Recall Pneumonitis Research Articles

Radiation Recall Pneumonitis: Imaging Appearance and Differential Considerations.

Radiation recall pneumonitis is an inflammatory reaction of previously radiated lung parenchyma triggered by systemic pharmacological agents (such as chemotherapy and immunotherapy) or vaccination. Patients present with non-specific symptoms such as cough, shortness of breath, or hypoxia soon after the initiation of medication or vaccination. Careful assessment of the patient's history, including the thoracic radiation treatment plan and timing of the initiation of the triggering agent, in conjunction with CT findings, contribute to the diagnosis. Once a diagnosis is established, treatment includes cessation of the causative medication and/or initiation of steroid therapy. Differentiating this relatively rare entity from other common post-therapeutic complications in oncology patients, such as recurrent malignancy, infection, or medication-induced pneumonitis, is essential for guiding downstream clinical management.

A Case of Radiation Recall Pneumonitis Caused by Nivolumab+Ipilimumab Combination Therapy

A Case of Radiation Recall Pneumonitis Caused by Nivolumab+Ipilimumab Combination Therapy

Radiation recall pneumonitis: PET/CT findings.

A 63-year-old woman with locally advanced lung cancer (Fig. 1A) who was treated with curative-intent chemoradiation therapy (cisplatin, etoposide and 60 Gy in 30 fractions) developed minimal radiation-induced fibrosis in the irradiated area 12 months after the end of the radiation therapy (Fig. 1B). The patient subsequently received consolidation therapy with durvalumab (anti-programmed cell death ligand-1). Twenty-four months after radiation therapy was administered, she was found to have on computed tomography (CT) a new-onset consolidation in the previously irradiated field (Fig. 1C), with normal appearance of the rest of the lung parenchyma. A transbronchial biopsy did not show signs of local recurrence. Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT confirmed a homogeneous mildly hypermetabolic lung consolidation (Fig. 1D), consistent with inflammatory changes. PET/CT did not show any intense FDG focal activity that would suggest lung cancer recurrence. Since the patient was asymptomatic, treatment with durvalumab was not discontinued and a presumptive diagnosis of radiation recall pneumonitis (RRP) was made. Subsequent CT studies showed spontaneous but slow progressive reduction in size of the lung consolidation (Fig. 1E).

Radiation Recall Pneumonitis: The Open Challenge in Differential Diagnosis of Pneumonia Induced by Oncological Treatments.

The treatment of primary and secondary lung neoplasms now sees the fundamental role of radiotherapy, associated with surgery and systemic therapies. The improvement in survival outcomes has also increased attention to the quality of life, treatment compliance and the management of side effects. The role of imaging is not only limited to recognizing the efficacy of treatment but also to identifying, as soon as possible, the uncommon effects, especially when more treatments, such as chemotherapy, immunotherapy and radiotherapy, are associated. Radiation recall pneumonitis is an uncommon treatment complication that should be correctly characterized, and it is essential to recognize the mechanisms of radiation recall pneumonitis pathogenesis and diagnostic features in order to promptly identify them and adopt the best therapeutic strategy, with the shortest possible withdrawal of the current oncological drug. In this setting, artificial intelligence could have a critical role, although a larger patient data set is required.

A Novel Workflow to Create a Checkpoint Inhibitor Pneumonitis Patient Registry.

Background Despite being a groundbreaking cancer therapy, immune checkpoint inhibitors (ICI) can lead to potentially life-threatening toxicity with checkpoint inhibitor pneumonitis (CIP). While treatable, it is easy for clinicians to miss the symptoms of CIP, which can lead to a delay in diagnosis and worsening respiratory function. There is no consensus approach to systematically identifying patients at risk of developing CIP. Thus, we sought to create a workflow that could inform patient selection for ICI therapy based on previously reported risk factors for CIP development. Materials and methods We retrospectively identified 250 patients with lung cancer treated with at least one dose of an ICI over 20 months. Data were collected on comorbidities, cancer type and stage, performance status, ICI cycles, biomarkers, prior curative treatment, diagnostic evaluation, antibiotics, steroids, progression, and survival. A single-blinded radiologist characterized radiographic patterns of suspected CIP cases. Results Among 97 patients who received steroids while admitted to the hospital, 12 (6%) had at least one sign or symptom suggestive of CIP. Chronic obstructive pulmonary disease and non-small cell lung cancer subtypes correlated with suspicion of having CIP. CIP was confirmed in five patients (42%) and ruled out (mimics) in seven (58%).Median times until symptoms were 17 months and one month for confirmed and mimic cases, respectively.The median time to confirm or exclude CIP was 5 ± 4 days. Most suspected cases underwent thoracic imaging, blood cultures, and empiric antibiotics. Radiographic patterns in suspected cases included ground glass opacities, organizing pneumonia, acute interstitial pneumonia/acute respiratory distress syndrome, bronchiolitis, radiation recall pneumonitis, hypersensitivity pneumonitis, and post-radiation fibrotic changes. Conclusions CIP mimics are common in clinical practice; therefore, it is reasonable to empirically treat suspected cases with shorter courses of steroids until diagnostic clarity is achieved. This proof-of-concept study demonstrates that this novel workflow can identify the true incidence of CIP, inform treatment decisions, and lead to the development of implementation studies to improve patient care directly.

Radiation Recall Pneumonitis Anticipates Bilateral Immune-Induced Pneumonitis in Non-Small Cell Lung Cancer

Radiation recall pneumonitis (RRP) is a rare inflammatory reaction that occurs in previously irradiated fields, and it may be caused by various triggering agents. Immunotherapy has been reported to potentially be one of these triggers. However, precise mechanisms and specific treatments have not been explored yet due to a lack of data in this setting. Here, we report a case of a patient who received radiation therapy and immune checkpoint inhibitor therapy for non-small cell lung cancer. He developed first radiation recall pneumonitis and subsequently immune-checkpoint inhibitor-induced pneumonitis (IIP). After presenting the case, we discuss the currently available literature on RRP and the challenges of differential diagnosis between RRP, IIP, and other forms of pneumonitis. We believe that this case is of particular clinical value since it highlights the importance of including RRP in a differential diagnosis of lung consolidation during immunotherapy. Furthermore, it suggests that RRP might anticipate more extensive ICI-induced pneumonitis.

Nivolumab-induced radiation recall pneumonitis in non-small-cell lung cancer patients with thoracic radiation therapy.

The role of previous thoracic radiation therapy as a risk factor of immune-related pneumonitis is unclear. Furthermore, some patients develop radiation recall pneumonitis, which is characterized by a radiation pneumonitis-like imaging pattern with consolidation progressing within a previous radiation field. In this multicenter retrospective study, we analyzed the relationship of previous thoracic radiation therapy with immune-related pneumonitis and the characteristics of radiation recall pneumonitis. The medical records of patients with non-small-cell lung cancer who had received nivolumab between December 2015 and March 2017 at five institutions were retrospectively reviewed. Incidence, imaging patterns, clinical course, and risk factors of immune-related pneumonitis and radiation recall pneumonitis were evaluated. A total of 669 patients were evaluated, and the incidences of all-grade and grade 3 or higher immune-related pneumonitis were 8.8% and 2.6%, respectively. The incidences of immune-related pneumonitis were 13.2% (34/257) and 6.1% (25/412) in patients with and those without previous thoracic radiation therapy, respectively. A history of previous thoracic radiation therapy was associated with immune-related pneumonitis (odds ratio, 2.11; 95% confidence interval, 1.21-3.69 in multivariate analysis). Among the patients with previous thoracic radiation therapy, 6.2% (16/257) showed radiation recall pattern. This study found an increased risk of nivolumab-induced immune-related pneumonitis associated with a history of thoracic radiation therapy. Radiation recall pattern was one of the major patterns of immune-related pneumonitis among the patients with previous thoracic radiation therapy. Incidence, risk factors, and clinical outcome of radiation recall pneumonitis were elucidated.

Risk Factors of Treatment-Related Pneumonitis after Thoracic Radiotherapy/Chemoradiotherapy Combined with Anti-PD-1 mAb in Esophageal Squamous Cell Carcinoma

<h3>Purpose/Objective(s)</h3> Treatment-related pneumonitis (TRP) and radiation recall pneumonitis (RRP) has recently been identified as a toxicity triggered by thoracic irradiation combined with anti-PD-1 mAb in esophageal squamous cell carcinoma (ESCC). However, the incidence, risk factors and dose-volume parameters remain unknown. <h3>Materials/Methods</h3> We analyzed 97 patients with ESCC who received thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 mAb. There were 74 patients of newly diagnosed/locally advanced unresectable esophageal cancer, 22 patients of recurrent after radical resection /metastatic esophagus cancer, and 1 patient of resectable esophageal cancer with neoadjuvant therapy. 41 patients received concurrent thoracic radiotherapy and anti-PD-1 mAb, 56 patients received sequential thoracic radiotherapy and anti-PD-1 mAb. The median radiation dose of PTV was 59.4Gy (range from 45Gy to 66Gy, 1.8Gy-2.2Gy per fraction). TRP and RRP were classified according to the CTCAE version 5.0 and the effect of dose-volume parameters of lung on TRP and RRP was analyzed. <h3>Results</h3> The average value of V_5, V_10, V_20, V₃₀ and MLD of lung was 49.2% (27.9%-73.6%), 35.9% (21.7%-48.6%), 21.3% (12.7%-29.9%), (1.5% -17.5%) and 1092.5cGy (666.9cGy-1569.6cGy), respectively. The incidence of TRP was 46.4% (45/97). 41.2% of patients developed grade 1 or 2 pneumonitis and 4.1% of patients was grade 3 pneumonitis. Of note, there was 1 death probably related with TRP. The incidence of RRP was 14.4% (14/97). 14.4% of patients developed grade 1 or 2 pneumonitis and there was no grade ≥3 RRP. The median onset time of TRP and RRP was 16 weeks after receiving anti-PD-1 mAb (2.6 weeks-65.9 weeks) and 48.9 weeks (27 weeks-91.1 weeks) after thoracic radiotherapy, respectively. Result of multivariate analysis showed that V₅ was an independent risk factor of grade ≥2 TRP (P=0.003, OR=1.106). The incidence of grade ≥2 TRP in the V₅≥55.7% group was significantly higher than that in the V₅<55.7% group (56.5% vs 16.2%). There was only a trend towards higher V₅, V₃₀, V₃₅, and MLD related to RRP without statistical significance. <h3>Conclusion</h3> We demonstrate a high risk of TRP in ESCC patients receiving thoracic radiotherapy/chemoradiotherapy combined with anti-PD-1 mAb and mostly pneumonitis was grade 1 and grade 2. While the occurrence of RRP is relatively less and the severity is mild. TRP (grade≥2) is associated with V₅≥55.7%, so clinicians should pay more attention to restriction of V₅ and V₅<55.7% might be a safer volume. Therapy strategy combined thoracic radiotherapy/chemoradiotherapy with anti-PD-1 mAb might be a safe choice, it is worth a further exploration.

Radiation Recall Pneumonitis: A Rare Syndrome That Should Be Recognized.

Simple SummaryA combination of radiotherapy and systemic antineoplastic agents is a common treatment strategy for lung cancer. However, Radiation recall pneumonitis (RRP) is a rare disease which has been mainly detected in the previously irradiated lung of patients with cancer after the application of triggering agents, including, but not limited to, antineoplastic agents. Physicians should be aware of this rare reaction, as the occurrence of RRP could impact the outcome of anti-cancer treatment. Given that current studies on RRP are primarily case reports and retrospectively reviewed data, the aim of our article was to review the current understanding and evidence on RRP and define the characteristics of RRP.Radiation recall pneumonitis (RRP) is a rare but severe condition which has been mainly detected in the previously irradiated lung of patients with cancer after administering inciting agents, most commonly antineoplastic regimens including chemotherapy, targeted therapy, or immunotherapy. More recently, coronavirus disease vaccines were found to induce RRP. In addition to typical radiation pneumonitis (RP) or drug-induced interstitial lung disease, the management of RRP requires withholding inciting agents and steroid therapy. Thus, the occurrence of RRP could significantly impact cancer treatment, given that inciting agents are withheld temporarily and even discontinued permanently. In the present review, we discuss the current understanding and evidence on RRP and provide additional insights into this rare but severe disease.

EP05.01-016 Radiation Recall Pneumonitis (RRP) Induced by Immune Checkpoint Inhibitors (ICIs) after Thoracic Radiotherapy for Lung Cancer

Radiation recall pneumonitis (RRP) describes inflammatory reactions at previously irradiated fields of pulmonary tissue after exposure to certain systemic agents. Immune checkpoint inhibitors (ICIs) have been reported as potential causal agents of RRP in lung cancer. Yet, the general characteristics and risk factors of ICI-related RRP remain unclear. This study investigates the incidence, characteristics, and risk factors of RRP induced by ICIs after thoracic radiotherapy in patients with lung cancer.

Comprehensive Pneumonitis Profile of Thoracic Radiotherapy Followed by Immune Checkpoint Inhibitor and Risk Factors for Radiation Recall Pneumonitis in Lung Cancer.

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.

RADIATION RECALL PNEUMONITIS COVID-19 INDUCED AFTER ADJUVANT BREAST CANCER RADIOTHERAPY: A CASE REPORT

TYPE: Late Breaking Case Report TOPIC: Chest Infections INTRODUCTION: A radiation recall pneumonitis is an inflammatory reaction within a previous radiation (RT) site. COVID-19 infection in previous irradiated lung could promote a recall pneumonitis as we report herein. CASE PRESENTATION: A 65-year-old woman was diagnosed with invasive stage III A ductal carcinoma of the right breast four years ago. After breast conserving surgery, standard adjuvant RT was provided. Four years later, in March 2020, she complained of mild dyspnea and cough. The COVID-19 swab was positive. The chest CT scan showed a straight and sharp opacity in the right lung miming the previous radiation treatment fields with several ground glass opacities in both lungs. She was admitted in a Covid Unit and treated per protocol. Chest CT scan 3 months later its resolution, a pulmonary fibrosis within the irradiated fields still was observed. DISCUSSION: A radiation recall pneumonitis is an inflammatory reaction localized within a previous irradiation site following the administration of drugs like immunotherapy. Immunity is considered to be an influencing factor, but the mechanism is still unknown. It is known that COVID-19 causes immune system reactions in the lung inducing an alveolar and interstitial damage as occurs in case of radiation induced lung injury. Probably an immune memory response of CD 4+ T cells activated by previous RT may have a role. CONCLUSIONS: We described a case in which radiation recall pneumonitis was observed after COVID-19 pneumonitis four years post adjuvant RT. There are still many uncertainties that are poorly understood about COVID-19 infection and radiation pneumonitis. DISCLOSURE: Nothing to declare. KEYWORD: pneumonitis

Pulmonary Lymphangitis Poses a Major Challenge for Radiologists in an Oncological Setting during the COVID-19 Pandemic.

Due to the increasing number of COVID-19-infected and vaccinated individuals, radiologists continue to see patients with COVID-19 pneumonitis and recall pneumonitis, which could result in additional workups and false-positive results. Moreover, cancer patients undergoing immunotherapy may show therapy-related pneumonitis during imaging management. This is otherwise known as immune checkpoint inhibitor-related pneumonitis. Following on from this background, radiologists should seek to know their patients’ COVID-19 infection and vaccination history. Knowing the imaging features related to COVID-19 infection and vaccination is critical to avoiding misleading results and alarmism in patients and clinicians.

Radiation recall pneumonitis triggered by an immune checkpoint inhibitor following re-irradiation in a lung cancer patient: a case report

BackgroundRadiation recall pneumonitis (RRP) is unpredictable but associated with severe radiation damage in previously irradiated fields. Chemotherapy and targeted drugs have been reported to contribute to RRP. Here we report a case of a patient with non-small cell lung cancer (NSCLC) who developed RRP following administration of immune checkpoint inhibitor (ICI) 18 months after the end of re-irradiation.Case presentationA 69-year-old man received adjuvant chemoradiotherapy post-operatively. He underwent thoracic re-irradiation for oligometastatic NSCLC. On second recurrence, pembrolizumab combined with nab-paclitaxel were administered. After six months, he developed symptoms of persistent cough and dyspnea, with consistent pneumonitis on CT images. The clinical time frame and significant radiographic evidence raised suspicion for RRP. Symptoms resolved after steroids.ConclusionsRRP is a rare occurrence. Patients undergoing immunotherapy after prior irradiation may be at increased risk of this rare radiation pneumonitis.

Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature.

BackgroundRadiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP.Case PresentationOur first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy.ConclusionsImmunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.

Incidence, risk factors, and CT characteristics of radiation recall pneumonitis induced by immune checkpoint inhibitor in lung cancer

Background and purposeRadiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. Immune checkpoint inhibitors (ICIs) have recently been identified as potential causal agents of RRP but its real incidence and potential risk factors remain unknown. Materials and methodsMedical records and CTs of patients treated with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors for advanced lung cancer between 2014 and 2019 at our tertiary center, and who had a previous history of lung irradiation were retrospectively analyzed. We identified RRP as lung CT modifications occurring in the irradiation field >6 months after conventionally fractionated radiotherapy completion and >1 year after stereotactic body radiation therapy. Clinical and dosimetric data were analyzed to identify potential risk factors for RRP. ResultsAmong 348 patients treated with ICIs, data from 80 eligible patients were analyzed (median age, 69 years [interquartile range, 11]; 45 men). Fifteen patients (18.8%) presented with RRP. Median time between end of radiotherapy and RRP was 450 days (range, 231–1859). No risk factor was significantly associated with RRP. ICI-related pneumonitis was associated with RRP in 33.3% of cases (p = 0.0021), developing either concomitantly or after RRP. Incidence of grade ≥ 3 pneumonitis in the RRP population was 13.3 %. ConclusionWe demonstrated a high incidence of RRP (18.8%) in our population of previously irradiated patients treated with ICIs for lung cancer. We identified no risk factors for RRP, but an association was noted between RRP and ICI-related pneumonitis.

Findings on Chest CT Performed in the Emergency Department in Patients Receiving Immune Checkpoint Inhibitor Therapy: Single-Institution 8-Year Experience in 136 Patients.

BACKGROUND. Patients undergoing immune checkpoint inhibitor (ICI) therapy may present to the emergency department (ED) with a wide range of immune-related adverse events. OBJECTIVE. The purpose of our study was to evaluate chest CT findings in patients receiving ICI therapy presenting to the ED and to explore these findings' associations with clinical parameters. METHODS. This retrospective study included 136 patients (75 men, 61 women; mean age, 65 ± 12 [SD] years) receiving ICI therapy who underwent chest CT at 163 ED visits between 2011 and 2018. Two radiologists independently reviewed chest CT examinations for various findings and resolved discrepancies by consensus. Clinical parameters, including survival at last available follow-up, were recorded. Chest CT findings were summarized, and interreader agreement was evaluated using kappa coefficients. Associations between CT findings and clinical parameters were explored using Fisher exact, chi-square, Wilcoxon, and Kruskal-Wallis tests. RESULTS. A total of 62.5% of patients had primary lung cancer; 52.9% received nivolumab monotherapy, and 30.1% received pembrolizumab monotherapy. A total of 55.8% of ED visits occurred within 60 days after ICI initiation. The most common CT findings were worsening lung tumor burden (60.1%), new consolidation unrelated to tumor (30.1%), new or worsening pleural effusion (23.9%), and ICI-associated pneumonitis (12.9%). The most common CT pneumonitis pattern was radiation recall pneumonitis (6/21, 28.6%). A total of 78.5% of ED visits with chest CT resulted in hospitalization; 66.9% of patients subsequently died. Survival was worse for patients with, versus without, worsening tumor (72.2% vs 49.1% of patients deceased vs alive at follow-up, p = .006) and for patients with, versus without, pleural effusion (39.2% vs 17.5% of patients deceased vs alive at follow-up, p = .04). Kappa values for interreader agreement of evaluated chest CT findings ranged from 0.66 (worsening tumor burden) to 1.00 (numerous findings). CONCLUSION. Most ED chest CT examinations in patients receiving ICI therapy exhibited worsening lung tumor burden, which was associated with worse survival. New consolidation and ICI-associated pneumonitis (most commonly radiation recall pneumonitis) were also commonly detected in the ED setting. CLINICAL IMPACT. Understanding pathologies detected on chest CT in patients undergoing ICI therapy who present to the ED may guide radiologists in interpreting such imaging.

CASE SERIES: SERIOUS PULMONARY TOXICITY SECONDARY TO PEMBROLIZUMAB; AN IMMUNE CHECKPOINT INHIBITOR

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Immune checkpoint inhibitors (ICIs) which target the programmed cell death 1 (PD-1) / programmed cell death ligand 1 (PDL-1) pathway [1,2,3] have been effective in cancer treatment. ICIs carry a high risk of lung injury with potential for permanent damage and death [1]. We describe 3 patients with lung injury from use of PD-1 Inhibitor (Pembrolizumab) that outlines the spectrum of injury and outcome. CASE PRESENTATION: Case one:74-year-old male was treated for metastatic urinary bladder carcinoma with pembrolizumab and 2 months later developed nonspecific interstitial pneumonia (NSIP)(Figure 1) leading to hypoxemic respiratory failure requiring ventilator support. This progressed over 1 month to fibrotic NSIP. Course was complicated by Sepsis and multi organ failure and the patient died. Case two:48-year-old male was treated for metastatic renal cell carcinoma with pembrolizumab. Two months later he developed hypoxemic respiratory failure secondary to organizing pneumonia (Figure 2). The drug was discontinued and in spite of treatment with steroids and mycophenolate, he progressed to fibrotic organizing pneumonia and now has poor functional status and is oxygen dependent. Also noted were abnormal liver function, raised troponin and raised lipase suggestive of drug induced toxicity.Case three:74-year-old with metastatic stage IV Non-small cell lung cancer treated with chemotherapy and pembrolizumab. Two months later he developed hypoxemic respiratory failure secondary to organizing pneumonia (Figure 3) but rapidly responded to steroid treatment. DISCUSSION: Patients treated with PD-1 inhibitors such as Pembrolizumab, are high risk for lung injury [1]. Patterns of Injury described include organizing pneumonia, nonspecific interstitial pneumonia (NSIP), Hypersensitivity pneumonitis, acute interstitial pneumonia, radiation recall pneumonitis and bronchiolitis. Median time to occurrence of lung injury is 3 months. More than 50 % of patients also exhibit signs of inflammatory dysfunction in the heart, skin, thyroid or colon. Up to 12% of patients progress to lethal disease despite immunosuppression [2,3]. Two of our patients developed lung injury in the form of organizing pneumonia with one responding to steroids and the other progressing to fibrotic disease and oxygen dependency. The third patient progressed to fibrotic NSIP and died with complications of sepsis and organ failure. CONCLUSIONS: Lung injury secondary to PD-1 inhibitor treatment can lead to severe and lethal outcomes [2,3] and we report our experience to highlight this. Close monitoring is recommended and early discontinuation at first sign of lung injury is essential. Response to immunosuppression is unpredictable and early recognition is the key. Reference #1: 1.Khunger, M. et al. Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials. Chest 152, 271–281 (2017). Reference #2: 2.Rickard, Frances et al. "Pneumonitis: a serious adverse effect of PD-L1 inhibitors including pembrolizumab.” BMJ case reports vol. 2018 bcr2018224485. 7 May. 2018, https://doi.org/10.1136/bcr-2018-224485 Reference #3: 3.Jun, Jiho et al. "Pneumonitis and concomitant bacterial pneumonia in patients receiving pembrolizumab treatment: Three case reports and literature review.” Medicine vol. 98,25 (2019): e16158. https://doi.org/10.1097/MD.0000000000016158 DISCLOSURES: No relevant relationships by Abdul Basit, source=Web Response No relevant relationships by Aaron Douen, source=Web Response No relevant relationships by Pushpinder Kaur, source=Web Response No relevant relationships by padmanabhan krishnan, source=Web Response No relevant relationships by David Michael, source=Web Response No relevant relationships by Nikolas St.Cyr, source=Web Response

Is checkpoint inhibitor pneumonitis underreported in patients with advanced non-small cell lung cancer (NSCLC) on PD-1 inhibitor monotherapy?

9579 Background: For patients with advanced non-small cell lung cancer (NSCLC), immunotherapy (ImT) has led to improvements in survival and quality of life. Checkpoint inhibitor pneumonitis (CIP) is an uncommon but sometimes life-threatening adverse event. While CIP is a diagnosis of exclusion, many oncologists believe the incidence of CIP is underreported. Radiomics, an image analysis technique that can extract imperceptible information from radiographic images, has been incorporated into predictive models for many cancers. Recent studies suggest that radiomic analysis of pre-ImT imaging can predict CIP. We hypothesized that for patients with advanced NSCLC treated with Nivolumab monotherapy, the rate of CIP is underreported and radiomics features can identify CIP that was clinically misclassified. Methods: From an IRB-approved database (DB) of 159 patients with advanced NSCLC treated with Nivolumab, chart review identified 8 patients diagnosed with CIP of any grade (5%). 42 additional patients from the same DB without diagnosis of CIP were randomly selected for analysis. For all 50 patients, uninvolved lung in the last pre-ImT CT imaging study was segmented, delineated, and analyzed for radiomics features associated with CIP. A logistic regression model incorporating radiomics assigned a CIP probability score to every patient. Results: Six radiomics features correlated with CIP ( p-values range from 0.02 to 0.03). Each feature had an AUC of ~0.79 (range 0.789 to 0.794) showing large effect size, with odds ratios greater than 3.50 (4 features) or less than 0.3 (2 features). The radiomics-based probability model assigned 7/42 patients (17.5%) without clinical diagnosis of CIP a greater than 50% probability of CIP. Chart review revealed that 6/7 “misclassified” patients exhibited symptoms or radiographic features highly suggestive of CIP within 5 months of initial immunotherapy treatment. These indications originally had been attributed to disease progression, overshadowed by more severe symptoms or simply mislabeled (e.g. a case of recall pneumonitis was described as "radiation pneumonitis"). Conclusions: For patients with advanced NSCLC treated with nivolumab, the incidence of checkpoint-inhibitor pneumonitis (CIP) is underreported and radiomics features can help identify CIP that has been clinically misclassified. Future directions include expansion of this study across the full database, correlation of radiomics features with blood biomarkers, and the inclusion of tumor burden as an additional covariate in the analysis.

Clinical characteristics of nivolumab-induced radiation recall pneumonitis in patients with non-small cell lung cancer: A multicenter real-world analysis of 669 patients.

88 Background: Immune checkpoint inhibitors can cause immune-related pneumonitis in lung cancer patients. Some of those patients with history of previous thoracic radiation therapy (TRT) are reported to show radiation recall pneumonitis (RRP) pattern. In this multicenter retrospective study, we analyzed the patient background and clinical characteristics of RRP. Methods: Medical records of non-small cell lung cancer patients, who received nivolumab between December 2015 and March 2017, were retrospectively reviewed. Incidence of pneumonitis, and incidence, risk factors and clinical characteristics of RRP were analyzed at 5 institutions. Person’s chi-square test (age, sex, smoking history, performance status at the start of nivolumab treatment, background lung disease, history of previous radiation pneumonitis, total dose, volume receiving more than 20Gy, 30Gy, mean lung dose of TRT, and duration after TRT) was conducted to identify potential risk factors of RRP. RRP was defined as fibrosis or consolidation occurring in the previous TRT field, and imaging analysis was conducted by two individual radiologists. Results: A total of 669 patients were evaluated, and the incidences of all-grade and ≥ grade 3 pneumonitis were 8.8% (59/669) and 6.2% (18/669), respectively. Incidence of RRP was 5.4% (14/257) among patients with history of previous TRT. There were no significant risk factors for RRP. Although we did not find significant difference between the severity of RRP pattern and other radiological patterns of pneumonitis, patients with RRP showed better outcome. All patients recovered from RRP without no exacerbation or death, compared to 9.3% of exacerbation or death in other patterns of pneumonitis. Conclusions: Incidence of RRP was 5.4% among patients with history of previous TRT, although there were no significant risk factors of RRP. Patients with RRP pattern showed relatively better outcome.