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A Primer on Interstitial Lung Disease and Thoracic Radiation

Open ArchivePublished:February 24, 2020DOI:https://doi.org/10.1016/j.jtho.2020.02.005

      Abstract

      Interstitial lung disease (ILD) is a term used to describe a heterogeneous group of lung disorders with characteristic clinical and imaging features. Patients with ILD are at an increased risk of developing NSCLC, which is frequently medically comorbid, often precluding operative management. In this scenario, radiotherapy (RT) is generally recommended; however, ILD is known to increase the risk of RT-related toxicity. Recommendations for treatment with appropriately individualized risks and benefits are thus dependent on integration of patient-, ILD-, and cancer-specific factors. We aim to provide an overview of ILD for the thoracic oncologist, an assessment of risk of thoracic RT in patients with ILD, and evidence-based recommendations for treatment in a variety of clinical scenarios.

      Keywords

      Introduction

      Interstitial lung disease (ILD) is a term used to describe a heterogeneous group of disorders affecting the lung parenchyma. Patients with ILD are at a higher risk of developing lung cancer, and have worse outcomes than patients without ILD who develop lung cancer.
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      Interstitial lung abnormalities in treatment-naïve advanced non-small-cell lung cancer patients are associated with shorter survival.
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      Outcomes of older patients with pulmonary fibrosis and non-small cell lung cancer.
      Emerging evidence suggests that patients with ILD undergoing any treatment, including thoracic radiotherapy (TRT), are at a higher risk of treatment-related toxicities, compounding their baseline risk of morbidity from life-threatening ILD exacerbations.
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      Treatment-related toxicity in patients with early-stage non-small cell lung cancer and coexisting interstitial lung disease: a systematic review.
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      Impact of interstitial lung disease classification on the development of acute exacerbation of interstitial lung disease and prognosis in patients with stage III non-small-cell lung cancer and interstitial lung disease treated with chemoradiotherapy.
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      Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities.
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      Characteristics and prognostic impact of pneumonitis during systemic anti-cancer therapy in patients with advanced non-small-cell lung cancer.
      Thus, patients with concomitant diagnoses of ILD and lung cancer represent a unique challenge in oncologic management. Despite the urgent need for cancer therapy, any treatment requires careful consideration of patient-, ILD-, and cancer-specific factors.
      Management of lung cancer in the setting of ILD is a common clinical scenario, with approximately 5% to 10% of patients with lung cancer having a concurrent diagnosis of ILD.
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      Lung cancer and interstitial lung disease: a literature review.
      Radiation oncologists may not be familiar with the aspects of ILD that are relevant to their clinical practice, given the relatively recent identification of ILD as a risk factor for substantial morbidity in patients receiving high-dose techniques such as stereotactic radiation, and the changes in ILD classifications and diagnostic criteria that have been implemented over the past decade. The aim of this review is to provide an overview of ILD, along with guidance and evidence-based recommendations to aid the thoracic radiation oncologist with the provision of safe and high-quality treatment for this vulnerable patient population.

      What Is ILD?

      ILD is also known as diffuse parenchymal lung disease. Diffuse parenchymal lung disease and ILD are the umbrella terms for more than 200 different noninfectious, acute, or chronic diseases affecting the parenchyma of the lung. ILD can involve the alveolar epithelium, interstitium, perivascular, or perilymphatic tissue. Identifiable or idiopathic injuries trigger an abnormal healing response resulting in inflammation and fibrosis.
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      Interstitial lung disease.
      Identifiable causes can include environmental triggers, pneumotoxic drugs, occupational exposures, radiation therapy, and systemic diseases (e.g., connective tissue disease).
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      Newly recognized occupational and environmental causes of chronic terminal airways and parenchymal lung disease.
      ,
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      Interstitial lung disease in connective tissue disease—mechanisms and management.
      ILD is associated with substantial morbidity and mortality even in the absence of lung cancer. Patients with ILD often present with nonspecific symptoms that include impaired exercise tolerance, progressive dyspnea, and cough. Pulmonary function tests typically exhibit a restrictive pattern (decreased forced vital capacity and total lung capacity) and impaired gas exchange (reduced diffusion capacity for carbon monoxide [DLCO]), leading to a decreased arterial oxygen saturation.

      How Is ILD Classified?

      ILD was historically approached according to whether the underlying cause was known or unknown but is now typically subclassified as fibrotic or nonfibrotic, given the greater clinical relevance of this stratification.
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      An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
      Fibrotic ILDs are likely to be more relevant as predictors of radiation toxicity. The distinction between fibrotic and nonfibrotic ILD is typically made on the basis of high-resolution computed tomography (HRCT) findings of fibrosis, specifically including findings of reticulation, traction bronchiectasis, and honeycombing (Fig. 1).
      • 1.
        Fibrotic ILDs: Fibrotic ILDs are typically progressive disorders that can be further subclassified as either idiopathic pulmonary fibrosis (IPF) or non-IPF ILD. Virtually all fibrotic ILDs are characterized by reticulation or traction bronchiectasis, which can both occur with or without honeycombing. Fibrotic ILDs can have an element of inflammation; however, it is the presence of fibrosis that typically drives prognosis and response to therapy. IPF is a form of idiopathic interstitial pneumonia that has a distinctly poor prognosis and often a different approach to pharmacotherapy compared with non-IPF fibrotic ILDs. Non-IPF fibrotic ILDs include a variety of connective tissue disease–associated ILDs (CTD-ILDs), fibrotic hypersensitivity pneumonitis, some drug-induced ILDs, pneumoconioses, and many other less common subtypes.
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        Heterogeneity in unclassifiable interstitial lung disease. A systematic review and meta-analysis.
      • 2.
        Nonfibrotic ILDs: Nonfibrotic ILDs include a variety of inflammatory, multinodular, and cystic lung diseases. These are collectively less common than fibrotic ILDs and almost always have a better prognosis and response to therapy.
      Figure thumbnail gr1
      Figure 1Computed tomography images of dense fibrosis with reticulation (A), traction bronchiectasis (B), honeycombing (C), and patchy ground-glass opacity (D).
      Further characterization is summarized in Table 1; an overview of these classifications is given in Figure 2, with imaging findings of selected patterns given in Figure 3.
      Table 1A Practical Classification of ILD Subtypes
      SubtypeCharacteristics
      FibroticIPFDistinctly poor prognosis and often a different approach to pharmacotherapy compared with non-IPF fibrotic ILDs.
      CTD relatedMost CTDs can cause ILD, most typically rheumatoid arthritis, systemic sclerosis, inflammatory myopathies (e.g., polymyositis-dermatomyositis), Sjögren syndrome, mixed CTD, and undifferentiated CTD.
      Hypersensitivity pneumonitisAn immune-mediated reaction caused by recurrent exposure to overt or occult environmental antigens, including avian droppings, feathers (e.g., pigeon breeder’s disease), mold, and certain fungi (e.g., farmer’s lung). Can also result in nonfibrotic ILD (see the “multinodular” category).
      Drug-inducedCommon medications known to cause ILD include amiodarone, nitrofurantoin, certain chemotherapeutics (e.g., gemcitabine, pemetrexed, and docetaxel) and immunotherapy with different immune checkpoint inhibitors.
      PneumoconiosesPneumoconioses are frequently occupationally related, occurring secondary to inorganic antigens, such as coal, silica, or asbestos.
      Other or unclassifiedMany other less common subtypes of fibrotic ILD exist; in addition, approximately 12% of patients with fibrotic ILD remain unclassifiable despite a thorough search for an underlying cause.
      CharacteristicsEtiologies
      NonfibroticInflammatoryCharacterized by HRCT findings of widespread ground-glass or multifocal consolidation. Patients typically present with an acute onset of pulmonary and often systemic symptoms that begin over a few hours to a few weeks but also respond rapidly and usually completely to elimination of the underlying cause or immunosuppressive medication.- Various causes of organizing pneumonia

      - Acute or chronic eosinophilic pneumonia

      - Vasculitis

      - Some drug exposures

      - Many other rare diseases
      Multinodular

      (subcategorized by distribution of nodularity)
      Centrilobular nodules are usually ground glass in attenuation and are suggestive of diseases that result in inflammation in the bronchioles or small arteries located at the center of the secondary pulmonary lobule. These conditions are occasionally persistent and progressive but often respond well to treatment of the underlying cause.- Nonfibrotic acute or subacute HP

      - Small-vessel vasculitides

      - Infectious causes
      Perilymphatic nodularity is characterized by typically solid nodules along the bronchovascular bundles, interlobular septae, and pleural surfaces.- Sarcoidosis (most common)

      - Silicosis

      - Lymphangitic carcinomatosis
      Random nodularity, often termed a miliary pattern, is characterized by many (often hundreds) small solid nodules that do not conform to either a centrilobular or perilymphatic pattern.- Most often seen with hematogenously disseminated infections (e.g., tuberculosis and some fungal infections)

      - Metastases (occasionally)
      CysticSimilar to multinodular ILDs, these can be persistent and progressive but can also be relatively dormant and not require specific therapy.- Uncommon conditions, such as lymphangioleiomyomatosis, lymphocytic interstitial pneumonia, Langerhans cell histiocytosis, and other rare entities
      ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; CTD, connective tissue disease; HRCT, high-resolution computed tomography; HP, hypersensitivity pneumonitis.
      Figure thumbnail gr2
      Figure 2A practical method for classification of interstitial lung disease (ILD), highlighting the distinction between fibrotic and nonfibrotic ILDs, including their radiologic patterns, relevant radiologic subpatterns, and an abbreviated list of potential clinical diagnoses. A major challenge in distinguishing ILD subtypes is that many of the radiologic and histopathologic patterns can be seen in multiple forms of ILD. UIP, usual interstitial pneumonia; NSIP, nonspecific interstitial pneumonia; HP, hypersensitivity pneumonitis; GGO, ground-glass opacity; IPF, idiopathic pulmonary fibrosis; CTD-ILD, connective tissue disease–associated ILDs; LAM, lymphangioleiomyomatosis; LIP, lymphocytic interstitial pneumonia; LCH, Langerhans cell histiocytosis. ∗Fibrotic ILDs can also have other concurrent features (e.g., inflammation and multiple nodules).
      Figure thumbnail gr3
      Figure 3Representative images of idiopathic pulmonary fibrosis (A), non-idiopathic pulmonary fibrosis fibrotic interstitial lung disease (B and C), and nonfibrotic interstitial lung disease (D). Panel (A) illustrates features of usual interstitial pneumonia in a patient with idiopathic pulmonary fibrosis, including lower lung-predominant peripheral or subpleural reticulation, traction bronchiectasis, and peripheral honeycombing, without considerable ground glass, nodularity, or gas trapping. Panel (B) illustrates the features of nonspecific interstitial pneumonia, including peripheral and lower lung-predominant fine reticulation, traction bronchiectasis, and ground glass with sparing of the immediate subpleural region. Panel (C) illustrates features of fibrotic hypersensitivity pneumonitis, including diffuse and patchy fibrosis and the “head cheese” sign that is characterized by 3 different densities corresponding to ground glass, normal lung attenuation, and hyperlucency. Panel (D) illustrates a patient with nonfibrotic hypersensitivity pneumonitis, including ground-glass opacities mostly anteriorly with large areas of sparing and without evidence of fibrosis.
      This review will focus on fibrotic ILDs because these ILD subtypes are most often associated with radiation toxicity. Nonfibrotic ILDs are less frequently associated with malignancy and complications arising from treatment of malignancy when this is required. Nonfibrotic ILDs are thus not as relevant in planning radiation therapy. Subsequently, we provide the general principles for differentiating the ILD subtypes, which is described in more detail in multiple recent consensus statements and clinical practice guidelines.
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      Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline.
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      Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society white paper.
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      Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project.

      How Is ILD Diagnosed?

      Once ILD is identified on chest imaging, it can be subclassified on the basis of a variety of features solicited by the patient history, physical examination, laboratory studies (e.g., autoimmune serology), HRCT scans, and when appropriate, bronchoalveolar lavage or lung biopsy. A multidisciplinary discussion among pulmonologists, radiologists, and pathologists experienced in the diagnosis of ILD increases diagnostic agreement and is considered the reference standard for diagnosing ILD.
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      Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis?.
      ,
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      • Richeldi L.
      • et al.
      Prevalence and prognosis of unclassifiable interstitial lung disease.
      Treatment choices and prognosis depend on the ILD subtype and etiology, and therefore, ascertaining the correct diagnosis is imperative.
      HRCT has an essential role in diagnosing ILD (Fig. 4) and is frequently able to support a confident diagnosis in the appropriate clinical context without the need for confirmatory lung tissue sampling. For example, patients lacking an identifiable cause of their ILD who have a usual interstitial pneumonia (UIP) pattern on HRCT can be provided a diagnosis of IPF without needing a lung biopsy. However, a major challenge in distinguishing ILD subtypes is that many of the radiologic and histopathologic patterns are common to multiple forms of ILD, making definitive diagnosis based on radiologic or pathologic findings alone impossible. For example, the radiologic and histopathologic UIP pattern seen in IPF is also frequently seen in CTD-ILDs. As a result, the first step for the accurate diagnosis of ILD is to search for an identifiable cause. If a thorough search does not reveal an identifiable cause, many patients will require histopathologic tests to establish a definitive diagnosis.
      Figure thumbnail gr4
      Figure 4Comparison of a high-resolution computed tomography (HRCT) versus a standard computed tomography image taken on the same day in a 75-year-old male patient with idiopathic pulmonary fibrosis. The HRCT with 1.25 mm slice thickness provides superior visualization of the lung architecture compared with the standard computed tomography with 5 mm slice thickness. The HRCT reveals features consistent with a usual interstitial pneumonia pattern, which allows a confident noninvasive diagnosis of idiopathic pulmonary fibrosis in this patient who lacked an alternative etiology after a comprehensive multidisciplinary assessment.

      What Is IPF?

      IPF is a chronic, progressive, fibrotic ILD that is ultimately fatal. Median survival is 3.8 years after diagnosis,
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      Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.
      ,
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      • et al.
      Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001–11.
      with most patients with IPF dying from chronic, progressive, hypoxemic respiratory failure. IPF is more common in smoking men and rare in people younger than 50 years; the median age of patients at diagnosis is approximately 65 years. The worldwide prevalence of IPF ranges from approximately 10 to 500 cases per 100,000.
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      IPF is characterized by a pathologic pattern of UIP, which typically consists of subpleural fibrosis with fibroblast foci and temporal (or spatial) heterogeneity. The term UIP can also be used to refer to imaging findings that are suggestive of an underlying UIP pathologic pattern, which includes peripheral, subpleural, and bibasilar reticular opacities, associated with architectural distortion, honeycombing, and traction bronchiectasis (Figs. 1 and 3). HRCT findings are often not definitive, and therefore, the current IPF diagnostic algorithm includes criteria for the following four levels of certainty regarding the UIP pattern on HRCT: typical UIP, probable UIP, indeterminate UIP, or suggesting an alternative diagnosis. The “typical” UIP requires all the features outlined previously, whereas the “probable” label is used when all the features are present except honeycombing. Both the typical and probable radiologic UIP patterns are suggestive of an underlying pathologic UIP pattern, particularly in older men.
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      • Sverzellati N.
      • Travis W.D.
      • et al.
      Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society white paper.
      Importantly, UIP may be associated with other forms of ILD (i.e., CTD); however, a UIP pattern is diagnostic for IPF when no cause is identified despite a thorough search.
      Each year, approximately 10% of patients with IPF have an acute exacerbation, characterized by hypoxemic respiratory failure with bilateral ground-glass opacities and consolidations on HRCT superimposed on the pre-existent UIP pattern (Fig. 5). The acute exacerbations can be idiopathic; however, similar accelerations can be triggered by infections, aspiration, drug toxicity, or radiotherapy.
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      • Ryerson C.J.
      • Corte T.J.
      • et al.
      Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report.
      Management options are limited, and median survival from the onset of an acute exacerbation of IPF is approximately 3 months. Guidelines make weak recommendations for the use of glucocorticoids and do not recommend the use of mechanical ventilation unless there is an option for lung transplantation.
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      • Collard H.R.
      • Egan J.J.
      • et al.
      An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
      Figure thumbnail gr5
      Figure 5A high-resolution computed tomography in a patient with an acute exacerbation of idiopathic pulmonary fibrosis revealing bilateral ground-glass opacities superimposed on a pre-existent usual interstitial pneumonia pattern.

      ILD and Lung Cancer

      ILD and NSCLC share common risk factors (e.g., older age, cigarette smoking), but there is also a recognized link between ILD itself and the development of lung cancer, even when controlling for other risk factors. In a recent literature review, the relative risk of lung cancer was 3.5 to 7.3 times higher in the presence of ILD. Lung cancer incidence was estimated at 10% to 20% in ILD, with more than 15% of patients with ILD likely to die from malignancy.
      • Naccache J.M.
      • Gibiot Q.
      • Monnet I.
      • et al.
      Lung cancer and interstitial lung disease: a literature review.
      In a systematic review analyzing the association between IPF and lung cancer, the estimated incidence rate ratio was 6.42 when adjusted for age, sex, and smoking, and IPF was found to be an independent risk factor for lung cancer even after accounting for smoking status.
      • Brown S.W.
      • Dobelle M.
      • Padilla M.
      • et al.
      Idiopathic pulmonary fibrosis and lung cancer: a systematic review and meta-analysis.

      ILD and Radiation

      ILD in the Thoracic Radiation Oncology Clinic

      The increased risk of treatment-related toxicity in patients with NSCLC and ILD is well established, with some suggestion in the literature of increased risk of toxicity even in the setting of subclinical ILD.
      • Niska J.R.
      • Schild S.E.
      • Rule W.G.
      • Daniels T.B.
      • Jett J.R.
      Fatal radiation pneumonitis in patients with subclinical interstitial lung disease.
      Thoracic radiation oncologists should remain vigilant for the signs and symptoms of ILD in this high-risk population. In addition to a standard history and physical examination, clinicians should inspect available computed tomography (CT) images for radiographic evidence of fibrosis or more subtle interstitial lung abnormalities (ILAs), typically characterized by mild peripheral reticulation and ground-glass abnormalities. However, because it seems that fibrotic ILD changes are most associated with radiation toxicity, fibrosis should be the primary concern of the multidisciplinary tumor board.
      Referral to a pulmonologist with expertise in ILD should be considered before making recommendations regarding oncologic treatment when clinical signs support undiagnosed, subclinical, or poorly managed ILD. Pulmonology consultation allows for expert assessment of a patient’s baseline lung function and provides opportunities for medical optimization, including antifibrotic therapy when appropriate, before potentially toxic oncologic therapy. Patients who are initiated on antifibrotic therapy should be managed carefully in a multidisciplinary approach to decrease the risk of synergistic toxicity from the interplay of antifibrotic and antineoplastic therapies.
      To expedite management, HRCT scan of the thorax should be ordered at the time of referral (Fig. 4). HRCT is optimized for high spatial resolution through the utilization of thin (0.5–1.25 mm) slices that offer the most detailed images of the lungs of current imaging modalities. Use of HRCT can often supplant the need for lung biopsy in patients with fibrotic ILD.
      • Verschakelen J.A.
      The role of high-resolution computed tomography in the work-up of interstitial lung disease.
      A lung biopsy for histopathology should only be considered when the clinical and radiologic information are nondiagnostic. Given the risks of periprocedural morbidity, including an approximate 3% risk of fatal complication in patients with ILD, biopsy should only be offered in consultation with an expert ILD team and avoided in high-risk patients, including those with severely impaired lung function, high oxygen requirements, pulmonary hypertension, or other substantial pulmonary comorbidities.
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      • et al.
      Diagnostic yield and postoperative mortality associated with surgical lung biopsy for evaluation of interstitial lung diseases: a systematic review and meta-analysis.

      Estimating ILD Severity and Clinical Course

      Patients with ILD have a variable prognosis, with some individuals surviving years after diagnosis with only a modest decline in lung function, whereas others experience rapid respiratory decline and death within months. Accurate prognostication is critical to allow patients and physicians to weigh trade-offs between treatment options and observation. The ILD gender age physiology (ILD-GAP) index is a model for mortality risk prediction in patients with ILD. It was originally derived and validated as the “GAP risk prediction model” for patients with IPF alone but subsequently extended to other types of ILD (Table 2). This modified ILD-GAP index was clinically validated in a study of approximately 1200 patients with ILD.
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      Predicting survival across chronic interstitial lung disease: the ILD-GAP model.
      Table 2ILD-GAP Index
      PredictorPoints
      ILD Subtype
       IPF0
      ILD Unclassifiable ILD0
       CT-ILD or Idiopathic NSIP−2
       Chronic HP−2
      Sex
      G Female0
       Male1
      Age
      A ≤600
       61–651
       >652
      Physiology
       FVC, % predicted
      >75%0
      50%–75%1
      <50%2
      P DLCO, % Predicted
      >55%0
      36%–55%1
      ≤35%2
      Cannot perform3
      Total possible points8
      ILD, interstitial lung disease; GAP, gender age physiology; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia; FVC, forced vital capacity, DLCO, diffusion capacity for carbon monoxide; CT, computed tomography; HP, hypersensitivity pneumonitis.
      The ILD-GAP model integrates sex, age, pulmonary physiology (forced vital capacity and DLCO), and ILD subtype to provide a score ranging from 0 to 8. In patients with ILD-GAP score of 0 to 1, three-year mortality is estimated at 10%, whereas scores greater than five are associated with a predicted 3-year mortality of 75% (Table 3).
      Table 3Predicted Mortality on the Basis of ILD-GAP Score
      ILD-GAP IndexPredicted Mortality
      1 year2 years3 years
      0–13.16.610.2
      2–38.818.026.9
      4–518.235.049.2
      >533.558.474.8
      ILD, interstitial lung disease; GAP, gender age physiology.
      Before recommending treatment, a radiation oncologist may wish to consider the patient’s ILD-related survival on the basis of their ILD-GAP score. Patients with lung cancer and lower ILD-GAP scores may be better candidates for curative therapy, given their improved ILD-specific survival, whereas patients with higher ILD-GAP scores may benefit from attenuated-intensity treatments or only observation. As discussed subsequently, it is hypothesized that patients with higher ILD-GAP scores have a higher risk of radiation toxicity.

      RT and Coexisting ILD in Early-Stage Lung Cancer

      The preferred treatment of early stage NSCLC (ES-NSCLC) involves an anatomical surgical resection. Patients undergo a comprehensive assessment of lung function before any resection. Although there is variability in the current guidelines, usually patients with predicted postoperative forced expiratory volume in 1 second and predicted postoperative DLCO less than 30% are considered inoperable.
      • Brunelli A.
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      • et al.
      ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy).
      Stereotactic ablative radiotherapy (SABR) is an effective and safe alternative to resection in medically inoperable patients. RTOG 0236 revealed a good safety profile for SABR in this population with a reported risk of grade 3-4 toxicities of 13% and 4%, respectively, and no grade 5 toxicities.
      • Timmerman R.
      • Paulus R.
      • Galvin J.
      • et al.
      Stereotactic body radiation therapy for inoperable early stage lung cancer.
      Prospective clinical trials investigating the efficacy of SABR in the medically operable population are ongoing, with current evidence suggesting clinical equipoise between operation and SABR in this population.
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      • Paul M.A.
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      Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials.
      ,
      • Chen H.
      • Laba J.M.
      • Boldt R.G.
      • et al.
      Stereotactic ablative radiation therapy versus surgery in early lung cancer: a meta-analysis of propensity score studies.
      Patients with ILD are frequently deemed to be medically inoperable owing to comorbidities and poor baseline pulmonary function. If operation is not an option, treatment with SABR is generally considered to provide the best chance of local control and cure
      • Ball D.
      • Mai G.T.
      • Vinod S.
      • et al.
      Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial.
      ; however, individuals with pre-existing ILD are at higher risk of SABR-related pulmonary toxicity. Chen et al.
      • Chen H.
      • Laba J.M.
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      • et al.
      Stereotactic ablative radiation therapy versus surgery in early lung cancer: a meta-analysis of propensity score studies.
      performed a systematic review of studies reporting outcomes for patients with ILD treated with SABR for ES-NSCLC. Most studies included patients on the basis of radiographic patterns consistent with ILD. Rates of treatment-related mortality and ILD-specific toxicity (defined as grade ≥3 radiation pneumonitis or acute exacerbation of ILD) were 15.6% and 25%, respectively. Patients with a diagnosis of IPF appeared to be at increased risk. SABR-related mortality and toxicity rates in the IPF population were 33% and 71%, respectively, compared with 14% and 22% for studies including other types of ILD (p = 0.092; p = 0.01).
      Radiation dosimetric parameters were examined for possible relationships with toxicity. On subgroup analysis, in studies in which the lung volume receiving 20 Gy or more (V20) was below 6.5%, treatment-related mortality and ILD-specific toxicity were 11% and 20%, compared with 32% and 38%, respectively, in studies with V20 greater than or equal to 6.5%. Similarly, treatment-related mortality and ILD-specific toxicity were 11% and 19%, respectively, for studies reporting mean lung doses (MLD) less than 4.5 Gy, compared with 33% and 42%, respectively, when MLD was greater than or equal to 4.5 Gy. Nevertheless, there are recognized limitations in this meta-analysis, including the possibility of publication bias. For example, an unexpected toxicity may be an impetus for reporting results that may otherwise not have been published. In addition, the authors note a wide range of reported toxicity rates suggesting that treatment planning or delivery may influence observed adverse events.
      • Chen H.
      • Senan S.
      • Nossent E.J.
      • et al.
      Treatment-related toxicity in patients with early-stage non-small cell lung cancer and coexisting interstitial lung disease: a systematic review.
      A major limitation of the literature is the lack of specification of the types of ILD associated with toxicity or even the criteria used to diagnose ILD, usually done using a retrospective approach for these studies. This precludes definitive conclusions regarding the relationships between different types of ILD and outcomes; however, many of the studies classified ILD on the basis of features associated with fibrotic ILDs, including reticulation, traction bronchiectasis, and honeycombing. Given that radiation itself is an etiologic agent for lung fibrosis, it is biologically plausible that it would potentiate any underlying fibrotic disease.

      RT and Coexisting ILD in Locally Advanced Lung Cancer

      Standard treatment for patients with unresectable locally advanced NSCLC (LA-NSCLC) is concurrent chemoradiotherapy (CCRT—most often 60 Gy in 30 fractions with concurrent platinum doublet),
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      Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
      followed by adjuvant immunotherapy for 12 months.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
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      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      An individual patient data meta-analysis reported a 30% rate of symptomatic pneumonitis and a 2% risk of fatal pneumonitis in patients receiving CCRT.
      • Palma D.A.
      • Senan S.
      • Tsujino K.
      • et al.
      Predicting radiation pneumonitis after chemoradiation therapy for lung cancer: an international individual patient data meta-analysis.
      Development of radiation pneumonitis has been correlated to various dosimetric parameters, with MLD and V20 among the most often cited. Chemotherapy increases the incidence of severe radiation pneumonitis.
      • Parashar B.
      • Edwards A.
      • Mehta R.
      • et al.
      Chemotherapy significantly increases the risk of radiation pneumonitis in radiation therapy of advanced lung cancer.
      Immune checkpoint inhibitors (ICIs) have been associated with pneumonitis, leading many clinical trials to exclude patients with ILD. Published reports suggest that ICI-related pneumonitis is variable in severity and that ICIs can be considered in patients with ILD with advanced lung cancer and poor response to other lines of therapy.
      • Antonia S.J.
      • Villegas A.
      • Daniel D.
      • et al.
      Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer.
      In addition, both established ILD and more subtle ILAs have been associated with decreased overall survival in patients with LA-NSCLC regardless of treatment.
      • Nishino M.
      • Cardarella S.
      • Dahlberg S.E.
      • et al.
      Interstitial lung abnormalities in treatment-naïve advanced non-small-cell lung cancer patients are associated with shorter survival.
      This suggests a complex interplay of disease-, patient-, and treatment-related factors leading to suboptimal response and disease control.
      Several contemporaneously reported retrospective series suggest an increased risk of developing severe radiation pneumonitis or acute exacerbation of ILD after definitive chemoradiotherapy for LA-NSCLC (Table 4). Kobayashi et al.
      • Kobayashi H.
      • Naito T.
      • Omae K.
      • et al.
      Impact of interstitial lung disease classification on the development of acute exacerbation of interstitial lung disease and prognosis in patients with stage III non-small-cell lung cancer and interstitial lung disease treated with chemoradiotherapy.
      retrospectively reviewed patients with ILD receiving chemoradiotherapy for LA-NSCLC at their center. Of 37 patients, 17 (46%) developed acute exacerbation of ILD greater than or equal to grade 3 within 1 year after radiation. The incidence of acute exacerbation of ILD was lower in patients with a non-UIP pattern than in those with a UIP pattern. Patients with V20 greater than or equal to 25% had a higher rate of acute exacerbation of ILD compared with those with V20 less than 25%. Median overall survival in patients with a non-UIP and a UIP pattern was significantly different at 43.0 and 12.2 months, respectively. Overall survival in patients with a non-UIP pattern was comparable with rates reported in prospective phase III trials of patients with LA-NSCLC undergoing chemoradiotherapy. The authors suggest that a UIP pattern on CT imaging may be a major risk factor for acute exacerbation of ILD.
      • Kobayashi H.
      • Naito T.
      • Omae K.
      • et al.
      Impact of interstitial lung disease classification on the development of acute exacerbation of interstitial lung disease and prognosis in patients with stage III non-small-cell lung cancer and interstitial lung disease treated with chemoradiotherapy.
      Table 4Selected Studies Reporting Outcomes With TRT in Patients With ILD
      StudyDiagnosisILD DiagnosisDoseToxicityOutcomes
      Glick et al.
      • Glick D.
      • Lyen S.
      • Kandel S.
      • et al.
      Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival in patients treated with lung stereotactic body radiation therapy (SBRT).
      ES-NSCLCCT images reviewed for ILD by two thoracic radiologistsDependent on tumor size and location (48 Gy in four fractions most common)Grade ≥2 pneumonitis: 20.5%; grade ≥3 pneumonitis: 10.3%Median OS: 27.4 mo
      Ueki et al.
      • Ueki N.
      • Matsuo Y.
      • Togashi Y.
      • et al.
      Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer.
      ES-NSCLCHRCT images reviewed for ILD by two physiciansDependent on tumor size and location (48 Gy in four fractions most common)Grade ≥2 pneumonitis: 55.0%; grade ≥3 pneumonitis: 10.0%3-Year OS: 53.8%
      Yoshitake et al.
      • Yoshitake T.
      • Nakamura K.
      • Sasaki T.
      • et al.
      Pulmonary interstitial changes is a predictive factor for radiation pneumonitis after stereotactic body radiation therapy for lung cancer patients.
      ES-NSCLCCT images reviewed for ILD by radiologist48 Gy in four fractionsGrade ≥2 pneumonitis: 50.0%; grade ≥3 pneumonitis: 39%; grade 5 pneumonitis: 16.7%2-Year OS: 49.6%
      Higo et al.
      • Higo H.
      • Kubo T.
      • Makimoto S.
      • et al.
      Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities.
      LA-NSCLCHRCT images reviewed for ILD by pulmonologist and two thoracic radiologistsTotal dose: 40–50 Gy with CCT most commonGrade ≥2 pneumonitis: 36%; grade ≥3: pneumonitis: 8%2-Year OS: 56.8%
      Kobayashi et al.
      • Kobayashi H.
      • Naito T.
      • Omae K.
      • et al.
      Impact of interstitial lung disease classification on the development of acute exacerbation of interstitial lung disease and prognosis in patients with stage III non-small-cell lung cancer and interstitial lung disease treated with chemoradiotherapy.
      LA-NSCLCCT images reviewed for ILD by two pulmonologists and two thoracic radiologists56 Gy with CCT most commonGrade ≥3 AE ILD: 46%; grade 5 AE ILD: 2.7%Median OS: 34.6 mo
      ILD, interstitial lung disease; CT, computed tomography; HRCT, high-resolution computed tomography; TRT, thoracic radiotherapy; ES-NSCLC, early-stage NSCLC; LA-NSCLC, locally advanced NSCLC; OS, overall survival; AE, acute exacerbation; CCT, concurrent chemotherapy..
      Higo et al.
      • Higo H.
      • Kubo T.
      • Makimoto S.
      • et al.
      Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities.
      retrospectively reviewed their experience with patients receiving chemoradiotherapy for LA-NSCLC. Of 77 patients, ILAs were present in 25 (32.5%), indeterminate in 24 (31%), and not present in 28 (36%). Notably, no patients were found to have honeycombing on HRCT, suggesting no patients in the series had a UIP pattern. Severe radiation pneumonitis (grade ≥2) was identified in 36% of patients with ILA. On multivariable analysis, V20 greater than 25% was a risk factor for severe radiation pneumonitis, but ILA was not. Two-year survival rates (56.8% and 74.1% for patients with and without ILA, respectively) were not significantly different.
      • Higo H.
      • Kubo T.
      • Makimoto S.
      • et al.
      Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities.

      Should We Treat or Not?

      When employing TRT in a patient with ILD, a comprehensive pretreatment risk assessment, informed consent discussion, and strict planning criteria are imperative. At the time of consultation, patients should be reviewed for prior diagnoses, symptoms, or signs suggestive of ILD. CT images should be carefully inspected to screen for subclinical ILAs. Patients with ILA should be referred to a pulmonologist for a comprehensive assessment to identify a potential cause and for optimization and comanagement. Determining a specific ILD subtype may allow for risk mitigation strategies such as avoidance of ongoing exposure in patients with hypersensitivity pneumonitis.
      Recommending treatment for NSCLC in a patient with ILD is a complex decision and requires clinical integration of patient-, ILD-, and cancer-specific factors. Use of the ILD-GAP index may allow for an informed discussion about the risk of death from NSCLC versus the competing ILD-related mortality calculated for that individual patient. Any treatment decision should be individualized for a patient’s overall clinical situation and goals of care. Careful and robust discussions surrounding expected risks and benefits are necessary when obtaining informed consent. Patients with incidentally detected lung cancers (e.g., lung cancers found during routine imaging done for ILD) or cancers arising from ground-glass opacities and adenocarcinoma in situ may have a more indolent course, altering the risk-to-benefit ratio.

      ES-NSCLC

      Patients with untreated ES-NSCLC have a 60% to 70% risk of mortality at 1 year and a median overall survival of 10 to 12 months.
      • Palma D.
      • Visser O.
      • Lagerwaard F.J.
      • Belderbos J.
      • Slotman B.J.
      • Senan S.
      Impact of introducing stereotactic lung radiotherapy for elderly patients with stage I non-small-cell lung cancer: a population-based time-trend analysis.
      • Chadha A.S.
      • Ganti A.K.
      • Sohi J.S.
      • Sahmoun A.E.
      • Mehdi S.A.
      Survival in untreated early stage non-small cell lung cancer.
      • Rosen J.E.
      • Keshava H.B.
      • Yao X.
      • Kim A.W.
      • Detterbeck F.C.
      • Boffa D.J.
      The natural history of operable non-small cell lung cancer in the National Cancer Database.
      The patient is therefore presented with the dilemma of accepting a treatment that may be associated with perhaps a 10% to 20% risk of death versus forgoing what would be their best option of local control if operation is contraindicated. Given that patients with an ILD-GAP index greater than five have a predicted 1-year mortality of 33%, this would suggest that lung cancer, if left untreated, is a larger threat to mortality than ILD, even in patients with severe ILD. In such a situation, SABR may be considered despite its potential complications. Alternatives to SABR include radiofrequency ablation and other ablative techniques, but these are associated with inferior local control and have toxicity risks. In the systematic review by Chen et al.
      • Chen H.
      • Laba J.M.
      • Boldt R.G.
      • et al.
      Stereotactic ablative radiation therapy versus surgery in early lung cancer: a meta-analysis of propensity score studies.
      Radiofrequency ablation-related mortality and ILD-specific toxicity were 8.7% and 25%, respectively; direct comparison of these outcomes with the SABR outcomes is hampered by confounders, including baseline patient fitness and tumor size, which may have driven treatment selection.
      • Chen H.
      • Senan S.
      • Nossent E.J.
      • et al.
      Treatment-related toxicity in patients with early-stage non-small cell lung cancer and coexisting interstitial lung disease: a systematic review.
      If electing to treat with SABR, there is very little evidence to suggest the optimal radiation dose and fractionation. Although several dose fractionations are likely acceptable, one attractive option is a dose of 50 Gy in five fractions, which is the starting dose of a current trial of SABR in patients with ILD called ASPIRE-ILD, discussed subsequently. This fractionation was chosen for the trial because it is a slight de-escalation compared with standardly used fractionations, while still maintaining a biologically effective dose of 100 in accordance with accepted standards for radical treatment. Strict dosimetric constraints of V20 smaller than or equal to 6.5% and MLD smaller than or equal to 4.5 Gy should be adhered to wherever possible. Plans should maintain a high degree of conformality with careful attention paid to the ratio of prescription isodose volume to planning target volume (PTV) (R100%), ratio of 50% prescription isodose volume to PTV (R50%), and maximal dose 2 cm from the PTV in any direction as a percentage of prescription dose (D 2 cm). Detailed prescription parameters are available in the published ASPIRE-ILD clinical trial protocol (ASPIRE-ILD, NCT03485378), but similar to most SABR trials, they allow the dose prescription to correspond to an isodose line between 60% and 90% of the dose at the normalization point. Patients should be appropriately counseled on an approximately 20% risk of ILD-related toxicity and a 10% risk of treatment-related mortality.

      LA-NSCLC

      Patients with LA-NSCLC are at high risk of death from untreated NSCLC in the near term, and overall survival in this population is limited, even with radical treatment.
      • Bradley J.D.
      • Paulus R.
      • Komaki R.
      • et al.
      Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.
      ,
      • Wao H.
      • Mhaskar R.
      • Kumar A.
      • Miladinovic B.
      • Djulbegovic B.
      Survival of patients with non-small cell lung cancer without treatment: a systematic review and meta-analysis.
      On balance, the risk of death from LA-NSCLC likely outweighs the risk of death from ILD but treatment paradigms are generally more intensive and morbid than for ES-NSCLC, risking severe toxicity in patients with ILD. Any treatment decision should be individualized for a patient’s overall clinical situation and goals of care.
      Studies examining the administration of definitive CCRT in this population are sparse but suggest that treatment can be safely delivered. Appropriate radiotherapy schedules for this population include single-fraction, high-dose palliative, or radical fractionations, including chemotherapy. When considering chemotherapy, it may be reasonable to avoid taxane-containing regimens. Evidence suggests that patients with pre-existing ILD are at an increased risk of pneumonitis when treated with paclitaxel or docetaxel.
      • Watanabe N.
      • Niho S.
      • Kirita K.
      • et al.
      Second-line docetaxel for patients with platinum-refractory advanced non-small cell lung cancer and interstitial pneumonia.
      Given the risk of ICI-induced pneumonitis and limited evidence, immunotherapy (adjuvantly or otherwise) should not be considered standard treatment in this population but may be considered after careful discussion of risks and benefits with the patient. Patients with pre-existing autoimmune disease have generally been excluded from immunotherapy trials. Nevertheless, very limited emerging data suggest that immune-related adverse event rates are similar in such patients. Further research is needed, including larger studies and studies specific to patients with ILD, before firm conclusions can be drawn.
      • Cortellini A.
      • Buti S.
      • Santini D.
      • et al.
      Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study.
      The risk of severe side effects with CCRT is the highest in patients with a diagnosis of IPF, and extreme caution should be utilized when planning treatment in this population. Definitive CCRT in patients with IPF should be reserved for very select cases, and a thorough understanding of the risk of treatment-related mortality should be included in a shared decision-making process. A dosimetric constraint of V20 smaller than or equal to 25% should be adhered to wherever possible for all patients undergoing TRT for LA-NSCLC.
      • Kobayashi H.
      • Naito T.
      • Omae K.
      • et al.
      Impact of interstitial lung disease classification on the development of acute exacerbation of interstitial lung disease and prognosis in patients with stage III non-small-cell lung cancer and interstitial lung disease treated with chemoradiotherapy.
      ,
      • Higo H.
      • Kubo T.
      • Makimoto S.
      • et al.
      Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities.

      Metastatic Disease

      Patients with metastatic NSCLC have poor outcomes with limited overall survival. Given the risks of toxicity, TRT for patients with metastatic NSCLC and ILD should be offered only in select cases in which treatment is expected to provide symptom relief or prevent disease-related morbidity. Attenuated-intensity radiation schedules should be employed with selection of the exact fractionation on the basis of the treatment objectives. For example, tumor-related hemorrhage may be treated with a single fraction rather than a prolonged course of treatment. Radiation dose to the uninvolved lung and surrounding structures should be maintained as low as reasonably achievable.
      Patients with evidence of intrathoracic metastatic disease from extrathoracic primaries may be candidates for palliative radiotherapy along either an oligometastatic or symptom-control paradigm. In patients with pre-existing ILD, appropriate measures should be taken as previously discussed to quantify and qualify patient-specific risks of radiation-related toxicity or acute exacerbation of ILD before recommending treatment. Treatment recommendations should balance patient-specific risks, goals of care, and the potential for intrathoracic disease control or symptom relief. Appropriate dose and fractionation schedules vary on the basis of patient- and disease-specific factors and could include conventionally fractionated or stereotactic treatments. A robust discussion surrounding the risks and benefits of treatment is imperative when obtaining informed consent.

      Future Directions

      There remains a lack of high-quality evidence to guide the treatment of NSCLC in patients with ILD. A prospective phase II study of patients with coexisting ILD and early stage NSCLC (ASPIRE-ILD, NCT03485378) is investigating the safety and efficacy of SABR in this population. Patients enrolled in the trial are stratified by ILD-GAP score, which is hypothesized to predict toxicity risk, and therefore, the trial will allow for assessment of the ILD-GAP score as a predictor of toxicity. ASPIRE-ILD assigns all patients to a dose of 50 Gy in five fractions, and the primary end point is overall survival compared with historical controls. If high toxicity rates are encountered, ASPIRE-ILD includes prespecified de-escalation measures where the dose can be reduced, although de-escalation is likely to reduce local control.
      Treatment paradigms in IPF and other types of ILD continue to evolve. The increasing use of antifibrotic agents or other therapies may shift the risk-to-benefit ratio of treatment for NSCLC in this patient population. In addition, further work is urgently needed to identify and validate novel strategies to decrease pulmonary toxicity.

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