Radiation-Induced Lung Injury

29/11/2020 Radiation-induced lung injury - UpToDate
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Radiation-induced lung injury

Authors: Kenneth R Olivier, MD, Tobias Peikert, MD, Dawn Owen, MD, PhD
Section Editors: James R Jett, MD, Steven E Schild, MD
Deputy Editor: Helen Hollingsworth, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2020. | This topic last updated: Jun 01, 2020.
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 "Patterns of relapse and
long-term complications of therapy in breast cancer survivors" 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,
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lipids, and DNA 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 'Pathology'.)
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" and
"Patterns of relapse and long-term complications of therapy in breast cancer survivors", section
on 'Pulmonary'.)
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 '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 non-small cell lung cancer (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) and immune
checkpoint inhibitors are administered to a patient who has received prior radiation therapy to
the lung [73,82-89]. 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 [61,65,67,82,90-92].
● Smoking – Smoking has been reported as a risk-modifying factor in some studies [90,91]. 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 [93]. 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 [82,94-97]. In a retrospective study, patients with more severe COPD were
found to have less symptomatic radiation pneumonitis than those with more normal lungs
[94]. 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 [95]. 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 [98]. 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 [99,100].
ILD has been associated with a significant risk of Grade 4 and 5 radiation pneumonitis
[99,101]. 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 [102]. 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 [103]. 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 [104].
Predicting radiation lung injury — Data from studies based upon various radiation therapy
parameters have been used to predict the likelihood of RILI [105,106]. 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
[107,108]. 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
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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
180 to 200 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) [109]. 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 [110].
● In patients with breast cancer, radiation-associated organizing pneumonia occurs in 1 to 3

percent [31,34,111,112] 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 [113].
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 [114,115]:
● 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
[116].
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 [117]. 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 computed tomography (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 [32,91]. 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 [118].
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 [119,120].
● 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 [121].
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 [65,122,123]. 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 [124], 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 [125]. (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 [126]. 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 [127].
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 [128,129].
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 "Coronavirus disease 2019 (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 [65,130]. Patients who have established
fibrosis due to prior irradiation are unlikely to benefit from glucocorticoid therapy [115]. 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 "Treatment of subacute and chronic
cough in adults", section on 'Nonspecific treatment'.)
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 [131]. 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 [65,130].
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 [132]. 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 'Pretreatment considerations and monitoring' and
"Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients", 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 [133,134].

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 [111,112]. 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 [31,32,112]. 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 [134].
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 [135]. 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
[136-138].
Early reports suggested that amifostine might decrease RILI without diminishing the
therapeutic effect of radiation [136,139]. 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 [137]. 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 [64,140].

● Angiotensin converting enzyme inhibitors – The angiotensin converting enzyme inhibitor

(ACEI) captopril has been shown to reduce radiation-induced lung fibrosis in rats [141]. 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 [142].
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 [143].
● 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 [144]. (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 [122,145].
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 [5,33,90,146-148]. 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 radiation-induced lung injury (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 computed tomography (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 'Pretreatment considerations
and monitoring' and "Treatment and prevention of Pneumocystis pneumonia in HIV-
uninfected patients", 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 editorial staff at UpToDate would like to acknowledge William Merrill, MD, who contributed
to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 4331 Version 30.0

GRAPHICS
Thoracic effects of radiation
Radiation dermatitis
Rib fractures
Bronchitis
Pleural effusion
Hemoptysis
Airway obstruction
Pneumonitis
Pulmonary fibrosis
Pulmonary vascular damage
Esophagitis
Pericarditis
Pneumothorax
Graphic 79716 Version 1.0

Contributor Disclosures
Kenneth R Olivier, MD Nothing to disclose Tobias Peikert, MD Nothing to disclose Dawn Owen, MD,
PhD Nothing to disclose James R Jett, MD Employment: Oncimmune [Biomarkers for early cancer
detection]; Biodesix [Biomarkers of early lung and advanced lung cancer]. Equity Ownership/Stock
Options: Oncimmune [Biomarkers for early cancer detection]. Steven E Schild, MD Nothing to
disclose Helen Hollingsworth, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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• Clinically, the most extensively studied radiation-induced cytokine is transforming

• The proinflammatory cytokines, tumor necrosis factor-alpha (TNFa) and interleukin 1-

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• CD40 is displayed by antigen-presenting cells including B lymphocytes, macrophages,

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Volume of lung irradiated — The risk of radiation-induced injury is directly related to the

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Dose of radiation — The dose of radiation delivered to the lung is a critical factor in

Method of irradiation — Radiation oncologists continue to work to improve the targeting of

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● In a retrospective study of chemoradiation for NSCLC, rates of pneumonitis from two

Stereotactic body radiation therapy — Clinically significant radiation pneumonitis develops

Induction chemotherapy — The use of induction chemotherapy prior to chemoradiotherapy

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chemoradiotherapy, neoadjuvant approaches, and postoperative adjuvant therapy for localized

Concurrent chemotherapy — Several chemotherapeutic agents are known sensitizers to

● Anthracyclines – Concurrent rather than sequential chemotherapy appears to increase the

● Paclitaxel – It is likely that sequential administration of paclitaxel and radiation therapy

● Gemcitabine – Gemcitabine is included in many lung cancer treatment protocols and is a

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● Immune checkpoint inhibitors – Immune checkpoint inhibitor (ICI) therapy is

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cisplatin-based chemotherapy and irradiation, COPD was associated with an increased

● In patients with breast cancer, radiation-associated organizing pneumonia occurs in 1 to 3

Symptoms caused by acute radiation pneumonitis usually develop approximately 4 to 12 weeks

● A nonproductive cough, which may occur during therapy as a manifestation of bronchial

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● 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.

● Tachypnea, cyanosis, or signs of pulmonary hypertension may be seen in more advanced

Laboratory studies — No commonly employed laboratory test identifies the development of

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Imaging studies — Chest radiographic abnormalities following thoracic irradiation need to be

Chest radiograph — Chest radiographs may be normal in symptomatic subjects during the

● Perivascular haziness is an early radiation-induced abnormality on chest radiograph, often

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A few cases have been reported of radiographic abnormalities attributed to radiation

The key step in the evaluation of radiation pneumonitis is comparison of pretreatment CT

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Pulmonary function tests — Pulmonary function tests (PFTs) can be helpful in differentiating

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The differential diagnosis of radiation pneumonitis most commonly includes infection;

Antitussive therapy, such as dextromethorphan or codeine, may provide symptomatic relief of

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Patients with minimal or no symptoms — Patients who are asymptomatic or have minimal

Symptomatic patients with subacute radiation pneumonitis — Many experts, including the

Glucocorticoids — Prednisone (approximately 40 to 60 mg/day) is generally given for two to

Other immunosuppressive agents — Azathioprine and cyclosporine were both effective in

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/radiation-induced-lung-injury/print?search=HYPERSENSITIVE NEUMONITIS&source=search_res… 18/38

Radiation-associated organizing pneumonia — For patients with radiation-associated

Radiation-induced pulmonary fibrosis — There are no established guidelines for the

Supportive care such as oxygen supplementation, pulmonary rehabilitation, mucociliary

● Pentoxifylline – Pentoxifylline is a xanthine derivative that inhibits platelet aggregation and

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/radiation-induced-lung-injury/print?search=HYPERSENSITIVE NEUMONITIS&source=search_res… 19/38

● Inhibitors of collagen synthesis – Since excess collagen deposition is a key

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/radiation-induced-lung-injury/print?search=HYPERSENSITIVE NEUMONITIS&source=search_res… 20/38

● Angiotensin converting enzyme inhibitors – The angiotensin converting enzyme inhibitor