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Radiation-induced lung injury

Radiation-induced lung injury
Literature review current through: Jan 2024.
This topic last updated: Sep 26, 2023.

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, esophageal, 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, drug induced lung injury/pneumonitis, 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".)

(See "Overview of gastrointestinal toxicity of radiation therapy".)

(See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse".)

(See "Stereotactic body radiation therapy for lung tumors".)

EPIDEMIOLOGY — The incidence of radiation pneumonitis varies depending upon the radiation regimen used and upon the radiation field, both of which are influenced by the underlying neoplasm type and distribution. In addition, there is frequently a discrepancy between evidence of radiation changes on imaging and clinically relevant symptoms. The severity of radiation pneumonitis is graded based on impact on patient function and quality of life, not radiographic changes (table 2). Estimated incidence of symptomatic (grade 2 or higher) RILI is described below for common tumor types:

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 who received more than 20 Gy (V20) over 22 to 31 percent of the lung volume [9]. The incidence of symptomatic RILI increased to 13 percent in those with a V20 of 32 to 40 percent. In addition, 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 [10].

In patients with breast cancer, symptomatic RILI occurs in approximately 1 to 9 percent depending on the extent of the radiation field and whether concurrent chemotherapy is administered [11]. One to 3 percent of patients may also develop a less typical secondary organizing pneumonia [12-15]. (See 'Typical disease course' below and 'Chest computed tomography' below.)

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 (table 2) [16].

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 more often indirectly via the interaction of the ionizing radiation with tissue water producing free radicals. These free radicals damage DNA strands as the primary method for radiation to kill cells.

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. Epithelial cell cytotoxicity largely proceeds directly as a consequence of DNA damage, which results in loss of cell division capability (clonogenic death) and apoptosis. The accompanying development of inflammation and fibrosis is mediated by cytokine activity and patient immune responses.

Several proinflammatory cytokines are elevated in serum and tissues after radiation therapy, including transforming growth factor-beta 1 (TGF-beta), tumor necrosis factor-alpha (TNFa), interleukin- (IL-) 1a, and IL-6 [17-21]. Some studies have found [17,18,22-31] elevated pretreatment plasma IL-6 and posttreatment TGF-beta concentrations correlate with an increased risk of developing RILI [17-20,32]. The role of immune regulation is supported by the observation that disruption of CD40/CD40 ligand interactions between antigen-presenting cells and CD40 ligand-bearing cells (T lymphocytes, mast cells, and eosinophils) reduces pathologic markers of injury in a murine model of RILI [33].

These inflammatory responses to injury are likely mitigated by other signals of inflammation regulation and injury repair. For example, exogenous interferon-gamma administration reduced alveolar inflammation (neutrophil and protein levels) and pathologic features of radiation injury in a rat model of RILI [34,35].

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. Although data from studies based upon various radiation therapy parameters or gene polymorphisms have been studied as predictors of RILI [36-38], these predictors are not yet clinically useful. We weigh the factors below in determining the risk of RILI after radiation therapy.

Volume of lung irradiated — The risk of radiation-induced injury is directly related to the volume of irradiated lung [39,40]. 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 [41]), and the use of concurrent compared with sequential chemotherapy (8.8 versus 1.3 percent in one series) [42]. 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 [43]. (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 [39,44-48]. 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 20 Gy or greater [39].

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 with conventionally fractionated (daily doses of 1.8 to 2.0 Gy/day) radiotherapy [39]. 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 [49]. However, in a subsequent 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 [50]. 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 [51]. (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'.)

Intensity-modulated radiation therapy – Although its impact on RILI has not been fully characterized, IMRT is increasingly recognized as a preferred option in locally advanced NSCLC. Observational data support the idea that the technical alterations in lung dosing with this technique reduce the likelihood of RILI. (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 three-dimensional (3D) CRT to 255 [52]. 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 sequential time periods were compared [53]. In the earlier period, patients received 3D-CRT, while in the later period, 4D (four-dimensional; 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 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 [54-57]. This is likely attributable to lower irradiated lung volumes and a lower MLD. The risk of RILI increases once the V20 exceeds 10 percent or the MLD is higher than 6 Gy [58]. Thus, the increased accuracy of newer radiation models appears to reduce global measures of lung irradiation and radiation pneumonitis as well. Most recently, the HyTEC analyses were published and suggested that ipsilateral MLD be limited to <15 Gy to maintain a risk of <20 percent for grade 2 and above radiation pneumonitis [59].

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, only 1 of 102 patients across four studies developed radiation pneumonitis [60]. Similarly, 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 [61]. Initial data from an observational study of 16 patients suggest that proton beam therapy may be safer than other radiation approaches in high-risk patients with fibrotic interstitial lung diseases (ILDs) who are undergoing radiation therapy for lung cancer [62].

Prospective Phase II randomized data on the role of passive scatter proton therapy and intensity modulated radiation in definitive chemoradiation for lung cancer showed improved sparing of lung doses, although there was a learning curve with proton radiotherapy in lung cancer [63]. There is an ongoing larger randomized trial of proton therapy versus IMRT as a component of stage II-IIIB NSCLC treatment (RTOG 1308).

More modern proton techniques (intensity-modulated proton therapy [IMPT]) may offer advances in organ sparing and may markedly reduce the rates of pneumonitis compared with photon IMRT [64]. In one retrospective comparison, one study found that IMPT was associated with a highly reduced rate of grade ≥3 pneumonitis at one year compared with IMRT with photons (0 versus 11 percent) [64]. (See "Radiation therapy techniques in cancer treatment", section on 'Proton beam'.)

Induction chemotherapy — The use of induction chemotherapy prior to chemoradiotherapy may increase the risk of radiation pneumonitis [65-67]. 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) [67]. (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 [11,65,68-71]. Patients receiving these drugs are at a higher risk of developing RILI. In addition, several of the drugs themselves are associated with lung injury (table 3). By contrast, other drugs may sensitize tumor cells to the effects of radiation without an increase in lung injury [72]. (See "Bleomycin-induced lung injury" and "Cyclophosphamide pulmonary toxicity" and "Taxane-induced pulmonary toxicity" and "Pulmonary toxicity associated with antineoplastic therapy: Cytotoxic agents" and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

A 2012 meta-analysis of eight studies and 1607 patients demonstrated an increased risk of radiation pneumonitis (odds ratio [OR] 1.6, 95% CI 1.1-2.3) in patients receiving concurrent compared with sequential chemotherapy. Other risk factors identified included older age, pulmonary comorbidities and mid- or lower-lung tumor location [73]. Risks associated with particular agents are discussed further below.

Anthracyclines – Concurrent rather than sequential chemotherapy appears to increase the risk of radiation pneumonitis in females undergoing anthracycline-based adjuvant chemotherapy plus radiotherapy for breast cancer [42,65]. In one report, the risk of pneumonitis in females treated with a supraclavicular field and concurrent versus sequential chemotherapy was 9 versus 1.3 percent, respectively [42]. 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, females 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 [74]. 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 [75]. 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, followed by durvalumab'.)

Among patients receiving concurrent gemcitabine, toxicity appears less with conformal (3D) compared with two-dimensional treatment planning [76]. 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) [66,76-78].

Pemetrexed – The exact interaction of pemetrexed with irradiation is not known, although it appears to have some radiosensitizing and radiation recall effects [79-81]. 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 [82]. The overall incidence of pneumonitis was higher with the pemetrexed-cisplatin group than with etoposide-cisplatin (17 versus 11 percent), although the incidence of pneumonitis grade ≥3 was not increased (1.8 versus 2.6 percent) (table 2). (See "Management of stage III non-small cell lung cancer", section on 'Choice of chemotherapy'.)

Immune checkpoint inhibitors – Immune checkpoint inhibitors (ICIs) are commonly used in lung cancer and other malignancies, but are associated with an inherent risk of ICI-associated pneumonitis of up to 19 percent [83] as well as a possible increased risk of RILI. Teams caring for patients receiving ICI and radiotherapy should remain vigilant for symptoms of RILI and counsel patients regarding pneumonitis risks along with the associated benefits of ICI therapy. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Pneumonitis'.)

The potentiation of radiation pneumonitis by immunotherapy remains controversial. Although some retrospective studies have suggested increased risk of radiation injury with immunotherapy, data from immunotherapy trials do not show large differences in severe RILI [84-87]. There is also clinical equipoise about the interaction of targeted agents such as tyrosine kinase inhibitors (TKIs) with radiotherapy.

A pooled analysis of 16,835 patients from 68 trials who received immunotherapy within 90 days of radiation therapy showed no increased risk of adverse events (including pneumonitis) with immunotherapy [87].

The PACIFIC study, which randomized patients 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 [84]. 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 (table 2) was similar (3.4 versus 2.6 percent), suggesting the use of ICI following chemoradiotherapy was relatively safe. (See "Management of stage III non-small cell lung cancer", section on 'Incorporation of immunotherapy'.)

In contrast, a meta-analysis of EGFR TKI and concurrent chemoradiotherapy for unresectable NSCLC noted a possible increased risk of pneumonitis, although this was not significant (OR 1.76, 95% CI 0.98-3.15) [88].

A subsequent prospective trial of 133 patients with widely metastatic NSCLC who received palliative radiotherapy and concurrent EGFR TKI noted a 6 percent incidence of grades 3 to 4 pneumonitis (table 2) [89]. This is consistent with data indicating an increased risk of recall pneumonitis with earlier generation TKI agents; an overlap time of >20 days may be a relevant risk factor [90,91].

Interstitial lung disease — One of the most significant predictors of RILI is the presence of baseline ILD [92,93]. ILD has been associated with a significant risk of respiratory failure or death from radiation pneumonitis [92,94]. In one large single-center series, 39 of 537 patients treated with SBRT had preexisting ILD (13 with usual interstitial pneumonitis [UIP] and 24 with possible UIP) [95]. The rate of symptomatic radiation pneumonitis was much higher (20.5 versus 5.8 percent) in the patients with ILD, who also accounted for two out of three deaths due to RILI. A high rate of mortality was confirmed in a multicenter cohort reporting 17 fatal cases of radiation pneumonitis (6.9 percent mortality) among 242 patients with early-stage lung cancer and preexisting ILD treated with SBRT. The biggest risk factor for fatal radiation pneumonitis was the dose of radiation received by normal lung (mean percentage normal lung volume receiving more than 20 Gy (V20) >10 percent) [96].

In a 2020 consensus statement, the International Association for the Study of Lung Cancer (IASLC) emphasized not only identification of subclinical ILD, but also careful risk-benefit assessment of radiation therapy in the context of progressive fibrotic interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF) [97]. Patients with more advanced disease and poorer prognosis due to ILD likely have higher risk of severe RILI and a lower likelihood of benefit from radiation treatment. For patients with IPF, the use of validated prognostic scores (eg, the ILD-GAP score (table 4)) may inform individualized discussions about the risks and benefits of radiotherapy.

Prior radiation (recall) — Radiation recall pneumonitis can occur when certain chemotherapy 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 [79,98-107]. 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), female sex, endocrine therapy for breast cancer, and glucocorticoid withdrawal during radiotherapy have all been reported to influence the risk of radiation pneumonitis [11,68,73,98,108-110].

Smoking – Smoking history has been reported as a risk factor for RILI in some studies [108,109]. However, one retrospective study of 405 female smokers and nonsmokers who underwent radiotherapy for treatment of breast or esophageal cancer found that none of the actively smoking patients developed RILI [111].

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 [98,112-118]. One prospective single-center study of 153 patients with lung cancer demonstrated pulmonary emphysema as an independent risk factor for the development of symptomatic (grade ≥2) or severe (≥3) radiation pneumonitis (table 2) [117]. Similarly, 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 [98].

However, a single course of lung SBRT in stage I NSCLC has not been associated with a decrement in lung function in patients with poor baseline pulmonary function and COPD in prospective trials [116]. In addition, one retrospective study found that patients with more severe COPD developed less symptomatic radiation pneumonitis than those with more normal lungs [112]. 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 [113].

Endocrine therapy for breast cancer – Some studies suggest that concurrent (but not sequential) use of tamoxifen may increase the rate of RILI in females treated for breast cancer; however, this has not been a consistent finding across studies [119]. In general, higher rates of symptomatic (grade 2 or higher) pneumonitis have not been seen. In contrast, the frequency of radiation-induced organizing pneumonia may be increased by concurrent endocrine therapy. For example, in one retrospective series of 702 females with breast cancer who received breast conserving therapy, organizing pneumonia was associated with concurrent radiation and endocrine therapy (6.2 versus 1.1 percent, OR 3.05, 95% CI 1.09-8.54) [12].

Genetic background – Animal and human studies suggest that there is a significant role for genetic susceptibility to irradiation injury [22-24]. Contemporary studies of patients receiving irradiation for breast cancer have shown suggestive associations between certain genetic factors and development of fibrosis following irradiation [26,27]. 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 [28]. In separate studies of lung cancer patients, polymorphisms of the ataxia telangiectasia mutated (ATM) gene and TGF-beta gene were associated with an increased risk of radiation pneumonitis [29,30,38]. In contrast, single nucleotide polymorphisms of the heat shock protein pathway member HSPB1 have been associated with lower rates of radiation pneumonitis in a retrospective study [53].

TYPICAL DISEASE COURSE — The pathologic and clinical changes in the lung following irradiation may be understood as an evolution through five phases, although these phases are not always clinically apparent (table 5) [120]:

Immediate phase – The immediate phase begins within hours to days following radiation exposure and is generally clinically asymptomatic. Pathologically, it is characterized by hyperemic, congested mucosa with leukocytic infiltration and increased capillary permeability, resulting in localized 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].

Latent phase – During the next two to three weeks, thick secretions frequently accumulate in irradiated lung due to an increase in the number of goblet cells combined with ciliary dysfunction. These changes can result in cough for those with large radiation ports, but they are generally clinically silent. Outside of the radiation field, an asymptomatic CD4+ lymphocytic alveolitis consistent with a mild hypersensitivity pneumonitis-like reaction commonly appears throughout the lung, including on the contralateral side [121]. This phenomenon does not predict progression to clinically significant radiation pneumonitis.

Acute exudative phase – The acute exudative phase occurs 3 to 12 weeks following exposure. Clinical manifestations of radiation pneumonitis most frequently occur in this phase and include [122,123]:

Fevers (typically mild)

Dyspnea with exertion or breathlessness

Cough, generally nonproductive

Chest pain, frequently pleuritic, but may also be substernal (esophagitis or pleuritis may contribute)

Malaise and weight loss

On physical examination, crackles and a pleural rub may be heard over the affected area, and small pleural effusions are detectable in about 10 percent of patients. In contrast to malignant effusions, radiation-induced effusions do not increase in size after a period of observed stability. There may also be signs of skin erythema over the radiation port, but these do not correlate with radiation pneumonitis presence or severity. Frank signs of severe pulmonary dysfunction (tachypnea, cyanosis, pulmonary hypertension) occur in the most severe cases.

Pathologically, this phase consists of sloughing of endothelial and epithelial cells with narrowing of the pulmonary capillaries and microvascular thrombosis. Hyaline membranes form due to the alveolar pneumocyte desquamation and subsequent 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.

Intermediate phase – The intermediate phase is characterized by resolution of the acute exudative process, usually accompanied by a gradual diminishment in clinical symptoms, if present. For most patients, there will be resolution of the alveolar exudate and dissolution of the hyaline membranes throughout much of the radiation port. However, more pathologic healing frequently occurs in the most injured tissue and results in fibroblast migration and proliferation in the alveolar walls and spaces, collagen deposition, and thickening of the interstitium [124,125].

Radiation fibrosis – This final phase may occur as early as six months and can progress over years, and its estimated incidence is between five and fifteen percent [126,127]. Radiation fibrosis follows from fibroblast-predominant healing in the intermediate phase, and it is characterized by increasing collagen and myofibroblast proliferation in both interstitial and alveolar spaces. Some patients present clinically during this phase of injury, most frequently with cough and dyspnea rather than other manifestations. Fibrotic regions will demonstrate dry crackles on exam. The fibrotic process results in focal loss of lung volume, which is frequently accompanied by traction bronchiectasis. Bronchiectatic areas may also be complicated by chronic infection, especially in patients who are immunocompromised due to their cancer treatments. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Less typically, a secondary organizing pneumonia may be seen approximately 3 to 17 months after radiotherapy [12,13,128,129]. Organizing pneumonia is characterized clinically by the same symptoms of radiation pneumonitis, but there is generally radiographic involvement of areas outside the radiation field, often including the contralateral lung. Histopathologically, there is a proliferation of fibroblastic granulation tissue within the alveolar ducts and alveoli without disruption of the lung architecture. (See "Cryptogenic organizing pneumonia", section on 'Histopathologic diagnosis of organizing pneumonia'.)

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 (ILD), or heart failure [8].

Imaging studies — Chest imaging is the cornerstone of the diagnostic evaluation in patients who present with typical clinical manifestations. Radiographic abnormalities within the radiation port at the appropriate time following thoracic radiation are highly suspicious.

Chest radiograph — Chest radiographs are often obtained early upon patient presentation prior to computed tomography (CT) imaging. Typical findings vary by phase of disease (table 5). Perivascular haziness is an early finding, which often progresses to patchy alveolar filling densities in the radiation port during the acute exudative phase. Chronic radiation fibrosis is characterized by volume loss with coarse reticular or dense opacities. A straight-line effect, in which opacities do not conform to anatomical units but rather to the confines of the radiation port, is virtually diagnostic of RILI. However, obvious straight lines on chest radiograph are now seen less frequently due to newer radiation techniques that involve three-dimensional (3D) modeling. (See 'Method of irradiation' above.)

Small pleural effusions and rib fractures may be seen, but lymphadenopathy does not generally occur. Radiographic abnormalities outside of the irradiation port may be seen [109,128]. This may be due to radiation scatter, lymphatic obstruction, immunologic (hypersensitivity-like) mechanisms, or secondary organizing pneumonia.

Chest computed tomography — Chest CT is more sensitive than the chest radiograph and allows better comparison to the radiation port for evaluation of likely radiation injury. Cross-sectional imaging is appropriate for any patient with suspected radiation pneumonitis. The CT scan may take the form of a CT pulmonary angiogram (CTPA) to exclude pulmonary thromboembolism if this is also in the differential. (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 after development of symptoms. Lung involvement in CT images of radiation pneumonitis typically aligns closely with the irradiated area. Comparisons between pre- and posttreatment images may sometimes 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 aid in this process [130].

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 [131,132]. The radiographic phases are different than the clinicopathologic phases of disease (table 5). (See 'Diagnostic evaluation' above.)

Initial phase – The initial radiographic phase, which corresponds to the acute and early intermediate phases pathologically, occurs three to five months after completion of radiation therapy and shows ground-glass attenuation within the area of irradiated lung.

Organizing phase – The organizing phase follows the initial phase and can last up to six months. The ground-glass attenuations morph patchy areas of consolidation, which in turn coalesce to form a relatively sharp edge that conforms to the radiation therapy portals rather than anatomic structures. These patchy areas sometimes appear nodular.

Fibrotic phase – Over several months following the organizing phase, opacities may resolve with minimal scarring or may become fibrotic. Radiation fibrosis is 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) [46]. (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'.)

The less typical pattern of secondary organizing pneumonia may occur 3 to 17 months following radiation therapy and is characterized most typically by dense peripheral consolidations outside of the radiation field and even in the contralateral lung. Additional potential radiographic findings in organizing pneumonia are discussed separately. (See "Cryptogenic organizing pneumonia", section on 'Chest imaging'.)

Pulmonary function tests — Pulmonary function tests (PFTs) are most helpful in excluding obstructive pulmonary processes and in characterizing the severity of respiratory impairment. Typically, spirometry (before and after bronchodilator), lung volumes, diffusing capacity for carbon monoxide (DLCO), and a six-minute walk test with oximetry are obtained as a baseline prior to radiation therapy in patients expected to have large volumes of lung irradiated.

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 [11,133,134]. For patients with large areas affected, tidal volumes are also decreased and the respiratory rate elevated. As with other causes of interstitial or fibrotic lung disease, ambulatory or resting 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 [135], but this finding is nonspecific, as it can also be reduced in emphysema and ILD. 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 [136]. (See "Diffusing capacity for carbon monoxide".)

Bronchoscopy — The main role for flexible fiberoptic bronchoscopy in patients with suspicion for RILI is to evaluate for infection, bleeding, drug hypersensitivity, or spread of the underlying malignancy. Bronchoscopy with bronchoalveolar lavage (BAL) is performed in the majority of patients but can be deferred in patients with typical clinical and radiographic findings. Transbronchial biopsy specimens may sometimes 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".)

BAL fluid findings in radiation pneumonitis are not specific but usually show increased leukocytes with a lymphocytic predominance, as expected based on increased lymphocyte numbers after radiation injury [137,138]. The majority of BAL lymphocytes postirradiation are CD4+ and are activated. The number of neutrophils, eosinophils, and macrophages may also be increased, but a predominance of neutrophils or eosinophils would be unusual.

Tissue specimens via transbronchial biopsies are too small to establish a diagnosis of RILI. They are only occasionally used to rule out specific infections 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".)

Tests of low utility

Laboratory studies — No commonly employed laboratory test identifies the development of radiation pneumonitis. Nonspecific signs of inflammation are frequently present, including low-grade peripheral blood polymorphonuclear leukocytosis and modest elevations of sedimentation rate, serum lactic dehydrogenase (LDH), and C-reactive protein [139]. Evaluation typically includes work-up for infection, heart failure, and bleeding.

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 'Typical disease course' 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 [140,141].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of radiation pneumonitis most commonly includes infection, thromboembolic disease, drug-induced pneumonitis, spread of the underlying malignancy, and acute exacerbation of cardiopulmonary disease (chronic obstructive pulmonary disease [COPD], interstitial lung disease [ILD], or heart failure). Viral pneumonias, including SARS-CoV-2 pneumonia, can be particularly challenging to distinguish from radiation pneumonitis if they occur 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, esophagitis, and early radiation pneumonitis that has not yet manifested in radiographic abnormalities.

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 [11,142]. Patients who have established fibrosis due to prior irradiation are unlikely to benefit from glucocorticoid therapy [123]. It is unknown whether drugs that inhibit collagen synthesis and deposition will slow further fibrosis. (See "Treatment of idiopathic pulmonary fibrosis".)

Supportive care, for all patients — Supportive care may include antitussive therapy, supplemental oxygen, and treatment of comorbid cardiopulmonary diseases that may contribute to symptoms. Antitussive therapy, such as dextromethorphan or codeine, may provide symptomatic relief of cough, although formal study in the setting of RILI 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 (SpO2) ≤88 percent, although this oxygen need may be transient for patients presenting in the acute exudative phase. (See 'Typical disease course' above and "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. Antitussive agents and bronchodilators are occasionally helpful in patients with mild to moderate symptoms.

Alternatively, improvement in mild symptoms has been described with high-dose inhaled glucocorticoids, which are probably equivalent to low-dose oral corticosteroid therapy. In a single-center study, 24 patients with pneumonitis following irradiation for lung cancer were initially treated with high-dose inhaled glucocorticoids (budesonide 800 mcg twice a day) for 14 days [143]. 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 — We 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), or evidence of impaired respiratory function. This approach, which is in accordance with other expert advice [11,142], is based on both clinical experience and multiple reports of a prompt response to oral glucocorticoid therapy.

We treat with prednisone 0.75 mg/kg ideal body weight (approximately 40 to 60 mg/day) for two to four weeks followed by a taper over 3 to 12 weeks, although the guidelines for tapering are poorly defined [11]. We monitor symptoms closely during tapering. If the patient experiences relapse of symptoms, we return to full dose for two weeks and attempt a slower taper, particularly when the dose is 20 mg per day or less.

We suggest prophylaxis for Pneumocystis pneumonia when the prednisone dose exceeds 20 mg a day for more than a month [144]. Steps to monitor and prevent the various adverse effects associated with systemic glucocorticoids are discussed separately. (See "Major adverse 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 who do not tolerate or do not respond to glucocorticoid therapy, use of azathioprine and cyclosporine have been reported, but are not frequently used [145,146].

Patients with radiation-associated organizing pneumonia — For patients with radiation-associated organizing pneumonia OP based on clinical and radiographic features or increased suspicion due to recurrent disease relapse upon prednisone tapering, we follow the treatment approach usually used for cryptogenic organizing pneumonia (COP). (See 'Typical disease course' above and 'Chest computed tomography' above and "Cryptogenic organizing pneumonia".)

Patients with radiation-induced pulmonary fibrosis — There are no established guidelines for the management of radiation-induced lung fibrosis. There is interest in studying antifibrotic therapy, such as nintedanib, for progressive fibrosing disease, but there are limited data to support efficacy. Two small studies have suggested that the use of the TKI nintedanib may prevent radiation pneumonitis and/or decrease the risk of recurrence of radiation pneumonitis in combination with prednisone [147,148]. However, more definitive data are needed before such protocols are adopted for routine clinical use. 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'.)

PROGNOSIS — Significant improvements in the perfusion and ventilation of radiation-injured lung tissue frequently occur 3 to 18 months after radiation therapy during the organizing phase, often leading to reduced dyspnea, hypoxemia, and cough. (See 'Typical disease course' above.)

After 18 months, however, radiation fibrosis of the most affected areas is established, and further improvement is unusual [133,149]. Radiation fibrosis can progress in some patients to include other previously noninjured areas of lung. This progression is thought to be related to the pathogenesis of other fibrotic lung diseases, but it is not well understood. (See "Pathogenesis of idiopathic pulmonary fibrosis", section on 'Progression'.)

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 [39]. No specific pharmacotherapies have been well-established to prevent radiation injury in the lung. (See 'Risk factors' above.)

Several routinely used therapies, including glucocorticoids, antibiotics, and heparin, have been studied in the hope that they might protect against RILI, but none have been effective in this role [5,108,129,150-152].

Several other experimental agents have also been assessed for a potential role in the prevention of RILI and radiation-induced fibrosis in other organs. These include pentoxifylline and amifostine, which both showed benefit in early studies that have not been successfully replicated [146,153]. Angiotensin-converting enzyme (ACE) inhibitors have also showed a protective effect in preclinical models and a retrospective series [154,155], but trial data are lacking. (See "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis".)

In China, Aidi (Z52020236, China Food and Drug Administration [CFDA]), an injectable agent composed of the extracts from Astragalus, Eleutherococcus senticosus, Ginseng, and Cantharidin, is often administered. Although a meta-analysis of many small studies shows a potential reduced risk of RILI after pretreatment with Aidi [156], lack of availability or evaluation outside of China limits its use.

SUMMARY AND RECOMMENDATIONS

Risk factors

Patients who undergo thoracic irradiation for the treatment are at risk for RILI, including pneumonitis and fibrosis. (See 'Introduction' above.)

Many factors affect the risk for RILI, including the method, dose, and frequency of irradiation, the volume of irradiated lung, associated chemotherapy, comorbid interstitial lung disease (ILD), and the genetic background of the patient. (See 'Risk factors' above.)

Disease course and findings

Disease course – Symptoms caused by radiation pneumonitis usually develop in the acute exudative phase, approximately 3 to 12 weeks following irradiation. The injury often improves over the subsequent intermediate phase, but 5 to 15 percent of patients develop radiation fibrosis in the regions of greatest injury after 6 to 12 months (table 5). Typical symptoms for both radiation pneumonitis and radiation fibrosis include dyspnea, cough, chest pain, fever, and malaise. (See 'Typical disease course' above.)

Imaging characteristics – Compared with radiographs, Chest CT provides much better evaluation of subtle changes and allows closer comparison between radiographic abnormalities and the radiation therapy ports or dosimetry modeling. In the acute exudative phase, chest CT may show patchy alveolar ground-glass or consolidative opacities. Over the ensuing weeks to months, these consolidations coalesce. A straight-line effect, in which abnormalities conform to within radiation port edges rather than anatomical units, is diagnostic of RILI, but may not occur in patients treated with conformal and stereotactic radiation. Chronic changes are characterized by volume loss with coarse reticular or dense opacities. (See 'Imaging studies' above.)

Diagnosis – The diagnosis of radiation pneumonitis is based on correlations between the onset of symptoms and signs, the timing of irradiation, 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 required. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Treatment

For patients who are asymptomatic or have minimal symptoms, we provide supportive care only (eg, antitussives). (See 'Supportive care, for all patients' above and 'Patients with minimal or no symptoms' above.)

For patients with moderate to severe symptoms or change in pulmonary function four weeks to six months after initiation of radiation therapy, we suggest administering prednisone rather than observation alone (Grade 2C). We typically use 0.75 mg/kg up to 60 mg/day for two to four weeks, followed by a gradual taper based on patient response . (See 'Symptomatic patients with subacute radiation pneumonitis' above and "Major adverse 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 based on disease time-course, typical radiographic pattern, and/or characteristic-appearing relapse during tapering of oral glucocorticoids, we advise following the treatment approach used for cryptogenic organizing pneumonia (COP). (See 'Patients with 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. Other antifibrotic therapies have not been well studied in these patients. (See 'Treatment' above and "Treatment of idiopathic pulmonary fibrosis".)

Prognosis – Dyspnea and hypoxemia frequently decrease over 3 to 18 months due to improvements in perfusion and ventilation of radiation-injured lung tissue over this timeframe. Subsequent improvement is unusual.

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges William Merrill, MD and Kenneth R Olivier, MD, who contributed to earlier versions of this topic review.

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Topic 4331 Version 43.0

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