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BMC Cancer Oct 2023The PACIFIC study has demonstrated that the administration of durvalumab following concurrent chemoradiotherapy can significantly improve both overall survival and... (Meta-Analysis)
Meta-Analysis
The timing of durvalumab administration affects the risk of pneumonitis in patients with locally advanced non-small cell lung cancer: a systematic review and meta-analysis.
PURPOSE
The PACIFIC study has demonstrated that the administration of durvalumab following concurrent chemoradiotherapy can significantly improve both overall survival and progression-free survival rates in patients with locally advanced unresectable non-small cell lung cancer. While the latest NCCN guidelines recommend this combination regimen, they do not specify the optimal timing for administering durvalumab after completing radiotherapy. The PACIFIC study suggested initiating durvalumab within 42 days of completing radiotherapy, but early administration of the drug may increase the incidence of pneumonitis. Therefore, we conducted this study to investigate whether the time interval between completion of radiotherapy and initiation of durvalumab treatment is associated with the risk of pneumonitis (Grade ≥ 3), which is the primary endpoint, as well as progression-free survival, which is the secondary endpoint.
METHODS
A comprehensive search of clinical trials in PubMed and EMBASE was conducted up to March 2023 to identify clinical trials involving locally advanced unresectable non-small cell lung cancer patients who were treated with durvalumab following chemoradiotherapy. Meta-analysis was performed on single-arm studies to estimate the incidence of pneumonitis (Grade ≥ 3) and progression-free survival in all studies, as well as in studies that administered durvalumab within 42 days after completion of radiotherapy.
RESULTS
This meta-analysis consisted of nine studies with a total of 2560 patients. The analysis showed that the incidence of pneumonitis (Grade ≥ 3) was 5.36% [95%CI (0.03, 0.08), I = 18.41%, p = 0.29], while the 1-year progression-free survival rate was 57.91% [95%CI (0.53, 0.63), I = 10.57%, p = 0.35]. Furthermore, when the duration between completion of radiotherapy and initiation of durvalumab treatment was shorter than 42 days, the incidence of pneumonitis (Grade ≥ 3) was 4.12% [95%CI (0.02, 0.06), I = 0.00%, p = 0.56], with a 1-year progression-free survival rate of 61.03% [95%CI (0.51, 0.71), I = 59.06%, p = 0.09].
CONCLUSION
Overall, based on the available evidence, it appears that there is no significant increase in pneumonitis or decrease in progression-free survival (PFS) when the time interval is less than 42 days and a shorter interval between treatment sessions does not necessarily have a detrimental effect on the rate of pneumonitis. We recommend that clinicians carefully evaluate the specific circumstances of each patient to determine the optimal timing for initiating immunotherapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Antibodies, Monoclonal; Chemoradiotherapy; Pneumonia
PubMed: 37817073
DOI: 10.1186/s12885-023-11472-3 -
Viruses May 2021There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter...
There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABA-R-specific agonist homotaurine, but not the GABA-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.
Topics: Animals; Coronavirus Infections; GABA-A Receptor Agonists; Lung; Mice; Murine hepatitis virus; Pneumonia; Severity of Illness Index; Treatment Outcome; Viral Load; Weight Loss; gamma-Aminobutyric Acid
PubMed: 34071034
DOI: 10.3390/v13060966 -
Journal For Immunotherapy of Cancer Jun 2020Immune-related (IR)-pneumonitis is a rare and potentially fatal toxicity of anti-PD(L)1 immunotherapy. Expert guidelines for the diagnosis and management of...
Immune-related (IR)-pneumonitis is a rare and potentially fatal toxicity of anti-PD(L)1 immunotherapy. Expert guidelines for the diagnosis and management of IR-pneumonitis include multidisciplinary input from medical oncology, pulmonary medicine, infectious disease, and radiology specialists. Severe acute respiratory syndrome coronavirus 2 is a recently recognized respiratory virus that is responsible for causing the COVID-19 global pandemic. Symptoms and imaging findings from IR-pneumonitis and COVID-19 pneumonia can be similar, and early COVID-19 viral testing may yield false negative results, complicating the diagnosis and management of both entities. Herein, we present a set of multidisciplinary consensus recommendations for the diagnosis and management of IR-pneumonitis in the setting of COVID-19 including: (1) isolation procedures, (2) recommended imaging and interpretation, (3) adaptations to invasive testing, (4) adaptations to the management of IR-pneumonitis, (5) immunosuppression for steroid-refractory IR-pneumonitis, and (6) management of suspected concurrent IR-pneumonitis and COVID-19 infection. There is an emerging need for the adaptation of expert guidelines for IR-pneumonitis in the setting of the global COVID-19 pandemic. We propose a multidisciplinary consensus on this topic, in this position paper.
Topics: Antineoplastic Agents, Immunological; B7-H1 Antigen; Betacoronavirus; COVID-19; Consensus; Coronavirus Infections; Humans; Infectious Disease Medicine; Interdisciplinary Communication; Lung; Medical Oncology; Neoplasms; Pandemics; Pneumonia; Pneumonia, Viral; Practice Guidelines as Topic; Pulmonary Medicine; Radiology; SARS-CoV-2; United States
PubMed: 32554619
DOI: 10.1136/jitc-2020-000984 -
The American Journal of Case Reports Aug 2020BACKGROUND Rifampicin-induced pneumonitis is an infrequent occurrence, with only a few cases reported in the literature. Furthermore, this condition constitutes a...
BACKGROUND Rifampicin-induced pneumonitis is an infrequent occurrence, with only a few cases reported in the literature. Furthermore, this condition constitutes a diagnostic challenge, particularly in the era of COVID-19 infection. Here, we report a case of rifampicin-induced pneumonitis with clinical, imaging, and histological features of acute respiratory distress syndrome (ARDS), which required severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to exclude a diagnosis of coronavirus disease 2019 (COVID-19) pneumonia. CASE REPORT A 43-year-old man on anti-TB treatment for TB meningitis developed new-onset fever, fatigue, hypoxemic respiratory failure, and bilateral pulmonary opacities. His clinical, chest X-ray, and CT thorax findings of ARDS were similar to both rifampicin-induced pneumonitis and severe COVID-19 pneumonia. However, reverse transcription polymerase chain reaction (RT-PCR) testing from a nasopharyngeal swab and bronchoalveolar lavage (BAL) via the GeneXpert system was negative for SARS-CoV-2. A detailed workup, including lung biopsy, revealed drug-induced pneumonitis as the cause of his presentation. His pneumonitis improved after discontinuation of rifampicin and recurred following the rifampicin challenge. CONCLUSIONS This case highlights the importance of early, rapid, and accurate testing for SARS-CoV-2 during the COVID-19 pandemic for patients presenting with acute respiratory symptoms, so that accurate diagnosis and early patient management are not delayed for patients with treatable causes of acute and severe lung diseases. Timely identification of rifampicin-induced pneumonitis via a high clinical suspicion, detailed workup, and histopathological analysis is required to avoid permanent damage to the lungs.
Topics: Adult; Antibiotics, Antitubercular; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Male; Pandemics; Pneumonia; Pneumonia, Viral; Rifampin; SARS-CoV-2; Tomography, X-Ray Computed; Tuberculosis, Meningeal
PubMed: 32840240
DOI: 10.12659/AJCR.927586 -
Journal For Immunotherapy of Cancer Feb 2021Pneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are...
BACKGROUND
Pneumonitis related to immune checkpoint blockade is uncommon but can be severe, fatal or chronic. Steroids are first-line treatment, however, some patients are refractory or become resistant to steroids. Like many immune-related adverse events, little is known regarding the outcomes and optimal management of patients in whom steroids are ineffective.
METHODS
We performed a single-center retrospective cohort study at a high-volume tertiary cancer center to evaluate the clinical course, management strategies and outcomes of patients treated for immune checkpoint pneumonitis with immune modulatory medications in addition to systemic steroids. Pharmacy records were queried for patients treated with both immune checkpoint blockade and receipt of additional immune modulators. Records were then manually reviewed to identify patients who received the additional immune modulators for immune checkpoint pneumonitis.
RESULTS
From 2013 to 2020, we identified 26 patients treated for immune checkpoint pneumonitis with additional immune modulators in addition to steroids. Twelve patients (46%) were steroid-refractory and 14 (54%) were steroid-resistant. Pneumonitis severity included grade 2 (42%) or grade 3-4 (58%). Additional immune modulation consisted of tumor necrosis factor-alpha inhibitor (77%) and/or mycophenolate (23%). Durable improvement in pneumonitis following initiation of additional immune modulators occurred in 10 patients (38%), including three patients (12%) in whom pneumonitis resolved and all immunosuppressants ceased. The rate of 90-day all-cause mortality/hospice referral was 50%. At last follow-up, mortality attributable to pneumonitis was 23%. In addition to mortality from pneumonitis and cancer, 3 patients (12%) died due to infections possibly associated with immunosuppression.
CONCLUSIONS
Steroid-refractory or -resistant immune checkpoint pneumonitis is uncommon but associated with significant morbidity and mortality. Additional immunomodulators can yield durable improvement, attained in over one third of patients. An improved understanding of the underlying biology of immune-related pneumonitis will be crucial to guide more precise and effective treatment strategies in the future.
Topics: Aged; Drug Resistance; Female; Humans; Immune Checkpoint Inhibitors; Immunomodulating Agents; Male; Middle Aged; New York City; Pneumonia; Retrospective Studies; Steroids; Time Factors; Treatment Outcome
PubMed: 33568350
DOI: 10.1136/jitc-2020-001884 -
Practical Radiation Oncology 2023Although published data have supported the use of hypofractionated regional nodal irradiation (HF-RNI) for breast cancer, limited dosimetric data exist to evaluate...
Dosimetry and Toxicity Outcomes in Patients Treated with Hypofractionated Regional Nodal Irradiation for Breast Cancer: What is the Best Dose-Volume Limit to Minimize Risks of Radiation Pneumonitis?
PURPOSE
Although published data have supported the use of hypofractionated regional nodal irradiation (HF-RNI) for breast cancer, limited dosimetric data exist to evaluate predictors of lung toxicity. The ongoing RT CHARM trial limits the percentage of ipsilateral lung volume that receives ≥18 Gy to 35 to 40%. We assessed dosimetry, toxicity, and disease outcomes in patients with breast cancer treated with HF-RNI with a particular focus on pneumonitis.
METHODS AND MATERIALS
We retrospectively reviewed all patients with breast cancer treated with HF-RNI (40-43 Gy in 15-16 fractions) after either lumpectomy or mastectomy at The University of Pittsburgh Medical Center from September 2018 to December 2021 to collect dosimetric and outcomes data. All post-radiation therapy chest computed tomography (CT) scans were manually reviewed for evidence of acute (≤6 months postradiation) or chronic (>6 months postradiation) pneumonitis.
RESULTS
One-hundred-ninety-one patients qualified with a median follow-up of 20.3 months (range, 5.1-42.2). Acute grade 1 (G1) pneumonitis was observed in 6.8% of the overall cohort (13 of 191 patients) and 39.4% of the patients (13 of 33) who received a chest CT ≤6 months postradiation therapy. Only 1 patient developed acute G2 pneumonitis. Chronic G1 pneumonitis was observed in 29.8% of the overall cohort (57 of 191 patients) and 77% of patients (57 of 74 patients) who received a chest CT >6 months postradiation therapy. No patients developed acute G3+ or chronic G2+ pneumonitis.
CONCLUSIONS
Rates of symptomatic pneumonitis were low in this cohort of patients treated with HF-RNI, even with integration of HER2/neu-directed therapy, chemotherapy, hormone therapy, and internal mammary nodal irradiation. Lung V20Gy <26% appeared safe in this cohort to limit symptomatic pneumonitis, though this is not meant to represent the safe upper limit. Given the low event rate of symptomatic pneumonitis, data from larger cohorts will be needed to assess dosimetric predictors and the safe upper limit of lung dose.
Topics: Humans; Female; Breast Neoplasms; Radiation Pneumonitis; Mastectomy; Retrospective Studies; Radiotherapy Dosage; Pneumonia
PubMed: 36332799
DOI: 10.1016/j.prro.2022.10.007 -
The Korean Journal of Internal Medicine Sep 2022Pulmonary toxicities of coronavirus disease 2019 (COVID-19) vaccination are exceedingly rare. However, there are a few reported cases after mRNA vaccination, especially... (Review)
Review
BACKGROUND/AIMS
Pulmonary toxicities of coronavirus disease 2019 (COVID-19) vaccination are exceedingly rare. However, there are a few reported cases after mRNA vaccination, especially from Asian countries. The purpose of this study was to report the clinical characteristics of patients with COVID-19 vaccine-related pneumonitis (CV-P) and to review cases reported in the literature.
METHODS
We performed a prospective, observational case series analysis.
RESULTS
Eleven patients with a median age of 80 years were enrolled. Ten patients developed CV-P after BNT162b2-mRNA vaccination and one after ChAdOx1 nCoV-19 vaccination. We identified various patterns of CV-P, including transient infiltration, life-threatening acute respiratory distress syndrome, and aggravation of underlying interstitial lung disease. Most patients showed favorable outcomes with good responses to corticosteroid therapy.
CONCLUSION
Identifying the mechanism of CV-P requires further investigation; however, radiological and laboratory findings in our case series support inflammatory dysregulation in the lung parenchyma after vaccination. Clinicians should consider CV-P in patients with atypical lung infiltration, no specific etiologies, and recent COVID-19 vaccination.
Topics: Aged, 80 and over; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; ChAdOx1 nCoV-19; Humans; Pneumonia; Prospective Studies; RNA, Messenger; Vaccination
PubMed: 35989064
DOI: 10.3904/kjim.2022.072 -
Frontiers in Immunology 2021
Topics: Animals; Disease Susceptibility; Humans; Immunity, Innate; Lung Diseases; Models, Biological; Ozone; Pneumonia
PubMed: 34276707
DOI: 10.3389/fimmu.2021.714161 -
Cancer Medicine Jul 2023Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) have shown remarkable clinical activity in patients with non-small-cell lung cancer (NSCLC). However,... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK TKIs) have shown remarkable clinical activity in patients with non-small-cell lung cancer (NSCLC). However, pneumonitis is a serious side effect of ALK TKIs in NSCLC patients. In this meta-analysis, we aimed to determine the incidence of ALK-TKI-associated pneumonitis.
MATERIALS AND METHODS
We searched electronic databases to identify relevant studies published until August 2022. The incidence of pneumonitis was calculated using a fixed-effects model when no substantial heterogeneity was observed. Otherwise, a random-effects model was used. Subgroup analyses of different treatment groups were performed. Statistical analyses were conducted using STATA 17.0.
RESULTS
Twenty-six clinical trials involving 4752 patients were eligible for analysis. All-grade pneumonitis incidence was 2.92% (95% confidence interval [CI]: 1.79%-4.27%), high-grade (Grade 3-4) pneumonitis incidence was 1.42% (95% CI: 0.84%-2.12%) and Grade 5 pneumonitis incidence was 0.09% (95% CI: 0.00%-0.28%). The subgroup analysis showed that brigatinib was associated with the highest incidence of both all-grade and high-grade pneumonitis (7.09% and 3.06%, respectively). ALK TKI treatment after chemotherapy was associated with a higher incidence of all-grade and high-grade pneumonitis than first-line ALK TKI treatment (7.73% vs. 2.26% and 3.64% vs. 1.26%, respectively). Cohorts from Japanese trials had a higher incidence of all-grade and high-grade pneumonitis.
CONCLUSION
Our study provides precise data on the incidence of pneumonitis in patients receiving treatment with ALK TKIs. Overall, ALK TKIs have tolerable pulmonary toxicity. Early pneumonitis identification and treatment are required to prevent further deterioration in patients receiving treatment with brigatinib and in those who received prior chemotherapy, particularly in the Japanese population.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein-Tyrosine Kinases; Anaplastic Lymphoma Kinase; Tyrosine Kinase Inhibitors; Incidence; Protein Kinase Inhibitors; Pneumonia; Drug-Related Side Effects and Adverse Reactions
PubMed: 37017467
DOI: 10.1002/cam4.5913 -
Thoracic Cancer Oct 2023Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still...
Exploratory analysis to predict pneumonitis during durvalumab consolidation therapy for patients with locally advanced non-small cell lung cancer from proteomic profiling of circulating extracellular vesicles.
BACKGROUND
Risk factors for predicting pneumonitis during durvalumab consolidation after chemoradiotherapy (CRT) in locally advanced non-small cell lung cancer (LA-NSCLC) are still lacking. Extracellular vesicles (EVs) play a crucial role in intercellular communication and are potential diagnostic tools for various diseases.
METHODS
We retrospectively collected predurvalumab treatment serum samples from patients treated with durvalumab for LA-NSCLC, isolated EVs using anti-CD9 and anti-CD63 antibodies, and performed proteomic analyses. We examined EV proteins that could predict the development of symptomatic pneumonitis (SP) during durvalumab treatment. Potential EV-protein biomarkers were validated in an independent cohort.
RESULTS
In the discovery cohort, 73 patients were included, 49 with asymptomatic pneumonitis (AP) and 24 with SP. Of the 5797 proteins detected in circulating EVs, 33 were significantly elevated (fold change [FC] > 1.5, p < 0.05) in the SP group, indicating enrichment of the nuclear factor kappa B (NF-κB) pathway. Patients with high levels of EV-RELA, an NF-κB subunit, had a higher incidence of SP than those with low levels of EV-RELA (53.8% vs. 13.4%, p = 0.0017). In the receiver operating characteristic analysis, EV-RELA demonstrated a higher area under the curve (AUC) than lung V20 (0.76 vs. 0.62) and was identified as an independent risk factor in the multivariate logistic regression analysis (p = 0.008, odds ratio 7.72). Moreover, high EV-RELA was also a predictor of SP in the validation cohort comprising 43 patients (AUC of 0.80).
CONCLUSIONS
Circulating EV-RELA may be a predictive marker for symptomatic pneumonitis in patients with LA-NSCLC treated with durvalumab.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Consolidation Chemotherapy; Retrospective Studies; NF-kappa B; Proteomics; Pneumonia; Chemoradiotherapy
PubMed: 37614219
DOI: 10.1111/1759-7714.15077