Radiation pneumonitis in patients with non-small-cell lung cancer receiving chemoradiotherapy and an immune checkpoint inhibitor: a retrospective study.
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ABSTRACT: Background
Immunotherapy has been administered to many patients with non-small-cell lung cancer (NSCLC). However, only few studies have examined toxicity in patients receiving an immune checkpoint inhibitor (ICI) after concurrent chemoradiotherapy (CCRT). Therefore, we performed a retrospective study to determine factors that predict radiation pneumonitis (RP) in these patients.Methods
We evaluated the size of the planning target volume, mean lung dose (MLD), and the lung volume receiving more than a threshold radiation dose (VD) in 106 patients. The primary endpoint was RP ≥ grade 2, and toxicity was evaluated.Results
After CCRT, 51/106 patients were treated with ICI. The median follow-up period was 11.5 months (range, 3.0-28.2), and RP ≥ grade 2 occurred in 47 (44.3%) patients: 27 and 20 in the ICI and non-ICI groups, respectively. Among the clinical factors, only the use of ICI was associated with RP (p = 0.043). Four dosimetric variables (MLD, V20, V30, and V40) had prognostic significance in univariate analysis for occurrence of pneumonitis (hazard ratio, p-value; MLD: 2.3, 0.009; V20: 2.9, 0.007; V30: 2.3, 0.004; V40: 2.5, 0.001). Only V20 was a significant risk factor in the non-ICI group, and MLD, V30, and V40 were significant risk factors in the ICI group. The survival and local control rates were superior in the ICI group than in the non-ICI group, but no significance was observed.Conclusions
Patients receiving ICI after definitive CCRT were more likely to develop RP, which may be related to the lung volume receiving high-dose radiation. Therefore, several factors should be carefully considered for patients with NSCLC.
SUBMITTER: Jang JY
PROVIDER: S-EPMC8642976 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPatients with non-small cell lung cancer may develop pneumonitis after thoracic radiotherapy (RT) and immune checkpoint inhibitors (ICIs). We hypothesized that distinct morphologic features are associated with different pneumonitis etiologies.Materials and methodsWe systematically compared computed tomography (CT) features of RT- versus ICI-pneumonitis. Clinical and imaging features were tested for association with pneumonitis severity. Lastly, we constructed an exploratory radiomics-based machine learning (ML) model to discern pneumonitis etiology.ResultsBetween 2009 and 2019, 82 patients developed pneumonitis: 29 after thoracic RT, 23 after ICI, and 30 after RT + ICI. Fifty patients had grade 2 pneumonitis, 22 grade 3, and 7 grade 4. ICI-pneumonitis was more likely bilateral (65% vs. 28%; p = .01) and involved more lobes (66% vs. 45% involving at least three lobes) and was less likely to have sharp border (17% vs. 59%; p = .004) compared with RT-pneumonitis. Pneumonitis morphology after RT + ICI was heterogeneous, with 47% bilateral, 37% involving at least three lobes, and 40% sharp borders. Among all patients, risk factors for severe pneumonitis included poor performance status, smoking history, worse lung function, and bilateral and multifocal involvement on CT. An ML model based on seven radiomic features alone could distinguish ICI- from RT-pneumonitis with an area under the receiver-operating curve of 0.76 and identified the predominant etiology after RT + ICI concordant with multidisciplinary consensus.ConclusionRT- and ICI-pneumonitis exhibit distinct spatial features on CT. Bilateral and multifocal lung involvement is associated with severe pneumonitis. Integrating these morphologic features in the clinical management of patients who develop pneumonitis after RT and ICIs may improve treatment decision-making.Implications for practicePatients with non-small cell lung cancer often receive thoracic radiation and immune checkpoint inhibitors (ICIs), both of which can cause pneumonitis. This study identified similarities and differences in pneumonitis morphology on computed tomography (CT) scans among pneumonitis due to radiotherapy (RT) alone, ICI alone, and the combination of both. Patients who have bilateral CT changes involving at least three lobes are more likely to have ICI-pneumonitis, whereas those with unilateral CT changes with sharp borders are more likely to have radiation pneumonitis. After RT and/or ICI, severe pneumonitis is associated with bilateral and multifocal CT changes. These results can help guide clinicians in triaging patients who develop pneumonitis after radiation and during ICI treatment.
| S-EPMC8488797 | biostudies-literature
Project description:BACKGROUND:Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ?12 weeks of immunosuppression. METHODS:Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ?12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available. RESULTS:Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ?10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper. CONCLUSIONS:A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ?12 weeks, and has distinct clinicopathological features.
| S-EPMC7304886 | biostudies-literature
Project description:PurposeWhilst survival benefits of thoracic radiotherapy (TRT) followed by immune checkpoint inhibitor (ICI) have been reported in patients with lung cancer, the potential high risk of treatment-related pneumonitis remains a concern. Asians may be more sensitive to lung toxicity than other races. This retrospective study intended to provide a comprehensive pneumonitis profile of TRT followed by ICI and investigate the risk factors from a Chinese cohort of lung cancer.Methods and materialsFrom January 2016 to July 2021, 196 patients with lung cancer who received TRT prior to ICI were retrospectively analyzed. Treatment-related pneumonitis, including checkpoint inhibitor pneumonitis (CIP), radiation pneumonitis (RP), and radiation recall pneumonitis (RRP), were recorded and graded through medical records and chest computed tomography. Characteristics predictive of pneumonitis were assessed using logistic regression models, and the receiver operating characteristic analyses were performed to identify optimal cut points for quantitative variables.ResultsWith a median follow-up of 18 months, a total of 108 patients (55.1%) developed treatment-related pneumonitis during ICI therapy, with an incidence of 25.5% for grade 2 or higher (G2+) and 4.1% for G3+. The overall rates of CIP, RP and RRP were 8.2% (n=16), 46.9% (n=92) and 7.1% (n=14), respectively. With a total mortality rate of 1.5%, vast majority of the patients recovered from pneumonitis or remained stable. No patients died of RRP. Half of the patients with G2+ RP who withheld ICI therapy restarted ICI safely after resolution of RP. The history of chronic pulmonary diseases (P=0.05), mean lung dose (MLD, P=0.038), percent volume of lung receiving ≥5 Gy (V5, P=0.012) and percent volume of lung receiving ≥20 Gy (V20, P=0.030) predicted the occurrence of RRP in univariate analyses. Interval between TRT and ICI less than 3 months was an independent predictor for G2+ treatment-related pneumonitis in a multivariate model (Odds ratio OR=2.787, P=0.004).ConclusionsTreatment-related pneumonitis, especially RRP, is acceptable and manageable in the setting of TRT followed by ICI in this Asian population. Dosimetric parameters MLD, V5 and V20 may improve the predictions of RRP in clinical practice.
| S-EPMC9251068 | biostudies-literature
Project description:PurposeConsolidation immunotherapy after completion of chemoradiotherapy has become the standard of care for unresectable locally advanced non-small cell lung cancer and can induce potentially severe and life-threatening adverse events, including both immune checkpoint inhibitor-related pneumonitis (CIP) and radiation pneumonitis (RP), which are very challenging for radiologists to diagnose. Differentiating between CIP and RP has significant implications for clinical management such as the treatments for pneumonitis and the decision to continue or restart immunotherapy. The purpose of this study is to differentiate between CIP and RP by a CT radiomics approach.MethodsWe retrospectively collected the CT images and clinical information of patients with pneumonitis who received immune checkpoint inhibitor (ICI) only (n = 28), radiotherapy (RT) only (n = 31), and ICI+RT (n = 14). Three kinds of radiomic features (intensity histogram, gray-level co-occurrence matrix [GLCM] based, and bag-of-words [BoW] features) were extracted from CT images, which characterize tissue texture at different scales. Classification models, including logistic regression, random forest, and linear SVM, were first developed and tested in patients who received ICI or RT only with 10-fold cross-validation and further tested in patients who received ICI+RT using clinicians' diagnosis as a reference.ResultsUsing 10-fold cross-validation, the classification models built on the intensity histogram features, GLCM-based features, and BoW features achieved an area under curve (AUC) of 0.765, 0.848, and 0.937, respectively. The best model was then applied to the patients receiving combination treatment, achieving an AUC of 0.896.ConclusionsThis study demonstrates the promising potential of radiomic analysis of CT images for differentiating between CIP and RP in lung cancer, which could be a useful tool to attribute the cause of pneumonitis in patients who receive both ICI and RT.
| S-EPMC9306809 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) are new and promising therapeutic agents for non-small cell lung cancer (NSCLC). However, along with demonstrating remarkable efficacy, ICIs can also trigger immune-related adverse events. Checkpoint inhibitor pneumonitis (CIP) has been reported to have a morbidity rate of 3% to 5% and a mortality rate of 10% to 17%. Moreover, the incidence of CIP in NSCLC is higher than that in other tumor types, reaching 7% to 13%. With the increased use of ICIs in NSCLC, CIP has drawn extensive attention from oncologists and cancer researchers. Identifying high risk factors for CIP and the potential mechanism of CIP are key points in preventing and monitoring serious adverse events. In this review, the results of our analysis and summary of previous studies suggested that the risk factors for CIP may include previous lung disease, prior thoracic irradiation, and combinations with other drugs. Our review also explored potential mechanisms closely related to CIP, including increased T cell activity against associated antigens in tumor and normal tissues, preexisting autoantibodies, and inflammatory cytokines.
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Project description:Immunotherapy that includes programmed cell death-1 (PD-1), programmed cell death- ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors has revolutionized the therapeutic strategy in multiple malignancies. Although it has achieved significant breakthrough in advanced non-small cell lung cancer patients, immune-related adverse events (irAEs) including checkpoint inhibitor pneumonitis (CIP), are widely reported. As the particularly worrisome and potentially lethal form of irAEs, CIP should be attached more importance. Especially in non-small cell lung cancer (NSCLC) patients, the features of CIP may be more complicated on account of the overlapping respiratory signs compromised by primary tumor following immunotherapy. Herein, we included the previous relevant reports and comprehensively summarized the characteristics, diagnosis, and management of CIP. We also discussed the future direction of optimal steroid therapeutic schedule for patients with CIP in NSCLC based on the current evidence.
| S-EPMC8195248 | biostudies-literature
Project description:BackgroundImmunotherapy is becoming a standard of care for non-small cell lung cancer (NSCLC). Checkpoint inhibitor-associated pneumonia (CIP) is a rare and potentially life-threatening event that can occur at any time during tumor immunotherapy. However, there may be differences in the radiological patterns and prognosis of CIP during different periods. This study aimed to investigate the radiographic features and prognosis of early- and late-onset immune-related pneumonitis.MethodsWe retrospectively analyzed the clinical data of 677 NSCLC patients receiving immunotherapy to identify 32 patients with CIP, analyzed the clinical and radiographic data, and summarized the radiological features and prognosis of early- and late-onset CIP.ResultsCIP had an incidence of 4.7%, a median onset time of 10 weeks, and a mortality of 28.1%. Among these, CIP included 14 early-onset cases, where grade ≥ 3 CIP accounted for 92.9%, main radiographic pattern was organizing pneumonia (OP)-like pattern, and mortality was 50.0%. We also identified 18 late-onset CIPs, where grade ≥ 3 CIP accounted for 50.0%, main radiographic pattern was nonspecific interstitial pneumonia (NSIP)-like pattern, and mortality was 11.1%. The overall survival rate of the early-onset group was significantly lower than that of the late-onset group (P < 0.05).ConclusionEarly-onset CIP cases were higher in the Common Terminology Criteria for Adverse Events (CTCAE v5.0) grade and mainly presented with an OP-like radiographic pattern; whereas, late-onset CIP cases were lower in CTCAE grade and mainly presented with an NSIP-like radiographic pattern. Finally, the prognosis of the early-onset CIP group was poorer than that of the late-onset CIP group. We believe that this study will be helpful for clinicians for making early diagnosis and deciding treatment modalities for patients with CIP.
| S-EPMC8164260 | biostudies-literature
Project description:IntroductionThe increasing application of immune checkpoint inhibitors (ICIs) will cause more checkpoint inhibitor-related pneumonitis (CIP), which is a common cause of ICI-related death. The clinical management of CIP needs further optimization.MethodsPatients who were managed at Peking Union Medical College Hospital (PUMCH) between February 2017 and December 2019 with a diagnosis of CIP were retrospectively analyzed. Clinical data including clinical manifestations, radiologic data, laboratory and bronchoscopy results, treatments, and outcomes were collected and analyzed. The Mann-Whitney test was used to compare patients with and without co-infections.ResultsIn total, 48 CIP cases in 42 patients were analyzed. The median time from the first dose of ICI to the onset of CIP was 1.9 months (range: 0.1-13.7). Grade 3-4 (G3-4) accounted for 30 cases (71.4%). The most common symptoms were cough (88.1%) and dyspnea (78.6%). The median starting dose of equivalent prednisone (EP) was 55 mg (range: 30-200) for all patients. The median total duration of glucocorticosteroids (GCS) treatment was 42.5 days (range: 15-89). Three patients (7.14%) died because of infection. A higher starting dose and longer duration of GCS (≥30 mg/day; p = 0.001) were associated with opportunistic infection. Chest computed tomography (CT) showed diverse and asymmetrical lesions. Twelve patients were re-challenged, and six patients developed recurrent CIP.ConclusionsThe clinical and imaging manifestations of CIP are various, and differential diagnosis of exclusion is essential. GCS at 1-2 mg/kg is feasible to treat CIP, but the duration of GCS ≥30 mg/day should be used with caution, given the high risk of acquired infections. Re-challenges of ICI are feasible, but the recurrence of CIP needs to be closely monitored.
| S-EPMC7826478 | biostudies-literature
Project description:IntroductionCheckpoint inhibitor pneumonitis (CIP) is a serious toxicity of anti-programmed death-(ligand) 1 immunotherapy. Whether pretreatment differences in pulmonary function exist in patients who develop CIP is unknown. We analyzed the pulmonary function tests (PFTs) of patients with NSCLC treated with immune checkpoint inhibitors (ICIs) to evaluate whether pretreatment lung function was associated with CIP development.MethodsPatients were included if they completed greater than or equal to 1 PFT within 2 years preceding ICI initiation. CIP status (CIP+: developed CIP, CIP-: did not develop CIP) was determined clinically. Generalized estimating equation-based linear regression was used to evaluate the effects of time and CIP on lung function. Primary outcomes included the following: percent-predicted forced expiratory volume in 1 second (FEV1pp), percent-predicted forced vital capacity (FVCpp), and FEV1/FVC.ResultsA total of 43 patients (34 CIP-, 9 CIP+) with 79 PFTs (59 CIP-, 20 CIP+) were included. CIP+ patients had a 21.7% lower pretreatment FEV1pp compared with the CIP- group (95% confidence interval: -38.6 to -4.7). No statistically significant differences in FVCpp or FEV1/FVC were observed. The prevalence of obstructive lung disease was similar in both groups at 67% and 62% for the CIP+ and CIP- cohorts, as was the prevalence of current/former smoking at 100% and 93%, respectively.ConclusionsPretherapy differences in lung function were evident between patients who did and did not develop CIP, though the prevalence of obstructive lung disease was similar. Prospective studies are needed to validate these findings, inform potential risk factors for CIP, and investigate the effects of ICI treatment and CIP on pulmonary function in patients with NSCLC.
| S-EPMC8552105 | biostudies-literature
Project description:BackgroundWhile immune checkpoint inhibitors (ICIs) are a beacon of hope for non-small cell lung cancer (NSCLC) patients, they can also cause adverse events, including checkpoint inhibitor pneumonitis (CIP). Research shows that the inflammatory immune microenvironment plays a vital role in the development of CIP. However, the role of the immune microenvironment (IME) in CIP is still unclear.MethodsWe collected a cohort of NSCLC patients treated with ICIs that included eight individuals with CIP (CIP group) and 29 individuals without CIP (Control group). CIBERSORT and the xCell algorithm were used to evaluate the proportion of immune cells. Gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) were used to evaluate pathway activity. The ridge regression algorithm was used to analyze drug sensitivity.ResultsCIBERSORT showed significantly upregulated memory B cells, CD8+ T cells, and M1 Macrophages in the CIP group. The number of memory resting CD4+ T cells and resting NK cells in the CIP group was also significantly lower than in the Control group. The XCell analysis showed a higher proportion of Class-switched memory B-cells and M1 Macrophages in the CIP group. Pathway analysis showed that the CIP group had high activity in their immune and inflammatory response pathways and low activity in their immune exhaustion related pathway.ConclusionsIn this study, we researched CIP patients who after ICIs treatment developed an inflammatory IME, which is characterized by significantly increased activated immune cells and expression of inflammatory molecules, as well as downregulated immunosuppressive lymphocytes and signaling pathways. The goal was to develop theoretical guidance for clinical guidelines for the treatment of CIP in the future.
| S-EPMC8790088 | biostudies-literature