# Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients

J. Pluvy, A. Zaccariotto, P. Habert, J. Bermudez, A. Mogenet, J.Y. Gaubert, P. Tomasini, L. Padovani, L. Greillier

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## To cite this version:

J. Pluvy, A. Zaccariotto, P. Habert, J. Bermudez, A. Mogenet, et al., Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients. Respiratory Medicine and Research, 2023, 83, pp.100984. 10.1016/j.resmer.2022.100984. hal-03962927

HAL Id: hal-03962927

https://amu.hal.science/hal-03962927

Submitted on 5 Apr 2024

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# Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients

J. Pluvy, A. Zaccariotto, P. Habert, J. Bermudez, A. Mogenet, J.Y. Gaubert, P. Tomasini, L. Padovani, L. Greillier

► To cite this version:

J. Pluvy, A. Zaccariotto, P. Habert, J. Bermudez, A. Mogenet, et al., Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients. Respiratory Medicine and Research, 2023, 83, pp.100984. 10.1016/j.resmer.2022.100984. hal-03962927

HAL Id: hal-03962927

https://amu.hal.science/hal-03962927v1

Submitted on 5 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-Asian patients.

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**Authors:** J.Pluvy, A.Zacariotto, P.Habert, J.Bermudez, A.Mogenet, JY.Gaubert, P.Tomasini, L.Padovani, L.Greillier;

**Affiliations:**

Dr PLUVY Johan, MD, Department of Multidisciplinary Oncology and Therapeutic Innovations Assistance
Publique Hôpitaux de Marseille AP-HM, Hôpital Nord, Marseille, France

Dr ZACCARIOTTO Audrey, MD, Department of Radiation Oncology, Assistance Publique Hôpitaux de
Marseille AP-HM, Marseille, France

Dr. Paul HABERT, MD PhD Radiology department, Hôpital Nord, AP-HM, Aix Marseille Univ, LIIE, Marseille, France; Aix Marseille Univ, CERIMED, Marseille, France

Dr. Julien BERMUDEZ, MD, Department of Respiratory Medicine and Lung Transplantation, Assistance
Publique - Hôpitaux de Marseille APHM, Hôpital Nord, Marseille ; Aix -Marseille University, France

Dr MOGENET Alice, MD, Aix Marseille University, Department of Multidisciplinary Oncology and
Therapeutic Innovations Assistance Publique Hôpitaux de Marseille AP-HM, Hôpital Nord, Marseille, France

Pr GAUBERT Jean Yves, MD, Radiology Department, Hôpital Nord, Assistance Publique Hôpitaux de
Marseille AP-HM, Marseille, France

Dr TOMASINI Pascale MD, PhD Aix Marseille University, Assistance Publique Hôpitaux de Marseille AP-HM, Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France; Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France.

Pr PADOVANI Laeticia MD Department of Radiation Oncology, Assistance Publique Hôpitaux de Marseille
AP-HM, Marseille, France

Pr GREILLIER Laurent MD, PhD, Aix Marseille University, APHM, INSERM, CNRS, CRCM, Hôpital Nord,
Multidisciplinary Oncology and Therapeutic Innovations Department, Marseille, France

Address correspondence to Dr Johan PLUVY, Multidisciplinary Oncology and Therapeutic Innovations
Department, AP-HM, Marseille, France
Landline: +33491965901
E-mail: johan.pluvy@ap-hm.fr

**Author contributions**

JP had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: JP,AZ,PH,LP,PT,LG Acquisition, analysis, or interpretation of the data: all authors. Drafting of the manuscript: JP,PH Critical revision of the manuscript for important
1 Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage
2 lung cancer with interstitial lung disease (ILD): An observational and exploratory
case series of non-Asian patients.
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4
5
6
7 **Authors:** J.Pluvy, A.Zacariotto, P.Habert, J.Bermudez, A.Mogenet, JY.Gaubert, P.Tomasini, L.Padovani,
L.Greillier;
8
9
10 **Affiliations:**
11 Dr PLUVY Johan, MD, Department of Multidisciplinary Oncology and Therapeutic Innovations Assistance
12 Publique Hôpitaux de Marseille AP-HM, Hôpital Nord, Marseille, France
13
14 Dr ZACCARIOTTO Audrey, MD, Department of Radiation Oncology, Assistance Publique Hôpitaux de
15 Marseille AP-HM, Marseille, France
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17 Dr. Paul HABERT, MD PhD Radiology department, Hôpital Nord, AP-HM, Aix Marseille Univ, LIIE, Marseille,
France; Aix Marseille Univ, CERIMED, Marseille, France
18
19
20 Dr. Julien BERMUDEZ, MD, Department of Respiratory Medicine and Lung Transplantation, Assistance
21 Publique - Hôpitaux de Marseille APHM, Hôpital Nord, Marseille ; Aix -Marseille University, France
22
23 Dr MOGENET Alice, MD, Aix Marseille University, Department of Multidisciplinary Oncology and
24 Therapeutic Innovations Assistance Publique Hôpitaux de Marseille AP-HM, Hôpital Nord, Marseille, France
25
26 Pr GAUBERT Jean Yves, MD, Radiology Department, Hôpital Nord, Assistance Publique Hôpitaux de
27 Marseille AP-HM, Marseille, France
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29 Dr TOMASINI Pascale MD, PhD Aix Marseille University, Assistance Publique Hôpitaux de Marseille AP-HM,
30 Department of Multidisciplinary Oncology and Therapeutic Innovations. Marseille, France; Centre de
31 Recherche en Cancérologie de Marseille (CRCM), Inserm UMR1068, CNRS UMR7258, Marseille, France.
32
33 Pr PADOVANI Laeticia MD Department of Radiation Oncology, Assistance Publique Hôpitaux de Marseille
34 AP-HM, Marseille, France
35
36 Pr GREILLIER Laurent MD, PhD, Aix Marseille University, APHM, INSERM, CNRS, CRCM, Hôpital Nord,
37 Multidisciplinary Oncology and Therapeutic Innovations Department, Marseille, France
38
39
40 Address correspondence to Dr Johan PLUVY, Multidisciplinary Oncology and Therapeutic Innovations
Department, AP-HM, Marseille, France
41
42 Landline: +33491965901
E-mail: johan.pluvy@ap-hm.fr
43
44
45 **Author contributions**
46 JP had full access to all of the data in the study and take responsibility for the integrity of the data and the
accuracy of the data analysis. Concept and design: JP,AZ,PH,LP,PT,LG Acquisition, analysis, or interpretation
of the data: all authors. Drafting of the manuscript: JP,PH Critical revision of the manuscript for important
49

intellectual content: all authors. Statistical analysis: JP Administrative, technical, or material support: all

50

authors Supervision: JYG,LP,PT,LG

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**Declaration of competing interests**

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JP,AZ,PH,JB,AM,GJY,PT,LP,LG nothing to disclose related to the work

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intellectual content: all authors. Statistical analysis: JP Administrative, technical, or material support: all

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authors Supervision: JYG,LP,PT, LG

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52

**Declaration of competing interests**

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JP,AZ,PH,JB,AM,GJY,PT,LP, LG nothing to disclose related to the work

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Keywords: Stereotactic Radiation Therapy; Interstitial Lung Disease; Carcinoma, Non-Small Cell Lung, Follow-up Studies

**Abstract:** (225 words): Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients' outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting: 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.
Keywords: Stereotactic Radiation Therapy; Interstitial Lung Disease; Carcinoma, Non-Small Cell Lung, Follow-up Studies

**Abstract:** (225 words): Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients' outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting: 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.
## Introduction:

Lung cancer (LC) shares common pathophysiology and risk factors with interstitial lung disease (ILD) (1). LC incidence is increased in patients with idiopathic pulmonary fibrosis (IPF) (2). A French cohort identified ILD in approximately five percent of newly diagnosed LC cases (3). Interstitial lung disease-lung cancer (LC-ILD) refers to patients with co-existing LC and ILD.

ILD has an impact on the diagnosis and prognosis of LC: in a French cohort, 19% of patients with combined pulmonary fibrosis and emphysema (CPFE) did not have histologically proven LC (2). Furthermore 42% of patients in this study did not receive the appropriate standard of care. According to a Japanese cohort of LC-ILD patients who underwent surgical resection, death was related to an exacerbation of interstitial pneumonia in approximately 10% of patients (189/1763 patients). Independent predictors of mortality in this study were low forced vital capacity (%FVC), histopathologic stage, male gender, type of surgical procedure, and tumor location (4). These patients also had a higher risk of cancer (50% relapse).

Stereotactic body radiation therapy (SBRT) is the preferred treatment for early-stage LCs without a history of ILD refusing surgery, medically inoperable or at high operative risk. SBRT is defined as a radiotherapy technique with modern targeting and planning technologies to deliver higher doses with lower fractions (60Gy 3-8 fractions). This technique can decrease short-term toxicity with higher rates of local control and promising potential long-term cancer control (5,6).

Conventional radiotherapy is contraindicated for patients with severe ILD because of the high risk of radiation-induced pneumonia or flare of existing interstitial pneumonia. Data are limited to series showing a higher risk of radiation-induced pneumonia and death (7,8) but these series over represent Asian patients. This risk appears to be increased in subclinical ILD (9). SBRT may spare healthy lung but serious and increasing risks of radiation pneumonitis have been reported to date in patients with subclinical ILD. In a nationwide Japanese survey, most of grade V radiation pneumonitis had underlying ILD (10).
## Introduction:

Lung cancer (LC) shares common pathophysiology and risk factors with interstitial lung disease (ILD) (1). LC incidence is increased in patients with idiopathic pulmonary fibrosis (IPF) (2). A French cohort identified ILD in approximately five percent of newly diagnosed LC cases (3). Interstitial lung disease-lung cancer (LC-ILD) refers to patients with co-existing LC and ILD.

ILD has an impact on the diagnosis and prognosis of LC: in a French cohort, 19% of patients with combined pulmonary fibrosis and emphysema (CPFE) did not have histologically proven LC (2). Furthermore 42% of patients in this study did not receive the appropriate standard of care. According to a Japanese cohort of LC-ILD patients who underwent surgical resection, death was related to an exacerbation of interstitial pneumonia in approximately 10% of patients (189/1763 patients). Independent predictors of mortality in this study were low forced vital capacity (%FVC), histopathologic stage, male gender, type of surgical procedure, and tumor location (4). These patients also had a higher risk of cancer (50% relapse).

Stereotactic body radiation therapy (SBRT) is the preferred treatment for early-stage LCs without a history of ILD refusing surgery, medically inoperable or at high operative risk. SBRT is defined as a radiotherapy technique with modern targeting and planning technologies to deliver higher doses with lower fractions (60Gy 3-8 fractions). This technique can decrease short-term toxicity with higher rates of local control and promising potential long-term cancer control (5,6).

Conventional radiotherapy is contraindicated for patients with severe ILD because of the high risk of radiation-induced pneumonia or flare of existing interstitial pneumonia. Data are limited to series showing a higher risk of radiation-induced pneumonia and death (7,8) but these series over represent Asian patients. This risk appears to be increased in subclinical ILD (9). SBRT may spare healthy lung but serious and increasing risks of radiation pneumonitis have been reported to date in patients with subclinical ILD. In a nationwide Japanese survey, most of grade V radiation pneumonitis had underlying ILD (10).
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Despite the risks, a recent international survey (DIAMORFOSIS) (11) identified radiation therapy as the preferred treatment choice (54.1 % of physicians) for patients with mild-to-moderate ILD (DLCO>35% and FVC > 50 %) with stage I or II LC.

This leads to a clinical dilemma: on the one hand, SBRT may cause respiratory adverse effects, but the other options are high-risk surgery or even systemic therapy. It is also difficult to identify patients who might benefit from each treatment or avoidance of treatment in this setting.

In this study, we aimed to retrospectively identify patients with pre-existing ILD associated with stage I lung cancer or an unproven highly suspicious nodule treated with SBRT and to describe their clinical, functional and radiological outcomes.

## Materials and methods

We performed a single-centre retrospective study of a cohort of consecutive patients with LC-ILD managed between April 2015 and December 2021 in the Department of Thoracic Oncology and Radiation Oncology in Marseille. LC-ILD patients were identified through electronic patients' records. We enrolled patients with histologically or cytologically proven LC or with a high probability of LC (evolving nodule, PET-CT hypermetabolism) but a high risk of complication after biopsy as defined by multidisciplinary board discussion according to European guidelines (12).

Demographic, clinical and treatment (radiotherapy modality, total dose, total treatment time, number of fractions and dose per fraction, V20, V12.5 and mean lung dose (MLD)) data were collected retrospectively. We performed ILD-GAP when indicated. Available CT scans performed at diagnosis and before/after SBRT were reviewed by a thoracic radiologist to examine the ILD pattern and to assess the evolution of images before and after SBRT.

Early death or grade 3-4 respiratory adverse events (AEs) were the co-primary study endpoints. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0); early death was defined as occurring within 6 months after SBRT.
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Despite the risks, a recent international survey (DIAMORFOSIS) (11) identified radiation therapy as the preferred treatment choice (54.1 % of physicians) for patients with mild-to-moderate ILD (DLCO>35% and FVC > 50 %) with stage I or II LC.

This leads to a clinical dilemma: on the one hand, SBRT may cause respiratory adverse effects, but the other options are high-risk surgery or even systemic therapy. It is also difficult to identify patients who might benefit from each treatment or avoidance of treatment in this setting.

In this study, we aimed to retrospectively identify patients with pre-existing ILD associated with stage I lung cancer or an unproven highly suspicious nodule treated with SBRT and to describe their clinical, functional and radiological outcomes.

## Materials and methods

We performed a single-centre retrospective study of a cohort of consecutive patients with LC-ILD managed between April 2015 and December 2021 in the Department of Thoracic Oncology and Radiation Oncology in Marseille. LC-ILD patients were identified through electronic patients' records. We enrolled patients with histologically or cytologically proven LC or with a high probability of LC (evolving nodule, PET-CT hypermetabolism) but a high risk of complication after biopsy as defined by multidisciplinary board discussion according to European guidelines (12).

Demographic, clinical and treatment (radiotherapy modality, total dose, total treatment time, number of fractions and dose per fraction, V20, V12.5 and mean lung dose (MLD)) data were collected retrospectively. We performed ILD-GAP when indicated. Available CT scans performed at diagnosis and before/after SBRT were reviewed by a thoracic radiologist to examine the ILD pattern and to assess the evolution of images before and after SBRT.

Early death or grade 3-4 respiratory adverse events (AEs) were the co-primary study endpoints. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0); early death was defined as occurring within 6 months after SBRT.
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Secondary objectives were the description of disease-free survival (DFS) and overall survival (OS) but also the description of specific clinical, functional, radiological outcomes before and after SBRT. Clinical events were assessed according to CTCAE v5.0. Functional worsening was defined by 10 % decrease in predicted FVC or 15 % decrease in Diffusing Capacity for Carbon monoxide (DLCO) predicted over 12 months. Imaging characteristics were assessed by a radiologist as: location of the nodule in healthy or pathological parenchyma; progressive ILD before SBRT; visual quantification of fibrosis: mild (<10%), moderate (10-25%), high (25-50%), severe (50-75%) and extreme (>75%) following the recently published classification to evaluate the severity of COVID-19 pneumonia (13). The radiologist also assessed imaging progression after SBRT: radiotherapy scar (volume and maximum 2D size), occurrence of radiation pneumonitis, progression of the extent of fibrosis and type (densification or new lesions).

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This is an exploratory study, conducted to design and estimate the feasibility of recruiting a definitive, adequately powered, larger-scale multicenter retrospective cohort. Descriptive analysis was performed using headcounts for discrete variables, median values and interquartile range (IQR) for continuous data. Because of the limited sample size, we could not perform statistical analysis to identify parameters involved in early death or grade III-IV respiratory AEs. OS was defined as the time from Day 1 of SBRT to patient death from any cause. DFS was defined as the time from Day 1 of SBRT and disease progression or death from any cause. Data were censored at the end of the study (December 2021). Kaplan Meier curves were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, N.Y., USA).

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In accordance with French regulation on retrospective observational studies, no objection to the use of anonymously retrospective data was identified. The study was registered at RGPD/AP-HM (registration number #2021-52) and approved by local Institutional Review Board.

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## Results:

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Between April 2015 and December 2021, 1361 patients with ILD were identified in our center, including 38 patients identified with LC-ILD. Of these, three had small-cell lung cancer and 16 had advanced non-small cell lung cancer. Of the 19 patients with early-stage LC-ILD, three received conventional
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Secondary objectives were the description of disease-free survival (DFS) and overall survival (OS) but also the description of specific clinical, functional, radiological outcomes before and after SBRT. Clinical events were assessed according to CTCAE v5.0. Functional worsening was defined by 10 % decrease in predicted FVC or 15 % decrease in Diffusing Capacity for Carbon monoxide (DLCO) predicted over 12 months. Imaging characteristics were assessed by a radiologist as: location of the nodule in healthy or pathological parenchyma; progressive ILD before SBRT; visual quantification of fibrosis: mild (<10%), moderate (10-25%), high (25-50%), severe (50-75%) and extreme (>75%) following the recently published classification to evaluate the severity of COVID-19 pneumonia (13). The radiologist also assessed imaging progression after SBRT: radiotherapy scar (volume and maximum 2D size), occurrence of radiation pneumonitis, progression of the extent of fibrosis and type (densification or new lesions).

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This is an exploratory study, conducted to design and estimate the feasibility of recruiting a definitive, adequately powered, larger-scale multicenter retrospective cohort. Descriptive analysis was performed using headcounts for discrete variables, median values and interquartile range (IQR) for continuous data. Because of the limited sample size, we could not perform statistical analysis to identify parameters involved in early death or grade III-IV respiratory AEs. OS was defined as the time from Day 1 of SBRT to patient death from any cause. DFS was defined as the time from Day 1 of SBRT and disease progression or death from any cause. Data were censored at the end of the study (December 2021). Kaplan Meier curves were performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, N.Y., USA).

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In accordance with French regulation on retrospective observational studies, no objection to the use of anonymously retrospective data was identified. The study was registered at RGPD/AP-HM (registration number #2021-52) and approved by local Institutional Review Board.

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## Results:

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Between April 2015 and December 2021, 1361 patients with ILD were identified in our center, including 38 patients identified with LC-ILD. Of these, three had small-cell lung cancer and 16 had advanced non-small cell lung cancer. Of the 19 patients with early-stage LC-ILD, three received conventional
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radiotherapy, seven received surgery and nine SBRT (Figure 1). Among these nine patients who received SBRT for the treatment of LC-ILD, 6 were men, with a median age of 71 (range 59–89). 8 out 9 patients were heavy smokers (> 40 pack-years), including 4 active smokers. All were ECOG Performance Status (PS) 0 or 1 at the time of radiotherapy. Baseline demographics, pulmonary characteristics and disease and treatment data of LC-ILD patients treated with SBRT or surgery are detailed in Figure 1.

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4 patients had no cytologically or pathologically proven LC. Of those who had a tissue sample, all were performed by CT-guided Trans-thoracic Needle Aspiration. All were stage I (12 to 21 mm) in various peripheral sites. Baseline clinical, functional, imaging data with pattern and evolution after SBRT are reported in Table 1. All patients had a diagnosis of ILD at the time of SBRT and underwent multidisciplinary discussion. Coexisting emphysema was found in 5 patients. All patients underwent a pretherapeutic workup with pulmonary functional test (PFT).

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After SBRT, 5 patients experienced clinical respiratory AE. None of the patients experienced grade III-IV treatment related respiratory AE. For patient #2, corticosteroid dose was temporarily increased with a one-week course of antibiotics and patient #9 received one week of antibiotics and two weeks of prednisone (20 mg/day).

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Two patients died within 6 months after SBRT and for both, death was related to metastatic relapse. Median OS was 17.4 months (IC95% 8.4-26.4), and further risk factors analyses were not possible because of the small size of this population. Median DFS was 13.5 month (IC95%:5.7-21.2) (Figure 2). Three patients had functional worsening, but data were missing for two patients.

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All patients had baseline and follow-up imaging. Two patients (#5 and #8) did not have any PET-CT before SBRT. These patients did not experience early relapse. Expert radiologists quantified the extent of ILD by visual assessment ranging from mild to severe and found a deterioration of ILD before SBRT in 5 patients. Five other patients had radiation pneumonitis on CT scan during the first year after SBRT and most of them had worsening of ILD (new lesion and extent of ILD) during follow up. Evolution of

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radiotherapy, seven received surgery and nine SBRT (Figure 1). Among these nine patients who received SBRT for the treatment of LC-ILD, 6 were men, with a median age of 71 (range 59–89). 8 out 9 patients were heavy smokers (> 40 pack-years), including 4 active smokers. All were ECOG Performans Status (PS) 0 or 1 at the time of radiotherapy. Baseline demographics, pulmonary characteristics and disease and treatment data of LC-ILD patients treated with SBRT or surgery are detailed in Figure 1.

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4 patients had no cytologically or pathologically proven LC. Of those who had a tissue sample, all were performed by CT-guided Trans-thoracic Needle Aspiration. All were stage I (12 to 21 mm) in various peripheral sites. Baseline clinical, functional, imaging data with pattern and evolution after SBRT are reported in **Table 1**. All patients had a diagnosis of ILD at the time of SBRT and underwent multidisciplinary discussion. Coexisting emphysema was found in 5 patients. All patients underwent a pretherapeutic workup with pulmonary functional test (PFT).

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After SBRT, 5 patients experienced clinical respiratory AE. None of the patients experienced grade III-IV treatment related respiratory AE. For patient #2, corticosteroid dose was temporarily increased with a one-week course of antibiotics and patient #9 received one week of antibiotics and two weeks of prednisone (20 mg/day).

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Two patients died within 6 months after SBRT and for both, death was related to metastatic relapse. Median OS was 17.4 months (IC95% 8.4-26.4), and further risk factors analyses were not possible because of the small size of this population. Median DFS was 13.5 month (IC95%:5.7-21.2) (Figure 2). Three patients had functional worsening, but data were missing for two patients.

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All patients had baseline and follow-up imaging. Two patients (#5 and #8) did not have any PET-CT before SBRT. These patients did not experience early relapse. Expert radiologists quantified the extent of ILD by visual assessment ranging from mild to severe and found a deterioration of ILD before SBRT in 5 patients. Five other patients had radiation pneumonitis on CT scan during the first year after SBRT and most of them had worsening of ILD (new lesion and extent of ILD) during follow up. Evolution of

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radiotherapy scar volume (cm³) was also collected (Figure 3). For example, we displayed Patient #2 imaging
follow-up and parenchyma evolution after SBRT on figure 4.

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Discussion:

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In this case series, SBRT was performed as salvage therapy for LC-ILD in nine patients. Two of them died less than sixth months after SBRT but in both cases, death was related to metastatic relapse and not to a respiratory AE. An initial assessment of oncologic disease should be performed using PET-CT and brain MRI, especially in such risky circumstances, to prevent early relapse, especially for high-risk treatment. In addition, unlike surgery, SBRT does not assess mediastinal lymph node involvement. It should also be noted that the good outcomes can also be explained by the fact that 4 patients did not have histologically proven LC and that, despite criteria suggesting malignancy, the nodules seen in these 4 patients could be benign. Furthermore, OS was not significantly better than DFS, which could be explained by the fact that 5 patients had metastatic relapse and that systemic treatment options after relapse may be limited for these patients due to their general condition and limited access to innovative therapies such as immune checkpoint inhibitors or targeted therapies and a worse expected tolerance to chemotherapy with a higher risk of ILD exacerbation.

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It is very important to say that 5 patients had respiratory AE but fortunately none of them experienced grade III or IV events. Therapeutic management (by antibiotics, diuretics or corticosteroids) of pulmonary AEs was assessed in our study, but these data are questionable as reports may be missing especially for outpatient management.

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ILD is considered as a risk factor for severe radiation pneumonitis after conventional 3D conforming
radiotherapy: subclinical ILD was associated to grade II to V radiation pneumonitis in previously reported
studies (9). Four of the patients who died in a Korean retrospective study had diffuse interstitial change in
pre-RT CT-scan (14). Standard radiotherapy is therefore contra-indicated in current guidelines for patients
with ILD.

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SBRT may spare healthy lung, but some studies also identified pre-existing ILD as a risk factor of
radiation-induced pneumonitis: pre-existing interstitial pneumonitis shadow, on CT-scan was well
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radiotherapy scar volume (cm³) was also collected (Figure 3). For example, we displayed Patient #2 imaging
follow-up and parenchyma evolution after SBRT on figure 4.

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Discussion:

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In this case series, SBRT was performed as salvage therapy for LC-ILD in nine patients. Two of them died less than sixth months after SBRT but in both cases, death was related to metastatic relapse and not to a respiratory AE. An initial assessment of oncologic disease should be performed using PET-CT and brain MRI, especially in such risky circumstances, to prevent early relapse, especially for high-risk treatment. In addition, unlike surgery, SBRT does not assess mediastinal lymph node involvement. It should also be noted that the good outcomes can also be explained by the fact that 4 patients did not have histologically proven LC and that, despite criteria suggesting malignancy, the nodules seen in these 4 patients could be benign. Furthermore, OS was not significantly better than DFS, which could be explained by the fact that 5 patients had metastatic relapse and that systemic treatment options after relapse may be limited for these patients due to their general condition and limited access to innovative therapies such as immune checkpoint inhibitors or targeted therapies and a worse expected tolerance to chemotherapy with a higher risk of ILD exacerbation.

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It is very important to say that 5 patients had respiratory AE but fortunately none of them experienced grade III or IV events. Therapeutic management (by antibiotics, diuretics or corticosteroids) of pulmonary AEs was assessed in our study, but these data are questionable as reports may be missing especially for outpatient management.

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ILD is considered as a risk factor for severe radiation pneumonitis after conventional 3D conforming
radiotherapy: subclinical ILD was associated to grade II to V radiation pneumonitis in previously reported
studies (9). Four of the patients who died in a Korean retrospective study had diffuse interstitial change in
pre-RT CT-scan (14). Standard radiotherapy is therefore contra-indicated in current guidelines for patients
with ILD.

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SBRT may spare healthy lung, but some studies also identified pre-existing ILD as a risk factor of
radiation-induced pneumonitis: pre-existing interstitial pneumonitis shadow, on CT-scan was well

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correlated to severe radiation pneumonitis (1-year cumulative incidence of 57 % with existing interstitial
pneumonitis shadow versus 2 % without) in Yamashita study (15). The implementation of such pre-
screening reduced the incidence of radiation pneumonitis. Another Japanese study identified 16 % of
subclinical ILD: grade II-V radiation pneumonitis was identified in three out of 16 patients with subclinical
ILD. In terms of disease control, no significant differences were identified in OS and 3 years local control
rates between the group with and without ILD (16). These results should be taken with caution and further
research is needed to clarify this issue (17). Ueki (18) study retrospectively included 157 patients treated
with SBRT including 20 ILD patients. Pre-existing ILD was also identified as a risk factor for grade II (HR: 5.52
[2.43-12.5]) and grade ≥III (HR 6.96 [0.98-49.7]) radiation pneumonitis.

In the LC-ILD population, Median Lung Dose (MLD), V20, V30 and normal tissue complication
probability (NTCP) seem well correlated to the incidence and severity of radiation pneumonitis for
standard radiotherapy (14).

In a systematic review of 13 different studies of SBRT, authors suggest that V20 ≤ 6.5% and mean lung dose
≤ 4.5 Grays (Gy) were associated to reduced mortality (19). In another study, severe radiation pneumonitis
was not correlated with dose-volume histogram parameters (15). In our series, only two patients had a V20
>6.5% and MLD > 4.5 Gy, and both had worsening ILD extension and appearance of new ILD lesions
without determining the potential SBRT imputability due to the small size of the series. It is very important
to understand that the use of dosimetric data as a risk factor for SBRT such as V20 should be done with
caution. Indeed, the modalities of SBRT prescription and dose are complex and are not always available in
published studies (maximum dose, prescription isodoses, type of radiotherapy, overall treatment course)
and therefore the published data are only valid for the patients of the center. This heterogeneity in
treatment modalities prevents extrapolation of results presented in the literature. A quality control of
dosimetry would be mandatory in order to be able to conclude on this point in future studies.

Chronic ILD are heterogeneous. Accurate diagnosis and classification influence both prognosis and
treatment. IPF has the poorest prognosis of the fibrosing ILD due to the predominance of fibrosis, whereas
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correlated to severe radiation pneumonitis (1-year cumulative incidence of 57 % with existing interstitial
pneumonitis shadow versus 2 % without) in Yamashita study (15). The implementation of such pre-
screening reduced the incidence of radiation pneumonitis. Another Japanese study identified 16 % of
subclinical ILD: grade II-V radiation pneumonitis was identified in three out of 16 patients with subclinical
ILD. In terms of disease control, no significant differences were identified in OS and 3 years local control
rates between the group with and without ILD (16). These results should be taken with caution and further
research is needed to clarify this issue (17). Ueki (18) study retrospectively included 157 patients treated
with SBRT including 20 ILD patients. Pre-existing ILD was also identified as a risk factor for grade II (HR: 5.52
[2.43-12.5]) and grade ≥III (HR 6.96 [0.98-49.7]) radiation pneumonitis.

In the LC-ILD population, Median Lung Dose (MLD), V20, V30 and normal tissue complication
probability (NTCP) seem well correlated to the incidence and severity of radiation pneumonitis for
standard radiotherapy (14).

In a systematic review of 13 different studies of SBRT, authors suggest that V20 ≤ 6.5% and mean lung dose
≤ 4.5 Grays (Gy) were associated to reduced mortality (19). In another study, severe radiation pneumonitis
was not correlated with dose-volume histogram parameters (15). In our series, only two patients had a V20
>6.5% and MLD > 4.5 Gy, and both had worsening ILD extension and appearance of new ILD lesions
without determining the potential SBRT imputability due to the small size of the series. It is very important
to understand that the use of dosimetric data as a risk factor for SBRT such as V20 should be done with
caution. Indeed, the modalities of SBRT prescription and dose are complex and are not always available in
published studies (maximum dose, prescription isodoses, type of radiotherapy, overall treatment course)
and therefore the published data are only valid for the patients of the center. This heterogeneity in
treatment modalities prevents extrapolation of results presented in the literature. A quality control of
dosimetry would be mandatory in order to be able to conclude on this point in future studies.

Chronic ILD are heterogeneous. Accurate diagnosis and classification influence both prognosis and
treatment. IPF has the poorest prognosis of the fibrosing ILD due to the predominance of fibrosis, whereas
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inflammation may coexist or pre-exist with fibrosis in non-IPF ILD. Gender, age and lung function tests (FVC and DLCO) are important predictors of survival, but the ILD subtype should be considered as it influences survival in risk prediction models such as the ILD-GAP model (20).

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A subset of patients may have a progressive decline affecting outcomes and treatment choice: progressive fibrosing interstitial lung disease (PF-ILD) is characterised by a decline over the past 2 years defined as relative FVC of at least 10% of predicted value, decline in relative FVC of 5-10% of predicted value, and worsening of respiratory symptoms or increase in the extent of fibrosis on high-resolution CT.

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Antifibrotic therapy with nintedanib or pirfenidone can slow down the decline in lung function in IPF, with an expanded indication for PF-ILD with nintedanib (21). We tried to identify the radiological course of ILD before radiotherapy. It might be interesting to study whether such a prior course is associated with a more negative effect of radiotherapy or other local treatments. The evolution of the radiotherapy scar on CT-Scan was also explored (Figure 3) and different evolutionary patterns could emerge such as hypertrophic, stable or regression for this type of population and it could be interesting to correlate it with functional decline and to different isodoses.

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Remarkably, 8 patients had a LC located in the parenchyma affected by ILD. This seems to be consistent with the literature where tumor nodules are usually found in fibrotic areas in about 68% of cases (1). Whether the treatment of a nodule located in a fibrotic area might have better results compared with a healthy parenchyma by preserving it remains an open question. But on the other hand, a proximal nodule could have a different histology with a worse prognosis, such as small cell lung cancer, or treatment of the fibrotic area could trigger an exacerbation of fibrosis in the healthy parenchyma.

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Moreover, our study involves non-Asian patients whereas most existing studies in LC-ILD involve Japanese patients. Epidemiological data suggest ethnic differences between the Japanese population, and the rest of the world, potentially related to genetic factors: acute exacerbation of IPF may be more frequent and respiratory AE induced by EGFR (Epidermal Growth Factor Receptor) Tyrosine Kinase

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inflammation may coexist or pre-exist with fibrosis in non-IPF ILD. Gender, age and lung function tests (FVC and DLCO) are important predictors of survival, but the ILD subtype should be considered as it influences survival in risk prediction models such as the ILD-GAP model (20).

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A subset of patients may have a progressive decline affecting outcomes and treatment choice: progressive fibrosing interstitial lung disease (PF-ILD) is characterised by a decline over the past 2 years defined as relative FVC of at least 10% of predicted value, decline in relative FVC of 5-10% of predicted value, and worsening of respiratory symptoms or increase in the extent of fibrosis on high-resolution CT.

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Antifibrotic therapy with nintedanib or pirfenidone can slow down the decline in lung function in IPF, with an expanded indication for PF-ILD with nintedanib (21). We tried to identify the radiological course of ILD before radiotherapy. It might be interesting to study whether such a prior course is associated with a more negative effect of radiotherapy or other local treatments. The evolution of the radiotherapy scar on CT-Scan was also explored (Figure 3) and different evolutionary patterns could emerge such as hypertrophic, stable or regression for this type of population and it could be interesting to correlate it with functional decline and to different isodoses.

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Remarkably, 8 patients had a LC located in the parenchyma affected by ILD. This seems to be consistent with the literature where tumor nodules are usually found in fibrotic areas in about 68% of cases (1). Whether the treatment of a nodule located in a fibrotic area might have better results compared with a healthy parenchyma by preserving it remains an open question. But on the other hand, a proximal nodule could have a different histology with a worse prognosis, such as small cell lung cancer, or treatment of the fibrotic area could trigger an exacerbation of fibrosis in the healthy parenchyma.

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Moreover, our study involves non-Asian patients whereas most existing studies in LC-ILD involve Japanese patients. Epidemiological data suggest ethnic differences between the Japanese population, and the rest of the world, potentially related to genetic factors: acute exacerbation of IPF may be more frequent and respiratory AE induced by EGFR (Epidermal Growth Factor Receptor) Tyrosine Kinase

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Inhibitors is also more frequent in Japan (22). This suggests the importance of performing the same analysis for non-Japanese patients and determine whether the results are similar.

In our study, radiological patterns were reviewed by expert radiologist and all patients had Multidisciplinary discussion, Heterogeneity of ILD patterns, function status and types of treatments is another important issue for further studies. An effort should be made for accurate collection of these data in order to identify the best predictive model. As already studied before surgery, the role of preventive anti-inflammatory or antifibrotic therapy and the identification of the potential target population has to be studied in this setting.

Here we studied the role of SBRT, but a literature review of different treatments (19) identified that the weighted proportion of treatment-related mortality (and ILD-specific toxicity) depended on the type of treatment: 2.2 (12%) after surgery, 15.6 (25%) after SBRT, 4.3 (18,2%) after particle beam therapy and 8.7 (25%) after radiofrequency ablation (RFA). Efforts must also be made to define the best therapeutic decision for this population.

A prospective Canadian phase II study is recruiting patients treated with SBRT for LC-ILD (T1-2N0M0). Survival and toxicity outcomes of 3 different cohorts stratified by the severity of ILD (ILD-GAP index) are being assessed. In this study, SBRT (50Gy in 5 fractions with pre-specified de-escalation rules) is delivered using rotational therapy (volumetric modulated arc therapy, or Tomotherapy) or static beams (3D conformal or intensity modulated radiotherapy) (23).

Our study was a feasibility study, with some limits since not all patients had histologically proven LC, but this reflects the daily practice with some patients not eligible for biopsy due to the high risk of pneumothorax or haemoptysis induced by the procedure.

Another challenge was to identify these rare patients: we used the ICD-10 diagnosis code. This method unambiguously identifies ILD, it nevertheless involves a selection bias with potentially more severe patients but reflecting the reality of the practice and on the other hand avoiding recall bias. In our cohort, we identified about 3% of lung cancers among the 1361 patients followed for ILD, which means that we
Inhibitors is also more frequent in Japan (22). This suggests the importance of performing the same analysis for non-Japanese patients and determine whether the results are similar.

In our study, radiological patterns were reviewed by expert radiologist and all patients had Multidisciplinary discussion, Heterogeneity of ILD patterns, function status and types of treatments is another important issue for further studies. An effort should be made for accurate collection of these data in order to identify the best predictive model. As already studied before surgery, the role of preventive anti-inflammatory or antifibrotic therapy and the identification of the potential target population has to be studied in this setting.

Here we studied the role of SBRT, but a literature review of different treatments (19) identified that the weighted proportion of treatment-related mortality (and ILD-specific toxicity) depended on the type of treatment: 2.2 (12%) after surgery, 15.6 (25%) after SBRT, 4.3 (18,2%) after particle beam therapy and 8.7 (25%) after radiofrequency ablation (RFA). Efforts must also be made to define the best therapeutic decision for this population.

A prospective Canadian phase II study is recruiting patients treated with SBRT for LC-ILD (T1-2N0M0). Survival and toxicity outcomes of 3 different cohorts stratified by the severity of ILD (ILD-GAP index) are being assessed. In this study, SBRT (50Gy in 5 fractions with pre-specified de-escalation rules) is delivered using rotational therapy (volumetric modulated arc therapy, or Tomotherapy) or static beams (3D conformal or intensity modulated radiotherapy) (23).

Our study was a feasibility study, with some limits since not all patients had histologically proven LC, but this reflects the daily practice with some patients not eligible for biopsy due to the high risk of pneumothorax or haemoptysis induced by the procedure.

Another challenge was to identify these rare patients: we used the ICD-10 diagnosis code. This method unambiguously identifies ILD, it nevertheless involves a selection bias with potentially more severe patients but reflecting the reality of the practice and on the other hand avoiding recall bias. In our cohort, we identified about 3% of lung cancers among the 1361 patients followed for ILD, which means that we
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could not identify with this method patients with undiagnosed ILD or patients with interstitial lung
abnormalities (ILAs) which are an independent risk of mortality with predominantly subpleural fibrosis
(24). The prevalence of ILAs is 4 to 9% in smokers over 60 years old. The study of the effects of lung cancer
treatments on patients with ILAs is another important research topic.

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In conclusion this feasibility study has identified various retrospective data that are readily available
in order to define what could be useful for a larger retrospective cohort. Defining poor prognosis criteria
for such heterogeneous population could be valuable for designing clinical trials with the objective to
prevent potential harmful toxicities and adequately select patients who could benefit from the treatment.
The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to
heterogeneous and complex dose delivery and various modalities of prescription which is a specific
concern to take in account for future studies.

(3016)

words
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could not identify with this method patients with undiagnosed ILD or patients with interstitial lung
abnormalities (ILAs) which are an independent risk of mortality with predominantly subpleural fibrosis
(24). The prevalence of ILAs is 4 to 9% in smokers over 60 years old. The study of the effects of lung cancer
treatments on patients with ILAs is another important research topic.

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In conclusion this feasibility study has identified various retrospective data that are readily available
in order to define what could be useful for a larger retrospective cohort. Defining poor prognosis criteria
for such heterogeneous population could be valuable for designing clinical trials with the objective to
prevent potential harmful toxicities and adequately select patients who could benefit from the treatment.
The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to
heterogeneous and complex dose delivery and various modalities of prescription which is a specific
concern to take in account for future studies.

(3016)

words
<table><thead><tr><th>Patients<br>Variables</th><th>#1</th><th>#2</th><th>#3</th><th>4#</th><th>#5</th><th>#6</th><th>#7</th><th>#8</th><th>#9</th></tr></thead><tbody><tr><td>Gender (age year)</td><td>M (59)</td><td>M (72)</td><td>M (80)</td><td>M (66)</td><td>F (66)</td><td>M(75)</td><td>M (71)</td><td>F(71)</td><td>F(89)</td></tr><tr><td>Smoking<br>(pack-year)</td><td>active(10)</td><td>never</td><td>former (40)</td><td>former (40)</td><td>former (75)</td><td>former (50)</td><td>active (60)</td><td>active (60)</td><td>active (45)</td></tr><tr><td>Date of ILD Diagnosis</td><td>2000</td><td>2005</td><td>2016</td><td>2011</td><td>2016</td><td>1999</td><td>2003</td><td>2019</td><td>2019</td></tr><tr><td>Biopsy TTNA</td><td>Yes (ADC)</td><td>No</td><td>No</td><td>No</td><td>Yes (ADC)</td><td>No</td><td>Yes (Sq)</td><td>Yes (ADC)</td><td>Yes (ADC)</td></tr><tr><td>Emphysema</td><td>Yes</td><td>0</td><td>Yes</td><td>0</td><td>Yes</td><td>Yes</td><td>Yes</td><td>0</td><td>0</td></tr><tr><td>Radiology Pattern</td><td>NSIP</td><td>UIP</td><td>NSIP</td><td>UIP</td><td>UIP</td><td>CBD</td><td>UIP</td><td>OP</td><td>OP</td></tr><tr><td>MDD diagnosis</td><td>CTD-ILD</td><td>CTD-ILD</td><td>CPFE</td><td>IPF</td><td>CPFE</td><td>CBD</td><td>CTD-ILD</td><td>OP</td><td>OP induced by statin</td></tr><tr><td>Nodule in Pathological<br>parenchyma</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>ILD imaging worsening<br>before radiotherapy</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Visual Fibrosis<br>quantification</td><td>Moderate<br>10-25</td><td>Moderate<br>10-25</td><td>High<br>25-50</td><td>High<br>25-50</td><td>Severe<br>50-75</td><td>Severe<br>50-75</td><td>High<br>25-50</td><td>Mild<br>&lt;10%</td><td>Moderate<br>10-25</td></tr><tr><td>Date of radiotherapy<br>treatment (type)</td><td>01/2019 (IMRT<br>tomotherapy)</td><td>09/2019 (IMRT<br>tomotherapy)</td><td>07/2019 (Cyber<br>knife®)</td><td>03/2018<br>(True Beam®)</td><td>04/2018<br>(True Beam®)</td><td>06/2020<br>(IMRT tomotherapy)</td><td>12/2018<br>(IMRT tomotherapy)</td><td>11/2019<br>(IMRT tomotherapy)</td><td>01/2020<br>(IMRT tomotherapy)</td></tr><tr><td>Dose (Gy) / Fraction /<br>Dose per fraction</td><td>60/8/7.5</td><td>60/8/7.5</td><td>54/3/18</td><td>50/10/5</td><td>60/8/7.5</td><td>45/5/9</td><td>59.5/7/8.5</td><td>60/5/12</td><td>60/8/7.5</td></tr><tr><td>Overall treatment<br>duration (d)</td><td>17</td><td>13</td><td>4</td><td>26</td><td>13</td><td>11</td><td>5</td><td>8</td><td>16</td></tr><tr><td>V20/V12,5/MLD</td><td>3%/6%/2.5Gy</td><td>4.3%/9%/4.2Gy</td><td>0.9%/1.3%/1.72Gy</td><td>5%/7.5%/3.6Gy</td><td>3.6%/7.5%/3.8Gy</td><td>1.5%/3.3%/6Gy</td><td>8.9%/13.5%/6Gy</td><td>2.7%/5.5%/2.5Gy</td><td>6.6%/13%/4.9Gy</td></tr><tr><td>Overall Survival<br>(month)</td><td>34.9</td><td>19</td><td>5.4</td><td>17.4</td><td>7.8</td><td>4.8</td><td>20.8</td><td>24.3</td><td>14.3</td></tr><tr><td>Relapse (Vital Status)</td><td>Metastatic<br>(Alive)</td><td>Metastatic<br>(Dead)</td><td>Metastatic<br>(Dead)</td><td>Metastatic<br>(Dead)</td><td>NO (Dead:<br>COPD<br>exacerbation)</td><td>Metastatic<br>(Dead)</td><td>Metastatic<br>(Dead)</td><td>NO<br>(Alive)</td><td>NO<br>(Dead :myeloid Leukemia)</td></tr><tr><td>DFS (months)</td><td>13.5</td><td>7.4</td><td>3.7</td><td>7.9</td><td>7.8</td><td>3.6</td><td>14.6</td><td>24.3</td><td>14.3</td></tr><tr><td>GAP-Index<br>(%1y mortality)</td><td>I<br>(5.6%)</td><td>III<br>(39.2%)</td><td>II<br>(16.2%)</td><td>III<br>(39.2%)</td><td>II<br>(16.2%)</td><td>N.A</td><td>II<br>(16.2%)</td><td>N.A</td><td>N.A</td></tr><tr><td>PFT before radiotherapy</td><td>12/2018</td><td>05/2019</td><td>11/2018</td><td>01/2018</td><td>10/2017</td><td>06/2020</td><td>11/2018</td><td>10/2015</td><td>01/2020</td></tr><tr><td>FVC (%Pred)</td><td>3130(77)</td><td>2600(63)</td><td>2710(77)</td><td>2480(52)</td><td>1700(79)</td><td>2230(61)</td><td>1810(66)</td><td>3000(114)</td><td>2470(103)</td></tr><tr><td>DLCO(%Pred)</td><td>39</td><td>23</td><td>24</td><td>29</td><td>22</td><td>24</td><td>60</td><td>NA</td><td>NA</td></tr><tr><td>Respiratory AE after RT<br>(grade)<br>Treatment</td><td>Yes (1)</td><td>Yes (2)<br>-Antibiotics 7days<br>-Temporary<br>Prednisone<br>increase dose</td><td>No</td><td>No</td><td>Yes (2)</td><td>No</td><td>No</td><td>Yes (1)</td><td>Yes (2)<br>-Antibiotics 7days<br>-Prednisone 14days<br>(20mg/d)</td></tr><tr><td>Lung function decline<br>(%FVC)</td><td>Yes<br>(-11%)</td><td>Yes<br>(-15%)</td><td>No<br>(-9%)</td><td>No<br>(-4%)</td><td>NA</td><td>NA</td><td>NA</td><td>No<br>(-9%)</td><td>Yes<br>(-23%)</td></tr><tr><td>Radiation pneumonitis<br>(time to occur)</td><td>No</td><td>Yes (5m)</td><td>No</td><td>Yes (11m)</td><td>No</td><td>No</td><td>Yes (11m)</td><td>Yes (3m)</td><td>Yes (3m)</td></tr><tr><td>CT ILD acute worsening</td><td>Yes (6m)</td><td>No</td><td>Yes (3m)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes (3m)</td></tr><tr><td>CT ILD chronic<br>worsening; Extent<br>(month)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes (11m) Yes (18m)</td><td>No</td><td>Yes (8m)</td></tr><tr><td>CT ILD worsening new<br>lesions (month)</td><td>No</td><td>Yes (14m)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes (20m)</td><td>Yes (13m)</td><td>Yes (8m)</td></tr></tbody></table>
<table><thead><tr><th>Patients<br>Variables</th><th>#1</th><th>#2</th><th>#3</th><th>4#</th><th>#5</th><th>#6</th><th>#7</th><th>#8</th><th>#9</th></tr></thead><tbody><tr><td>Gender (age year)</td><td>M (59)</td><td>M (72)</td><td>M (80)</td><td>M (66)</td><td>F (66)</td><td>M(75)</td><td>M (71)</td><td>F(71)</td><td>F(89)</td></tr><tr><td>Smoking<br>(pack-year)</td><td>active(10)</td><td>never</td><td>former (40)</td><td>former (40)</td><td>former (75)</td><td>former (50)</td><td>active (60)</td><td>active (60)</td><td>active (45)</td></tr><tr><td>Date of ILD Diagnosis</td><td>2000</td><td>2005</td><td>2016</td><td>2011</td><td>2016</td><td>1999</td><td>2003</td><td>2019</td><td>2019</td></tr><tr><td>Biopsy TTNA</td><td>Yes (ADC)</td><td>No</td><td>No</td><td>No</td><td>Yes (ADC)</td><td>No</td><td>Yes (Sq)</td><td>Yes (ADC)</td><td>Yes (ADC)</td></tr><tr><td>Emphysema</td><td>Yes</td><td>0</td><td>Yes</td><td>0</td><td>Yes</td><td>Yes</td><td>Yes</td><td>0</td><td>0</td></tr><tr><td>Radiology Pattern</td><td>NSIP</td><td>UIP</td><td>NSIP</td><td>UIP</td><td>UIP</td><td>CBD</td><td>UIP</td><td>OP</td><td>OP</td></tr><tr><td>MDD diagnosis</td><td>CTD-ILD</td><td>CTD-ILD</td><td>CPFE</td><td>IPF</td><td>CPFE</td><td>CBD</td><td>CTD-ILD</td><td>OP</td><td>OP induced by statin</td></tr><tr><td>Nodule in Pathological<br>parenchyma</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td><td>No</td></tr><tr><td>ILD imaging worsening<br>before radiotherapy</td><td>No</td><td>No</td><td>No</td><td>Yes</td><td>No</td><td>Yes</td><td>Yes</td><td>Yes</td><td>Yes</td></tr><tr><td>Visual Fibrosis<br>quantification</td><td>Moderate<br>10-25</td><td>Moderate<br>10-25</td><td>High<br>25-50</td><td>High<br>25-50</td><td>Severe<br>50-75</td><td>Severe<br>50-75</td><td>High<br>25-50</td><td>Mild<br>&lt;10%</td><td>Moderate<br>10-25</td></tr><tr><td>Date of radiotherapy<br>treatment (type)</td><td>01/2019 (IMRT<br>tomotherapy)</td><td>09/2019 (IMRT<br>tomotherapy)</td><td>07/2019 (Cyber<br>knife®)</td><td>03/2018<br>(True Beam®)</td><td>04/2018<br>(True Beam®)</td><td>06/2020<br>(IMRT tomotherapy)</td><td>12/2018<br>(IMRT tomotherapy)</td><td>11/2019<br>(IMRT tomotherapy)</td><td>01/2020<br>(IMRT tomotherapy)</td></tr><tr><td>Dose (Gy) / Fraction /<br>Dose per fraction</td><td>60/8/7.5</td><td>60/8/7.5</td><td>54/3/18</td><td>50/10/5</td><td>60/8/7.5</td><td>45/5/9</td><td>59.5/7/8.5</td><td>60/5/12</td><td>60/8/7.5</td></tr><tr><td>Overall treatment<br>duration (d)</td><td>17</td><td>13</td><td>4</td><td>26</td><td>13</td><td>11</td><td>5</td><td>8</td><td>16</td></tr><tr><td>V20/V12,5/MLD</td><td>3%/6%/2.5Gy</td><td>4.3%/9%/4.2Gy</td><td>0.9%/1.3%/1.72Gy</td><td>5%/7.5%/3.6Gy</td><td>3.6%/7.5%/3.8Gy</td><td>1.5%/3.3%/6Gy</td><td>8.9%/13.5%/6Gy</td><td>2.7%/5.5%/2.5Gy</td><td>6.6%/13%/4.9Gy</td></tr><tr><td>Overall Survival<br>(month)</td><td>34.9</td><td>19</td><td>5.4</td><td>17.4</td><td>7.8</td><td>4.8</td><td>20.8</td><td>24.3</td><td>14.3</td></tr><tr><td>Relapse (Vital Status)</td><td>Metastatic<br>(Alive)</td><td>Metastatic<br>(Dead)</td><td>Metastatic<br>(Dead)</td><td>Metastatic<br>(Dead)</td><td>NO (Dead:<br>COPD<br>exacerbation)</td><td>Metastatic<br>(Dead)</td><td>Metastatic<br>(Dead)</td><td>NO<br>(Alive)</td><td>NO<br>(Dead:myeloid Leukemia)</td></tr><tr><td>DFS (months)</td><td>13.5</td><td>7.4</td><td>3.7</td><td>7.9</td><td>7.8</td><td>3.6</td><td>14.6</td><td>24.3</td><td>14.3</td></tr><tr><td>GAP-Index<br>(%1y mortality)</td><td>I<br>(5.6%)</td><td>III<br>(39.2%)</td><td>II<br>(16.2%)</td><td>III<br>(39.2%)</td><td>II<br>(16.2%)</td><td>N.A</td><td>II<br>(16.2%)</td><td>N.A</td><td>N.A</td></tr><tr><td>PFT before radiotherapy</td><td>12/2018</td><td>05/2019</td><td>11/2018</td><td>01/2018</td><td>10/2017</td><td>06/2020</td><td>11/2018</td><td>10/2015</td><td>01/2020</td></tr><tr><td>FVC (%Pred)</td><td>3130(77)</td><td>2600(63)</td><td>2710(77)</td><td>2480(52)</td><td>1700(79)</td><td>2230(61)</td><td>1810(66)</td><td>3000(114)</td><td>2470(103)</td></tr><tr><td>DLCO(%Pred)</td><td>39</td><td>23</td><td>24</td><td>29</td><td>22</td><td>24</td><td>60</td><td>NA</td><td>NA</td></tr><tr><td>Respiratory AE after RT<br>(grade)<br>Treatment</td><td>Yes (1)</td><td>Yes (2)<br>-Antibiotics 7days<br>-Temporary<br>Prednisone<br>increase dose</td><td>No</td><td>No</td><td>Yes (2)</td><td>No</td><td>No</td><td>Yes (1)</td><td>Yes (2)<br>-Antibiotics 7days<br>-Prednisone 14days<br>(20mg/d)</td></tr><tr><td>Lung function decline<br>(%FVC)</td><td>Yes<br>(-11%)</td><td>Yes<br>(-15%)</td><td>No<br>(-9%)</td><td>No<br>(-4%)</td><td>NA</td><td>NA</td><td>NA</td><td>No<br>(-9%)</td><td>Yes<br>(-23%)</td></tr><tr><td>Radiation pneumonitis<br>(time to occur)</td><td>No</td><td>Yes (5m)</td><td>No</td><td>Yes (11m)</td><td>No</td><td>No</td><td>Yes (11m)</td><td>Yes (3m)</td><td>Yes (3m)</td></tr><tr><td>CT ILD acute worsening</td><td>Yes (6m)</td><td>No</td><td>Yes (3m)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes (3m)</td></tr><tr><td>CT ILD chronic<br>worsening; Extent<br>(month)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes (11m) Yes (18m)</td><td>No</td><td>Yes (8m)</td></tr><tr><td>CT ILD worsening new<br>lesions (month)</td><td>No</td><td>Yes (14m)</td><td>No</td><td>No</td><td>No</td><td>No</td><td>Yes (20m)</td><td>Yes (13m)</td><td>Yes (8m)</td></tr></tbody></table>
**Captions :**

Figure 1: Study Flow chart: Distribution of patients with probable lung cancer and Interstitial Lung Disease (LC-ILD) and Baseline Oncological and demographic data of patients with early-stage LC-ILD treated with SBRT and Surgery N: headcounts, IQR: Interquartile Range, CT: Computed Tomography, TTNA: Trans-thoracic Needle Aspiration, ADK: Adenocarcinoma Sq: Squamous

Figure 2: Kaplan Meier Curves for Overall survival and Disease-Free Survival for the 9 patients. OS and DFS were considered for all patients: the time origin was set at the first day of radiotherapy treatment and the status of each patient (alive, dead, or lost to follow-up, relapse) was determined on the study termination date (set at December, 2021)

Figure 3: Radiotherapy scar volume evolution after SBRT (cm³)

Figure 4: Example of patient #2 with Sjögren's syndrome and interstitial lung disease (ILD). A) Axial parenchyma view of unenhanced chest CT showing traction bronchiolectasis (arrowhead) and scissural distortion (white thin arrow). B) Two years after during follow-up, ILD was stable but a subpleural nodule appears in the lingula, C) with hypermetabolic activity on PET-CT. This nodule was a biopsy proven adenocarcinoma and was treated by stereotactic body lung radiation therapy, D) follow-up six months after the end of SBRT showed an acute radiation pneumonitis (white arrow with black line) and E) one year after a consolidation of the radiation pneumonitis with a mild extend of ILD without new lesions.

Table: Baseline and evolution of clinical, function and imaging after stereotaxic radiotherapy.
ADC: adenocarcinoma, AE: adverse events, CBD: chronic berylium disease, CPFE: combined pulmonary fibrosis and emphysema, CTD-ILD: connective tissue disease associated with ILD, DLCO: diffusion capacity of the lung for carbon monoxide, FVC: forced vital capacity, Gy: Gray, ILD: interstitial lung disease, IMRT: intensity-modulated radiation therapy, IPF: idiopathic pulmonary fibrosis, OP: organizing pneumonia, UIP: usual interstitial pneumonia, NSIP: Non Specific Interstitial Pneumonia, PFT: pulmonary function test, RT: radiotherapy, Sq: squamous cell, TTNA: Trans-thoracic Needle Aspiration
**Captions :**

Figure 1: Study Flow chart: Distribution of patients with probable lung cancer and Interstitial Lung Disease (LC-ILD) and Baseline Oncological and demographic data of patients with early-stage LC-ILD treated with SBRT and Surgery N: headcounts, IQR: Interquartile Range, CT: Computed Tomography, TTNA: Trans-thoracic Needle Aspiration, ADK: Adenocarcinoma Sq: Squamous

Figure 2: Kaplan Meier Curves for Overall survival and Disease-Free Survival for the 9 patients. OS and DFS were considered for all patients: the time origin was set at the first day of radiotherapy treatment and the status of each patient (alive, dead, or lost to follow-up, relapse) was determined on the study termination date (set at December, 2021)

Figure 3: Radiotherapy scar volume evolution after SBRT (cm³)

Figure 4: Example of patient #2 with Sjögren's syndrome and interstitial lung disease (ILD). A) Axial parenchyma view of unenhanced chest CT showing traction bronchiolectasis (arrowhead) and scissural distortion (white thin arrow). B) Two years after during follow-up, ILD was stable but a subpleural nodule appears in the lingula, C) with hypermetabolic activity on PET-CT. This nodule was a biopsy proven adenocarcinoma and was treated by stereotactic body lung radiation therapy, D) follow-up six months after the end of SBRT showed an acute radiation pneumonitis (white arrow with black line) and E) one year after a consolidation of the radiation pneumonitis with a mild extend of ILD without new lesions.

Table: Baseline and evolution of clinical, function and imaging after stereotaxic radiotherapy.
ADC: adenocarcinoma, AE: adverse events, CBD: chronic berylium disease, CPFE: combined pulmonary fibrosis and emphysema, CTD-ILD: connective tissue disease associated with ILD, DLCO: diffusion capacity of the lung for carbon monoxide, FVC: forced vital capacity, Gy: Gray, ILD: interstitial lung disease, IMRT: intensity-modulated radiation therapy, IPF: idiopathic pulmonary fibrosis, OP: organizing pneumonia, UIP: usual interstitial pneumonia, NSIP: Non Specific Interstitial Pneumonia, PFT: pulmonary function test, RT: radiotherapy, Sq: squamous cell, TTNA: Trans-thoracic Needle Aspiration
References:

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2) Girard N, Marchand-Adam S, Naccache JM, Borie R, Urban T, Jouneau S et al. Lung cancer in combined pulmonary fibrosis and emphysema: a series of 47 Western patients. J Thorac Oncol. 2014 Aug;9(8):1162-70. doi: 10.1097/JTO.0000000000000209. PMID: 25157769.

3) Gibiot Q, Monnet I, Levy P, Brun AL, Antoine M, Chouaïd C et al. Interstitial Lung Disease Associated with Lung Cancer: A Case-Control Study. J Clin Med. 2020 Mar 5;9(3):700. doi: 10.3390/jcm9030700. PMID: 32150840; PMCID: PMC7141363.

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10) Nagata Y, Hiraoka M, Mizowaki T, Narita Y, Matsuo Y, Norihisa Y et al. Survey of stereotactic body radiation therapy in Japan by the Japan 3-D Conformal External Beam Radiotherapy Group. Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):343-7. doi: 10.1016/j.ijrobp.2009.02.087. PMID: 19735861.

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1) Naccache JM, Gibiot Q, Monnet I, Antoine M, Wislez M, Chouaid C et al. Lung cancer and interstitial lung disease: a literature review. J Thorac Dis. 2018 Jun;10(6):3829-3844. doi: 10.21037/jtd.2018.05.75. PMID: 30069384; PMCID: PMC6051867.

2) Girard N, Marchand-Adam S, Naccache JM, Borie R, Urban T, Jouneau S et al. Lung cancer in combined pulmonary fibrosis and emphysema: a series of 47 Western patients. J Thorac Oncol. 2014 Aug;9(8):1162-70. doi: 10.1097/JTO.0000000000000209. PMID: 25157769.

3) Gibiot Q, Monnet I, Levy P, Brun AL, Antoine M, Chouaïd C et al. Interstitial Lung Disease Associated with Lung Cancer: A Case-Control Study. J Clin Med. 2020 Mar 5;9(3):700. doi: 10.3390/jcm9030700. PMID: 32150840; PMCID: PMC7141363.

4) Sato T, Watanabe A, Kondo H, Kanzaki M, Okubo K, Yokoi K et al. Long-term results and predictors of survival after surgical resection of patients with lung cancer and interstitial lung diseases. J Thorac Cardiovasc Surg. 2015 Jan;149(1):64-9, 70.e1-2. doi: 10.1016/j.jtcvs.2014.08.086. Epub 2014 Sep 18. PMID: 25439777.

5) Videtic GMM, Donington J, Giuliani M, Heinzerling J, Karas TZ, Kelsey CR and al Stereotactic body radiation therapy for early-stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Pract Radiat Oncol. 2017 Sep-Oct;7(5):295-301. doi: 10.1016/j.prro.2017.04.014. Epub 2017 Jun 5. PMID: 28596092.

6) Chang JY, Mehran RJ, Feng L, Verma V, Liao Z, Welsh JW et al. Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery. Lancet Oncol. 2021 Oct;22(10):1448-1457. doi: 10.1016/S1470-2045(21)00401-0. Epub 2021 Sep 13. PMID: 34529930; PMCID: PMC8521627.

7) Ozawa Y, Abe T, Omae M, Matsui T, Kato M, Hasegawa H et al. Impact of Preexisting Interstitial Lung Disease on Acute, Extensive Radiation Pneumonitis: Retrospective Analysis of Patients with Lung Cancer. PLoS One. 2015 Oct 13;10(10):e0140437. doi: 10.1371/journal.pone.0140437. PMID: 26460792; PMCID: PMC4603947.

8) Fujimoto T, Okazaki T, Matsukura T, Hanawa T, Yamashita N, Nishimura K et al. Operation for lung cancer in patients with idiopathic pulmonary fibrosis: surgical contraindication? Ann Thorac Surg. 2003 Nov;76(5):1674-8; discussion 1679. doi: 10.1016/S0003-4975(03)00966-4. PMID: 14602310.

9) Yamaguchi S, Ohguri T, Matsuki Y, Yahara K, Oki H, Imada H et al. Radiotherapy for thoracic tumors: association between subclinical interstitial lung disease and fatal radiation pneumonitis. Int J Clin Oncol. 2015 Feb;20(1):45-52. doi: 10.1007/s10147-014-0679-1. Epub 2014 Mar 11. PMID: 24610080.

10) Nagata Y, Hiraoka M, Mizowaki T, Narita Y, Matsuo Y, Norihisa Y et al. Survey of stereotactic body radiation therapy in Japan by the Japan 3-D Conformal External Beam Radiotherapy Group. Int J Radiat Oncol Biol Phys. 2009 Oct 1;75(2):343-7. doi: 10.1016/j.ijrobp.2009.02.087. PMID: 19735861.

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13) Revel MP, Boussouar S, de Margerie-Mellon C, Saab I, Lapotre T, Mompoint D et al. Study of Thoracic CT in COVID-19: The STOIC Project. Radiology. 2021 Oct;301(1):E361-E370. doi: 10.1148/radiol.2021210384. Epub 2021 Jun 29. PMID: 34184935; PMCID: PMC8267782.

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<figure><img src="image_3.png" /><figcaption>Figure 1:</figcaption></figure>

9 early-stage LC-ILD treated with Stereotaxic radiotherapy

<table><thead><tr><th rowspan="2"></th><th rowspan="2"></th><th colspan="2">Total population</th></tr><tr><th>N or (median)</th><th>[IQR]</th></tr></thead><tbody><tr><td>Age</td><td></td><td>(71)</td><td>[66-77]</td></tr><tr><td>Gender</td><td>Women/Men</td><td>3/6</td><td></td></tr><tr><td rowspan="2">Origin</td><td>Caucasian</td><td>8</td><td></td></tr><tr><td>North Africa</td><td>1</td><td></td></tr><tr><td rowspan="4">Smoking Status</td><td>Never smoker</td><td>1</td><td></td></tr><tr><td>Former smoker</td><td>4</td><td></td></tr><tr><td>Active smoker</td><td>4</td><td></td></tr><tr><td>Pack-Year</td><td>47.5</td><td>[40-60]</td></tr><tr><td rowspan="2">ECOG PS</td><td>0</td><td>7</td><td></td></tr><tr><td>1</td><td>2</td><td></td></tr><tr><td rowspan="2">Histologic biopsy</td><td>No biopsy</td><td>4</td><td></td></tr><tr><td>Biopsy</td><td>5 (all CT-scan guided TTNA)</td><td></td></tr><tr><td rowspan="3">TNM</td><td>T1aN0</td><td>4</td><td></td></tr><tr><td>T1bN0</td><td>3</td><td></td></tr><tr><td>T1cN0</td><td>2</td><td></td></tr><tr><td>Size (mm)</td><td></td><td>(16)</td><td>[14.5-18.5]</td></tr><tr><td>FVC (mL)</td><td></td><td>(2480)</td><td>[2020-2855]</td></tr><tr><td>FVC (%Pred)</td><td></td><td>(77)</td><td>[62-91]</td></tr><tr><td>VEMS (mL)</td><td></td><td>(1750)</td><td>[1460-2065]</td></tr><tr><td>VEMS (%Pred)</td><td></td><td>(74)</td><td>[52-87]</td></tr><tr><td>DLCO(%Pred)</td><td></td><td>24</td><td>[23-39]</td></tr><tr><td>Overall Survival</td><td></td><td>17.4</td><td></td></tr><tr><td>Relapse</td><td></td><td>6 relapse/9</td><td></td></tr><tr><td>DFS (months)</td><td></td><td>13.5</td><td></td></tr></tbody></table>

7 early-stage LC-ILD treated with surgery:

<table><thead><tr><th rowspan="2"></th><th rowspan="2"></th><th colspan="2">Total population</th></tr><tr><th>N or (median)</th><th>[IQR]</th></tr></thead><tbody><tr><td>Age</td><td></td><td>(72)</td><td>[67-76]</td></tr><tr><td>Gender</td><td>Women/Men</td><td>1/6</td><td></td></tr><tr><td rowspan="2">Origin</td><td>Caucasian</td><td>5</td><td></td></tr><tr><td>North Africa</td><td>2</td><td></td></tr><tr><td rowspan="2">Smoking Status</td><td>Never smoker</td><td>2</td><td></td></tr><tr><td>Former smoker</td><td>5</td><td></td></tr><tr><td>Pack-Year</td><td></td><td>50</td><td>[0-60]</td></tr><tr><td rowspan="2">ECOG PS</td><td>0</td><td>4</td><td></td></tr><tr><td>1</td><td>3</td><td></td></tr><tr><td>Histology</td><td></td><td>Sq : 6</td><td>ADC 1</td></tr><tr><td rowspan="5">TNM</td><td>T1cN0</td><td>1</td><td></td></tr><tr><td>T2a</td><td>1</td><td></td></tr><tr><td>T4</td><td>2</td><td></td></tr><tr><td>T1cN2</td><td>1</td><td></td></tr><tr><td>T4N1</td><td>1</td><td></td></tr><tr><td>Size (mm)</td><td></td><td>(35)</td><td>[25-45]</td></tr><tr><td>FVC (mL)</td><td></td><td>(3310)</td><td>[2400-3460]</td></tr><tr><td>FVC (%Pred)</td><td></td><td>(99)</td><td>[80-108]</td></tr><tr><td>VEMS (mL)</td><td></td><td>(2560)</td><td>[1800-2940]</td></tr><tr><td>VEMS (%Pred)</td><td></td><td>(106)</td><td>[82-114]</td></tr><tr><td>DLCO(%Pred)</td><td></td><td>(58%)</td><td>[56-71]</td></tr><tr><td>Overall Survival</td><td></td><td>Median not reach (2death)</td><td>28 &14 months</td></tr><tr><td>Relapse</td><td></td><td>1 relapse/7 (24 months)</td><td></td></tr><tr><td>DFS (months)</td><td></td><td>Not Reach</td><td></td></tr></tbody></table>
<figure><img src="image_2.png" /><figcaption>Figure 1:</figcaption></figure>

9 early-stage LC-ILD treated with Stereotaxic radiotherapy

<table><thead><tr><th rowspan="2"></th><th rowspan="2"></th><th colspan="2">Total population</th></tr><tr><th>N or (median)</th><th>[IQR]</th></tr></thead><tbody><tr><td>Age</td><td></td><td>(71)</td><td>[66-77]</td></tr><tr><td>Gender</td><td>Women/Men</td><td>3/6</td><td></td></tr><tr><td rowspan="2">Origin</td><td>Caucasian</td><td>8</td><td></td></tr><tr><td>North Africa</td><td>1</td><td></td></tr><tr><td rowspan="4">Smoking Status</td><td>Never smoker</td><td>1</td><td></td></tr><tr><td>Former smoker</td><td>4</td><td></td></tr><tr><td>Active smoker</td><td>4</td><td></td></tr><tr><td>Pack-Year</td><td>47.5</td><td>[40-60]</td></tr><tr><td>ECOG PS</td><td>0</td><td>7</td><td></td></tr><tr><td rowspan="2">Histologic biopsy</td><td>1</td><td>2</td><td></td></tr><tr><td>No biopsy</td><td>4</td><td></td></tr><tr><td rowspan="3">TNM</td><td>Biopsy</td><td>5 (all CT-scan guided TTNA)</td><td></td></tr><tr><td>T1aN0</td><td>4</td><td></td></tr><tr><td>T1bN0</td><td>3</td><td></td></tr><tr><td></td><td>T1cN0</td><td>2</td><td></td></tr><tr><td>Size (mm)</td><td></td><td>(16)</td><td>[14.5-18.5]</td></tr><tr><td>FVC (mL)</td><td></td><td>(2480)</td><td>[2020-2855]</td></tr><tr><td>FVC (%Pred)</td><td></td><td>(77)</td><td>[62-91]</td></tr><tr><td>VEMS (mL)</td><td></td><td>(1750)</td><td>[1460-2065]</td></tr><tr><td>VEMS (%Pred)</td><td></td><td>(74)</td><td>[52-87]</td></tr><tr><td>DLCO(%Pred)</td><td></td><td>24</td><td>[23-39]</td></tr><tr><td>Overall Survival</td><td></td><td>17.4</td><td></td></tr><tr><td>Relapse</td><td></td><td>6 relapse/9</td><td></td></tr><tr><td>DFS (months)</td><td></td><td>13.5</td><td></td></tr></tbody></table>

7 early-stage LC-ILD treated with surgery:

<table><thead><tr><th rowspan="2"></th><th rowspan="2"></th><th colspan="2">Total population</th></tr><tr><th>N or (median)</th><th>[IQR]</th></tr></thead><tbody><tr><td>Age</td><td></td><td>(72)</td><td>[67-76]</td></tr><tr><td>Gender</td><td>Women/Men</td><td>1/6</td><td></td></tr><tr><td rowspan="2">Origin</td><td>Caucasian</td><td>5</td><td></td></tr><tr><td>North Africa</td><td>2</td><td></td></tr><tr><td rowspan="2">Smoking Status</td><td>Never smoker</td><td>2</td><td></td></tr><tr><td>Former smoker</td><td>5</td><td></td></tr><tr><td></td><td>Pack-Year</td><td>50</td><td>[0-60]</td></tr><tr><td>ECOG PS</td><td>0</td><td>4</td><td></td></tr><tr><td rowspan="2">Histology</td><td>1</td><td>3</td><td></td></tr><tr><td>Sq : 6</td><td></td><td></td></tr><tr><td rowspan="5">TNM</td><td>ADC : 4 Sq : 1</td><td>Sq : 6</td><td></td></tr><tr><td>T1cN0</td><td>1</td><td></td></tr><tr><td>T2a</td><td>1</td><td></td></tr><tr><td>T4</td><td>2</td><td></td></tr><tr><td>T1cN2</td><td>1</td><td></td></tr><tr><td></td><td>T4N1</td><td>1</td><td></td></tr><tr><td>Size (mm)</td><td></td><td>(35)</td><td>[25-45]</td></tr><tr><td>FVC (mL)</td><td></td><td>(3310)</td><td>[2400-3460]</td></tr><tr><td>FVC (%Pred)</td><td></td><td>(99)</td><td>[80-108]</td></tr><tr><td>VEMS (mL)</td><td></td><td>(2560)</td><td>[1800-2940]</td></tr><tr><td>VEMS (%Pred)</td><td></td><td>(106)</td><td>[82-114]</td></tr><tr><td>DLCO(%Pred)</td><td></td><td>(58%)</td><td>[56-71]</td></tr><tr><td>Overall Survival</td><td></td><td>Median not reach (2death)</td><td>28 & 14 months</td></tr><tr><td>Relapse</td><td></td><td>1 relapse/7 (24 months)</td><td></td></tr><tr><td>DFS (months)</td><td></td><td>Not Reach</td><td></td></tr></tbody></table>
<figure><img src="image_4.png" /><figcaption>Figure 2:</figcaption></figure>
<figure><img src="image_3.png" /><figcaption>Figure 2:</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Figure 3:</figcaption></figure>
<figure><img src="image_4.png" /><figcaption>Figure 3:</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>Figure 4 :</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Figure 4 :</figcaption></figure>