How Do Cytotoxic Lymphocytes Kill Cancer Cells? Figure 10c. Immunotherapy was subsequently held, and steroid therapy was administered. The left lower lobe mass also increased in size (white arrow). Although not specifically addressed in published guidelines given the potential for high steroid doses administered for extended periods, infectious prophylaxis may be warranted. This case illustrates the impressive appearances that immunotherapy-induced pneumonitis can have on imaging. Figure 3b. Patients treated with checkpoint inhibitors may show variable computed tomography (CT) features on follow-up imaging, and it is unclear how reliable conventional response criteria are to determine patient management and outcomes. Patient and drug-related factors predicting the development of pneumonitis are currently under investigation. These ICI agents have adverse effects including the uncommon but potentially serious pulmonary toxicity of pneumonitis. The overlapping pulmonary toxicity induced by thoracic RT and programmed death 1/programmed death ligand-1 (PD-1/PD-L1) blockades is an important issue of clinical investigation in combination treatment. (b) Follow-up axial CT image obtained 4 months later after administering nivolumab therapy shows multiple predominantly peripheral and subpleural airspace consolidative opacities (arrows), findings consistent with an OP pneumonitis pattern. The size of the left lower lobe mass (arrow) decreased, suggesting a pseudoprogression on the previous study. Illustration shows the global effect of irAEs with associated manifestations. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. Check for errors and try again. cases.29 On CT, radiographic findings might be variable, with reported patterns including cryptogenic organising pneumonia, non­specific interstitial pneumonia, hyper­ sensitivity pneumonitis, and bronchiolitis (figure 217,30–33). AIP–ARDS pattern is not a prevalent pattern of ICI therapy–related pneumonitis, although it is associated with the most severe clinical course and extent of lung involvement at imaging, manifesting with median CTCAE grade 3 symptoms (31). The patient was receiving anti-PD1 (nivolumab) to treat her advanced metastatic melanoma. Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. Truly idiopathic AIP tends to occur in those without pre-existing lung disease and typically affects middle-aged adults (mean ~ 50 years 5). Findings of radiation recall pneumonitis include consolidative or ground-glass opacities limited to a prior radiation field (Fig 8). (2018) memo - Magazine of European Medical Oncology. Enter your email address below and we will send you the reset instructions. Its mechanism is likely multifactorial and is thought to be an autoimmune response with T-cell upregulation and ultimately increased granuloma formation. ), and Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (N.H.R., K.R.L., A.G.). Patients with grade 2 pneumonitis (symptomatic pneumonitis) should receive prednisone, 0.5–1 mg/kg/d, or the equivalent, and patients with grade 3 pneumonitis should receive a higher dose: 1–2 mg/kg or the equivalent. 5, World Chinese Journal of Digestology, Vol. Treatment is often effective, although recurrence is possible. Radiologic response to respective treatments (ie, bronchopulmonary hygiene physical therapy and antibiotic therapy) is also often helpful. (b) Axial chest CT image obtained 2 months later after starting pembrolizumab therapy shows bilateral lower lobe ground-glass and reticular opacities (black arrows), with regions of immediate subpleural sparing (white arrows). Grade 2 pneumonitis can be managed in the outpatient setting by withholding the ICI therapy and initiating steroid therapy, with initial dose burst followed by a 4- to 6-week taper. National Institutes of Health, National Cancer Institute, Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary, Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy, Ipilimumab-Induced Organizing Pneumonia on 18F-FDG PET/CT in a Patient With Malignant Melanoma, Pneumonitis Related to Melanoma Immunotherapy, PD-1 Inhibitor-Related Pneumonitis in Advanced Cancer Patients: Radiographic Patterns and Clinical Course, A Case of Organizing Pneumonia (OP) Associated with Pembrolizumab, Lung CT: Part 2—The interstitial pneumonias: clinical, histologic, and CT manifestations, Drug-Related Pneumonitis in the Era of Precision Cancer Therapy, Bronchiolitis obliterans after combination immunotherapy with pembrolizumab and ipilimumab, Pembrolizumab-Induced Bronchiolitis in a Patient with Stage IV Non-Small Cell Lung Cancer (abstr), Radiation recall pneumonitis induced by chemotherapy after thoracic radiotherapy for lung cancer, Nivolumab-Induced Radiation Recall Pneumonitis, Nivolumab induced radiation recall pneumonitis after two years of radiotherapy, Sarcoidosis-Like Reactions Induced by Checkpoint Inhibitors, Granulomatous/sarcoid-like lesions associated with checkpoint inhibitors: a marker of therapy response in a subset of melanoma patients, Pembrolizumab-induced Sarcoid-like Reactions during Treatment of Metastatic Melanoma, PD-1 inhibitors increase the incidence and risk of pneumonitis in cancer patients in a dose-independent manner: a meta-analysis, Diagnosis and management of pulmonary toxicity associated with cancer immunotherapy, PD-1 inhibitor-related pneumonitis in lymphoma patients treated with single-agent pembrolizumab therapy, Open in Image Normally, an important function of T cells is in the cell-mediated clearance of tumor cells. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. (a) Baseline axial chest CT image shows a medial left lower lobe lung mass with surrounding ground-glass halo sign (arrow), a finding corresponding to adenocarcinoma. ICI therapies are increasingly being used as first- and second-line agents in the treatment of a growing number of malignancies. Treatment-naïve patients have also demonstrated higher rates of pneumonitis relative to those patients who were previously treated (23). We describe the findings of a SARS-CoV-2 infection on PET/CT with 18 F- FDG in a 51-year-old man with metastatic renal cell carcinoma under treatment with nivolumab . With ongoing ICI clinical trials, the number of approvals and combinations and complexity of treatment regimens is expected to grow in the foreseeable future. (c) Axial chest CT image obtained 5 months after discontinuation of therapy shows minimal residual (although markedly improved) pneumonitis (arrow) in the left lower lobe. Immunotherapy-induced pneumonitis - metastatic melanoma. ICI therapy–related pneumonitis manifests as several distinct radiologic patterns that overlap with other infectious and inflammatory conditions. A high index of suspicion and prompt recognition of pneumonitis by the radiologist are critical to initiate prompt treatment and prevent further morbidity and mortality for these patients. The diagnosis of immunotherapy-induced pneumonitis was made after careful exclusion of other pulmonary conditions such as infection and malignancy. Viewer, https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf, https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2018.197.1_MeetingAbstracts.A4008, Nonspecific Interstitial Pneumonia: Radiologic, Clinical, and Pathologic Considerations, Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper from the Fleischner Society, Thoracic Complications of Precision Cancer Therapies: A Practical Guide for Radiologists in the New Era of Cancer Care, Bronchiolitis: A Practical Approach for the General Radiologist, Hypersensitivity Pneumonitis: A Historical, Clinical, and Radiologic Review, 3D Multiplanar Imaging in the Diagnosis and Management of Lung Transplantation Complications, Patterns of Drug-Related Pulmonary Injury: A Pictorial Review, Update of the International Multidisciplinary Classification of the Idiopathic Interstitial Pneumonias: Revised Concepts and Radiologic Implications. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. Associated focal ground-glass and consolidative opacities may be visualized, although this should not the predominant feature. NSIP-associated connective tissue and autoimmune disorders are generally long-standing processes in the setting of other known comorbid conditions. (a) Axial chest CT image obtained 5 months after starting nivolumab therapy shows diffuse centrilobular ground-glass nodules (arrows). Imaging. Going forward, given the potential complexity of diagnosis and management of ICI therapy–related pneumonitis, radiologists must work in conjunction with a broader multidisciplinary team to provide optimal care for these patients. Purpose: Investigate the clinical characteristics, radiographic patterns, and treatment course of PD-1 inhibitor–related pneumonitis in advanced cancer patients. AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. (b) Follow-up coronal chest CT image obtained 1 month later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis, with a return to near-baseline findings. However, early diagnosis may be challenging, especially in cancer patients under treatment with immunotherapy as drug-induced pneumonitis can present similar clinical and radiological features. Recurrent pneumonitis cases were further subcategorized as either provoked by treatment renewal or unprovoked. Lucian Beer, Maximilian Hochmair, Helmut Prosch. AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. Immunotherapy was subsequently held, and steroid therapy was administered. However, a combination of immunotherapy (pembrolizumab) with chemotherapy was not linked to an increased risk of pneumonitis in lung cancer . (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). However, in some cases, nodules may be nodular and masslike with spiculated margins, simulating findings of malignancy (34). (2015) Cancer immunology research. irAEs have been shown to occur in up to 90% of patients undergoing CTLA-4 inhibitor therapy and 70% of those undergoing PD-1 and/or PD-L1 inhibitor therapy (17). The symptoms improved on discontinuation of atezolizumab and a course of prednisone. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma, Immune-related adverse events with immune checkpoint blockade: a comprehensive review, Nivolumab plus ipilimumab in advanced melanoma, Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy, Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis, 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, Toxicities of Immunotherapy for the Practitioner, Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients, U.S. Department of Health and Human Services. (c) Axial chest CT image obtained 5 months after discontinuation of therapy shows minimal residual (although markedly improved) pneumonitis (arrow) in the left lower lobe. 11 (2): 138. A circumferential consolidative opacity surrounding an interior area of ground-glass attenuation (ie, reversed halo or atoll sign), a relatively specific marker for OP in the nontreatment setting, has also been reported in ICI therapy–related pneumonitis (32). Histopathologic findings include cellular interstitial pneumonitis, organizing pneumonia (OP), and less commonly diffuse alveolar damage (21). Illustrations show the mechanisms of action (left) of ICIs and the downstream tumor effects (right) for PD-1 and PD-L1 (a) and CTLA-4 (b) inhibitors. Given the cytotoxic effect of conventional therapies, therapy success (for example in the Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria) is determined by the interval disappearance of or decrease in the size of lesions, with treatment failure suggested by increased lesion size or the appearance of new lesions (8). Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. (b) Axial chest CT image obtained 4 months later after nivolumab therapy shows multifocal peripheral and subpleural mid- and lower-lung airspace consolidations (arrows), a finding consistent with an OP pattern of pneumonitis. A complete response was achieved following treatment with pembrolizumab, with lower limb rashes the only adverse events occurring during therapy. Active immunotherapy, on the other hand, stimulates the immune system to target tumor antigens and attack tumor cells. While better recognized with conventional chemotherapy agents, cases of radiation recall pneumonitis have now been described with ICI therapy (40,41). Spectrum of treatment-related pneumonitis among various therapy types. In addition, undergoing combination immunotherapy, concurrent radiation therapy, and previous high-dose chemotherapy are also thought to be risk factors (48). NSIP pattern is the second most commonly described pattern of ICI therapy–related pneumonitis, although it is diagnosed in a minority of reported cases. 28, No. Patients with grades 3 and 4 pneumonitis require permanent discontinuation of ICI therapy and more intensive care, requiring inpatient admission with close monitoring. With conventional agents, the median time of onset of radiation recall pneumonitis after the end of radiation therapy is 95 days, although onset of 2 years after radiation therapy has been reported with nivolumab (38,41). Pneumonitis is a potentially lethal side effect of immune checkpoint inhibition, occurring in 1–5% of patients enrolled in trials [2–11]. Abstract. However, in certain conditions such as leflunomide-induced acute interstitial pneumonia, patients have pre-existing lung disease. The patient was receiving anti-PD1 (nivolumab) to treat her advanced metastatic melanoma. Experimental Design: Among patients with advanced melanoma, lung cancer, or lymphoma treated in trials of nivolumab, we identified those who developed pneumonitis. As OP pattern can manifest with new masslike consolidative opacities, an important differential diagnosis is progression of an underlying malignancy. Radiation recall is an inflammatory reaction occurring within a previously irradiated area after exposure to an inciting agent that has been observed in multiple organs and systems, including skin, lung, digestive tract, muscle, and central nervous system. Treatment typically includes administering corticosteroids and/or discontinuing therapy (42). 2. (a) Baseline axial chest CT image shows a medial left lower lobe lung mass with surrounding ground-glass halo sign (arrow), a finding corresponding to adenocarcinoma. However, PET lacks in diagnostic specificity in this scenario, given the potential overlap of hypermetabolic activity with malignancy and infectious processes. The patient died 1 week later. Thus, blockade of key portions of either or both of these immune checkpoint pathways is thought to be responsible for the antitumoral activity with ICIs (Fig 1). (b) Axial CT image obtained 2 weeks after starting nivolumab therapy shows a region of centrilobular solid and ground-glass nodularity (black arrows) in the right lower lobe. This axial CT image in lung windowing shows multifocal alveolar consolidations in a subpleural and peribronchovascular location, predominating at the level of the left upper lobe. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. Patients initially diagnosed with grade 3 or 4 pneumonitis generally discontinue therapy permanently (47). (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. Other immune cells and mediators such as B cells, granulocytes, and cytokines have also been implicated (16). The left lower lobe mass also increased in size (white arrow). Several key differences in the response patterns of ICI therapeutic agents compared with those of cytotoxic agents include the potential initial transient worsening of disease burden, either through lesion enlargement or the appearance of new lesions (ie, pseudoprogression), and delayed time to treatment response (10). Figure 2. Figure 10a. On review of her medical history, she has started immunotherapy 2 months ago for her advanced metastatic melanoma. Figure 3c. Figure 8a. Pneumonitis may manifest with other irAEs, such as dermatitis, colitis, and endocrinopathies (21). (c) Axial CT image in a 57-year-old man undergoing imatinib therapy for metastatic gastrointestinal stromal tumor shows small patchy peripheral ground-glass opacities (arrows) in the bilateral lower lobes. 1115, © 2021 Radiological Society of North America, Improved survival with ipilimumab in patients with metastatic melanoma, Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents, Mechanisms of action and rationale for the use of checkpoint inhibitors in cancer. In passive therapy, immunoglobulins are administered and bind to tumor-associated antigens, prompting clearance by the immune system. (a) Baseline axial chest CT image shows a medial left lower lobe lung mass with surrounding ground-glass halo sign (arrow), a finding corresponding to adenocarcinoma. NSIP pattern should be distinguished from atypical infectious processes, which can often be determined on the basis of clinical parameters. history of melanoma on the left side of the face (resected in December 2012) and metastasis to the left lung upper lobe (resected in November 2016). Figure 9c. 3. Although the disruption of the immune checkpoint pathway is the principle mechanism behind stimulating immune response against tumor cells, this same pathway is also responsible for various irAEs. A majority of patients do not develop recurrence after restarting immunotherapy, although reports of rechallenge mainly describe patients with initial grade 1 or 2 pneumonitis. ICIs act through a unique mechanism of action when compared with those of conventional chemotherapeutic agents. Immunotherapy with immune checkpoint inhibitors (ICIs) has significantly improved outcomes in a range of malignancies but are associated with a range of potentially fatal immune-mediated toxicities such as pneumonitis. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. Subpleural sparing of the posterior and dependent lower lobes has also been reported as a specific finding (34). Although this occurs through multiple mechanisms, the CTLA-4 and PD-1 pathways play an important role for tumor proliferation. There are two tiny subcutaneous nodules in the medial aspect of the right breast. 16, The British Journal of Radiology, Vol. During the process of T-cell activation, various inhibitor receptors also become upregulated, acting as immune checkpoints to limit the overstimulation of the immune response (3). ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. While the increased activation of the immune system is responsible for the therapeutic efficacy of ICI therapy, it is also the driver behind the immune-related adverse events (irAEs) of these therapies. HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. Infection was excluded on the basis of clinical findings. Despite treatment of pneumonitis, approximately one-fourth of patients will develop recurrence (21) (Fig 10). These adverse events can be temporary or chronic, mild or life-threatening, and may involve nearly any organ system, sometimes multiple sites simultaneously (Fig 2). We compared treatment associated pneumonitis (TAP) related to immune checkpoint inhibitors (ICI) or chemotherapies (chemo) in advanced non-small cell lung cancer (aNSCLC) patients (pts) with and without (+/-) past medical history (PMH) of Pn, using data from clinical trials (CT… Patient symptoms and pulse oximetry results should be closely monitored every 3 days, and if no improvement is seen 48–72 hours after starting steroid therapy, care should be escalated. The patient previously underwent radiation therapy for multiple left posterior rib metastases. (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). Background: Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non-small-cell lung cancer (NSCLC). Described findings of HP pattern mirror those typically found in cases of subacute HP depicted in other settings. 3 (10): 1185-92. 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