2025+AIRO共识建议：肺癌和间质性肺疾病患者的放疗

A B S T R A C T

Aim: Interstitial lung diseases(ILD) are a group of disorders affecting the lung parenchyma. ILD patients have a higher risk of lung cancer and worse prognosis, with increased susceptibility to radiotherapy (RT)-related tox-icities due to ILD exacerbations. There are no clear guidelines for managing lung cancer patients with ILD un-dergoing RT, alone or with systemic therapies. This work aims to establish a consensus on ILD assessment,patient selection, risk/benefit analysis, and clinical management for those eligible for thoracic RT.

Methods: Using the Estimate-Talk-Estimate method, a board of experts (4 radiation oncologists, 2 pneumologists,1 radiologist, 1 medical oncologist) identified key items. Each expert drafted statements for these items, and an extended panel of 24 experts (12 radiation oncologists, 6 pneumologists, 3 radiologists, 3 medical oncologists)rated the statements on a 9-point scale. Consensus was defined as a median score ≥ 7.

NSCLC

ILD

RT

CHT

Immunotherapy

AIRO

<EndOfPara>pulmonary function tests (PFTs) and an impaired gas exchange. ILD can be categorized into fibrotic and non-fibrotic types [1].

Fibrotic variants include idiopathic pulmonary fibrosis(IPF),con-nective tissue disease-associated ILD (CTD-ILD), idiopathic non-specific interstitial pneumonia, hypersensitivity pneumonitis, drug-induced

1.Introduction

Interstitial lung disease(ILD) encompasses a diverse array of con-ditions characterized by inflammation and fibrosis diffusely affecting pulmonary tissue. These conditions lead to a restrictive pattern in

P. Borghetti et al.

$$\text{Lung Cancer 210(2025) 108807}$$

pneumoconiosis, and unclassifiable ILD. Non-fibrotic ILD is classified as inflammatory, multimodular, and cystic[1,2].

Approximately 5-10% of lung cancer cases also involve ILD, wors-ening prognosis and increasing treatment-related toxicity risks[3] These patients have a higher risk of developing lung cancer and show a worse prognosis than patients without ILD. Furthermore, ILDs make the pa-tient more prone to developing treatment-related toxicity, due to exac-erbations of ILD itself[4,5]. For patients with unresectable stage III non-small cell lung cancer(NSCLC), definitive concurrent chemo-radiotherapy(CRT) followed by immunotherapy(IO) as maintenance is the standard treatment[6,7]. In inoperable early-stage NSCLC, stereo-tactic body radiotherapy(SBRT) is preferred, with data supporting its use in operable cases[8,9]. SBRT is also expanding in oligometastatic disease, often combined with systemic therapies.[10,11].

Novel therapies increasingly focus on integrating radiotherapy(RT)with chemotherapy, immunotherapy, and targeted therapies. This approach complicates the management of patients with ILD, as there is a growing need for more data on the safety of combined treatments, along with clearer guidelines and recommendations. Managing patients with ILD and lung cancer requires collaboration with a team of pneumologists and radiologists specialized in ILD diagnosis and treatment. This multidisciplinary approach allows for better evaluation of baseline lung conditions and optimization of systemic therapies before combined treatments. Currently, there are no specific guidelines for assessing,treating, and managing toxicities in these patients. This Delphi consensus aims to offer valuable recommendations for their management.

2. Material and methods

The use of the Estimate-Talk-Estimate(ETE) method or“mini-Del-phi”[12,13] is a way for reaching consensus within a selected group of experts. It combines a nominal group activity restricting verbal inter-action with face-to-face interaction processes. Firstly, a multidisci-plinary board(MB) of 4 radiation oncologists, two pneumologists, one medical oncologist, and one radiologist individually generated some points of interest(items) deserved to be explored and discussed. A senior clinical epidemiologist expert in gaining consensus among stakeholders(facilitator) then harmonized these items, which were then presented to the MB. During the first meeting, harmonized items were discussed face-to-face to reach an agreement between the facilitator's work and the experts' opinions. Afterward, clinicians finalized ten items to draft one or more statements for each item individually. This process resulted in a certain number of statements.

In the second and last face-to-face meeting, the MB and the facilitator reviewed and further discussed the harmonized statements, reaching a

final version of 16 statements.

The 16 statements were then delivered through an invitation, sent by e-mail, to a panel of experts(PE) composed of 12(50%) radiation on-cologists, 6(25%) pneumologists, 3(12.5%) medical oncologists and 3(12.5%) radiologists, all of them with extensive experiences in the management of lung cancer and ILD. PE components expressed their agreement level on each statement using the RAND 9-point scale(ranging from 1= entirely disagree to 9= entirely agree). Fig. 1 de-scribes the consensus process workflow.

Consensus was reached when a statement had the median score was≥7 without disagreement, according to the RAND/UCLA Appropriate-ness Method User's Manual[14].

The members of the MB were selected among physicians in Italy who are mainly dedicated to thoracic oncology, whether as radiation on-cologists, medical oncologists, pulmonologists or radiologists. The se-lection was carried out in compliance with the hospital and university background, as well as a balanced representation of males and females and origins from different geographical areas of the country. The same criteria were generally adopted for the selection of the PE. Due to the nature of the consensus technique, the MB and PE sought the assistance of an external supporting figure to provide material preparation,meeting facilitation, and scientific and methodological accuracy.

An expert external radiation oncologist, independent from the consensus procedure, then reviewed the final results before the final approval from AIRO scientific committee.

3. Results

All statements reached agreement in the first round of voting, being approved with a median score>= 7. Table 1 summarizes all the items and statements produced by the MB and the relative medians and range of the votes by the EP.

3.1. ITEM A. Role of High-Resolution Computed Tomography(HRCT) in ILD

Statement1. HRCT of the chest represents the most effective non-invasive diagnostic method for the detection and pattern classification of ILD at diagnosis and to define the risk of ILD progression and radiation toxicity during follow-up.

Statement 2. The radiology report should include information about the HRCT pattern of ILD and clearly define the presence of fibrotic changes and findings indicative of usual interstitial pneumonia(UIP)pattern because radiation toxicity is more common in fibrotic ILD,specifically in those with a UIP pattern.

Radiological imaging is a vital tool for establishing a confident

 Fig.1. Project workflow.

P. Borghetti et al.

$$\text{Lung Cancer 210(2025) 108807}$$

Table 1

Item and statement voted by the EP with median and range of the consensus reached.(HRCT: High-Resolution Computed Tomography,ILD: Interstitial Lung Disease, UIP: Usual Interstitial Pneumonia, RT: Radiation Therapy, MLD: Mean Lung Dose, TKI: Tyrosine Kinase Inhibitors, ADC: Antibody Drug-Conjugated,MDT: Multidisciplinary Team).

|Item|Statement|Median (range)| |---|---|---| |A. Role of HRCT in ILD|1.HRCT of the chest represents the most effective non-invasive diagnostic method for the detection and pattern classification of ILD at diagnosis and to define the risk of ILD progression and radiation toxicity during follow- up. 2. The radiology report should include information about the HRCT pattern of ILD and clearly define the presence of fibrotic changes and findings indicative of UIP pattern because radiation toxicity is more common in fibrotic ILD, specifically in those with a UIP pattern.|9(6-9)| |B. Risk stratification of exacerbation/progression of interstitial disease|3. Considering the greater pulmonary toxicity RT in patients affected by ILD, the indication to RT should be evaluated in a multidisciplinary setting and should be dependent on a thorough assessment of the risk of exacerbation and progression by the pneumologists.|9(7-9)| |C. Definition of the risk of RT-related toxicity|4.RT complications in patients with ILD depend, in addition to dosimetric factors, on patient characteristics, disease location, respiratory function, premedication and concomitant therapies. 5. The method of quantifying the risk of toxicity, regardless of clinically validated prognostic indices, cannot overlook individual assessment|9(7-9)| |D. Prediction of RT complications|6. In patients eligible for SBRT, predictive dosimetric factors for a higher incidence of toxicity include mean dose(MLD), V5, V10, and V20 (for bilateral lungs). 7. In patients eligible for non-stereotactic radical RT, predictive dosimetric factors for increased toxicity include mean dose(MLD), V5, V20(for bilateral lungs). 8. The prevention of complications of RT for in patients with ILD might be carried out by means of antifibrotic therapy(progressive fibrosing disease) or corticosteroids, immunosuppressive and biologic agents(disease with predominant inflammatory component). 9.SBRT can be considered in patients with ILD only after careful evaluation of the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to respiratory comorbidity, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, (including fatal ones) are evaluated. 10. Chemoradiotherapy in patients with locally advanced disease and ILD should be proposed only after careful assessment of the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to a respiratory comorbidity, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, (including fatal ones) are evaluated. 9.Chemoradiotherapy in patients with locally advanced disease and ILD should be proposed only after careful assessment of the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to a respiratory comorbidity, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the including fatal ones) are evaluated. 10.Chemoradiotherapy in patients with locally advanced disease and ILD should be proposed only after careful assessment of the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to a respiratory comorbidity, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the including fatal ones) are evaluated. 10.Chemoradiotherapy in patients with locally advanced disease and ILD should be proposed only after careful assessment of the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to a respiratory comorbidity, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the including fatal ones) are evaluated. 10.Chemoradiotherapy in patients with locally advanced disease and ILD should be proposed only after careful assessment of the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to a regulatory comorbidity, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the including fatal ones) are evaluated. 10.Chemoradiotherapy in patients with locally advanced disease and ILD should be proposed only after careful assessment of the benefit/harm ratio with the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to a regulatory comorbidity, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the life expectancy of the patient, the presenting characteristics of the lesion to be treated, the possible toxicities, the life at the level of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the full of the||

Table 1(continued)

|Item|Statement|Median| |---|---|---| ||within a multidisciplinary context in which the type of ILD, the presence of symptoms related to respiratory comorbidity, the patient's life expectancy, the presentation characteristics of the lesion to be treated, the possible toxicities(including fatal ones) are evaluated. However, the use of the highest technological standards is essential.|8.5(6-9)| |H.RT combined with systemic treatment and ILD|11. In case of combined treatment with chemotherapy and RT in NSCLC patients with ILD, cytotoxic drugs that could be considered are cisplatin, carboplatin, vinorebine, weekly(nab-) paclitaxel. Gemcitabine and docetaxel should be avoided 12. Maintenance immunotherapy after curative chemo-radiotherapy should not be always excluded upfront in patients with suspected ILD., Immunotherapy could be an option in patients with advanced NSCLC and concomitant ILD with a close monitoring of respiratory function. 13. Thoracic RT for patients with ILD, treated with targeted therapy (TKI or ADC), is limited from the risk of pneumonitis related to these treatments.|9(6-9) 9(6-9)| |I. Follow-up after RT treatment with or without systemic treatment|14. The clinical and radiological follow-up of patients affected by ILD undergoing radiotherapy should be carried out in centres with experience and within a multidisciplinary context.|9(7-9) 9(7-9)| |J. Role of MDT|15. The follow-up should also be personalized to identify any potential radiation toxicity early on. 16. Multidisciplinary team should identify specified“tailored” journeys regarding the initial evaluation, treatment and monitoring of patients affected by lung cancer and ILD, especially when candidates to RT.|9(5-9) 9(5-9)|

diagnosis of ILD. Chest radiography is the first-line radiological test for identifying parenchymal lung changes. However, chest radiography has inadequate sensitivity in assessing interstitial lung abnormalities(ILA),specifically in mild or early-stage disease[15,16]. Therefore, to opti-mally evaluate ILA, HRCT is considered the most effective non-invasive diagnostic method for the detection and pattern classification of a sus-pected ILD[15,16]. This technique provides morphological images capable of depicting with high accuracy the fine details of lung paren-chyma and the typical CT findings of ILD(i.e., ground-glass opacities,reticulation, architectural distortion, traction bronchiectasis/bronchi-ectasis, and honeycombing)[15,16]. The accurate information provided by HRCT requires correlation with clinical/functional/laboratory data to reach a confident diagnosis of a newly detected ILD.

Honeycombing and traction bronchiectasis/bronchiectasis are the most specific CT findings of pulmonary fibrosis; both are the key features of the UIP pattern(typical/probable) and can predict ILD progression.While traction bronchiectasis/bronchiectasis represents the irreversible and irregular dilatation of airways due to fibrosis in the surrounding parenchyma, honeycombing represents the end-stage of pulmonary fibrosis. On CT images, honeycombing appears as subpleural clustered cystic spaces, usually 10 mm or less in diameter. In contrast, traction

P. Borghetti et al.

Lung Cancer 210(2025) 108807

bronchoietacts/bronchiectasis appears as irregular bronchial or bron-chiolar dilatation with a varicose/corkscrew shape [17-19].

According to the literature data, fibrotic changes and CT findings indicative of UIP patterns(typical/probable), such as honeycombing and traction bronchiectasis/bronchiectasis, are associated with an increased risk of radiation toxicity. Therefore, in cases of newly detected ILD, the HRCT report should distinguish between fibrotic versus non-fibrotic ILD and between UIP and non-UIP patterns. This information is crucial in the risk stratification of patients undergoing radiation treat-ment[4,20].

3.2. ITEM B. Risk stratification of exacerbation/progression of interstitial disease

Statement 3. Considering the greater pulmonary toxicity RT in pa-tients affected by ILD, the indication to RT should be evaluated in a multidisciplinary setting and should be dependent on a thorough assessment of the risk of exacerbation and progression by the pneumologists.

It is established that thoracic RT may result in lung injury[20].Pulmonary damage consists of two stages: an acute inflammatory phase(radiation pneumonitis) and a late fibrotic phase(radiation-induced pulmonary fibrosis)[20] which consists in persistent inflammation, with deposition of collagen matrix and formation of scar tissue[21].

The presence of an ILD represents a known factor of higher risk of development of radiation-induced lung injury, which may also appear as an ILD exacerbation[22-24].

Patients with a large extension of ILD at HRCT, especially in the presence of fibrotic changes such as honey combing, have a higher risk of severe(high-grade) radiation-induced lung injury[25-27], so the presence of an extended ILD should be considered a potential contra-indication to pulmonary RT. The impact of the ILD on lung injury de-pends on the severity of the ILD itself[23-25]. Pragmatically, the overall extent and distribution of fibrosis and the location of the target in relation to the areas of greatest fibrotic involvement could be useful information to establish a different probability and severity of risk of developing RT toxicity. This means that radiation oncologists, radiolo-gists and pneumologists should share all information to best stratify the risk of exacerbation or progression of ILD.

The ILDs are a vast group of disorders very heterogeneous in etiol-ogy, clinical behavior, prognosis, and effective treatment possibilities.Tools for assessing the severity of ILDs are many radiological(HRCT),functional(PFTs, 6-minute walking test(6MWT), blood gas), and clin-ical(medical history, dyspnea scales, physical examination). The pre-cision of diagnosis(i.e., idiopathic pulmonary fibrosis has a worse outcome than other ILDs), the previous disease behavior, and the response to treatment are all essential elements for a prognostic judg-ment personalized and calibrated for each individual patient[2,18,26].All these items contribute to the assessment of the risk of pulmonary toxicity in patients with ILD candidates for RT.

3.3. ITEM C. Definition of the risk of RT-related toxicity

Statement 4. RT complications in patients with ILD depend, in addition to dosimetric factors, on patient characteristics, disease loca-tion, respiratory function, premedication and concomitant therapies.

Statement 5. The method of quantifying the risk of toxicity,regardless of clinically validated prognostic indices, cannot overlook individual assessment.

Defining the risk of radiation toxicity in patients with ILD depends on three essential points: the type of ILDs, the general and respiratory status of the patient, and the treatment to be applied.

ILDs are the clinical forms of lung diseases at higher risk, and among these, idiopathic pulmonary fibrosis(IPF) must be distinguished from all other interstitial patterns[3,27].

This differentiation is primarily achieved through radiologic

imaging. HRCT has potentially an important diagnostic role. An expe-tienced radiologist may identify fibrotic interstitial diseases with UIP patterns from non-UIP patterns. The UIP pattern is associated with a higher risk of developing lung cancer compared to other forms, with an incidence 10-20% higher than in patients without pulmonary intersti-tial disease[18,28]. More recently, reporting early interstitial alterations(ILP) has also been recommended because they are associated with a potentially increased risk of toxicity.

A disadvantage in interpreting HRCT for early-stage malignant nodules can be due to the differential diagnosis between the presence of a new nodule and focal fibrosis areas[18,29].

Biochemical and endoscopic evaluation should complete the diag-nostic phase and should be associated with broncho-alveolar lavage(BAL) and any biopsies or cryo-biopsies to better define the case[27].

The patient's medical and professional history, as well as smoking history, are essential in defining the risk of toxicities, as well as clinical objectivity, particularly the presence of Velcro crackles(high correlation with UIP pattern). Cigarete smoking is considered a risk factor in the development of idiopathic pulmonary fibrosis. However, it is unclear how the trigger for fibrose differentiation occurs compared to the evolution towards emphysema in smokers. Combined forms of fibrosis/emphysema(CPFE) are often found[30].

The Gender, Age, Physiology Index(GAP Index multidimensional)has been proposed as a scoring tool to predict mortality risk in patients with IPF[31]. Scores above five are associated with a 33% chance of survival at 12 months. However, the GAP Index has limitations: the parameters for respiratory functional evaluation are represented only by forced vital capacity(FVC) and diffusing capacity(DLCO). It has weak predictive ability in fibroosing patterns secondary to connective tissue diseases[32,33] and does not consider essential clinical parameters such as PaO2 values and the 6MWT. Multidimensional expansion, for example, associated with the Charlson Comorbidity Index(ILD-GAPC),can be a corrective factor, but currently, few studies mainly concern Asian populations[34].

Therefore, discussing individual cases in a multidisciplinary meeting composed of experienced specialists confident in managing currently available antifibric drugs [35] is considered essential nowadays, even though there is currently no evidence of protective efficacy during RT.Few studies have been produced exclusively for patients eligible for surgery in the early stages of neoplasia [36], where protective efficacy is still demonstrated.

Finally in early-stage NSCLC, SBRT can spare surrounding healthy tissue with a reduction in damage compared to the locally advanced disease. However, it must be reiterated that the mortality rate in this population correlates both with the presence of UIP patterns and with the doses of RT administered, with a high risk of mortality[37].

In patients with locally advanced disease, chemotherapy and immunotherapy may increase the risk of radiation pneumonia. This event, in the course of fibrosing ILD, affects up to 46% of patients with pneumonia grades even higher than grade 3 within 12 months of the last application. The course in this subgroup of patients is characterized by a higher risk of“In-Hospital” mortality[37].

Patients with lung cancer and ILD are at higher risk of severe adverse events, especially if subjected to combined treatments in stage III unresectable NSCLC. It is undeniable that the UIP pattern represents the most significant obstacle both in terms of toxicity and survival, also attesting to the worst objective responses compared to patients with non-UIP ILD[24].

3.4. ITEM D. Prediction of RT complications

Statement

Statement 6. In patients eligible for SBRT, predictive dosimetric factors for a higher incidence of toxicity include mean dose(MLD), V5,V10, and V20(for bilateral lungs).

Statement 7. In patients eligible for non-stereotactic radical RT,

P. Borghetti et al.

Lung Cancer 210(2025) 108807

predictive dosimetric factors for increased toxicity include mean dose(MLD), V5, and V20(for bilateral lungs).

In patients affected by ILD, thoracic RT can be burdened by severe or even fatal radiation pneumonitis(RP)[20].

In patients with early-stage lung cancer treated with SBRT, dosi-metric predictive factors are mean dose(MLD= Mean Lung Dose) and V doses(such as V5, V10, and V20) [38].

A recent review analysed 3056 records and 50 journal articles. V20$>6.5\%$ and mean lung dose(MLD) $>$ 4.5 Gy were associated with 32%and 33% mortality, respectively. V20Gy $<$ 6.5% and MLD less or equal to 4.5 Gy were associated with a mortality of about 10%[39].

Yoshitake et al. analyzed 260 consecutive patients with primary lung cancer treated with SBRT. Grade 2 or higher RP was observed in 9(50.0%) patients with interstitial changes(IC) and 14(6.7%) in the non-IC group, respectively. MLD< 4 Gy, V5< 18%, and V10< 12% were recommended to reduce toxicity[40].

ASPIRE-ILD-was a single-arm Phase II prospective trial[41] specif-ically designed to evaluate the efficacy and safety of SBRT for NSCLC in patients with co-existing ILD. The starting SBRT dose is 50 Gy in 5 fractions every other day(biologically effective: 100 Gy10 or 217 Gy3).Still, the radiation dose can be de-escalated twice to 50 Gy in 10 frac-tions daily(75 Gy10 or 133 Gy3) and 45 Gy in 15 fractions daily(58 Gy10 or 90 Gy3). This study recognized the role of the"Complementary Vol-ume," i.e., a critical volume for both lungs of 1500 cc not receiving more than 12.5 Gy.

Table 2 summarizes the dose constraints for SBRT and normo-fractionated RT in patients with and without ILD. In radical non-stereotactic RT treatments, the dosistic predictive factors for lung toxicity are mean dose(MLD= Mean Lung Dose), V5, and V20.

Li et al. retrospectively analysed 87 patients with subclinical ILD treated with IMRT with a prescription dose≥ 50 Gy, with or without concurrent chemotherapy. Incidence of≥ G2 and≥ G3 RP at one year was 51.0% and 20.9%, respectively. MLD> 12 Gy was significant risk factor for G2 or more severe RP and V5> 50%[42].

Higo et al. analysed 77 patients with ILA. Radiation pneumonitis≥G2 occurred in 36.0%; multivariate analysis showed that V20> 25% was a risk factor for severe radiation pneumonitis[43].

In a recent study, 113 patients who received definitive CRT and consolidative durvalumab were analysed. Durvalumab was dis-continued due to interstitial pneumonia in 15 patients(1.3%). MLD>12 Gy and V20>25% were predictors of lung toxicity in patients with ILD treated with standard therapy[44].

3.5. ITEM E. Prevention of RT complications

Statement 8. The prevention of complications of RT for in patients

Table 2

Dose constraint in SBRT and normofractionated RT in patients with and without ILD.(MLD: Mean Lung Dose; V5: Volume of lung receiving 5 Gy; V10: Volume of lung receiving 10 Gy; V20: Volume of lung receiving 20 Gy; CV12.5: volume of tissue receiving the 12.5 Gy or less).

|DOSE constraints IN SBRT|Dose constraints in normofractionated RT||||| |---|---|---|---|---|---| ||ILD|Non-ILD|ILD|Non-ILD|| |MLD[38]||<4.5 Gyg|<8Gy[4]|<4.5 Gyg|<12Gy| |V20[38]||<4 Gyg<6.5%|<10% Optimal [4]|<6.5|V20< 25%| |V10[39]||<12%|$\begin{array}{c}\\\\\\\\\end{array}$|<12%|<50%| |V5[39]||<18%|$-$|<18%|$-$| |CV12.5(complementary volume)[41]||150%%||||

with ILD might be carried out by means of antifibrotic therapy(pro-gressive fibrosing disease) or corticosteroids, immunosuppressive and biologic agents(disease with predominant inflammatory component).

ILDs may be characterized by a variable degree of inflammation and fibrosis; both components may be present as dominant or exclusive features. Actually, in ILDs, RT for lung cancer may be an enhancing factor for acute exacerbation[22]. The main fibrotic ILD is IPF, a pro-gressive disease with poor prognosis. Other ILDs may have the same(progressive) course with similar outcomes, showing progressive pul-monary fibrosis(PPF)[27]. Two drugs(pirfenidone and nintedanib) are the mainstay for the treatment of IPF, while only nintedanib is approved for the treatment of PPF. These agents lower the risk of acute exacer-bation of IPF[45-51] and PPF[52].

In murine models, treatment with pirfenidone and nintedanib re-duces the incidence of radiation-induced pulmonary inflammation and fibrosis by inhibiting the production of chemokines and molecular pathways of inflammation and fibrogenesis[55-57].

Instead, the course of ILDs with an inflammatory component(e.g.,hypersensitivity pneumonitis, CTD-ILDs) may be characterized by acute exacerbations, likewise, IPF, although more rarely[53-57]. The treat-ment of exacerbations relies on high dose immunomodulant drugs(corticosteroids, immunoppressants, rituximab), which are often the primary treatment of the underlying disease, unlike IPF[55-58]. In CTD-ILDs, a baseline immunosuppressive treatment may reduce the risk of exacerbation, positively impacting the prognosis[58].

The maintenance and optimization of the baseline treatment with Nintedanib and pirfenidone may play a vital role in the reduction of the risk of RT-induced exacerbations[22].

3.6. ITEM F. SBRT for early-stage lung cancer and ILD

Statement 9. SBRT can be considered in patients with ILD only after careful evaluation of the benefit/harm ratio within a multidisciplinary context in which the type of ILD, the presence of symptoms related to respiratory comorbidity, the life expectancy of the patient, the pre-senting characteristics of the lesion to be treated, the possible toxicities,(including fatal ones) are evaluated.

SBRT for early-stage lung cancer is the standard treatment for inoperable patients. The presence of ILD combined with lower pulmo-nary function results in a typical condition of unfitness for surgery. SBRT is an effective treatment option when delivering an ablative dose,reaching a biologically equivalent dose higher than 100 Gy[59]. The impact on survival for stage I-II lung cancer patients and IPF is contro-versial. Kim et al. showed that combined pulmonary fibrosis and radical RT, or SBRT, was associated with poorer overall survival(OS)[60]. On the other hand, three studies in the same clinical setting did not show a statistically significant difference in PFS or OS, regardless of whether they were patients with ILD or not[25,61,62] However, an increased toxicity rate could be expected for these patients. In the systematic re-view by Saha et al., the median incidence of RP for SBRT was 32%(range 19-55%),11.9%(range 8-38.9%),and 6.25%(range 0-60%)for grade≥ 2,3 and 5, respectively. Severe pneumonitis(≥ G3) was more common in the presence of UIP pattern or IPF and when patients had a smoking history and low FVC and FEV1 at the pre-treatment PFTs[20]. Lung toxicity rates reported in a series of patients treated with magnetic resonance-guided-RT or particle beam RT are promising, but limited evidences are actually available.

3.7. ITEM G.RT for locally advanced disease and ILD

Statement 10. CRT in patients with locally advanced disease and ILD should be proposed only after careful assessment of the benefit/harm ratio within a multidisciplinary context in which the type of ILD,the presence of symptoms related to respiratory comorbidity, the pa-tient's life expectancy, the presentation characteristics of the lesion to be treated, the possible toxicities(including fatal ones) are evaluated.

P. Borghetti et al.

$$\text{Lung Cancer 210(2025) 108807}$$

However, the use of the highest technological standards is essential.

Unresectable stage III NSCLC and limited stage small cell lung cancer(LS-SCLC) benefit from concurrent CRT as radical treatment[6,63]. The advent of immunotherapy as maintenance improves survival in unre-sectable stage III NSCLC when indicated[7]. Given the radical intent, all patients who are potential candidates for CRT should be carefully evaluated despite most being frail or elderly[6]. ILD brings the addi-tion of a relevant comorbidity for patients who are commonly current or former smokers and are affected by chronic obstructive pulmonary disease(COPD)[64]. In the systematic review by Saha et al., 2-year OS was lower, but not significant, for patients with stage III NSCLC treated with radical RT or CRT with or without ILA(56,8% and 74.1%).

Furthermore, patients with LS-SCLC and IPF who underwent CRT had longer PFS and OS compared to chemotherapy, demonstrating that combined treatment may offer the best chance of cure even in these patients[20]. The median incidence of Grade≥ 2, Grade 3, and Grade 5 RP for RT/CRT and ILD patients reported by Saha et al. resulted in 50%(range 12-64%),31.8%(range 8-46%), and 2.7%(range 0-6.6%),respectively[20]. Therefore, the benefit/harm ratio must be carefully considered to balance the potential clinical benefits and related toxic-ities in this scenario. Since subclinical or radiological ILD was an inde-pendent predictor of Grade≥ 2 or Grade≥ 3 radiation pneumonitis,multidisciplinary evaluation is mandatory for these cases to define variables capable of predicting the risk of lung toxicity. The presence of UIP or IPF pattern, the history of smoking, the low FVC and FEV1 values in pre-treatment PFTs, and the previous use of chemotherapy with gemcitabine are associated with a higher risk of G3 radiation pneumo-nitis.[19]. Technological advances in RT may allow the achievement of dosimetric objectives aimed at preserving healthy lungs. The adoption of the highest technological standards is crucial for these treatments[19].

3.8. ITEM H. RT combined with systemic treatment and ILD

Statement 11. In case of combined treatment with chemotherapy and RT in NSCLC patients with ILD, cytotoxic drugs that could be considered are cisplatin, carboplatin, vinorelbine, weekly(nab-) paci-taxel. Gemcitabine and docetaxel should be avoided.

Few clinical trials have prospectively evaluated the combination of cytotoxic drugs in NSCLC patients with ILD. Four single-arm phase II Japanese studies investigated the combination of carboplatin with weekly taxanes. The number of patients enrolled in each trial varied from 18 to 94. The proportion of patients with IPF ranged from 33% to 100% and many suffered from stage III disease. The studies showed good activity of the chemotherapy combinations, with response rates ranging from 51% to 70%. About 5% of patients treated with weekly nab-paclitaxel developed pulmonary toxicity, while in the two studies with weekly placitzel combined with carboplatin, pulmonary adverse events happened in 5.6% and 12.1%, respectively[65-68].

The risk of ILD or IPF exacerbation can be different according to specific cytotoxic drugs. Even if data have been derived from retro-spective analyses feasible agents seem to be platinum derivatives(such as cisplatin and carboplatin), bas-paclitaxel, placatelix, and vinorelibne.The highest acute exacerbation risks were related to docetaxel and gemcitabine[69,70].

Platinum-pemetrexed combination has not been prospectively eval-uated in patients with ILD. In retrospective Japanese studies, acute exacerbation of ILD occurred in about 21% of patients treated with platinum-pemetrexed doublet chemotherapy in the first-line setting.Pemetrexed monotherapy was associated with pulmonary toxicity in 12% of patients with ILD versus 1.1% in patients without ILD[71,72].

The possible role of chemotherapy combined with antifibrotic drugs must still be defined. In NSCLC patients with IPF, the phase III J-SONIC trial failed to show a benefit in exacerbation-free survival from the addition of Nintedanib 150 mg twice daily to carboplatin and naba-paclitaxel compared with chemotherapy alone. However, a benefit in OS was detected in non-squamous and GAP stage I subgroups[73].

In conclusion, platinum-based combinations are feasible in NSCLC patients with concomitant ILD. Vinorelbine or weekly(nab-)paclitaxel can be considered in the platinum-based combination; gemcitabine and docetaxel should be avoided. No data from clinical trials are available about the combination of chemotherapy plus immunotherapy in NSCLC patients with concomitant ILD.

Statement 12. Maintenance immunotherapy after curative CRT should not be always excluded upfront in patients with suspected ILD.,Immunotherapy could be an option in patients with advanced NSCLC and concomitant ILD with a close monitoring of respiratory function.

Immunotherapy has significantly improved patient survival and radically changed the therapeutic algorithm in NSCLC. However, pa-tients with ILD have been excluded from phase III clinical trials evalu-ating immune-checkpoint inhibitors(ICI) activity. Retrospective series showed an increased rate of pneumonitis in ILD patients treated with ICI[29,74]. Despite concerns about toxicity, ICI efficacy seems similar in NSCLC patients, regardless of the concomitant ILD. A retrospective analysis of 461 NSCLC patients treated with ICI showed a better response rate and no significant differences in PFS and OS between patients with and without ILD. The analysis confirmed the higher pneumonitis rate in the ILD subgroup, with no increase in the rate of non-pulmonary toxicities[75].

A systematic review of studies reporting ICI safety and efficacy data in NSCLC patients with ILD identified ten studies. All the enrolled population was Asiatic and received ICI; ECOG PS ranged from 0 to 4.The meta-analysis showed an overall response rate higher in patients with ILD than in those without ILD(OR 1.99; 95%CI 1.31-3.00);pneumonitis was more frequent in the subgroup of patients with ILD,even if often mild and easily manageable with ICI discontinuation and steroids[76].

Several small Japanese phase II clinical trials prospectively evalu-ated the role of ICI treated NSCLC patients with pre-existing ILD.Inclusion and exclusion criteria were different: studies with anti-PD-1 nivolumab did not include patients with UIP patterns, while they were enrolled in another study with atezolizumab[77,78].

Overall survival was almost 15 months with both nivolumab and azolizumab. No grade≥ 3 pneumonitis was detected with nivolumab,while 23.5% of patients treated with atezolizumab suffered from grade≥3 pneumonitis, and one patient died. Data from international litera-ture, mostly retrospective, supported the use of ICI as a therapeutic option in NSCLC patients with pre-existing ILD. However, what is the best setting, and the best drug are still an unmet need. A retrospective analysis of NSCLC patients with PD-L1 expression≥ 50%, treated with first line anti-PD-1 pembrolizumab, did not show any significant dif-ferences in PFS, OS and adverse events between ILD and non-ILD sub-groups[79].

A meta-analysis on prospective clinical trials that excluded patients with concomitant ILD showed a higher pneumonitis rate in treatment-naive patients than in pretreated patients[80], probably due to less immunosuppression of the chemo-naive immune system. In the same meta-analysis, a higher pneumonitis rate was detected with anti-PD-1 agents in comparison with anti-PD-L1 drugs. A possible explanation is the role of PD-L2 in promoting respiratory tolerance[81]; unlike anti-PD-L1 drugs, anti-PD-1 ICI can inhibit PD-1/PD-L2 binding, conse-quently affecting this tolerance function. Even if retrospective analyses were confident for ICI administration in NSCLC patients with pre-existing ILD, because of the minimal prospective data, a case-by-case discussion with the patient and within a multidisciplinary team is mandatory to confirm the indication both in the unresectable locally advanced disease after definitive CRT and in the advanced setting.

Pneumologists' evaluation with respiratory function testing should be assessed before and during ICI administration.

Statement 13. Thoracic RT for patients with ILD, treated with tar-gested therapy(Tyrosine Kinase Inhibitors or Antibody-drug conjugates),is limited from the risk of pneumonitis related to these treatments.

Different from PD-L1 expression, which seems to be similar

P. Borghetti et al.

$$\text{ Lung Cancer 210(2025) 108807}$$

compared to patients without ILD, some targetable driver alterations are less frequent in NSCLC patients with pre-existing ILD. In resected specimens from a large Japanese series, idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas, especially those arising from honeycomb lesions, showed distinct pathological features;EGFR mutations were significantly lower in patients with concomitant IPF than in patients without IPF[82]. In a smaller European series, no EGFR, ALK, or ROS-1 driver alterations were found in patients with IPF[83].

The standard treatment for oncogene-audicted NSCLC is generally a targeted therapy, composed frequently of Tyrosine Kinase Inhibitors(TKIs).ILD is one of the most critical clinical adverse events related to TKIs. Treatment-related ILD due to TKIs is more common in Asiatic than in the Caucasian population, and the risk of acute ILD events is increased in patients with pre-existing ILD[29,84]. Furthermore, since patients with concomitant ILD have been largely excluded from prospective clinical trials, data about ILD exacerbation from new TKIs and new drugs, such as antibody-drug conjugates(ADCs), need to be included.ILD has been one of the most relevant treatment-related adverse events for some ADCs, such as trastuzumab dercutrex [85].

According to the potentially selected drug and the type and the severity of ILD, the administration of targeted therapies in NSCLC pa-tients with concomitant ILD should be discussed case-by-case and sometimes avoided. The targeted treatment should be accompanied by close radiological and pneumological monitoring if feasible. To date,there are no clear data about the toxicity related to the combination of RT and targeted therapy in NSCLC patients with concomitant ILD. The addition of thoracic RT is limited by the risk of pneumonitis already associated with these targeted treatments. Therefore, the concomitant administration of RT and targeted therapy should be avoided in these patients; a temporary targeted treatment discontinuation is recom-mended during radiation.

3.9. ITEM I.: Follow-up after RT treatment with or without systemic treatment

Statement 14. The clinical and radiological follow-up of patients affected by ILD undergoing RT should be carried out in centres with experience and within a multidisciplinary context.

Statement 15. The follow-up should also be personalized to identify any potential radiation toxicity early on.

RT use for treating lung cancer in patients with pre-existing ILD poses unique challenges[86]. The statements underscore the necessity for specialized care and individualized monitoring in patients undergoing RT with ILD.

ILD patients receiving RT are at heightened risk of treatment-related toxicities, including exacerbation of ILD, pneumonitis, and pulmonary fibrosis[38]. Hence, a team comprising pneumologists, radiation on-cologists, radiologists, and other specialists is essential for comprehen-sive patient assessment and management[4]. Experts have highlighted the benefits of such collaborative approaches in optimizing treatment planning, minimizing complications, and improving patient outcomes[29].

The heterogeneity of ILD necessitates personalized monitoring stra-tegies during and after RT. Clinical and radiological surveillance should be tailored to the patient's specific ILD subtype, disease severity, and treatment regimen. Regular PFTs, imaging studies, and symptom assessment are pivotal in the early detection of RT-related complica-tions; however, we cannot suggest specific timing[4,22].

Centralizing the care of ILD patients, in experienced centers may offer several advantages. These centers possess specialized expertise in managing complex respiratory conditions and can provide access to advanced treatment modalities and supportive care services. Addition-ally, they facilitate communication among multidisciplinary team members, fostering coordinated decision-making and optimized patient outcomes[87].

3.10. ITEM J. Role of MDT

Statement 16. Multidisciplinary team should identify specified“tailored” journeys regarding the initial evaluation, treatment and monitoring of patients affected by lung cancer and ILD, especially when candidates to RT.

Lung cancer multidisciplinary teams(MDT) have a crucial role in managing patients affected by localized or advanced thoracic cancer.Their role is particularly important when frail patients are discussed due to advanced age, social issues, or comorbidities that may hardly influ-ence the therapeutic path. Nowadays, a challenging scenario is specif-ically represented by patients affected by synchronous ILD and malignant neoplasm[29].

In these patients, all therapies(local as well as systemic) are prone to a higher risk of severe toxicities, frequently life-threatening. For these reasons, MDT(represented by a CORE team of pneumologists, medical and radiation oncologists, surgeons, and thoracic radiologists) must discuss all clinical cases at the time of diagnosis and during the regular follow-up[88]. Indeed, patients with ILDs, being at higher risk of developing mild and severe side effects, should be followed up more strictly to detect early respiratory symptoms. These patients should then be referred to pneumologists, preferably specialized in ILD manage-ment, to proceed with a complete diagnostic framework and to start supportive care as soon as possible. Similarly, a regular follow-up of these patients may allow early diagnosis of relapse. Consequently, all following therapeutic strategies may be debated by all the MDT partic-ipants to find the safest choice taking into account risks and benefits.Finally, discussing patients by patients within the lung MDT may in-crease clinical outcomes such as PFS or OS due to the better selection of patients and the best evaluation of the risk/benefit balance for each treatment[89].

4. Discussion

The Delphi method is often applied in medicine when randomized clinical trials are lacking or insufficiently detailed for daily practice.This project used the Estimate-Talk-Estimate approach, which proved effec-tive in refining judgments. Given the limited evidence and unmet clin-ical needs, the aim was to achieve consensus on the role and management of radiotherapy(RT) in patients with interstitial lung dis-ease(ILD).

As there are no similar published experiences in the literature, the Italian Association of Radiotherapy and Clinical Oncology(AIRO)initiated this project to provide practical and up-to-date recommenda-tions for these complex cases.

It is important to clarify that the board and the expert panel are composed exclusively of Italian specialists. This ensures consistency but at the same time limits the generalizability of the results to other countries where different approaches to the management of ILD and thoracic neoplasia may exist. This consensus is framed within a national initiative that intends to lay the foundations for a broader debate,hop foring a progressive international validation.

ILDs are a heterogeneous group of diffuse parenchymal lung dis-eases. The concomitance of ILDs with lung cancer is a challenging condition that involves several critical issues. it is still unknown whether the two pathological conditions are connected, it is likely to hypothesize common aetiologies, such as smoking, environmental factors, and pathogenetic anomalies[4,20]. However, patients with ILDs and lung cancer have a poor prognosis and are at increased risk of developing severe or even fatal toxicities.

HRCT plays a central and irreplaceable role as a diagnostic tool for the detection and classification of ILD and is superior in terms of spec-icity and sensitivity to any other diagnostic method used in radiology.It is the premise for an experienced pneumologist to formulate a correct definition of the ILD subtype and an accurate stratification of the risk of exacerbation/progression if RT is proposed.

P. Borghetti et al.

$$\text{ Lung Cancer 210(2025) 108807}$$

Modern RT techniques such as Intensity-Modulated Radiation Therapy(IMRT),Image-Guided Radiation Therapy(IGRT) and organ motion management(4D-RT) have improved targeting while sparing healthy tissues. The availability of dedicated dose-constraints for pa-tients with ILD is a tool that can be used in clinical practice. Pragmati-cally, they can be considered a valid guide to make the best use of the technological armamentarium available in the modern RT. However,the co-presence of ILDs and lung cancer chooses to plan thoracic RT as a bold one, especially if combined with chemotherapy rather than new molecules such as IcIs, TKIs and ADCs.

Retrospective studies supported ICI use in non-small cell lung cancer(NSCLC) patients with pre-existing ILD, but due to limited prospective data, treatment decisions should be made on a case-by-case basis within a multidisciplinary team (MDT). Pneurogical evaluations and respi-ratory function tests should be conducted before and during ICI treatment.

Key points from the consensus include the need for thorough ILD assessments before therapy, the importance of multidisciplinary team with expert pneumologists and radiologists, the use of preventive mea-sures(e.g., anti-fibrotic drugs), and careful evaluation of toxicity risk factors. Patients must be fully informed about potential risks and al-ternatives, with decisions made through an MDT.

The high rate of agreement reported in the voting of the statements suggests that many of the points addressed were already part of shared clinical practice, at least among clinicians with expertise in this topic.However, it is absolutely essential that these indications are shared for the benefit of those who only sporadically have to make complex and challenging decisions such as those regarding the use of RT and inte-grated treatments in patients with ILD.

It is certainly possible that this consensus has not exhaustively addressed all aspects of the topic discussed, this may constitute a limi-tation of this document. One of this could be the role of biomarkers. KL-6 is a serological biomarker in LD and higher levels of KL-6 are associated with severe radiation pneumonitis or acute exacerbation of idiopathic interstitial pneumonitis[20]. Nevertheless, since KL-6 need further research to validate their role in predicting the severity of radiation pneumonitis it is not included in this consensus.

However, we hope this consensus will be the basis for further de-velopments of the topic both in the specialistic and multidisciplinary fields with the aim of increasing knowledge on the interaction between RT and ILD and improving skills in the clinical management of patients.

Many new therapeutic scenarios are emerging in the treatment of lung cancer with the advent of new molecules and combined treatments.This requires a constant effort to validate in clinical practice the efficacy of new treatments in contexts not represented by clinical trials, such as ILD. An example of this is the possibility, in the near future, of being able to prescribe maintenance treatment with TKIs in patients with unre-sectable oncogene-dicted lung adenocarcinoma treated with radio-chemotherapy. Recently, an international Delphi consensus on the management of radiation pneumonitis was published as evidence of the great interest in the topic of lung toxicities in the era of innovative and integrated treatments and of the validity of the methodology used[90].This consensus is a step toward addressing the complexities of treating lung cancer patients with ILD, but further work remains to optimize care and reduce toxicities in this high-risk population.

5. Conclusions

Despite the complexity of managing patients with ILD and synchro-nous lung cancer, this study lays the groundwork for developing stan-dardized, interdisciplinary guidelines to help choose the best therapeutic options. Involvement from various medical specialties makes multidisciplinary discussions challenging and time-consuming in everyday practice. However, even complex cases like neoplastic patients with ILD can be optimally managed with input from all relevant specialists.

Data availability statement for this work

Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

CRediT authorship contribution statement

Paolo Borghetti: Writing- review& editing, Writing- original draft, Resources, Project administration, Methodology, Investigation,Formal analysis, Conceptualization. Roland D'Angelillo: Writing-original draft, Investigation. Giorgio Facheris: Writing-original draft, Supervision, Software, Methodology, Investigation,Conceptualization. Andrea Borghesi: Writing-original draft, Investi-gation. Alessio Bruni: Writing-original draft, Investigation. Paolo Ceruti: Writing-original draft, Investigation. Katia Ferrari: Writing-inal draft, Investigation. Andrea Riccardo Filippi: Writing-orig-inal draft, Investigation. Sara Ramella: Writing-original draft, Inves-tigation. Diego Signorelli: Writing- original draft, Investigation.Giovanni Pappagallo: Writing-original draft, Investigation. Umberto Ricardi: Writing-review& editing, Writing-original draft, Method-ology,Investigation,Formal analysis,Data curation. Serena Badellino:Elisabetta Balestro.: Martina Bonifazi.: Stefania Cerri: Patrizia Ciamella:. Francescu Cuccia:. Roberto Ferrara:. Davide Fran-ceschini:. Niccolo Giaj Levra:. Anna Rita Larici:. Fabrizio Luppi:. Michele Mondoni:. Annalisa Nardone:. Valerio Nardone:. Stefano Palmucci: Sara Pilotto:. Gaia Piperno:. Vieri Scotti:. Matteo Sepulcri:. Nicola Sverzellati:. Marco Trovo:. Stefano Vagge:.Francesco Varone:. Fabiana Vitiello:.

Funding

None.

Declaration of competing interest

The authors declare the following financial interests/personal re-lationships which may be considered as potential competing interests:See the ICMJ modules attached to the submission.

Acknowledgment

The Authors thank the Scientific Committee and Board of the AIRO for the critical revision and final approval of the manuscript(Nr. 19/2024)

Appendix A

Collaborators.

Serena Badellino, Elisabeth Balestro, Martina Bonifazi, Stefania Cerri,Patrizia Ciamella, Francisco Cuccia, Roberto Ferrara, Davide France-sini, Niccolo Giaj Levra, Anna Rita Larici, Fabrizio Luppi, Michele Mon-doni, Annalisa Nardone, Valerio Nardone, Stefano Palmucci, Sara Pilotto,Gaia Piperno, Vieri Scotti, Matteo Sepulcri, Nicola Sversellati, Marco Trovo,Stefano Vagge, Francesco Varone, Fabiana Vitiello.

References

[1] A.U.Wells,N.Hirani, Interstitial lung disease guideline: the british thoracic society in collaboration with the thoracic society of Australia and New Zealand and the irishor thoracic society, Thorax 63(SUPPL 5)(2008), https://doi.org/10.1136/thx.2008.101691.

[2] W.D. Travis, et al., An official American thoracic society/european respiratory society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumoniaon, Am.J. Respir. Crit. Care Med.188(6)(2013)733-748,https://doi.org/10.1164/RCCM.201308-1483ST.

[3] D.J. Lederer, F.J. Martinez, Idiopathic pulmonary fibrosis, N. Engl. J. Med.378(19)(2018) 1811-1823, https://doi.org/10.1056/NEJMRA1705751.

P. Borgetheti et al.

$$\text{ Lung Cancer 210(2025) 108807}$$

[4] C.D.Goodman,et al.,A Primer on Interstitial Lung Disease and Thoracic Radiation,Evier Inc.,2020.10.1016/j.jtho.2020.02.005.

[4] G. Turkik et al., A. Idiipot, i.djiath, j.o2020.0255.15 perspectives of its importance in radiation oncology, Radiology. Oncol. 155(2021) 2697-227, https://doi.org/10.1016/j.RADONC.2020.11.020.

[6] A. Peraurin, et al. A reanalysis of concomitant versus sequential radiochemistry therapy in locally advanced non-small-cell lung cancer, J. Clin. Oncol.28(2013) 2181-2190, https://doi.org/10.1200/1.1200.Jc.2009.26.2543.

[5] J. Antonia, et al., Overall survival during survival after chemorodithography in stage III NSCL, N. Engl J. Med. J. 379(2014) 23812-2350, https://doi.org/10.1056/NEJMOA1809697.

[8]B.T.Besty,A.A.Weiner,Alternatives to surgery for early-stage non-small cell lung cancer:sterotic radiotherapy, W.B. Saunders(2020), https://doi.org/10.1016/j.ccm.2020.02.001.

[9] J.Y. Chang, et al., Stereotactic adiabatic radiotherapy versus lobectomy for operable stage I non-small cell lung cancer: a pooled analysis of two randomised trials.Lancet Oncol. 16(6) 2015(6) 630-637, https://doi.org/10.1016/S1470-204515(7010-368.3).

[10]S.G.C.Rooke,M.,Pavik,K.Sellamans,et al.,Metastases-directed stereatic body radiotherapy in combination with targeted therapy or immunotherapy; systematic review and consensus recommendations by the EORTC-ESTRO Oligo Care consortium, Lancet Oncol. 24(3)(2023), https://doi.org/10.1016/S1470-2045(22)00752-5 e121-e132.

[11] G.L. Cresoli, et al., Management of patients with extensive small-cell lung cancer in the immunotherapy era an identical through a Delphi approach, Crit. Rev. Oncol. Hematol.(2024) 104247,https://doi.org/10.1016/J.RC31881.

[12] D.H.Gustafson,R.K.Rshuk,Adelacq,B.W.Walter,A comparative study of differences in subjective likelihood estimates made by individuals, interacting groups,Delphi groups, and nominal groups, Organ. Behun. Hum. Perform. 9(2)(1973) 280-291,https://doi.org/10.1016/10.0016-50307(73)90052-4.

[13] D.Gallego, S. Bueno, Exploring the application of the delphi method as a forecasting tool in information systems and technologies research, Technol Anal Strogman Seag(2016)(2014) 987-999, https://doi.org/10.1080/09537325.2014.941348.

[14] K. Fitch et al., The RAND/CUCLA Appropriability Method User's Manual," 2001,Accused: 24, 2024.[44] R. P. K. Burgita, 2019; 2008; 99. https://doi.org/10.1080/monograph reports/16269.html.

[15] A. Borghesi, et al., High-resolution computed tomography technique and radiation draw on interstitial lung disease; peaks and pitfalls, J. Radiol. Rev. 8(2)(2021),https://doi.org/10.201376/25273-2284.2814.00126-9.

[16] S. Hobbs, J.H. Chung, J. Leb, K. Kaproth-Joslin, D. L.Alyn, Practical imaging interpretation in patients suspected of having idiopathic pulmonary fibrosis official recommendations from the radiology working group of the pulmonary fibrosis foundation, Radiol. Cardiothorium. Med 3(1)(2021), https://doi.org/10.1148/RYCT-2021200279.

[17] D.A. Lynch, et al., Diagnostic criteria for diopathic pulmonary fibrosis: A Fleischer science white paper, Lancet Respir. Med. 6.(2) 2018(2300) 138-153, https://doi.org/10.1016/S2213-226001730433-22.

[18]R. Gaghu F.,Nyberg, G. Morgan, The epidemiology of interstitial lung disease and its association with lung cancer, Br. J. Cancer 91(Suppl 2004)(2) S30-S13,https://doi.org/10.1038/SJIB.C6602061.

[19]K.S. Lee et al.,of pulmonary fibrosis: an pulmonary fibrosis: from the AJR special series on imaging of fibrosis, AJR A. J. Roentgenol. 22(2024), https://doi.org/10.2114/AJR.23.29119.

[20] A. Saha,P. Dickunik,R.Shukh,A.Silari,Male,S.Amin,�ar is. Thoracic radiotherapy an absolute contraindication for treatment of lung cancer patients with interstitial lung disease: A systematic review, Clin. Ocol.14(12)(2022) 93=504,https://doi.org/10.1016/j.clon.2022.04.023.

[21] Y. Huang, Z. Zhang, F. Yu, F. Gao, The cellular and molecular mechanism of radiation-induced lung injury, Med. Sci. Mon. Technol. 2013(2017) 3464-350, https://doi.org/10.1265/MSM.902353.

[22] G. Turkkan, et al. Dilutive Pulmonary Fibronary: Current Knowledge, Future Perspectives and its Importance in Radiation Oncology, Elsevier Ireland Ltd, 2021,10.1619/j.radonc.2020.11.020.

[23] Y.H. Lee, et al., Interstitial lung change in pre-radiation therapy computed tomography is a risk factor for severe radiation pneumonitis. Cancer Res. Treat.47(2015) 676-668,https://doi.org/10.4143/CRT.2014.180.

[24] H. Kobayashi, 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, J. Cancer 9 (11)(2018) 2054-2060, https://doi.org/10.7150/JCA.24936.

[25]N. Ueki, et al., Impact of pretreatment interstitial lung disease on radiation pneumonous and survival after stereotactic body radiation therapy for lung cancer,J.Thoroc. Oncol.10(1)(2015) 116-125, https://doi.org/10.1097/JTO.0000000000000000353.

[26] M. Demeds, U. Costabel, ATS/ERS international multidisciplinary consensus classification of the idiopathic interstitial pneumones, Eur. J. S. 199(2002)794-796, https://doi.org/10.1188/090031936.02.0492002.

[27] G.Raghu, et al., idiopathic pulmonary fibrosis( an update) and progressive pulmonary fibrosis in adults: an official SARS/IRAL clinical practice guideline, Am. J. Critir. Crit. Care Med. 205(9)(2022) E18-E47, https://doi.org/10.1164/RCCM.202202-0399ST.

[28] J.M. Naccacheet, al, Lung cancer and interstitial lung disease: a literature review,J. Thorac. Dis. 10(6)(2018) 3829-3844, https://doi.org/10.21037/JTD.2018.05.75.

[29] A.J. Frank, et al., Manager of lung cancer in the patient with interstitial lung disease, Oncology 28(1)(2023) 12-22, https://doi.org/10.1093/ONCOLO/AYCC22.

[30] M.P. Serrano Gordetransdon, S. Navarro Herrero, L. Gomez Izquierdo, J. A. Rodriguez Portalism, Smolging-related interstitial lung disease, Radiologia 64(Suppl 3)(2022)277-289,https://doi.org/10.1016/J.RXENG.2022.10.008.

[31] B. Ley, et al., A multidimensional index and staging system for idiopathic pulmonary fibrosis, Annn. Med. 156(10)(2012) 684-695, https://doi.org/10.7326/0003-4819-156-10-201205150-00004.

[32] J. Morisset, et al., The performance of the GAP model in patients with rheumatoid arthritis associated interstitial lung disease, Respir. Med.127(2017) 51-56,https://doi.org/10.1016/j.RMED.2017.04.012.

[33] R. Brusca, et al., The IL-DGAP risk prediction model performs poorly in myositis-associated interlung disease, Respir. Med. 150(2019) 63-65, https://doi.org/10.1016./JRMED.2019.02.015.

[43] F. Hujii, et al., ILD-GAP combined with the charson comorbidity index score(ILD-GAP) as a prognostic prediction model in patients with interstitial lung disease,Can.Reprl.J.2023(2023),https://doi.org/10.1155/2023/5088207.

[31]. P.J. Odalanchzuk, I., alidiopathic pulmonary fibrosis: state of the art for 2023,Eur.Res.61 J.(2024) 23),https://doi.org/10.1183/13993003.00957-2022.

[36] T. Twatis, et al., A phase II trial evaluating the efficacy and safety of perihole difpention for prevention of acute exacerbation of idiopathic pulmonary fibrosis in lung cancer patients undergoing pulmonary resection: West Japan Oncology Group 671 L11(PEPOLE Study), Respir. Res.17(1)(2016),https://doi.org/10.1186/S12931-016-0398-4.

[37] K. Karapinar, et al., Selection of the appropriate treatment for the combination of interstitial lung disease and lung cancer: a retrospective observational study,Medicine 103(6)(2024) E37186, https://doi.org/10.1097/MD.0000000000037186.

[38] H. Chen, et al., Treatment-related toxicity in patients with early-stage non-small lung cancer and coalescing interstitial lung disease: a systematic review, Int. J.Radiat Oncol. Biol. Phys.98(3)(2017) 622-631,https://doi.org/10.1016/J.IRDBP.2017.03.010.

[39 Y. Toshiteake, I., and Interstitial blood processing interstitial lung disease: a systematic reduction, Int. J.ROBP.2017.03.010.

[40. Sisbello et al., Dose-Volume Constraints f oRganS At risk In Radiotherapy(CORSAIR) An: All-in-One' Multicenter-Multidisciplinary Practical Summary,2022.MFOL. doi:10.1039/10.5390/curroncol29100552.

[41] D.A. Palma, H. Bahag, A. Hope, et al., Stereotactic radiation therapy in early non-small cell lung cancer and interstitial lung disease: a nonrandomized clinical trial,JAMA Oncol.10(5)(2024) 575-582,https://doi.org/10.1001/jamaocol.2023.7269.

F2. Li,F.Hu,Liu,S.Hu,Ling,Y.Xu,Risk factors for radiation pneumonitis in lung cancer patients with subbiological interstitial lung disease after thoracic radiation therapy, Radiant. Oncol.16(1)(2021),https://doi.org/10.1186/S13014-021-01798-2.

[43] H. Higo, et al., Chemoradiotherapy for locally advanced lung cancer patients with interstitial lung abnormalities, Jpn. J. Clin. Oncol. 49(5)(2019) 458-464, https://doi.org/10.1093/JCC/HYZ016.

[41] T. Kashihara, et al. Impact of interstitial lung abnormality chemotherapy for locally advanced non-small cell lung cancer, Radiother. Oncol. 180(2023), https://doi.org/10.1016/J.RADONC.2022:109454.

[45].H.R. Collard, et al., Acute exacerbation of idiopathic pulmonary fibrosis. an international working group report, Am. J. Respir. Crit. Care Med. 194(3)(2016)265-275,https://doi.org/10.1164/RCCM.2016040-0801Cl.

[46.P.Noble, et al., Pirfenidone in patients with idiopathic pulmonary fibrosis(CAPACITY) two randomised trials, Lancet 377(9779)(2011) 1760-1769,https://doi.org/10.1016/S0140-6736(11)60405-4.

[77] T. K. E., et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary pulmonary fibrosis. N. Engl. J. Med. 370(22)(2014) 2083-2092, https://doi.org/10.1056/NEJMA1402582.

[48] Licheldi, et al., Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis, N. Engl J. Med. J. Med. 365(12)(2011) 1079-1087, https://doi.org/10.1056/NEMOJ1103690.

[49] Licheldi, et al., Efficacy and safety of nintediban in idiopathic pulmonary fibrosis, N. Engl. J. Med. 370(22)(2014) 2071-2082, https://doi.org/10.1056/NEMOA1103690.

[50] M. Zurkova, et al., Effect of pirfenoiden on lung function decline and survival: 5-yr experience from a real-life of IPF cohort from the Czech EMPIRE registry, Respir. Res.(2010)(2019),https://doi.org/10.1018/S12931-019-0977-2.

[51].T. Petakal, P. Letrijanjong, C. Thongprayoon, T. Moua, Impact of antifibrotic therapy on mortality and acute exacerbation in idiopathic pulmonary fibrosis: a systematic review and meta-analysis, Chest 160(5)(2021) 1751-1763, https://doi.org/10.1016/J.CHEST.2021.06.049.

[52.KR.Falharety,et al.,Ninteanib in progressive fibrosing interstitial lung diseases,N.Engl.J.Med.381(18)(2019) 1718-1727,https://doi.org/10.1056/NEJMOA1908681.

[53].N. Park,et al.,Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis, Chest 132(1)(2007) 214-220, https://doi.org/10.1378/CHEST.07-0323.

P. Borgethi et al.

$$\text{ Lung Cancer 210(2025) 108807}$$

[54] F. Luppi, Sebastiani, C. Salvarani, E. Bendstrup, A. Manfredi, Acute exacerbation of interstitial lung disease associated with rheumatic disease. Nat.Revheumatol. 18(2)(2022) 85-96, https://doi.org/10.1038/S41584-021-00721-Z.

[55] M. Cao, et al., Acute exacerbations of fibrostrixtial lung disease associated with connective disease: a population-based study, BMC Pulm. Med. 19(1)(2019) Nov,https://doi.org/10.1186/S12890-019.0960-1.

[56] A. Suzuki, et al., Acute exacerbations of fibrotic interstitial lung diseases,Resirpology 25(5)(2020) 525-534,https://doi.org/10.1116/ESP.1368.

[57] J.Kang,Y.J.Kim,J.Choe,E.J.Wang,J.Song,Acuteexberation of fibrotic hypertension'sneutronisic tumourisic incidence and outcomes, Respir. Res. 22(1)(2021)Dec. https://doi.org/10.1186/S12931-0217-01478-2.

[5]Y. Toyoda, et al., Clinical features and outcome of acute exacerbation of interstitial pneumonia associated with connective tissue disease, J. Med. Investing, 63(3-4)(2016) 2949-299, https://doi.org/10.2152/JM63.2949.

[95] H. Onishi, et al., Stereotactic hypofrinated high-oxidation for stage I for stage I nonsmall cell lung carcinoma: clinical outcomes in 245 subjects in a Japanese multinistinal situation study, Cancer 101(7)(2004) 1623-1631,https://doi.org/10.1002/CNCR.20539.

[60] H. Kim, et al., Impact of underlying pulmonary diseases on treatment outcomes in early-stage non-small cell lung cancer treated with definitive radiotherapy, Int.J.Chron.Obrupt. Pulmon. Dis.14(2019) 2273-2281, https://doi.org/10.2147/SOPCD.S210759.

[61] Y. Liu, et al., Stereotactic body radiotherapy for early stage non-small cell lung cancer in patients with subclinical interstitial lung disease, Trans. Lung Cancer Res.9(6)(2020) 2328-2336,https://doi.org/10.21037/LCR-20-1050.

[62]D. Glick, et al., Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival in patients treated with lung stectoric radiotherapy in therapy(SRT), Clin. Lung Cancer 19(20) 2018, https://doi.org/10.1016/J.C.LC.2017.0621 e219-e226.

63(A.T. Turris, et al., Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide,N. Engl.J.Med.340(4)(1999) 265-271,https://doi.org/10.1056/NEJNI9901283400403.

[64] N. Girard, et al., Treatment characteristics and real-world progression-free survival in patients with unresectable stage III NSCLG who received survival underchemia:therapy of findings by the PACIFIC-R study, J. Thorac. Oncol. 18(2)(2023) 181-193,https://doi.org/10.1016/JJTHO.2022.10.003.

[65] K. Hemootsu,et al.,Phase II study of nabatplacit+ carboxilating for patients with non-small-cell lung cancer and interstitial lung disease. Cancer 110(120)(2019)378-3745,https://doi.org/10.1111/CAS.14217.

[66] A. Hasina, et al., A prospective phase II study of carboplatin and palabacitlined patients with advanced non-small cell lung cancer and concomitant interstitial lung disease(HOT1302), Lung Cancer 138(2019) 65-71, https://doi.org/10.1016/J.LUNGCAN.2019.09.020.

[67]Y. Minegishi, et al., The safety and efficacy of weekly pacitlex in combination with carboplatin for advanced non-small cell lung cancer with idiopathic interstitial pneumonias, Lung Cancer 71(1)(2011) 70-74, https://doi.org/10.1016/J.LUNGANC.2010.04.014.

[68]A. Fukuzumi, et al., Weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer complicated by idiopathic interstitial pneumonomias: a single-arm phase II study, Int. J. Clin. Oncol. 24(12)(2019)1543-1548, https://doi.org/10.1007/S10147-019-01516-9.

[69] H. Kenmotsu, et al., The risk of cytotoxic chemotherapy-related exacerbation of interstitial lung disease with lung cancer, J. Thorac. Oncol. 6(7)(2011)1242-1246,https://doi.org/10.1097/JTO.0B013E318216EE6B.

[70] N. Kanaji, et al., Impact of idiopathic pulmonary fibrosis on advanced non-small cell lung cancer survival, J. Cancer Res. Clin. Oncol. 142(8)(2016) 1855-1865,https://doi.org/10.1007/S00432-016-2199-Z.

[71] T. Fujita, et al., Pemetrexed plus platinum for patients with advanced non-small cell lung cancer and interstitial lung disease, In Vivo 33(6)(2019) 2059-2064,https://doi.org/10.21873/INVIVO.11704.

[72] M. Kato, et al., Pemetrexted for advanced non-small cell lung cancer patients with interstitial lung disease, BMC Cancer 14(1)(2014),https://doi.org/10.1186/1407-147-1408.

[73] K. Otsubo, J., alntenediab plus chemotherapy for nonsmall cell lung cancer with idiopathic pulmonary fibrosis: a randomised phase 3 trial, Eur. Respir. J. 60(0)2022(Dec) https://doi.org/10.1183/13993003.00380-2022.

[74] K. Shimoji, et al., Association of preexisting interstitial lung abnormalities with immune checkpoint inhibitor-induced interstitial lung disease among patients with non-lunscil cancers. JAMANETWORKOPEN.2020.22906.

[75] Y. Tasaka, et al., Non-inferior clinical outcomes of immune checkpoint inhibitors in non-small cell lung cancer patients with interstitial lung disease, Lung Cancer 155(2021) 120-126, https://doi.org/10.1016/J.LUNNGCAN.2021.03.014.

[76] M. Zhang,Y. Fan,L. Nie,G. Wang,K. Sun,Y. Cheng, Clinical outcomes of immune checkpoint inhibitor therapy in patients with advanced non-small cell lung cancer and preexisting interstitial lung diseases; a systematic review and meta-analysis,Chest 161(2026) 1675-1686,https://doi.org/10.1016/J.CHEST.2021.12.656

[77] D. Fujimoto, et al., Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic pulmonary fibrosis: A multicenter, open-label single-arm phase II lung, Cancer l134(2019) 274-278, https://doi.org/10.1016/J.LINGAN.2019.06.001.

[87] S. Keida, et al., etalizozimab for pretreated non-small cell lung cancer with idiopathic interstitial pneumonia: final analysis of phase II AMBITIOUS study,Oncologist 27(9)(2022) 720-702, https://doi.org/10.1093/ONCOLO/OYAC118.

Y. Omaguchi, et al., Pre-Exentrolistic interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression≥50% on first-line pembrolizumab, Thorac Cancer 12(3)(2021) 304-313, https://doi.org/10.1111/1759-7714.13725.

[80] M. Khunger,et al.,Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials, Chest 152(2)(2017) 271-281,https://doi.org/10.1016/J.CHEST.2017.04.177.

[81] Y.Xiao,et al,RGdB is a novel binding partner for PD-L2 and its engagement with PD-L2 promotes respiratory tolerance, J. Exp. Med. 211(5)(2014) 943-959,https://doi.org/10.1084/JEM.20130790.

[82]Y. Koijma, et al., The pathological features of idiopathic interstitial pneumonia associated pulmonary adenocinomas, Histopathology 70(4)(2017) 568-578,https://doi.org/10.1111/HIS.13103.

[83] A.Guyard,et al.,Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses, Respir. Res.18(2017),https://doi.org/10.1111/HIS.13103.

[84] A. Azuma, S. Kudoh, High prevalence of drug-induced Pneumonia in Japan, Japan Med. Assoc. J. 50(2007) 405-411.

[85] B.T.Li,et al.,Trastuzumato derextracen in HER2-mutant non-small-cell lung cancer,NEJMOA2112431.

[86] H. Bahig,et al.,Severe radiation pneumonitis after lung stereotactic ablative radiation therapy in patients with interstitial lung disease, Pract. Radiat. Oncol.6(5)(2016) 367-374, https://doi.org/10.1016/J.PRRO.2016.01.009.

[87] C.J.Ryerson,T.J.Corte,J.L. Myers,S.L.F. Walsh,S.A. Guler,A contemporary practical approach to the multidisciplinary management of unclassifiable interstitial lung disease, Eur. Respir. J. 58(6)(2021) Dec, https://doi.org/10.1183/13993003.00276-2021.

[89] E.Stone,et al.,Does presentation at multidisciplinary team meetings improve lung survival? Findings from a consecutive cohort study, Lung Cancer 124(2018) 199-204, https://doi.org/10.1016/J.LUNGAN.2018.07.032.

[89]C. Gaudioso, et al., Impact of a thoracic multidisciplinary conference on lung cancer outcomes, Ann. Thorac. Surg. 113(2)(2022) 392-398, https://doi.org/10.1016/J.ATHORACSUR.2021.03.017.

[90]S. L. Voruganti Maddali, C. Cunningham, L. McLeod, et al., Optimal management of radiation pneumonitis: findings of an international Delphi consensus study, Lung Cancer 192(2024) 107822, https://doi.org/10.1016/j.lungcan.2024.107822.

相关指南

• 2025 AIRO共识建议：肺癌和间质性肺疾病患者的放疗 · 呼吸内科 2025