The mechanisms behind radiation-induced lung injury remain poorly understood despite decades of study. A detailed review of the histopathological and molecular events occurring in radiation pneumonopathy is beyond the scope of this chapter; several excellent reviews have been published in the past decade.3–3 Irradiation damages endothelial cells, epithelial cells (particularly surfactant-producing type II pneumocytes), and reticuloendothelial cells within the lung through several mechanisms, including apoptosis and induction of stress-response genes. It is now generally agreed that cytokines such as transforming growth factor beta (TGF-β) play a major role in promoting radiation pneumonopathy, including development of long-term fibrosis.^4,5 It can be difficult histopathologically (or molecularly) to differentiate established radiation lung injury from other forms of end-stage lung disease, such as idiopathic pulmonary fibrosis, drug-induced injury, or even very advanced chronic obstructive pulmonary disease (COPD).

Traditional clinical understanding of radiation lung injury recognizes two distinct syndromes: radiation pneumonitis and radiation fibrosis of the lung. Radiation pneumonitis is characterized by intense interstitial inflammation and alveolar exudate. It develops over several weeks to months after irradiation and (if the host/patient survives) resolves within 6 to 12 months. Radiation pulmonary fibrosis, in contrast, generally does not begin until several months after radiation therapy but progresses relentlessly over years. Radiation pneumonitis usually responds well to corticosteroids; in fact, a dramatic response to steroids helps to distinguish this disorder from other diagnoses. In contrast, corticosteroids do not influence the progression of radiation pulmonary fibrosis.

In most cases, radiation lung injury is confined to the regions of the lung within the radiation field or portal. This conventional wisdom has been challenged by several researchers who have found evidence of “out-of-field” radiation injury, which may be manifested in a syndrome similar to bronchiolitis obliterans with organizing pneumonia.⁶ In the most severe cases, diffuse acute respiratory distress syndrome can result from partial lung irradiation even with steroid treatment.⁷ Autoimmunity has been hypothesized as a mechanism of out-of-field radiation lung injury, with the possibility that localized lung damage triggers diffuse lymphocyte-mediated hypersensitivity against pulmonary self-antigens.⁸

Radiation lung injury may have any of a variety of clinical and radiographic presentations, but the hallmark symptom is dyspnea out of proportion to other findings. The most common imaging finding is an interstitial infiltrate corresponding to the radiation portals, but it is not unusual to find consolidation, nodularity, or even pleural effusions. The extent of radiographic findings does not necessarily correlate with the extent of symptoms or the patient’s clinical course.⁹ This problem can make the differential diagnosis among recurrent/progressive cancer, infection, and radiation lung injury extremely difficult, particularly in patients with lung cancer. Positron emission tomography with fluorodeoxyglucose may be helpful for differentiating recurrence from radiation toxicity, although intense radiation pneumonitis and even actively developing fibrosis causes elevated fluorodeoxyglucose uptake.¹⁰

Incidence of Radiation Lung Injury and Predictive Factors

The most important factor influencing development of clinically relevant radiation lung injury is the volume of lung irradiated; this issue is extensively discussed in the radiation oncology literature.11–15 In radiation oncology, the lung is considered a parallel-architecture organ, meaning that destruction of very small portions of it should not cause overall organ dysfunction. This belief is supported by the fact that wedge resection of a small portion of lung tissue or stereotactic radiosurgery to a very small lung tumor is well tolerated by most patients. In contrast, other organs, such as the spinal cord, are considered series-architecture organs, in which destruction of one region will lead to irreversible dysfunction downstream from that injury.¹⁶ The series-architecture model of radiation-induced toxicity does apply to other tissues within the lung, such as major bronchi and/or pulmonary vessels, where the result of injury to a small volume can be catastrophic (e.g., fistula and massive hemorrhage).¹⁷

The percentage of lung irradiated is often expressed by radiation oncologists as the “Vx,” where x = a certain dose in Gy. V20 indicates the percentage of a patient’s total lung volume that was irradiated to a dose of at least 20 Gy. Mean lung dose (expressed in Gy) is another parameter commonly used to express the extent to which a patient’s lung volume has been irradiated. Most clinical trials for locally advanced lung cancer require that the V20 be under a certain threshold, such as 35%. However, no single parameter can express the total radiation exposure, which is best described by a two-dimensional graphical curve called a dose-volume histogram (Fig. 58-2 provides an example).

Figure 58-2 Graphic representation (*yellow curve*) of dose-volume histogram for total lung volume irradiated to a nominal dose of 63 Gy in a patient with lung cancer. In this case, the V20 (the percentage of total lung volume receiving >20 Gy) is approximately 36%, which is considered a moderate-risk dose level for clinical radiation pneumonopathy.

Irradiation of the entire lung volume (bilateral lungs) is uncommon today, except as part of total body irradiation for selected BMT conditioning regimens. As reviewed by Sampath and colleagues,¹⁸ the therapeutic index for whole-lung irradiation is extraordinarily narrow and highly dependent on total dose, fractionation, partial lung transmission shielding, and dose rate. A typical dose of 12 Gy total body irradiation has an approximately 11% rate of severe pneumonitis, compared with approximately 2% when lung transmission shielding is used to reduce the lung dose to 6 Gy.

At the other extreme, irradiation of small lung volumes, as with stereotactic body radiation therapy (SBRT, also known as radiosurgery) for early-stage non–small cell lung cancer (NSCLC) rarely results in high-grade RP, despite its use in a compromised patient population.21–21 The field of SBRT for lung cancer is evolving very quickly, and it is likely that with longer follow-up of patients, a greater understanding of the similarities and differences from conventional external beam radiation therapy (XRT) with regard to toxicity will be achieved.

In tangential irradiation of the breast (after lumpectomy) or chest wall (after mastectomy), the risk of clinically significant RP is approximately 1%, increasing to approximately 5% with the addition of irradiation of the regional (axillary/supraclavicular) nodes.²² An association between dose-volume irradiated and pneumonitis risk has also been shown in patients treated for esophageal carcinoma.²³

Level I evidence of a strong relationship between pneumonopathy and the volume irradiated comes from a randomized trial from China.²⁴ This study showed that the incidence of RP was significantly reduced from 29% to 17% with the use of “involved-field” radiotherapy, despite the use of higher tumor radiotherapy doses in the involved field arm.

Understanding the true incidence of radiation pneumonopathy is complicated by multiple factors, including ambiguities in scoring,²⁶ uncertainties related to concurrent medical conditions, and limitations of the historical and current standards for defining and grading this illness.²⁵ Kocak and colleagues²⁵ found that 28% of their suspected RP had confounding medical conditions that made the clinical diagnosis uncertain. Yirmibesoglu and colleagues²⁶ concluded that 48% of RP cases were “hard to score” (vs. “unambiguous”) because of confounding factors (e.g., tumor progression, acute exacerbation of COPD, and infection).

The traditional scoring system developed by the Radiation Therapy Oncology Group (RTOG), which dates back to the early 1970s, is shown in Table 58-1.²⁷ This system is no longer generally used because of limitations such as an arbitrary cutoff of 90 days between acute and late radiation lung injury²⁸; however, understanding of this system is important because numerous publications rely on it. Modern toxicity scoring is performed according to the Common Terminology Criteria (CTC), currently at version 4 (CTCv4).²⁹ The CTCv4 definitions and grading for select pulmonary events are shown in Table 58-2. A comparison of CTCv3 or the old RTOG criteria to CTCv4 shows that numerous changes have been made to the scoring criteria in the pulmonology section. Separate scales are no longer used for early and late radiation therapy-related events.

Table 58-1

Traditional Scoring System for Radiation Lung Injury Based on the Radiation Therapy Oncology Group

Grade	(Acute) Radiation Pneumonopathy (Within 90 Days of Start of External Beam Radiation Therapy)	(Late) Radiation Pneumonopathy (>90 Days after Start of External Beam Radiation Therapy)
1	Mild, dry cough; dyspnea on significant exertion	Asymptomatic (e.g., slight radiographic findings only) or mild symptoms (e.g., dry cough)
2	Dyspnea on minimal exertion and/or persistent cough (requiring narcotics)	Moderate symptomatic fibrosis and/or pneumonitis (severe cough), fever, patchy radiographic appearances
3	Obvious severe radiation pneumonitis with dyspnea at rest and/or severe cough unresponsive to narcotics; oxygen and/or steroids are indicated	Severe symptomatic fibrosis/pneumonitis with dense radiographic changes
3	Life-threatening respiratory insufficiency requiring continuous oxygen/mechanical ventilation	Life-threatening respiratory insufficiency requiring continuous oxygen/mechanical ventilation
5	Death	Death

Data from http://www.rtog.org/ResearchAssociates/AdverseEventReporting/AcuteRadiationMorbidityScoringCriteria.aspx and http://www.rtog.org/ResearchAssociates/AdverseEventReporting/RTOGEORTCLateRadiationMorbidityScoringSchema.aspx.

Table 58-2

Common Terminology Criteria Version 4 * Select Common Terminology Criteria for Adverse Events Related to the Lung

Event	Grade 1^†	Grade 2	Grade 3	Grade 4
Acute respiratory distress syndrome	N/A	N/A	Present with radiologic findings; intubation not required	Life-threatening respiratory or hemodynamic compromise; intubation required
Atelectasis	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic (e.g., dyspnea, cough), medical intervention indicated (e.g., chest physiotherapy, suctioning); bronchoscopic suctioning	Oxygen indicated; hospitalization or elective operative intervention indicated (e.g., stent, laser)	Life-threatening respiratory or hemodynamic compromise; intubation or urgent intervention indicated
Carbon monoxide diffusion capacity (DLCO)	3 to 5 units below LLN; for follow-up, a decrease of 3 to 5 units (mL/min/mm Hg) below the baseline value	6 to 8 units below LLN; for follow-up, an asymptomatic decrease of >5 to 8 units (mL/min/mm Hg) below the baseline value	Asymptomatic decrease of >8 units drop; >5 units drop along with the presence of pulmonary symptoms (e.g., >grade 2 hypoxia or >grade 2 or higher dyspnea)	N/A
Cough	Mild symptoms; nonprescription intervention indicated	Moderate symptoms, medical intervention indicated; limiting instrumental ADL	Severe symptoms; limiting self-care ADL	N/A
Dyspnea	Shortness of breath with moderate exertion	Shortness of breath with minimal exertion; limiting instrumental ADL	Shortness of breath at rest; limiting self-care ADL	Life-threatening consequences; urgent intervention indicated
FEV₁	99% to 70% of predicted value	60% to 69% of predicted value	50% to 59% of predicted value	≤49% of predicted value
Hypoxia	N/A	Decreased O₂ saturation with exercise (e.g., <88% pulse oximetry); intermittent supplemental oxygen	Decreased O₂ saturation at rest (e.g., <88% pulse oxymetry or PaO₂ ≤55 mm Hg)	Life-threatening airway compromise; urgent intervention indicated (e.g., tracheotomy or intubation)
Pleural effusion (nonmalignant)	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic, intervention indicated (e.g., diuretics or limited therapeutic thoracentesis)	Symptomatic with respiratory distress and hypoxia; surgical intervention including chest tube or pleurodesis indicated	Life-threatening respiratory or hemodynamic compromise; intubation or urgent intervention indicated
Pneumonitis/pulmonary infiltrates	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic; medical intervention indicated; limiting instrumental ADL	Severe symptoms; limiting self-care ADL; oxygen indicated	Life-threatening respiratory compromise; urgent intervention indicated (e.g., tracheotomy or intubation)
Pneumothorax	Asymptomatic; clinical or diagnostic observations only; intervention not indicated	Symptomatic; intervention indicated (e.g., tube placement without sclerosis) or temporary chest tube	Sclerosis and/or operation indicated; hospitalization indicated	Life-threatening consequences; urgent intervention indicated
Pulmonary fibrosis	Mild hypoxemia; radiologic pulmonary fibrosis <25% of lung volume	Moderate hypoxemia; evidence of pulmonary hypertension; radiographic pulmonary fibrosis 25%-50%	Severe hypoxemia; evidence of right-sided heart failure; radiographic pulmonary fibrosis >50%-75%	Life-threatening consequences (e.g., hemodynamic/pulmonary complications); intubation with ventilator support indicated; radiographic pulmonary fibrosis >75% with severe honeycombing

ADL, Activity of daily living; FEV1, forced expiratory volume in one second; LLN, lower limit of normal; N/A, not applicable; Pao₂, partial arterial oxygen tension.

^*This is an abbreviated/abridged version of the Common Terminology Criteria, Version 4; the complete version can be found at http://evs.nci.nih.gov/ftp1/CTCAE/About.html.

^†As with the older scoring systems, grade 5 (not shown) is death, and grade 0 is the absence of the particular toxicity. Note that for some adverse events, grades 1 to 2 (mild to moderate) might not be applicable (e.g., acute respiratory distress syndrome). Conversely, for some adverse events, grade 4 (life threatening) might not be applicable (e.g., cough).

Tucker et al.³⁰ found that the scoring system used (CTCv2 vs. CTCv3 vs. RTOG) greatly affected the results of analyses of the risk of RP and the radiation dose-volume factors associated with RP.

Although radiation dose-volume parameters are the major predictor of radiation pneumonopathy, the addition of systemic therapy must also be considered. It appears that neoadjuvant chemotherapy before radiotherapy does not greatly affect the risk of radiation pneumonopathy. However, concurrent chemoradiotherapy probably increases the risk significantly; the maximum tolerated dose of localized radiotherapy with concurrent chemotherapy for NSCLC is generally considered to be 74 Gy,³¹ whereas the maximum tolerated dose for radiotherapy alone is usually considered to be higher than that.¹⁴

A combination of concurrent radiotherapy and gemcitabine appears to have a particularly high rate of radiation pneumonopathy, and extreme caution is advised for this combination (Table 58-3).³² Several other drugs, most notably the anthracyclines (e.g., doxorubicin), methotrexate, and bleomycin, should be considered contraindicated during thoracic radiotherapy.³³ Concurrent thoracic radiotherapy plus a taxane (paclitaxel or docetaxel) is a commonly used and generally safe combination, although it has been suggested that the risk of radiation pneumonopathy might be slightly higher than expected from historical series based on older chemoradiotherapy regimens, particularly with weekly taxane schedules.^36–36 It may be especially prudent to use three-dimensional radiotherapy techniques and to carefully analyze lung dose-volume histogram parameters in patients who are receiving a concurrent taxane.

Table 58-3

Select Large Clinical Studies of the Incidence and Severity of Radiation Pneumonopathy

Study	Patient Population	Rate of Grade 2 Pneumonopathy (%)	Rate of Grade 3+ Pneumonopathy (%)	Comments
LUNG CANCER STUDIES
Byhardt et al.¹⁵⁶	388 patients treated with conventional (large field) chemo-RT in the RTOG experience	NS	17	2-dimensional, large-field XRT; grade 3 RP 20% with concurrent chemo-RT vs. 10% with sequential chemo-RT
Keller et al.¹⁵⁷	488 patients with moderate dose postoperative RT	NS	3.5	High performance status population of patients, moderate dose radiotherapy
Turrisi et al.¹⁵⁸	417 patients (limited stage small cell cancer) with concurrent chemo-RT	12	5	Small cell cancer (moderate dose RT); no difference between once daily and twice a day XRT
Wang et al.¹³	223 patients treated with 3D XRT + concurrent chemo	NS	32	Higher rate than other studies may reflect the use of actuarial statistics and CTCv3 definition
Hope et al.¹⁵⁹	219 patients treated with high-dose 3D XRT	12	11	Strong association of RP with tumor location, lung DVH characteristics
Palma et al.³⁶	836 patients in a multicenter individual patient meta-analysis	30 “symptomatic” pneumonitis		All patients received concurrent chemo—higher risk with taxane-based therapy
Movsas et al.⁶²	205 patients in an RTOG randomized trial of chemo-RT ± Amifostine	17	10	No significant differences with/without amifostine
STUDIES IN CANCERS OTHER THAN LUNG CANCER
Lind et al.¹⁶⁰	613 patients with breast cancer	2.4% of patients diagnosed with RP		RP was significantly more common with regional nodal irradiation
Yu et al.¹⁶¹	189 patients with breast cancer randomized between different chemo regimens prior to RT	5	<1	High rate (24% to 39%) of radiographic changes but low rate of clinical RP
Hughes-Davies et al.¹⁶²	172 patients with bulky intrathoracic Hodgkin disease	14	NS	1% fatal toxicity
Koh et al.¹⁶³	64 patients with Hodgkin disease	3	<1	RP associated with larger lung volume irradiated
Cooper et al.¹⁶⁴	117 patients with esophageal cancer treated with chemo-RT	NS	4
Ishikura et al.¹⁶⁵	139 patients with esophageal cancer treated with chemo-RT	2	2	In both of these studies, Radiation-induced cardiac complications and/or pleural effusions were more common than RP
Kato et al.¹⁶⁶	76 patients with esophageal cancer treated with chemoradiotherapy	NS	4

3D, Three-dimensional; chemo, chemotherapy; CTCv3, Common Terminology Criteria, version 3; DVH, dose-volume histogram; NS, not significant; RP, radiation pneumonopathy; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group; XRT, external beam radiation therapy.

Fewer data exist regarding other systemic agents, including biological agents. These agents are discussed briefly in Part II of this chapter.

Nontreatment factors that appear to be predictive of radiation lung injury have been studied. Not surprisingly, pretreatment performance status has been shown to correlate with development of clinical radiation pneumonopathy.³⁷ Underlying pretreatment pulmonary function is probably an important factor as well,³⁸ although study results have been inconsistent,^39,40 perhaps because in many cases, poor pretreatment pulmonary function is due to effects of the cancer itself; an effective treatment (such as radiotherapy) may then substantially improve rather than harm pulmonary function. Other possible risk factors for toxicity include prior thoracic irradiation, volume loss due to lung collapse, forced expiratory volume in one second <2 L for severe (grade ≥3) RP,³⁷ older age,³³ female gender,^21,33 never or current nonsmokers^33,41,42 and poor pretreatment performance status, and pretreatment COPD in patients with lung cancer.⁴³ Risk factors significantly associated with RP in patients with Hodgkin lymphoma were minimum lethal dose ≥13.5 Gy and V20 ≥33.5% when initial combined modality therapy consisted of Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine and mediastinal radiotherapy.⁴⁴ Use of angiotensin-converting enzyme (ACE) inhibitors may be associated with a lower risk of RP,⁴⁵ although this is controversial and not confirmed by any prospective data.

Risk of radiation-induced lung injury may be higher in patients with certain genetic variations. Studies have explored ataxia-telangiectasia mutated (ATM) gene ⁴⁶ or TGFβ1 gene polymorphisms⁴⁷ as they relate to radiation lung injury, although this parameter is not yet used clinically.

Diagnosis and Management of (Acute and Subacute) Radiation Pneumonitis

With modern, three-dimensional conformal, multifield radiation therapy, SBRT, or intensity-modulated radiation therapy, it is not possible to simply look for pathognomonic rectangular infiltrates on a chest radiograph to confirm RP. A patient who has undergone radiation treatment (particularly if a large volume of lung was irradiated to a dose >20 Gy) and has symptoms should undergo computed tomography (CT) scanning, in some cases with high-resolution CT imaging. CT angiography may also be indicated to rule out a pulmonary embolism. Imaging will typically reveal an interstitial infiltrate and/or ground-glass appearance, which can be very difficult to distinguish from an infection or tumor-related changes. Suspected moderate to severe radiation pneumonopathy should be evaluated by a pulmonologist for consideration of bronchoscopy to rule out infection, particularly if fever is present.⁴⁸

Pulse oximetry or arterial blood gas testing should be performed to assess the need for supplemental oxygen. Pulmonary function testing, especially the diffusion capacity of the lung for carbon monoxide (DLCO) test, is useful as part of the diagnostic workup, in particular to assess the severity of gas-exchange dysfunction, although pulmonary function tests are not strongly correlated to clinical symptoms of radiation-induced lung disease.³³ Spirometric parameters of pulmonary function are frequently reversible after radiation pneumonopathy, whereas DLCO abnormalities are less likely to improve.⁴⁹ The tests and procedures to be considered in the evaluation of patients with cancer who have suspected pneumonopathy are summarized in Table 58-4. This workup should be considered appropriate for either suspected radiation-related or chemotherapy-related pneumonopathy.

Table 58-4

Evaluation of Patients with Cancer Who Have Pulmonary Symptoms (Especially Dyspnea) and Suspected Radiation or Chemotherapy Pneumonopathy

Buy Membership for Hematology, Oncology and Palliative Medicine Category to continue reading. Learn more here

Study*	Rationale
BASIC, MINIMAL WORKUP
CT of chest, preferably both with and without contrast	Assess extent/appearance/location of infiltrates/effusions; correlate with radiation therapy and/or surgical data; rule out recurrent/progressive cancer and/or other etiologies for dyspnea
Pulse oximetry	Assess degree of hypoxia and possible need for supplemental oxygen
Pulmonary function testing (spirometry and DLCO)	Assess extent and type of pulmonary function (radiation/drug pneumonitis is a restrictive pattern, with DLCO often markedly abnormal compared with baseline levels)
CBC/differential; chemistry panel	Rule out leukocytosis and/or leukopenia (possible signs of infection), anemia, hepatic and/or renal insufficiency (all factors that can lead to pulmonary distress)
EXTENDED WORKUP^†