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Abstract

Background:

Current research presents conflicting evidence on whether pre-existing interstitial lung disease (ILD) serves as a risk factor for radiation pneumonitis (RP) and checkpoint inhibitor pneumonitis (CIP) in patients with lung cancer.

Objectives:

This study aims to systematically evaluate the impact of pre-existing ILD on the risk of developing RP and CIP in lung cancer patients.

Design:

A systematic review and meta-analysis was conducted using a random-effects model.

Data sources and methods:

PubMed, Embase, and Web of Science were searched to identify relevant studies. A random-effects model was applied to estimate the risk and incidence of RP and CIP in lung cancer patients with pre-existing ILD compared to those without ILD. Sensitivity analyses were performed to assess the robustness of the pooled findings, and potential publication bias was evaluated using Begg’s and Egger’s tests.

Results:

A total of 12 studies involving 2576 patients were included in the RP risk assessment, while 29 studies with 8037 patients were analyzed for CIP risk. The pooled results indicated that pre-existing ILD significantly increased the risk of developing any-grade RP (odds ratio (OR): 3.63, 95% confidence interval (CI): 2.26–5.83) and severe RP (OR: 6.10, 95% CI: 2.68–13.86) in lung cancer patients. Subgroup analyses identified stereotactic body radiation therapy as the modality associated with the lowest risk of any-grade RP in these patients. Similarly, pre-existing ILD was associated with a significantly higher risk of any-grade CIP (OR: 3.86, 95% CI: 2.65–5.61) and severe CIP (OR: 3.24, 95% CI: 2.07–5.07), with anti-programmed cell death 1 therapies showing the highest CIP risk.

Conclusion:

Pre-existing ILD markedly increases the risk of both RP and CIP in lung cancer patients. These findings underscore the critical importance of thorough ILD evaluation and the development of personalized treatment strategies to mitigate these risks prior to initiating cancer therapy.

Keywords

checkpoint inhibitor pneumonitis (CIP)interstitial lung disease (ILD)lung cancer meta-analysis radiation pneumonitis (RP)

Introduction

Lung cancer remains one of the leading causes of cancer-related morbidity and mortality worldwide, contributing significantly to annual cancer diagnoses and deaths.^1,2 This burden is particularly pronounced among individuals with a history of smoking, exposure to environmental pollutants, or genetic predispositions, which contribute to the complex etiology of the disease.³ Despite these challenges, significant advancements in lung cancer treatment have been achieved in recent years. For early-stage disease, surgical resection remains the cornerstone of curative therapy.⁴ However, as lung cancer is often diagnosed at advanced stages, a comprehensive and multifaceted therapeutic approach is required.⁴ Treatment options, such as chemotherapy, targeted therapy, radiotherapy, and immunotherapy, each play critical roles by employing distinct mechanisms to combat tumor growth and metastasis, particularly in advanced-stage disease.

Radiotherapy, a cornerstone of cancer treatment, is highly effective at controlling tumor progression and alleviating symptoms. However, its application is often limited by the risk of radiation pneumonitis (RP), a potentially severe complication that restricts therapeutic dosing. Similarly, immune checkpoint inhibitors (ICIs) have revolutionized lung cancer management by enabling immune-mediated tumor destruction, significantly reshaping the treatment landscape.⁵ However, ICIs are associated with immune-related adverse events, most notably checkpoint inhibitor pneumonitis (CIP), which can pose significant challenges in clinical practice.⁵ Given these risks, careful patient selection and monitoring are crucial to ensure both safety and efficacy. Identifying risk factors for RP and CIP is, therefore, a critical step toward minimizing adverse events and advancing precision oncology.

Interstitial lung disease (ILD) encompasses a diverse group of pulmonary disorders characterized by varying degrees of inflammation and fibrosis in the lung interstitium.⁶ Radiographic studies indicate that ILD is present in approximately 14% of treatment-naïve patients with advanced non-small-cell lung cancer (NSCLC), highlighting a significant overlap between these conditions.⁷ The coexistence of lung cancer and ILD presents unique challenges in clinical management, requiring careful balancing of overlapping symptoms and complex treatment protocols to optimize outcomes.⁸ The prevalence of lung cancer is higher among patients with pre-existing ILD compared to the general population, while lung cancer patients also exhibit an increased incidence of ILD, underscoring the bidirectional relationship between these diseases.^9–11 This overlap not only complicates diagnosis and treatment but also exacerbates the risks of treatment-related complications, such as RP and CIP.

Patients with pre-existing ILD experience more severe RP and worse clinical outcomes compared to those without ILD.¹² Similarly, they are at higher risk of developing severe CIP, further complicating the use of radiotherapy and immunotherapy in this population.^13,14 These challenges necessitate a deeper understanding of the risks posed by pre-existing ILD in lung cancer patients undergoing treatment. However, current research on the association between pre-existing ILD and the risks of RP and CIP remains limited, relying primarily on small-scale retrospective studies with inconsistent findings. To address this critical gap, our meta-analysis systematically evaluates the occurrence patterns and risk differences of RP and CIP in lung cancer patients with pre-existing ILD. By synthesizing available evidence, this study seeks to guide clinical decision-making and ensure safer, more effective treatment strategies.

Methods

Study selection

This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (Table S1)¹⁵ and was registered in the PROSPERO database (CRD42024609557). A comprehensive literature search was performed across PubMed, Embase, and Web of Science, encompassing each database’s inception through August 10, 2024. The search strategy incorporated keywords such as “lung cancer,” “interstitial lung disease,” “immune checkpoint inhibitor,” and “radiotherapy.” Both MeSH terms and free-text variations were employed to ensure the identification of all relevant studies. In addition, the reference lists of the included studies were reviewed to maximize comprehensiveness. The detailed search strategy is provided in Table S2.

Eligibility criteria

Studies were included based on the following criteria: (1) Study design: observational studies (cohort, case–control, cross-sectional) and clinical trials. (2) Participants: adult patients with a confirmed diagnosis of lung cancer and concurrent ILD. (3) Comparison: lung cancer patients without ILD. (4) Outcomes: reported incidence or risk (expressed as odds ratios (ORs) or hazard ratios (HRs)) of developing RP and/or CIP in patients with or without ILD. If ORs or HRs were not directly reported, they were indirectly calculated from the number of RP or CIP cases reported in the respective patient groups. Exclusion criteria included non-original research articles (e.g., reviews, meta-analyses, editorials, and conference abstracts) and articles not published in English.

Data extraction and quality assessment

Data extraction was independently conducted by two researchers using a standardized extraction form. The extracted data included study characteristics: author information, year of publication, country/region, study design, and sample size; patient demographics: age, gender distribution, and ILD subtype if available; treatment regimens: detailed information on radiation therapy and ICIs; outcome measures: the number and incidence of any-grade and severe RP/CIP in lung cancer patients with and without ILD. The quality of each observational study was assessed using the Newcastle–Ottawa Scale (NOS).¹⁶ Studies were scored on the selection of study groups, comparability, and outcome assessment, with a score above 6 indicating high quality.

Statistical analysis

Statistical analyses were conducted using STATA 12.0 (StataCorp LP, College Station, TX, USA). The I² statistic was calculated to assess heterogeneity among studies, with I² values of 25%, 50%, and 75% corresponding to low, moderate, and high heterogeneity, respectively.¹⁷ Due to the expected high heterogeneity in study populations, a random-effects model was applied to pool effect sizes and rates. The metan function was used to combine ORs/HRs and their 95% confidence intervals (CIs), evaluating the association between pre-existing ILD and the risk of any-grade and severe RP and CIP in lung cancer patients. The metaprop function was employed to pool rates, examining differences in the occurrence of any-grade and severe RP and CIP among lung cancer patients with and without ILD. Sensitivity analyses were performed with the metainf function to assess the robustness of the pooled results. Funnel plots were drawn using the metafunnel function, and publication bias was assessed using Begg’s and Egger’s tests with the metabias function. A p-value of <0.05 was considered statistically significant.

Results

General characteristics of the included studies

As of August 10, 2024, a total of 3998 studies were identified as potentially relevant to the occurrence of RP in lung cancer patients with pre-existing ILD. These included 983 studies from PubMed, 1919 from Embase, and 1096 from Web of Science. After removing 805 duplicates, 3193 studies remained for title and abstract screening. Following full-text review of 240 papers, 12 studies comprising 2576 patients were included in the final meta-analysis assessing RP risk.^18–29 The literature selection process is depicted in Figure 1(a). All included studies were conducted in Asia, originating from China (six studies), Japan (four studies), and South Korea (two studies). All were retrospective studies published between 2012 and 2024, with sample sizes ranging from 49 to 690. Nine studies^{18–20,22,24,25,27–29} included both NSCLC and small-cell lung cancer (SCLC) patients, two studies^21,23 focused exclusively on NSCLC patients, and one study²⁶ included only SCLC patients. The predominant radiotherapy types were stereotactic body radiation therapy (SBRT) and intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT), with four studies addressing each type. The quality assessment, based on the NOS, showed that seven studies scored above 6, qualifying them as high quality (Table S3). The basic characteristics and populations of the included studies are summarized in Table 1.

Figure 1.

Flowchart of study selection. (a) Literature screening process for studies investigating the relationship between pre-existing ILD and the risk of RP in lung cancer patients. (b) Literature screening process for studies examining the relationship between pre-existing ILD and the risk of CIP in lung cancer patients.

Table 1.

Basic characteristics of studies exploring the association between pre-existing ILD and the risk of RP in lung cancer patients.

First author	Study design	Publication year	Country/region	Sample size	Gender (male/female)	Age	Smoking status (former or current/never/unknown)	FEV1	DLCO	Pathological type	ECOG-PS (0–1/⩾2)	Radiotherapy type	Radiation dose	NOS
Yan¹⁸	RO	2024	China	690	559/131	64 (32–84)	390/300	81.6 ± 0.90	89.6 ± 1.17	NSCLC 543, SCLC 145, Mixed 2	641/49	3DCRT, VMAT, IMRT	<54 Gy 191, 54–60 Gy 283, ⩾60 Gy 216	5
Lee¹⁹	RO	2024	Korea	548	470/78	66 (8.5)	462/86	87.4	87.6	NSCLC 422, SCLC 120, Unknown 6	508/40	IMRT or VMAT	NA	8
Zhang²⁰	RO	2023	China	314	238/76	61 (30–85)	244/70	NA	NA	ADC 73, SCC 86, SCLC 155	NA	IMRT or VMAT	59.274 ± 2.977 Gy	7
Wu²¹	RO	2021	China	153	140/13	63 (40–85)	94/59	FEV1/FVC ⩾ 70: 71, FEV1/FVC < 70: 82	NA	ADC 28, SCC 93, Others 32	NA	3DCRT or IMRT	60 (58–66) Gy	6
Li²²	RO	2021	China	87	81/6	67	NA	74.38 ± 9.47	NA	ADC 17, SCC 24, SCLC 30, Others 16	NA	IMRT	NA	7
Liu²³	RO	2020	China	109	80/29	75 (47–88)	NA	NA	NA	ADC 33, SCC 27, Others 49	105/4	SBRT	Median dose: 50 Gy in 5 fractions	7
Ju²⁴	RO	2019	Korea	110	NA	65 (45–88)	NA	2.18 (0.72–3.59)	NA	ADC 33, SCC 70, SCLC 4, Others 3	NA	3DCRT, VMAT, SBRT	64.8 (50.0–70.2) Gy	6
Yamamoto⁵	RO	2018	Japan	49	35/14	77 (48–88)	Pack years: 29 (0–100)	NA	NA	ADC 11, SCC 8, Others 30	42/7	SBRT	39.7 (34.3–43.4) Gy	6
Li²⁶	RO	2018	China	95	85//10	61 (42–80)	NA	FEV1/FVC ⩾ 70: 31, FEV1/FVC < 70: 25	NA	SCLC 95	NA	IMRT	Limited-stage: ⩾60 Gy Extensive stage ⩾50 Gy	7
Uchida²⁷	RO	2017	Japan	100	82/18	72 (39–89)	83/17	NA	NA	ADC 27, SCC 33, SCLC 15, Others 25	NA	3DCRT or IMRT	30–66 Gy	8
Nakamura²⁸	RO	2016	Japan	56	39/17	78 (41–92)	Pack years: 40 (0–200)	76.9 (16.7–136.9)	NA	ADC 25 SCC 10, Others 21	48/8	SBRT	48–56 Gy	7
Takeda²⁹	RO	2012	Japan	265	187/78	78 (55–91)	NA	NA	NA	ADC 74 SCC 44, SCLC 4, Others 11	NA	SBRT	50 Gy 193, 40 Gy 72	6

3DCRT, 3D conformal radiotherapy; ADC, adenocarcinoma; CC, case–control study; DLCO, Diffusing capacity of the lungs for carbon monoxide; ECOG PS, Eastern Cooperative Oncology Group performance status; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; ILD, interstitial lung disease; IMRT, intensity-modulated radiation therapy; NA, not available; non-SCC, non-squamous cell carcinoma; NOS, Newcastle–Ottawa Scale; NSCLC, non-small-cell lung cancer; RO, retrospective study; RP, radiation pneumonitis; SBRT, stereotactic body radiation therapy; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer; VMAT, volumetric modulated arc therapy.

Regarding CIP, after reviewing 117 full texts, 29 studies involving 8037 patients were included.^{13,14,30–56} The screening process is shown in Figure 1(b). Most studies originated from Asia, with Japan contributing 20 studies, China 6 studies, and South Korea 1 study. Two additional studies were conducted in the United States. These studies were published between 2018 and 2024, with study designs comprising 25 retrospective cohort studies, two case–control studies, one prospective cohort study, and one phase II clinical trial. Sample sizes ranged from 17 to 2570. Most studies exclusively enrolled NSCLC patients, while six studies^{31,33,38,40,44,53} included both NSCLC and SCLC patients. No study focused solely on SCLC patients. The most commonly utilized ICIs were anti-programmed cell death-1 (PD-1) monoclonal antibodies (mAb), featured in 11 studies, while only 2 studies evaluated anti-programmed cell death ligand-1 (PD-L1) mAb. Quality assessment revealed that eight studies scored above 6 points, classifying them as high quality (Table S4). Details of the included studies and their populations are summarized in Table 2.

Table 2.

Basic characteristics of studies exploring the association between pre-existing ILD and the risk of CIP in lung cancer patients.

First author	Study design	Publication year	Country/region	Sample size	Gender (male/female)	Age	Smoking status (former or current/never/unknown)	Pathological type	ECOG-PS (0–1/⩾2)	ICI drug	ICI line (Adj/1st/⩾2nd)	NOS
Wang³⁰	RO	2024	China	206	168//38	62 (56–68)	151/55	Non-SCC 127, SCC 79	185/21	Anti-PD-L1 16 Anti-PD-1 190	0/82/119	6
Altan⁵⁴	RO	2023	USA	419	224/195	64 (57–70)	333/86	ADC 312, SCC 89, Others 18	NA	ATZ 44, DUR 20, NIVO 215, PEMB 140	0/339/80	5
Deng³¹	CC	2023	China	666	549/117	63 (22–88)	321/345	ADC 293, SCC 239, SCLC 91, Others 43	619/47	Anti-PD-1 633, Anti-PD-L1 33	0/473/193	5
Murata³²	RO	2023	Japan	264	196/68	70 (63–75)	202/62	ADC 164, SCC 71, NSCLC, NOSP 26, LCNEC 3	NA	NA	0/111/153	5
Osaki³³	RO	2023	Japan	173	146/27	74 (43–91)	151/22	ADC 97, SCC 55, NSCLC, NOSP 11, SCLC 4, Others 6,	136/37	NIVO 99, PEMB 46, ATZ 28	0/44/129	5
Sawa³⁴	RO	2023	Japan	328	279/49	71 ± 9.31	267/0	ADC 129, SCC 60, Others 4	NA	NA	NA	6
Daido³⁵	RO	2022	Japan	148	106/42	71 (43–86)	125/23	ADC 77, SCC 64, Others 7	145/3	DUR	Maintenance therapy after CRT	5
Ichimura³⁶	CC	2022	Japan	33	30/3	71 (50–81)	30/3	ADC 24, SCC 8, Others 1	NA	NIVO 18, PEMB 12, ATZ 3	0/8/25	8
Ikeda³⁷	Phase II clinical trial	2022	Japan	17	16/1	70 (66–73)	17/ 0	ADC 9, SCC 7, NSCLC, NOSP 1,	17/0	ATZ	NA	5
Jia⁵⁵	RO	2022	China	418	78/340	61 (27–78)	231/187/0	NSCLC	NA	NA	NA	6
Lin³⁸	RO	2022	China	45	37/8	65 (36–85)	28/17	ADC 11, SCC 23, SCLC 6, Others 5	43/2	Anti-PD-1 41, Anti-PD-L1 4	0/33/12	5
Ohe³⁹	PO	2022	Japan	2570	1797/773	69 (30–90)	NA	ADC 1920, SCC 440, LCNEC 40, Others 121, Unknown 49	2099/471	ATZ	0/0/2570	6
Yamaguchi⁵¹	RO	2022	Japan	125	83/42	67 (25–84)	86/39	ADC 92, SCC 17, Others 16	109/16	PEMB 88, ATZ 37	NA	5
Zeng⁵²	RO	2022	China	122	116/6	66 (45–89)	86/36	ADC 48, SCC 67, Others 7	120/2	Anti-PD-1	21/77/24	5
Atchley⁴⁰	RO	2021	USA	315	158/157	66 (58–73)	287/28	ADC 182, SCC 84, LCNEC 8, Others 21, SCLC 20	245/70	PEMB 70 NIVO 241 IPI plus NIVO 6	NA	6
Tasaka⁴⁷	RO	2021	Japan	461	337/124	69 (34−88)	366/81/14	ADC 259, SCC 158, NSCLC, NOSP 29, Others 15	375/86	NIVO 269 PEMB 192	0/111/350	8
Yamaguchi⁴⁹	RO	2021	Japan	72	61/11	70 (47–86)	64/8	ADC 40, SCC 13, Others 19	49/23	PEMB	0/72/0	8
Yamaguchi⁵⁰	RO	2021	Japan	96	68/28	68 (44–80)	75/21	NSCLC	82/14	NIVO	NA	5
Hata⁴¹	RO	2020	Japan	94	69/25	69.5 + 7.9	78/12/4	ADC 57, SCC 33, Others 4	94/0	NIVO	NA	5
Okada⁴⁴	RO	2020	Japan	102	77/25	NA	NA	ADC 66, SCC 18, Others 18	87/15	NIVO 29 PEMB 55 ATZ 11 DUR 7	NA	5
Shibaki⁴⁶	RO	2020	Japan	331	216/115	62 (30–84)	249/74	Non-SCC 262, SCC 69	289/42	NIVO 248 PEMB 83	0/41/290	7
Sugano⁵⁶	RO	2020	Japan	130	98/32	NA	108/22	ADC 64, SCC 52, Others 14	99/31	NIVO 67 PEMB 45 ATZ 18	NA	5
Zhang⁵³	RO	2020	China	94	70/24	NA	NA	ADC 55, SCC 19, SCLC 12, Others 8	69/25	NIVO 56 PEMB 25 Others 13	0/33/61	5
Komiya⁴²	RO	2019	Japan	61	54/7	NA	NA	Non-SCC 39, SCC 22	50/11	NIVO 40 PEMB 21	0/61/0	5
Nakanishi⁴³	RO	2019	Japan	83	58/25	68 (34–85)	66/17	Non-SCC 70, SCC 13	71/12	NIVO 57 PEMB 26	0/3/80	8
Shibaki⁴⁵	RO	2019	Japan	210	140/70	61 (30–83)	165/42	Non-SCC 170, SCC 40	185/25	NIVO 127 PEMB 83	0/39/171	7
Tone⁴⁸	RO	2019	Japan	71	54/17	69 (44–84)	NA	Non-SCC 54, SCC 16, Unknown 1	54/17	NIVO 40 PEMB 21 ATZ 10	NA	5
Cho¹⁴	RO	2018	Korea	167	128/39	NA	120/47	Non-ADC 61, ADC 106	147/20	NIVO	0/48/119	7
Kanai¹³	RO	2018	Japan	216	154/62	69 (30–89)	170/46	ADC 135, SCC 57, Others 23	160/56	NIVO	NA	8

ADC, adenocarcinoma; anti-PD-1, anti-programmed cell death-1; anti-PD-L1, anti-programmed cell death ligand-1; ATZ, atezolizumab; CC, case–control study; CIP, checkpoint inhibitor pneumonitis; CRT, chemoradiotherapy; DLCO, diffusing capacity of the lungs for carbon monoxide; DUR, durvalumab; ECOG PS, Eastern Cooperative Oncology Group performance status; ICI, immune checkpoint inhibitor; ILD, interstitial lung disease; IPI, ipilimumab; LCNEC, large-cell neuroendocrine carcinoma; NA, not available; NIVO, nivolumab; non-SCC, non-squamous cell carcinoma; NOS, Newcastle–Ottawa Scale; NOSP, not otherwise specified; NSCLC, non-small-cell lung cancer; PEMB, pembrolizumab; PO, prospective study; RO, retrospective study; SCC, squamous cell carcinoma; SCLC, small-cell lung cancer.

Correlation between pre-existing ILD and the risk of developing RP in lung cancer patients

To investigate the association between pre-existing ILD and the risk of developing RP in lung cancer patients, data from 11 studies were analyzed for any-grade RP risk. The heterogeneity test showed no significant heterogeneity (I² = 40.3%, p = 0.080). Using a random-effects model, pre-existing ILD was shown to significantly increase the risk of RP (OR: 3.63, 95% CI: 2.26–5.83, Figure 2(a)). Sensitivity analysis confirmed the robustness of these findings (Figure S1(A)), and no significant publication bias was detected (Begg’s test: p = 0.119, Egger’s test: p = 0.099; Figure S1(B)).

Figure 2.

Forest plot of meta-analysis for RP risk in lung cancer patients with pre-existing ILD. (a) Pooled analysis showing the association between pre-existing ILD and the risk of any-grade RP. (b) Pooled analysis showing the association between pre-existing ILD and the risk of severe RP.

A subgroup analysis based on the radiotherapy technique was conducted to examine its impact on RP risk. The results demonstrated that patients receiving SBRT had a lower risk of any-grade RP (OR: 2.09, 95% CI: 1.09–4.01) compared to those undergoing IMRT or VMAT (OR: 3.36, 95% CI: 2.11–5.37; Figure S2). By contrast, patients treated with 3D conformal radiotherapy (3DCRT) or other radiotherapy techniques exhibited the highest risk of any-grade RP (OR: 13.35, 95% CI: 4.89–36.42; Figure S2). A subgroup analysis based on pathological type revealed that patients with SCLC had a lower incidence of any-grade RP (OR: 3.01, 95% CI: 0.96–9.44; Figure S3) compared to patients with NSCLC (OR: 3.46, 95% CI: 0.35–34.61; Figure S3).

Four studies specifically reported OR for severe RP risk in patients with pre-existing ILD, showing no heterogeneity (I² = 0.0%, p = 0.785). The meta-analysis indicated that pre-existing ILD significantly increased the risk of severe RP (OR: 6.10, 95% CI: 2.68–13.86; Figure 2(b)). These findings were validated through sensitivity analysis (Figure S4(A)), and no publication bias was observed (Begg’s test: p = 0.089, Egger’s test: p < 0.001; Figure S4(B)). In summary, pre-existing ILD significantly increases the risk of both any-grade and severe RP in lung cancer patients.

Prevalence of RP in lung cancer patients with/without pre-existing ILD

We investigated the differences in RP incidence between lung cancer patients with and without pre-existing ILD. Eight studies reported the incidence of any-grade RP. Using a random-effects model, the incidence of any-grade RP was found to be 32% in patients without ILD (95% CI: 15%–49%; heterogeneity I² = 98.42%, p < 0.001; Figure 3(a)), compared to a significantly higher 50% in patients with ILD (95% CI: 42%–57%; heterogeneity I² = 0, p = 0.51; Figure 3(b)). For severe RP, the incidence was 12% in patients without ILD (95% CI: 8%–16%; heterogeneity I² = 3.47%, p = 0.35; Figure 3(c)) and 41% in patients with ILD (95% CI: 24%–57%; heterogeneity I² = 0, p = 0.69; Figure 3(d)). These findings highlight that pre-existing ILD significantly increases the incidence of both any-grade and severe RP in lung cancer patients.

Figure 3.

Forest plots of RP incidence in lung cancer patients with and without ILD. (a) Pooled prevalence of any-grade RP in lung cancer patients without ILD. (b) Pooled prevalence of any-grade RP in lung cancer patients with ILD. (c) Pooled prevalence of severe RP in lung cancer patients without ILD. (d) Pooled prevalence of severe RP in lung cancer patients with ILD.

Correlation between pre-existing ILD and the risk of developing CIP in lung cancer patients

We evaluated the risk of CIP in lung cancer patients with pre-existing ILD using data from 24 studies. The heterogeneity test revealed significant variability among the studies (I² = 59.8%, p < 0.001). A meta-analysis using a random-effects model indicated that pre-existing ILD significantly increases the risk of developing any-grade CIP (OR: 3.86, 95% CI: 2.65–5.61; Figure 4(a)). Sensitivity analysis confirmed the robustness of these pooled results (Figure S5(A)), and no significant publication bias was observed (Begg’s test: p = 0.130, Egger’s test: p = 0.222; Figure S5(B)). A subgroup analysis based on the type of ICIs was conducted to evaluate their impact on any-grade CIP risk. As shown in Figure S6(A), patients treated with anti-PD-1 mAb (OR: 4.27, 95% CI: 3.04–5.99) had a higher risk of any-grade CIP compared to those receiving anti-PD-L1 mAb (OR: 3.29, 95% CI: 1.98–5.48). Subgroup analysis by pathological type indicated that patients with NSCLC had a lower incidence of any-grade CIP (OR: 3.63, 95% CI: 2.46–5.35; Figure S6(B)).

Figure 4.

Forest plot of meta-analysis for CIP risk in lung cancer patients with pre-existing ILD. (a) Pooled analysis showing the association between pre-existing ILD and the risk of any-grade CIP. (b) Pooled analysis showing the association between pre-existing ILD and the risk of severe CIP.

In addition, 11 studies evaluated the relationship between pre-existing ILD and severe CIP risk. For these, no significant heterogeneity was identified (I² = 4.5%, p = 0.400). A random-effects meta-analysis revealed that pre-existing ILD significantly increases the risk of severe CIP (OR: 3.24, 95% CI: 2.07–5.07; Figure 4(b)). Sensitivity analysis further confirmed the stability of these findings (Figure S7(A)), and publication bias tests showed no significant bias (Begg’s test: p = 0.640, Egger’s test: p = 0.782; Figure S7(B)). Subgroup analysis of ICI types for severe CIP indicated that patients receiving anti-PD-1 mAb faced a higher risk (OR: 3.91, 95% CI: 2.17–7.08) compared to those treated with anti-PD-1/anti-PD-L1 mAb therapies (OR: 2.78, 95% CI: 1.21–6.39; Figure S8(A)). Similarly, subgroup analysis by pathological type showed that patients with NSCLC had a lower incidence of severe CIP (OR: 3.10, 95% CI: 1.85–5.19; Figure S8(B)). In summary, pre-existing ILD significantly increases the risk of both any-grade and severe CIP in lung cancer patients.

Prevalence of CIP in lung cancer patients with/without pre-existing ILD

We compared the incidence of CIP in lung cancer patients with and without pre-existing ILD. The results showed that the incidence of any-grade CIP was 11% in patients without ILD (95% CI: 9%–13%; heterogeneity I² = 86.39%, p < 0.001; Figure 5(a)), whereas it was significantly higher at 29% in those with ILD (95% CI: 23%–34%; heterogeneity I² = 78.31%, p < 0.001; Figure 5(b)). For severe CIP, the incidence was 5% in patients without ILD (95% CI: 3%–6%; heterogeneity I² = 61.38%, p = 0.01; Figure 5(c)), compared to 12% in patients with ILD (95% CI: 8%–15%; heterogeneity I² = 0, p = 0.630; Figure 5(d)). These findings clearly demonstrate that pre-existing ILD significantly increases the risk of both any-grade and severe CIP in lung cancer patients.

Figure 5.

Forest plots of CIP incidence in lung cancer patients with and without ILD. (a) Pooled prevalence of any-grade CIP in lung cancer patients without ILD. (b) Pooled prevalence of any-grade CIP in lung cancer patients with ILD. (c) Pooled prevalence of severe CIP in lung cancer patients without ILD. (d) Pooled prevalence of severe CIP in lung cancer patients with ILD.

Discussion

Previous studies have reported mixed findings regarding whether pre-existing ILD is a risk factor for RP and CIP in lung cancer patients. Our meta-analysis addresses this uncertainty by demonstrating a significant association between pre-existing ILD and an increased risk of both RP and CIP. To our knowledge, this is the first large-scale meta-analysis to systematically explore this relationship in lung cancer patients. Our findings reveal that individuals with pre-existing ILD have a markedly higher susceptibility to RP, with a 3.63-fold increased risk for any-grade RP and an even greater 6.10-fold increase for severe RP.

A recent review by Bensenane et al.⁵⁷ summarized the risk factors for RP in lung cancer patients, including patient and tumor characteristics, pretreatment pulmonary function, and dosimetric factors. However, only one study in their review specifically addressed the association between pre-existing ILD and RP risk. In our subgroup analysis, we found that SBRT was associated with the lowest incidence of any-grade RP in ILD patients, followed by IMRT or VMAT, while the highest risk was observed in patients treated with 3DCRT. Consistent with our findings, Bensenane et al.⁵⁷ reported that SBRT and IMRT significantly reduced radiation-induced morbidity and lung function impairments in lung cancer patients, although their analysis primarily focused on patients without ILD. This suggests that SBRT and IMRT/VMAT are preferable options for patients with pre-existing ILD when technically feasible, although further studies are needed to confirm the safest treatment protocols.

Regarding CIP, our analysis shows that lung cancer patients with pre-existing ILD are at a 3.86-fold higher risk for any-grade CIP and a 3.24-fold higher risk for severe CIP. These results are consistent with Zhang et al.,⁵⁸ who reported a higher incidence of CIP in NSCLC patients with ILD compared to those without, based on a meta-analysis of 179 patients across 10 studies. Our subgroup analysis further indicates that anti-PD-1 therapies are associated with a higher risk of both any-grade and severe CIP compared to anti-PD-L1 therapies. Similarly, Khunger et al.⁵⁹ found that PD-1 inhibitors were correlated to a greater incidence of CIP than PD-L1 inhibitors in NSCLC patients. However, even anti-PD-L1 therapies, which appear to carry a relatively lower risk, may not be ideal for patients with pre-existing ILD. For instance, the AMBITIOUS phase II trial, which evaluated atezolizumab in NSCLC patients with ILD, was terminated early due to 23.5% of participants developing grade 3 or higher CIP.⁶⁰

The increased risk of RP and CIP in patients with pre-existing ILD is likely due to complex pathophysiological interactions.⁶¹ ILD is characterized by chronic inflammation and fibrosis, which render lung tissue more vulnerable to damage from radiation and ICIs.⁶² Fibrotic changes in ILD alter vascular architecture and immune responses, potentially amplifying the adverse effects of these treatments.⁶³ In addition, the reduced reparative capacity of fibrotic lungs may prolong recovery and exacerbate injury after treatment. Radiotherapy induces DNA damage in normal lung tissue, prompting alveolar capillary epithelial cells to release cytokines that activate immune cells and myofibroblasts.⁶⁴ This process recruits additional T cells and enhances local T-lymphocyte infiltration, exacerbating inflammation in fibrotic lung tissue.⁶⁴ Similarly, ICIs can intensify inflammatory responses in fibrotic lungs through T-cell recruitment and cytokine release, further aggravating CIP.^65–67

From a clinical perspective, these findings underscore the importance of evaluating ILD status before initiating lung cancer treatment. Identifying ILD as a key risk factor allows healthcare providers to tailor therapeutic strategies accordingly. This may include advanced radiation techniques, such as proton therapy, to minimize exposure to healthy lung tissue, or selecting systemic therapies with a lower risk of pulmonary toxicity.^68,69 A multidisciplinary approach involving pulmonologists and oncologists is essential to develop personalized treatment plans that optimize safety and efficacy. Proactive monitoring, including regular pulmonary function tests and imaging, is crucial for the early detection and management of pneumonitis. Preventive strategies, such as prophylactic corticosteroids, may also help reduce the incidence and severity of RP.⁷⁰ Furthermore, educating patients to recognize early symptoms of pneumonitis and encouraging open communication with healthcare teams can enable timely interventions, potentially improving outcomes and quality of life.

While our study is pioneering in exploring the association between pre-existing ILD and the risks of RP and CIP in lung cancer patients through a large-scale meta-analysis, several limitations should be acknowledged. Many of the included studies were retrospective in design, which may introduce selection and confounding biases. In addition, some effect estimates were derived from univariate analyses without adjustment for potential confounders, potentially resulting in biased pooled outcomes. Key clinical aspects, such as late-onset RP and ICI-induced acute exacerbations of ILD, were not adequately addressed in the included studies despite their potential impact on patient outcomes. Moreover, the lack of sufficient follow-up data for ILD patients treated with ICIs limits our understanding of disease progression and treatment responses. The absence of routine bronchoscopy or lung biopsies for many patients further restricts diagnostic precision and the ability to fully evaluate the underlying causes of respiratory complications. Another limitation lies in the subgroup analyses of pathological subtypes. Few studies exclusively focused on NSCLC or SCLC within certain subgroups, potentially leading to instability in the results. Furthermore, the absence of detailed information on ILD patterns and severity, radiotherapy protocols, specific ICI regimens, and treatment lines constrained our ability to perform a comprehensive assessment of RP and CIP risks across diverse patient subgroups. These limitations underscore the need for high-quality, well-designed prospective studies with detailed clinical data to enhance our understanding of these critical associations and improve patient outcomes in the future.

Conclusion

In conclusion, our study establishes pre-existing ILD as a significant risk factor for increased incidence and severity of RP and CIP in lung cancer patients. These findings underscore the importance of routine ILD screening and personalized treatment strategies to mitigate the risks associated with radiotherapy and immunotherapy in this high-risk population. Future research should focus on validating these results in larger, more diverse cohorts and developing targeted interventions to reduce adverse outcomes. Addressing these aspects will enhance therapeutic outcomes and improve the quality of life for patients with pre-existing ILD undergoing lung cancer treatment.

Supplemental Material

sj-docx-1-tam-10.1177_17588359251338624 – Supplemental material for The impact of pre-existing interstitial lung disease on radiation and checkpoint inhibitor pneumonitis in lung cancer patients: a systematic review and meta-analysis

Supplemental material, sj-docx-1-tam-10.1177_17588359251338624 for The impact of pre-existing interstitial lung disease on radiation and checkpoint inhibitor pneumonitis in lung cancer patients: a systematic review and meta-analysis by Aimin Jiang, Haozheng Lu, Rui Zhao, Jupeng Yuan and Dawei Chen in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Aimin Jiang

Dawei Chen

Supplemental material

Supplemental material for this article is available online.

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