lung disease and irradiation-induced lung injury for over 20 years. In a study of 117 patients undergoing radiation therapy for lung cancer, raised serum levels of KL-6 and surfactant protein-D (SP-D) prior to therapy identified patients with evidence of interstitial lung disease on preradiation-therapy chest computed tomography (CT) and a high risk of severe worsening of this disease after radiation therapy [119]. However, measurement of serum KL-6 and SP-D seemed to add little to detection of these high-risk patients compared with chest CT.
Imaging studies — Chest radiographic abnormalities following thoracic irradiation need to be distinguished from other pulmonary diseases, such as infection, lymphangitic or direct extension of tumor, drug-induced pneumonitis, thromboembolism, hemorrhage, and cardiogenic edema [8]. In general, chest CT is preferred over conventional chest radiography, because CT provides greater sensitivity for more subtle changes, improved detail regarding the type of opacity, and more complete delineation of the radiation therapy ports.
Chest radiograph — Chest radiographs may be normal in symptomatic subjects during the subacute phase of radiation pneumonitis, or may show evolving radiographic patterns depending on the phase of lung injury (eg, acute exudative, organizing, and fibrotic).
●Perivascular haziness is an early radiation-induced abnormality on chest radiograph, often progressing to patchy alveolar filling densities.
●Radiographs taken during the chronic phase of radiation pneumonitis may show volume loss with coarse reticular or dense opacities.
●A straight line effect, which does not conform to anatomical units but rather to the confines of the radiation port, is virtually diagnostic of RILI. However, conformal and stereotactic treatment strategies, such as three-dimensional conformal radiation therapy (3D-CRT), stereotactic body radiation therapy (SBRT) and Tomotherapy, do not cause this "straight line" radiographic finding due to the complex distribution of the radiation therapy. With these techniques, a focal area of opacity with ill-defined margins is seen in the irradiated region. Better delineation of the radiation fields is possible with chest CT as described below. (See 'Chest computed tomography' below and "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy' and "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)
●Small pleural effusions and rib fractures may be seen, but lymphadenopathy does not occur.
A few cases have been reported of radiographic abnormalities attributed to radiation pneumonitis outside of the irradiation port, and even in the contralateral lung [32,93]. This may be due to radiation scatter, lymphatic obstruction, or immunologic (hypersensitivity-like) mechanisms.
Chest computed tomography — Chest CT is more sensitive than the chest radiograph for detecting subtle lung injury following radiation treatment and is often obtained in the evaluation of a patient with increased dyspnea or cough following radiation therapy, particularly if the patient does not respond to initial empiric antibiotic therapy for possible lung infection. The CT scan may take the form of a CT pulmonary angiogram (CTPA) to exclude pulmonary thromboembolism. (See "High resolution computed tomography of the lungs".)
The key step in the evaluation of radiation pneumonitis is comparison of pretreatment CT images, containing irradiation dosimetric information, with diagnostic CT images obtained at the time of symptom presentation by the radiation oncologist. Lung involvement in CT images of radiation pneumonitis typically aligns closely with the irradiated area. Comparisons between pre- and posttreatment images may be difficult due to tumor growth or shrinkage, changes in depth of respiration, and the complexity of the radiation port, but use of specialized software may help [120].
Similar to the plain chest radiograph, the CT scan appearance of radiation pneumonitis correlates with the phase of lung injury, although a given patient may present at any one of the phases [121,122].
●The initial phase, which occurs three to five months after completion of radiation therapy, typically shows ground-glass attenuation within the area of irradiated lung.
●The organizing phase is typically associated with patchy areas of consolidation that coalesce to form a relatively sharp edge that conforms to the radiation therapy portals rather than anatomic structures. These patchy areas sometimes appear nodular.
●The opacities associated with the organizing phase may resolve with minimal scarring or may evolve into a fibrotic phase, characterized on CT by linear opacities (scarring) or an area of dense consolidation and volume loss. The area of consolidation typically corresponds to the radiation port, although conformal and stereotactic treatment strategies do not yield the classic "straight line" radiographic finding, as described above. (See 'Chest radiograph' above.)
The exact radiographic pattern of lung involvement is influenced by the specific radiation therapy technique used, such as limited tangential beams (eg, for breast cancer treatment), conformal therapy (eg, for bronchogenic cancer), and complex portal arrangements (eg, margins around primary bronchogenic carcinoma and around regional lymph nodes) [42]. (See 'Risk factors' above and "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer" and "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy' and "Radiation therapy techniques in cancer treatment", section on 'Stereotactic radiation therapy techniques'.)
Nuclear medicine studies — Standard nuclear medicine scans add little to the diagnosis of radiation pneumonitis. However there is growing interest in single photon emission tomography (SPECT), functional magnetic resonance (MR) spectroscopy, and positron emission tomography (PET) scanning to better define and perhaps predict outcome. These interesting concepts are under active investigation [123].
Pulmonary function tests — Pulmonary function tests (PFTs) can be helpful in differentiating whether symptoms are due to a flare of COPD or an interstitial process and to determine the severity of respiratory impairment. Typically, spirometry (before and after bronchodilator), lung volumes, diffusing capacity for carbon monoxide, and a six-minute walk test with oximetry are obtained as a baseline prior to radiation therapy and repeated in response to symptoms.
In patients with RILI, PFTs generally demonstrate a reduction in lung volumes (total lung capacity [TLC], forced vital capacity [FVC], residual volume [RV]), diffusing capacity, and lung compliance [65,124,125]. Tidal volumes are also decreased, and the respiratory rate may be elevated. As with other causes of interstitial or fibrotic lung disease, resting and ambulatory pulse oxygen saturation (SpO2) may be reduced. (See "Overview of pulmonary function testing in adults" and "Measures of oxygenation and mechanisms of hypoxemia".)
The diffusing capacity for carbon monoxide (DLCO or transfer factor) is usually depressed in patients with radiation-induced lung damage [126], but this finding is nonspecific, as it can also be reduced in emphysema and interstitial lung disease. One trial suggested that failure of the DLCO to increase from the nadir value following myeloablative chemotherapy was more closely associated with the risk of progressive pulmonary dysfunction during subsequent irradiation than other parameters of lung function [127]. (See "Diffusing capacity for carbon monoxide".)
For patients with moderate-to-severe hypoxemia, arterial blood gas analysis may be indicated.
Bronchoscopy — The main role for flexible fiberoptic bronchoscopy is to evaluate for infection, bleeding, drug hypersensitivity, or spread of the underlying malignancy. Bronchoscopy with bronchoalveolar lavage is performed in the majority of patients. Transbronchial biopsy specimens may be useful for assessment of infection or lymphangitic spread of tumor in cases that are clinically atypical for RILI, but the size of the specimens is usually too small to establish a diagnosis of radiation pneumonitis. (See "Flexible bronchoscopy in adults: Indications and contraindications" and "Basic principles and technique of bronchoalveolar lavage" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
Bronchoalveolar lavage fluid (BALF) findings in radiation pneumonitis are not specific, usually showing an increased number of leukocytes (predominantly lymphocytes). The majority of BAL lymphocytes post-irradiation are CD4+. Lymphocyte numbers are increased in both the irradiated and nonirradiated lung [128]. The number of neutrophils, eosinophils, and macrophages may also be increased. In addition, there are more activated lymphocytes in the BALF of patients after irradiation than in controls. Finally, there is an increase in BALF total cell count, percentage of lymphocytes, and intercellular adhesion molecule 1 (ICAM-1)-positive T-cells in irradiated subjects with abnormal chest radiographs compared with those with normal chest films [129].
Tissue specimens are only occasionally required in the evaluation of patients suspected to have radiation pneumonitis. Transbronchial and transthoracic needle biopsy specimens are too small to establish a diagnosis, but may be useful for ruling out infection or lymphangitic spread of tumor in cases that are clinically atypical for RILI. (See "Flexible bronchoscopy in adults: Indications and contraindications" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
DIAGNOSIS — The diagnosis of RILI is usually based on a combination of typical symptoms (eg, cough, dyspnea, and sometimes fever), timing, dose, and location of radiation therapy, compatible imaging findings, and exclusion of other causes, such as infection including the novel coronavirus SARS-CoV-2 (COVID-19), heart failure, pulmonary embolism, drug-induced pneumonitis, bleeding, and progression of the primary tumor. For the majority of patients with RILI, the opacities on imaging conform to the radiation ports. An exception is radiation-associated organizing pneumonia, which generally occurs in patients with irradiation for breast or mediastinal malignancy rather than lung cancer. Lung biopsy is rarely required for diagnosis of RILI, usually only when an alternative diagnosis cannot be excluded. (See 'Clinical manifestations' above and 'Imaging studies' above.)
Radiation pneumonitis can be graded in several ways to reflect severity of symptoms and radiographic changes, although grading is used more for research purposes than routine clinical care [130,131].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of radiation pneumonitis most commonly includes infection; thromboembolic disease; drug-induced pneumonitis; spread of the underlying malignancy; and exacerbation of chronic obstructive pulmonary disease (COPD), interstitial lung disease, or heart failure. During the coronavirus disease 2019 (COVID-19) pandemic it is crucial to try to differentiate SARS-CoV-2 pneumonia from radiation pneumonitis which can be challenging due to the overlapping clinical and radiological features, especially if it occurs within three months of radiation therapy. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and "COVID-19: Epidemiology, virology, and prevention".)
For patients with chest discomfort, but without new lung parenchymal changes on chest imaging, potential causes include pericarditis and esophagitis.
TREATMENT — No prospective controlled studies have evaluated the efficacy of therapies for radiation pneumonitis in humans. Nevertheless, many experts recommend the use of glucocorticoids for symptomatic patients with a subacute onset of RILI [65,132]. Patients who have established fibrosis due to prior irradiation are unlikely to benefit from glucocorticoid therapy [117]. It is unknown whether drugs that inhibit collagen synthesis and deposition will slow further fibrosis. (See "Treatment of idiopathic pulmonary fibrosis".)
Supportive care — Supportive care may include antitussive therapy, supplemental oxygen, and treatment of comorbid diseases, such as chronic obstructive pulmonary disease (COPD) or heart failure, which may contribute to symptoms.
Antitussive therapy, such as dextromethorphan or codeine, may provide symptomatic relief of cough, although formal study in this setting is lacking. (See "Evaluation and treatment of subacute and chronic cough in adults", section on 'Unexplained chronic cough'.)
Therapy with supplemental oxygen is indicated for patients with a resting pulse oxygen saturation ≤88 percent. (See "Long-term supplemental oxygen therapy".)
Patients with minimal or no symptoms — Patients who are asymptomatic or have minimal symptoms may experience a spontaneous resolution, so we do not initiate treatment unless symptoms become bothersome or pulmonary function declines by more than 10 percent. We continue to monitor these patients at regular intervals with assessment of symptoms, chest radiography, and pulmonary function, as indicated. Patients may benefit from supportive care, such as antitussive therapy. (See 'Supportive care' above.)
Improvement in mild symptoms has been described with inhaled glucocorticoids. In a single center study, 24 patients with pneumonitis following irradiation for lung cancer were initially treated with high dose inhaled glucocorticoids (budesonide 800 micrograms twice a day) for 14 days [133]. Eighteen patients responded to inhaled budesonide, while six did not improve within two weeks and needed to be transitioned to oral glucocorticoids. Median treatment duration in the inhaled steroid group was 8.4 months.
Symptomatic patients with subacute radiation pneumonitis — Many experts, including the authors, suggest the use of oral glucocorticoids for patients with a subacute onset of radiation pneumonitis, moderate to severe symptoms (eg, dyspnea that interferes with activities of daily living), and evidence of impaired respiratory function [65,132].
Glucocorticoids — Prednisone (approximately 40 to 60 mg/day) is generally given for two to four weeks, with a gradual taper over 3 to 12 weeks, although the guidelines for tapering are poorly defined [65]. Generally speaking, the taper is done with close monitoring of symptoms. If the patient experiences relapse of symptoms we return to full dose for two weeks and try again with a slower taper, particularly when the dose is 20 mg per day or less. The recommendation for prednisone use is based upon clinical experience and multiple reports of a prompt response to therapy.
We suggest prophylaxis for Pneumocystis pneumonia when the prednisone dose exceeds 20 mg a day for more than a month [134]. Steps to monitor and prevent the various adverse effects associated with systemic glucocorticoids are discussed separately. (See "Major side effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring' and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
Other immunosuppressive agents — Azathioprine and cyclosporine were both effective in treating the symptoms of radiation pneumonitis in single case reports; these agents may be considered in patients who do not tolerate glucocorticoids or who have disease refractory to glucocorticoid therapy [135,136].
Radiation-associated organizing pneumonia — For patients with radiation-associated organizing pneumonia (OP), we follow the treatment approach usually used for cryptogenic organizing pneumonia (COP). For patients with minimal symptoms, we observe without specific therapy [113,114]. For patients with more bothersome symptoms and evidence of respiratory impairment, we suggest oral glucocorticoid therapy (eg, prednisone 0.75 to 1 mg/kg, or approximately 60 mg, per day) based on case reports of radiation-associated OP and the experience in COP [31,32,114]. We suggest maintaining the initial oral dose for four to eight weeks. If the patient is stable or improved, the prednisone dose is gradually tapered to 0.5 to 0.75 mg/kg per day (using ideal body weight) for the ensuing four to six weeks. After three to six months of oral prednisone, the dose is gradually tapered to zero if the patient remains stable or improved. (See "Cryptogenic organizing pneumonia".)
Radiation-induced pulmonary fibrosis — There are no established guidelines for the management of radiation-induced lung fibrosis. Inflammation is not prominent and anti-inflammatory therapy, specifically glucocorticoids, should be avoided to prevent unnecessary side effects.
Supportive care such as oxygen supplementation, pulmonary rehabilitation, mucociliary clearance, and vaccinations against influenza and pneumococcus should be instituted, as appropriate. (See "Pulmonary rehabilitation" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults" and "Bronchiectasis in adults: Maintaining lung health", section on 'Airway clearance therapy'.)
EXPERIMENTAL AGENTS — A number of experimental agents have been assessed for a potential role in the prevention or treatment of RILI and radiation-induced fibrosis in other organs. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)
●Pentoxifylline – Pentoxifylline is a xanthine derivative that inhibits platelet aggregation and enhances microvascular blood flow; it also has immunomodulating and anti-inflammatory properties that are probably mediated by inhibition of tumor necrosis factor (TNF) and interleukin 1. Pentoxifylline may have a role for the treatment of radiation-induced fibrosis involving the skin and subcutaneous tissues, and also inhibits experimental bleomycin-induced pulmonary fibrosis in rats, possibly via its anti-TNFa effects. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis" and "Bleomycin-induced lung injury".)
A modest benefit for pentoxifylline in the prevention of RILI was suggested in a trial in which 40 patients undergoing radiation therapy for breast or lung cancer were randomly assigned to pentoxifylline (400 mg three times daily) or placebo during treatment [136]. During six months of follow-up, the number of patients with grade 2 or 3 pulmonary toxicity was significantly less in the pentoxifylline group (20 versus 50 percent). Four patients in the placebo group (30 percent) with grade 3 lung impairment required oral glucocorticoids and oxygen, while only one patient who received pentoxifylline (5 percent) had clinical impairment from grade 2 pulmonary toxicity. The pentoxifylline group had a significantly better diffusing capacity for carbon monoxide at both three and six months following therapy (73 versus 58, and 72 versus 57 percent at three and six months, respectively), but there were no significant differences in spirometry between the two groups. A separate study involving patients with liver irradiation for metastases reported successful reduction in liver toxicity with pentoxifylline, but it suffers from small numbers of subjects and the use of a drug cocktail [137]. Although intriguing, these results require independent confirmation.
●Inhibitors of collagen synthesis – Since excess collagen deposition is a key histopathologic feature of radiation fibrosis, drugs that inhibit collagen synthesis, such as colchicine, penicillamine, interferon-gamma, or pirfenidone, may have the potential to modify the progression of fibrosis. However, there are no controlled studies with these agents in humans with RILI.
●Amifostine – Amifostine is a cytoprotective agent that appears to shield normal tissues from the toxic effects of chemotherapy and radiotherapy. It is a prodrug that is dephosphorylated by alkaline phosphatase in tissues to a pharmacologically-active free thiol metabolite, which can act as a scavenger of free radicals generated in tissues exposed to radiation. It is approved as therapy for xerostomia in patients following neck irradiation and has been investigated as an agent that might reduce the incidence and severity of RILI [138-140].
Early reports suggested that amifostine might decrease RILI without diminishing the therapeutic effect of radiation [138,141]. This possibility was supported by a randomized controlled trial of radiation plus amifostine compared with radiation alone in 146 patients with locally advanced lung cancer [139]. A significant decrease in pneumonitis (9 versus 43 percent) and also grade 3 esophagitis were noted with amifostine pretreatment. However, these results have not been replicated and current guidelines do not advise the use of amifostine for prevention of esophagitis or irradiation-induced pneumonitis [64,142].
●Angiotensin converting enzyme inhibitors – The angiotensin converting enzyme inhibitor (ACEI) captopril has been shown to reduce radiation-induced lung fibrosis in rats [143]. In a retrospective study of patients who underwent radiation therapy for lung cancer, those taking an ACEI demonstrated less clinically significant RILI, than those not on an ACEI [144]. A randomized trial of captopril for prevention of RILI (RTOG0123) was closed early due to slow patient recruitment. Of the 81 enrolled patients only 33 were randomized to receive captopril or standard of care from completion of radiation therapy for up to 52 weeks. Of these patients, only 20 were evaluable. Radiation pneumonitis occurred in 23 percent (3/13) of the control group and 14 percent (1/7) in the captopril group. The study was insufficient to answer the question whether captopril can prevent radiation pneumonitis [145].
●Aidi – Aidi (Z52020236, China Food and Drug Administration [CFDA]) is an injectable agent composed of the extracts from Astragalus, Eleutherococcus senticosus, Ginseng, and Cantharidin. Astragalus, Eleutherococcus senticosus, Cantharidin and Ginseng, and others are important traditional Chinese medicine. It is used in conjunction with chemotherapy in China. A meta-analysis suggests that Aidi can prevent RILI. With Aidi, the relative risk for radiation pneumonitis was 0.53 (95% CI 0.42-0.65) compared with placebo [146]. (See "Overview of herbal medicine and dietary supplements".)
PROGNOSIS — Significant improvements in the perfusion and ventilation of radiation-injured lung tissue may be noted from 3 to 18 months after radiation therapy. After 18 months, however, further significant improvement appears unusual [124,147].
PREVENTION — The best known strategies for reducing RILI are those that limit the radiation dose and volume of normal lung tissue irradiated. As noted above, a panel of physicians and physicists concluded that for routine clinical practice, the mean lung dose (MLD) should be kept below 20 Gy, when possible, and the volume of lung receiving more than 20 Gy (V20) should be kept below 35 to 40 percent to keep the risk of pneumonitis ≤20 percent [35]. (See 'Risk factors' above.)
While a number of agents, including glucocorticoids, antibiotics, and heparin, have been studied in the hope that they might protect against RILI, none has been demonstrated to be effective [5,33,92,148-150]. As noted above, preliminary data have suggested possible benefit to pentoxifylline, angiotensin converting enzyme inhibitors, and amifostine, but adequate randomized trials are lacking. (See 'Experimental agents' above.)
SUMMARY AND RECOMMENDATIONS
●Patients who undergo thoracic irradiation for the treatment of malignancy (eg, breast, laryngeal, lung, hematologic) are at risk for RILI, such as radiation pneumonitis and radiation fibrosis. (See 'Introduction' above.)
●Many factors affect the risk for RILI including the method of irradiation, the volume of irradiated lung, the total dosage and frequency of irradiation, associated chemotherapy, and possibly the genetic background of the patient. (See 'Pathogenesis' above and 'Risk factors' above.)
●Symptoms caused by subacute radiation pneumonitis usually develop approximately 4 to 12 weeks following irradiation, whereas symptoms of late or fibrotic radiation pneumonitis develop after six to 12 months. Typical symptoms for both types of lung injury include dyspnea, cough, chest pain, fever, and malaise. (See 'Clinical manifestations' above.)
●Physical examination of the lung may reveal crackles, a pleural rub, dullness to percussion, or may be normal. Skin erythema may outline the radiation port but is not predictive of the occurrence or the severity of radiation pneumonitis. (See 'Clinical manifestations' above.)
●In general, chest CT is preferred over conventional chest radiography, because CT is more sensitive for subtle changes and allows closer comparison between any radiographic abnormalities and the radiation therapy ports and dosimetry. In subacute radiation pneumonitis, the chest radiograph may show perivascular haziness and chest computed tomography may show patchy alveolar ground glass or consolidative opacities. (See 'Imaging studies' above.)
●Radiographs taken during the chronic phase of radiation pneumonitis may show volume loss with coarse reticular or dense opacities. A straight line effect, which does not conform to anatomical units but rather to the confines of the radiation port, is virtually diagnostic of RILI, but may not be apparent in patients treated with conformal and stereotactic treatment strategies. (See 'Imaging studies' above.)
●The diagnosis of radiation pneumonitis is based on the correlation between the onset of symptoms and signs with the timing of irradiation and between the pattern of radiographic changes and the radiation therapy portal. Careful exclusion of other possible diagnoses, such as infection, thromboembolic disease, drug-induced pneumonitis, pericarditis, esophagitis, tumor progression, or tracheoesophageal fistula, is key. (See 'Diagnosis' above.)
●The optimal treatment for RILI is not known. For patients who are asymptomatic or have minimal symptoms, we provide supportive care (eg, antitussive therapy), but do not initiate glucocorticoid treatment unless symptoms become bothersome or pulmonary function declines by more than 10 percent. (See 'Treatment' above.)
●For patients with moderate to severe symptoms, we suggest administering prednisone (approximately 60 mg/day) for two to four weeks, followed by a gradual taper over the next 3 to 12 weeks, although the guidelines for tapering are poorly defined (Grade 2C). Steps to minimize the adverse effects of systemic glucocorticoids, such as drug prophylaxis against Pneumocystis jirovecii infection, are discussed separately. (See 'Glucocorticoids' above and "Major side effects of systemic glucocorticoids", section on 'General treatment considerations and monitoring' and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis'.)
●For patients with radiation-associated organizing pneumonia, which is more commonly associated with irradiation for breast and mediastinal malignancy than lung cancer, we advise following the treatment approach used for cryptogenic organizing pneumonia. (See 'Radiation-associated organizing pneumonia' above and "Cryptogenic organizing pneumonia", section on 'Treatment'.)
●Patients who have established fibrosis due to prior irradiation are unlikely to benefit from glucocorticoid therapy. It is unknown whether drugs that inhibit collagen synthesis and deposition will slow further fibrosis. (See 'Treatment' above and "Treatment of idiopathic pulmonary fibrosis".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges William Merrill, MD, who contributed to earlier versions of this topic review.
