Pneumonitis In Cancer Patients Research Articles

Risk Factors for Immune Checkpoint Inhibitor-Related Pneumonitis in Cancer Patients: A Systemic Review and Meta-Analysis

Background: Immune checkpoint inhibitors (ICIs) can lead to one of the common and quite serious immune-related adverse events (irAEs) in a real-world setting, namely, checkpoint inhibitor pneumonitis (CIP). Objective: We aimed to investigate the potential risk factors for CIP in cancer patients treated by ICIs and quantify the association. Methods: We conducted a systematic literature review in PubMed, EMBASE, and Web of Science from January 1, 2000, to March 20, 2022, with no study design restrictions. Studies evaluating the risk factors for CIP in cancer patients treated with ICIs-containing regimes were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for risk factors of CIP by using random-effect model. Heterogeneity was assessed by sensitivity analysis and subgroup analysis regarding CIP severity, geographical regions, cancer types, treatment regimes, and ICI types. Results: A total of 35 studies comprising 142,703 patients were eventually included. The incidence of grade I–V and grade III–V CIP in cancer patients was 0.16 (95% CI: 0.14–0.18) and 0.06 (95% CI: 0.05–0.08), respectively. When combining the adjusted ORs, the following risk factors were significantly associated with the development of CIP: squamous cell carcinoma (OR: 1.31, 95% CI: 1.18–1.45), previous thoracic radiotherapy (OR: 2.07, 95% CI: 1.34–3.19), preexisting radiation-induced pneumonitis (OR: 3.62, 95% CI: 1.53–8.58), preexisting respiratory disease (OR: 2.43, 95% CI: 1.45–4.07), preexisting interstitial lung disease (OR: 5.78, 95% CI: 3.08–10.85), preexisting ground glass attenuation (OR: 11.48, 95% CI: 1.13–116.74), preexisting honeycombing (OR: 6.11, 95% CI: 2.37–15.79), preexisting pulmonary emphysema (OR: 2.72, 95% CI: 1.00–7.36), use of pembrolizumab (OR: 2.89, 95% CI: 1.56–5.35, I² = 0%), high PD-L1 expression (OR: 3.59, 95% CI: 1.23–10.50), and hypoalbuminemia (OR: 0.3, 95% CI: 0.14–0.64). When including the crude ORs, smoking history (OR: 1.39, 95% CI: 1.14–1.71), neutrophil-lymphocyte ratio (OR: 1.04, 95% CI: 1.01–1.08), and c-reactive protein (OR: 1.08, 95% CI: 1.01–1.16) were also risk factors for CIP. Conclusion: Histological characteristics, specific previous lung diseases and treatment history, treatment regimen, PD-L1 expression level, and serological biomarkers are all closely associated with the development of CIP. These findings would be useful for oncologists to optimize the appropriate options of ICIs and close monitoring during immunotherapy treatments, particularly for patients identified as having a higher risk for CIP.

ES17.03 Imaging of Pneumonitis

Pneumonitis is one of the major adverse events from systemic anti-cancer therapy and provides clinical challenges in oncology practice. Imaging plays a key role in detection, diagnosis, and monitoring of pneumonitis in cancer patients. This lecture will discuss 1) diagnosis and monitoring of pneumonitis using CT patterns on imaging, 2) spectrum of CT patterns of pneumonitis focusing on immune-checkpoint inhibitors (ICI) and epidermal growth factor receptor (EGFR) inhibitors, and 3) emerging challenges and pitfalls in the era of COVID-19 pandemic. When approaching pneumonitis on imaging, it is very important to note that pneumonitis represents lung’s response to injury. The lung’s response patterns to injury has several histologic manifestations with corresponding CT patterns, which are originally described in idiopathic interstitial pneumonias and are also noted in the setting of pneumonitis secondary to cancer therapy. The assessment of extent and distribution of the lung abnormalities on CT is very important to recognize the distinct CT patterns. The spectrum of CT patterns is noted in pneumonitis from cancer therapies, and are associated with clinical severity of pneumonitis. Recognition of CT patterns helps to diagnosis, monitor, and prognosticate pneumonitis in cancer patients. In terms of pneumonitis from individual agents, the lecture will focus on pneumonitis from ICI and EGFR inhibitors, which are two representative agents used in lung cancer that can cause pneumonitis. ICI pneumonitis is relatively rare, but clinically serious and potentially life-threatening toxicity from ICI therapy, and is a leading cause of anti-PD-1/PD-L1-related deaths. The incidence of ICI pneumonitis is higher in lung cancer than in other cancers, indicating that pneumonitis is a particularly important issue in patients with lung cancer. The representative CT patterns of ICI pneumonitis include AIP/ARDS pattern, COP pattern, NSIP pattern, and HP pattern. Among these patterns, COP pattern is most common, noted in about two thirds of the patients. AIP/ARDS patten has the most severe clinical presentation and requires immediate clinical attention. The details of each of these CT patterns will be described with case presentations to demonstrate the characteristic features with clinical correlation. Pneumonitis is also a recognized class-effect for EGFR inhibitors. A higher incidence rate in Japanese population is noted, with a high mortality rate in the cohort studies from Japan, which is confirmed by the recent meta-analysis of 153 EGFR inhibitor trials in non-small cell lung cancer. The spectrum of CT patterns is also noted in EGFR inhibitor pneumonitis, and correlates with clinical severity and outcome. As the emerging issues with the advances of cancer therapies and the recent COVID pandemic, pneumonitis from combination ICI and radiotherapy is discussed, featuring the imaging manifestations from both ICI pneumonitis and radiation pneumonitis. Finally, the overlapping imaging features of ICI pneumonitis and COVID-19 pneumonia are presented, to demonstrate a unique challenge in the era of COVID-19 pandemic. The lecture concludes emphasizing the importance of multidisciplinary approach to further understand these emerging challenges to optimize diagnosis and management of pneumonitis in cancer patients. Abbreviations: AIP = Acute Interstitial Pneumonia; ARDS = Acute Respiratory Distress Syndrome; COP = Cryptogenic Organizing Pneumonia; HP = Hypersensitivity Pneumonitis; NSIP = Non-Specific Interstitial Pneumonia

Correlation of HLA-B*35 and DRB1*11 alleles with a high risk of interstitial aseptic pneumonitis in cancer patients receiving PD-1/PDL1 immune-checkpoint blockade.

e15094 Background: Tumor infiltrating CTL-rescue by PD-1/PDL1 immune-checkpoint blockade is a recommended treatment for several malignancies including non-small-cell-lung-cancer (NSCLC), malignant melanoma, head and neck, kidney, and urothelial cancer. MAbs to either PD-1 (Nivolumab and Pembrolizumab) or PDL1 (Atezolizumab and Durvalumab) are considered as active drugs in these patients, however, their use may be complicated by unpredictable immune-related adverse events (irAEs) and in less extent by a dreaded interstitial aseptic pneumonitis (IAP). Methods: We carried out a retrospective multi-institutional analysis aimed to investigate possible clinical and biological parameters correlated with the occurrence of IAP in a cohort of 256 cancer patients (188 with mNSCLC and 78 with other malignancies) who received PD-1/PDL-1 blockade since November 2015. Association of IAP with clinical/biological factors was assessed by the chi-square test. Statistics were performed by the SPSS software 23.0. HLA molecular analysis was performed by reverse SSO DNA typing assays on patients’ PBMCs. Results: A centralised radiological review recorded a IAP in 29 patients (11.3%) whose 15 (5.8%) were free of symptoms. There was no correlation of IAP risk with tumor type, specific PD-1 or PDL1 blocking mAb, radiation therapy, inflammatory markers, and other irAEs. IAP was more frequent in males than females [RR = 2.03, (95% CI: 0.63-5.61) p > 0.05] and occurred more often in mNSCLC patients who had received metronomic chemotherapy +/- bevacizumab [RR = 3.05 (95% CI: 1.32-7.06),P = 0.005] or TKI [RR = 1.73 (95% CI: 0.75-4.00),P > 0.05] compared with other treatments prior PD-1/PDL1 blockade. Finally, IAP occurrence was strictly correlated to the expression of HLA-B*35 [RR = 1.73 (95% CI: 0.81-3.71) P < 0.05] and DRB1*11 [RR = 2.34 (95% CI: 1.02-5.39); P = 0.03], two alleles associated to common autoimmune diseases. Conclusions: Taken together, our findings may have relevant implications in predicting the risk of IAP in mNSCLC receiving PD-1/PDL1 blockade and provide the rationale for further immunological and clinical investigations.

Does radiation increase the risk of immunotherapy related pneumonitis in cancer patients with thorax radiotherapy combined immune checkpoint inhibitors: A meta-analysis.

e15099 Background: Thorax radiotherapy (TRT) combined with immunotherapy has shown promising results. However, it remains unclear whether TRT would increases the risk of immunotherapy related pneumonitis (IRP). Here, we performed a meta-analysis to compare the rates of IRP in patients treated with TRT to patients treated without TRT. Methods: A meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Two individual researchers conducted the platform searches on the PubMed upto Nov. 4th, 2019. Quality of studies was assessed independently by two researchers using the Cochrane Collaboration's tool for randomized clinical trials, and the Newcastle-Ottawa Scale for cohort studies. Any disagreements encountered were settled through senior authors. The single rate of pneumonitis along with the corresponding 95% confidence interval (CI) was estimated. The odds ratio (OR) and its 95% CI were computed using random-effects model after checking the heterogeneity across studies using the Cochran Q chi-square test and the I2 statistic. Data analyses were performed using R version 3.6.2, meta and metafor packages. Results: A total of 62 studies including 14648 patients on IRP were first selected. Thirteen studies had two arms data, 501 patients were in TRT arm, 1185 patients were in non-TRT arm. Two studies including 557 patients were treated with immunotherapy and concurrent/sequential TRT. The remaining 47 studies had no TRT patients or TRT data were unavailable. The pooled rate of any grade IRP of all 62 studies (14648 patients) was 6% (95% CI: 5%-8%). All grades IRP was significantly higher among patients treated with immunotherapy and TRT arm when compared to the non-TRT arm (OR = 1.44, 95% CI: 1.04-2.00, P = 0.030). In the subgroup analysis, no significance difference in IRP rate was found between patients with various cancer types or various types of immune checkpoint inhibitors (p = 0.7033, p = 0.7522, respectively). The rate of IRP in all TRT patients was 18% (95% CI: 13%-24%), comparing to 5% (95% CI: 4%-6%) in control group. Conclusions: This meta-analysis demonstrates that TRT combined immunotherapy had an elevated incidence of IRP compared to non-TRT (OR = 1.44, 95% CI: 1.04-2.00, P = 0.030). There remains a lack of data on risk factors of IRP in TRT patients, and future large-scale studies are warranted. To our knowledge, this is the first comprehensive meta-analysis of IRP for TRT patients.

Landscape of Immune-Related Pneumonitis in Cancer Patients with Asthma Being Treated with Immune Checkpoint Blockade

Introduction: Predicting the factors that increase the risk of immune-related pneumonitis, a potentially life-threatening complication of treatment with immune checkpoint inhibitors for cancer, is a clinical challenge. Baseline clinical factors such as asthma may portend the development of pneumonitis due to pre-existing airway inflammation prior to immunotherapy. Objective: The purpose of the study was to investigate whether a prior diagnosis of asthma is associated with an increased risk of immune-related pneumonitis in patients undergoing cancer immunotherapy. Methods: Patients at the Moores Cancer Center at UC San Diego Health undergoing immunotherapy were identified on an IRB-approved protocol. Clinical charts were reviewed for asthma documented in the medical records and CT scans were reviewed during and after treatment. Pneumonitis was defined as the onset of new pulmonary symptoms with characteristic imaging findings during or after a patient’s first course of immunotherapy that could not be readily explained as infection or a progression of malignancy. It was graded according to the Common Terminology Criteria for Adverse Events. Results: A total of 187 patients were included. A diagnosis of asthma was found in the records of 26 cases (13.9%). Pneumonitis was found in 10 cases (5.35%); 50% were grade 2 and 50% were grade 3–4. Two of the grade 3–4 cases (40%) occurred in patients with non-small-cell lung cancer. Three patients with asthma developed pneumonitis (11.5% of patients with asthma), all grade 3–4. Only 28.6% of the non-asthma-pneumonitis cases were grade 3–4. All (100%) of the asthma-pneumonitis patients were former smokers, while 71.4% of the non-asthma-pneumonitis patients were former smokers. Conclusion: A history of asthma may be associated with a higher grade of pneumonitis if it develops, and a history of smoking may augment this relationship.

Radiation-induced lung injury: latest molecular developments, therapeutic approaches, and clinical guidance.

Cancer research has advanced throughout the years with respect to the personalization of the treatments and to targeting cancer-related molecular signatures on different organs. Still, the adverse events of the treatments such as radiotherapy are of high concern as they may increase the mortality rate due to their severity. With the improved efficiency of cancer treatments, patient survival has been increasing. Consequently, the number of patients with adverse effects from radiotherapy is also expected to increase in the forthcoming years. Therefore, approaches for personalized treatments include the elimination of adverse events and decreasing the toxicity in healthy tissues while increasing the efficiency of cancer cytotoxicity. In this context, this paper aims to discuss the recent advances in the field of thorax irradiation therapy and its related toxicities leading to radiation pneumonitis in cancer patients. Molecular mechanisms involved in the radiation-induced lung injury and approaches used to overcome this lung injury are discussed. The discourse covers approaches such as therapeutic administration of natural products, current and prospective radioprotective drugs, and applications of mesenchymal stem cells for radiation-induced lung injury.

MS19.01 Drug-Induced Pneumonitis with IO: How worried should we be for our Lung Cancer Patients

MS19.01 Drug-Induced Pneumonitis with IO: How worried should we be for our Lung Cancer Patients

Refractory Atezolizumab-Induced Pneumonitis

SESSION TITLE: Drug-induced Lung Disease SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: The use Anti PD-1 antibodies have promising results in the management of advanced cancers. Immune-mediated side effects of these medications were described in clinical trials, including pneumonitis. Here we report a case of Atezolizumab induced pneumonitis. CASE PRESENTATION: A 62-year-old male with concurrent diagnoses of metastatic urethral cancer and metastatic colon cancer. He was started on FOLFOX and Atezolizumab regimen. Six weeks after Atezolizumab he developed mild Atezolizumab induced pneumonitis. Atezolizumab was held and he was started on oral prednisone. Due lack of clinical response he was admitted to the hospital and started on IV methylprednisolone, broad spectrum antibiotics, and oxygen support via high flow nasal cannula as he declined intubation. Bronchioalveolar Lavage cell count with 14% lymphocytes, infectious studies were negative. A repeat CT scan of the chest was done two weeks after admission showed increased bilateral ground glass opacities. Given the lack of improvement on steroid therapy, he was given Infliximab 5mg/kg with no improvement. His clinical condition continued to worsen so the patient and his family decided to start comfort care. The patient died peacefully three weeks after admission. DISCUSSION: PD-1 checkpoint inhibitors are well tolerated, however, the risk of developing pneumonitis is about 3%. Diagnosis depends on clinical and radiographic findings. The diagnosis is challenging; the need to rule out infection, pulmonary edema, and tumor progression is in the differential diagnosis of worsening symptoms in these patients. Medication-induced pneumonitis is usually reversible, while the cessation of immunotherapy medication is usually sufficient in mild cases. High-grade cases require hospitalization and initiation of steroid therapy. Cases refractory to steroids are uncommon. The current recommendation for refractory pneumonitis is for additional immunosuppression using Infliximab, Cyclophosphamide or Mycophenolate mofetil. However given small numbers of patients requiring such therapy and variable outcomes, the effectiveness of additional immunosuppression is unclear. CONCLUSIONS: Refractory Anti-PD-1 induced pneumonitis is rare. Immunosuppression is recommended despite limited evidence. More studies are needed to guide therapy. Reference #1: Sci Rep. 2017 Mar 8;7:44173. doi: 10.1038/srep44173. PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis. Wu J1, Hong D1, Zhang X2, Lu X1, Miao J1. DISCLOSURE: The following authors have nothing to disclose: Ibraheem Yousef, Muhammad Baraa Hammami No Product/Research Disclosure Information

PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis

Therapies that targeted PD-1 have shown remarkable rates of durable clinical responses in patients with various tumor types. However, the extent and knowledge of pulmonary toxicities associated with PD-1 blockade, mainly manifested as pneumonitis, remains obscure. In this study, a total of 6360 subjects from 16 phase II/III clinical trials were pooled for meta-analysis to evaluate the overall incidence and risk of PD-1 inhibitors-related pneumonitis in cancer patients. The incidence of pneumonitis during anti-PD-1 immunotherapy was 2.92% (95%CI: 2.18–3.90%) for all-grade and 1.53% (95%CI: 1.15–2.04%) for high-grade pneumonitis. Compared with routine chemotherapy, PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Moreover, among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Furthermore, no significant differences were detected in the incidences of all- and high-grade pneumonitis between high-dose and low-dose groups of PD-1 inhibitors. In conclusion, PD-1 inhibitors were probably associated with an increased risk of pneumonitis in a dose-independent manner, compared with routine chemotherapeutic agents. The frequency and severity of treatment-mediated pneumonitis was quite different in patients with various tumor types.

OA21.01 Pooled Analysis of the Incidence and Risk of Treatment-Related Pneumonitis with Anti-PD-1/PD-L1 Therapies in Cancer Patients

Blockade of programmed death 1 (PD-1), or its ligand, PD-L1, could restore T-cell immunity. Anti-PD-1/ or anti-PD-L1 antibodies have demonstrated promising efficacy in the treatment of cancer patients. The toxicity spectrum of PD-1/PD-L1 blockers is distinct from chemotherapy or other target agents. Pneumonitis is one of the major side effects of these drugs, and reported incidences vary substantially between clinical trials. We tried to investigate the overall incidence and risk of treatment-related pneumonitis with anti-PD-1/PD-L1 therapies in cancer patients. A systematic search of literature up to January 2016 was performed in EDLINE, EMBASE, and Cochrane databases to identify relevant clinical trials. Paired reviewers independently selected articles for inclusion and extracted data. Incidence and relative risk (RR) of hypertension were calculated using a random-effects or fixed effects model, depending on the heterogeneity of the included studies. A total of 23 clinical trials with 5333 patients were included. The overall incidence of all- and high-grade pneumonitis in cancer patients receiving anti-PD-1/PD-L1 therapies were 3.5% (95% CI, 2.9% to 4.3%) and 1.3% (95% CI, 1.1% to 1.9%), respectively. Anti-PD-1/PD-L1 antibodies were associated with a significantly increased risk of all-grade pneumonitis in patients with cancer with an RR of 5.47 (95% CI, 2.17 to 13.81; p<0.001) compared with controls. The risk of high-grade pneumonitis was also increased with the use of anti-PD-1/PD-L1 antibodies, though not statistically significant (RR 3.86; 95% CI 0.98 to 15.22; p=0.054). Patients with cancer receiving anti-PD-1/PD-L1 therapies have a significant risk of developing pneumonitis. Early and appropriate management is strongly recommended to avoid unnecessary dose reductions and transitory or definitive treatment discontinuations due to pneumonitis.

Risk of mTOR inhibitors induced severe pneumonitis in cancer patients: a meta-analysis of randomized controlled trials.

A meta-analysis of randomized controlled trials was performed to determine the overall risk of noninfectious severe pneumonitis associated with mTOR inhibitors (mTORi) in cancer patients. PubMed, EMBASE and oncology conference proceedings were searched for relevant studies. A total of 8377 patients from 16 randomized controlled trials were included. The incidence of severe pneumonitis associated with mTORi was 1.7% (95% CI: 1.1-2.5%). The use of mTORi significantly increased the risk of severe pneumonitis compared with controls (odds ratio: 3.36; 95% CI: 2.20-5.12). The analysis was stratified for drug types, tumor types, controlled therapy and mTORi-based regimens, but no significant differences in odds ratios were observed. mTORi significantly increase the risk of severe pneumonitis in cancer patients.

Impact of single-nucleotide polymorphisms on radiation pneumonitis in cancer patients.

Radiation pneumonitis (RP) is one of the most important dose-limiting toxicities in the radiotherapy of thoracic tumors, which reduces the rate of local tumor control and overall survival and severely affects the patients' quality of life. Single-nucleotide polymorphisms (SNPs) have recently attracted increasing attention as biomarkers for predicting the development of RP. SNPs in inflammation-related, DNA repair-related, stress response-related and angiogenesis-related genes were proved to be associated with RP, with different underlying mechanisms. Radiogenomics focuses on the differences in radiosensitivity caused by gene sequence variation, which may prove helpful in investigating the abovementioned associations. In this review, we aimed to investigate the associations between RP and SNPs reported in recent studies and highlight the main content and prospects of radiogenomics.

Risk of pneumonitis with mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus.

e13573 Background: Pneumonitis is associated with the use of mTOR inhibitors, everolimus and temsirolimus, which have been used widely in cancer therapeutics and clinical trials. Currently, the overall risk of pneumonits in patients treated with mTOR inhibitors has not been defined. We performed a systematic review and meta-analysis of published clinical trials to assess the risk of pneumonitis in cancer patients treated with mTOR inhibitors. Methods: Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2012 were searched to identify relevant studies. Eligible studies included prospective clinical trials in which patients received treatment with everolimus or temsirolimus as a single agent or in combination with other agents. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. Results: A total of 2,303 patients with a variety of tumors from 18 studies (everolimus: 12, temsirolimus: 6) were included for the analysis. The overall incidences of all-grade and high-grade pneumonitis with mTOR inhibitors were 6.5% (95% CI: 3.7-11.1%) and 2.5% (95% CI 1.2-5.4%) respectively. The risk of all-grade pneumonitis did not vary significantly with tumor types (P=0.079), but vary significantly with their combination with other agents (P&lt;0.001). There was no significant difference between everolimus and temsirolimus in the incidence of all-grade (P=0.22) and high-grade (P=0.28) pneumonitis. In comparison with controls, mTOR inhibitors significantly increased the risk of all-grade (RR=5.2, 95% CI: 2.09-12.93, P&lt;0.001) but not high-grade pneumonits (RR=2.63, 95% CI: 0.66-10.40, P=0.41). Conclusions: The risk of pneumonitis is increased in cancer patients receiving mTOR inhibitors without significant difference between everolimus and temsirolimus.

Steroid-withdrawal Radiation Pneumonitis in Cancer Patients

Two cancer patients developed steroid-withdrawal radiation pneumonitis. This complication is a recognized risk in the treatment of patients with Hodgkin's disease and other malignant lymphomas, but is under-recognized in patients receiving treatment for carcinoma.