In recent years, the use of immune checkpoint inhibitor (ICI) therapy has rapidly grown, with increasing U.S. Food and Drug Administration approvals of a variety of agents used as first- and second-line treatments of various malignancies. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. ■ Discuss the management of irAEs and the role of the radiologist in treatment course planning in these complex cases. A baseline coronal chest CT image obtained before starting immunotherapy (not shown) showed no airspace abnormalities. ICIs target the cell surface receptors cytotoxic T-lymphocyte antigen-4, programmed cell death protein 1, or programmed cell death ligand 1, which result in immune system–mediated destruction of tumor cells. Figure 2. Figure 6c. Normally, an important function of T cells is in the cell-mediated clearance of tumor cells. Background: Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non-small-cell lung cancer (NSCLC). (d) Axial CT image obtained after completing steroid therapy and restarting nivolumab therapy shows recurrence of an OP pneumonitis pattern with new areas of involvement (arrows). 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). (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. Immunotherapy can be classified as either passive or active. Purpose Immune-related adverse events (IrAEs) are auto-immune reactions associated with immune checkpoint inhibitor-based therapy (ICI). OP pattern in a 51-year-old man undergoing nivolumab therapy for stage IV gastric adenocarcinoma. Subpleural sparing of the posterior and dependent lower lobes has also been reported as a specific finding (34). (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. Published guidelines outline the treatment of ICI therapy–related pneumonitis based on the severity of symptoms. 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. (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). Intravenous steroid therapy with intravenous methylprednisolone along with empirical antibiotic therapy should be administered. Although not specifically addressed in the American Society of Clinical Oncology Practice Guideline, recurrent pneumonitis is often treated with methods similar to those used in the treatment of the initial occurrence. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. (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). Although checkpoint inhibitor pneumonitis (CIP) has a low clinical incidence, it is likely to cause the delay or termination of immunotherapy and treatment-related death in some severe cases. 5, World Chinese Journal of Digestology, Vol. ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. Immune check… Recurrent pneumonitis pattern, location of involvement, and severity may vary compared with those at initial presentation. The left lower lobe mass also increased in size (white arrow). The airways are unremarkable. 5, No. In May 2017, a follow-up chest CT demonstrated resolution of ground glass opacification (figure 1C,D) at which time nivolumab 3 mg/kg monotherapy was initiated and continued for 25 doses until April 2018 without recurrence of pneumonitis.In April 2018, brain MRI showed postsurgical changes without evidence of metastases and chest and abdominal CT scans showed interval additional … (d) Axial CT image obtained after completing steroid therapy and restarting nivolumab therapy shows recurrence of an OP pneumonitis pattern with new areas of involvement (arrows). Abstract. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. 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. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. Several distinct radiographic patterns of pneumonitis have been observed: (a) organizing pneumonia, (b) nonspecific interstitial pneumonia, (c) hypersensitivity pneumonitis, (d) acute interstitial pneumonia–acute respiratory distress syndrome, (e) bronchiolitis, and (f) radiation recall pneumonitis. On review of her medical history, she has started immunotherapy 2 months ago for her advanced metastatic melanoma. After completing this journal-based SA-CME activity, participants will be able to: ■ Describe the indications and mechanisms of action of ICIs and the pathophysiology of ICI therapy–related pneumonitis. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. ICI therapy–related pneumonitis is an irAE, potentially resulting in significant morbidity with possible discontinuation of therapy and possible mortality. 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. (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. Furthermore, the use of serum markers for the prediction and monitoring of ICI therapy–related pneumonitis is also an active area of investigation. As the clinical manifestation is often nonspecific, CT plays an important role in diagnosis and triage. Immune-related pneumonitis presenting as an organising pneumonia pattern in a patient with metastatic lung cancer that occurred after 13 cycles of anti-PD1 therapy. 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. ICIs ultimately act by inhibiting the signal pathways responsible for the suppression of T-cell–mediated tumor destruction. As with the NSIP pattern, changes of chronic HP including upper lobe fibrosis, volume loss, and traction bronchiectasis have not been reported with ICI therapy–related pneumonitis. The patient was receiving anti-PD1 (nivolumab) to treat her advanced metastatic melanoma. OP pattern most commonly manifests as patchy bilateral opacities with a peripheral or peribronchovascular predominance, often with a mid- to lower-lung predominance (Fig 3). 33 Everolimus and temsirolimus are specific inhibitors of mTOR and are used as anticancer therapeutic agents. The lungs and pleural spaces are clear, the mediastinal contours are within the normal limits. While many ICI therapies are initiated after failure of first-line or established therapies, several drugs are approved as first-line therapies. 3. (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. (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. Chest radiography can be considered to track evolving pneumonitis findings. Imaging. Airspace disease may manifest as either consolidative or ground-glass opacities or a combination of both, frequently depicted on air bronchograms with or without a component of bronchial dilatation. Immunotherapy was subsequently held, and steroid therapy was administered. 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). Immune-related adverse events are an increasingly recognized set of complications of ICI therapy that may affect any organ system. (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. In the melanoma cohort, the development of a sarcoidlike reaction has been associated with an eventual therapeutic response (43). Aspiration is typically found in the dependent lungs, with accompanying fluid or debris-filled airways, and esophagus, while infection can often be delineated clinically. (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. Interlobular septal thickening and a “crazy-paving” pattern may also be present (34). Sarcoidlike reaction may mimic recurrent or worsening malignancy, and lymphadenopathy may also be mistaken for reactive lymphadenopathy from an infectious process of other irAEs. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. (c) Axial chest CT image obtained 1 month later after withholding ICI therapy and administering steroid therapy shows residual, although significantly improved, airspace disease (arrows). 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. For example, pembrolizumab, a PD-1 inhibitor, has FDA approval as frontline treatment of advanced epidermal growth factor receptor and anaplastic lymphoma kinase wild-type non–small cell lung cancer in which tumors have at least 50% PD-L1 expression. HP pattern in a 52-year-old woman who underwent nivolumab therapy for stage IV lung adenocarcinoma. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). 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. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. García-Gómez FJ(1), Álamo-de la Gala MC(2), de la Riva-Pérez PA(1), de la Cruz-Merino L(2), de la Cinta Calvo-Morón M(1). Lucian Beer, Maximilian Hochmair, Helmut Prosch. An increasing number of CIP cases have been reported since 2015, which are attributed to the augment of approvals and uses of ICIs, but a comprehensive understanding of CIP is still lacking. Recurrence of metastasis to the bilateral lungs and left pleura was detected in April 2018. In the last decade, the introduction of immunotherapy has revolutionized the management and treatment approaches for a number of malignancies. More severe forms of pulmonary toxicity, such as acute interstitial pneumonia leading to acute respiratory Spectrum of treatment-related pneumonitis among various therapy types. The time to pneumonitis onset is widely variable, reported to range from 9 days to over 19 months after initiation of therapy, with a median time of onset of 2.8 months. 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. If the address matches an existing account you will receive an email with instructions to reset your password. Pneumonitis Related to Melanoma Immunotherapy. 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. Also, ICI therapy–related pneumonitis is more commonly associated with multiorgan involvement with other irAEs. Adjacent bronchial wall thickening is also frequently depicted (Fig 7). (d) Axial CT image obtained after completing steroid therapy and restarting nivolumab therapy shows recurrence of an OP pneumonitis pattern with new areas of involvement (arrows). Figure 10b. Figure 8c. NSIP-associated connective tissue and autoimmune disorders are generally long-standing processes in the setting of other known comorbid conditions. 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). Immunotherapy has been withheld and, some weeks later, the lungs have improved and there are some residual perihilar upper lobes infiltrates. It has been advised that the immune checkpoint inhibitor regimen not be restarted until CT scans show improvement or there is complete resolution of pneumonitis. A subset of irAEs is pneumonitis, which is an important and potentially fatal complication of ICI therapy and is the focus of this article. Patients with suspected pneumonitis should undergo initial clinical assessment with physical examination and pulse oximetry. (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. 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. The patient died 1 week later. It should be suspected in any patient with a history of radiation therapy with new airspace changes sharply demarcated from the adjacent lung in the appearance of a radiation field. (c) Axial chest CT image obtained 5 days later after further respiratory decompensation (despite withholding ICI therapy and initiating intravenous steroid therapy) shows increasing severity and confluence of ground-glass opacities (arrows), with little intervening normal lung parenchyma. Unable to process the form. 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). (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. (b) Axial chest CT image obtained 2 months after initiating trastuzumab therapy shows a focal region of ground-glass opacities within the posterior and medial left lower lobe (arrow), with a well-defined linear demarcation from the adjacent normal lung. Outside of the lung, the skin is a common site of involvement. Figure 9c. Extensive areas of consolidation and groundglass opacities with a relatively symmetrical distribution involving mostly the upper lobes. Figure 4a. AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. The results indicated the utility of a radiographic pattern–based approach as a guide for patient treatment and monitoring for immunotherapy-related pneumonitis. 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. (a) Axial CT image in a 65-year-old man undergoing ipilimumab therapy for metastatic melanoma shows large bilateral lower lobe pleural-based consolidative and ground-glass opacities (arrows). Two critical pathways for ICIs are the CTLA-4 and PD-1 pathways, which normally function to attenuate T-cell response and action (Fig 1) (5,6). (c) Follow-up axial chest CT image obtained 2 months later after steroid therapy shows resolved right lower lobe pneumonitis. Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. Immunotherapy was subsequently held, and steroid therapy was administered. (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). Infection, including atypical and fungal causes such as invasive aspergillosis, should also be considered and often can be distinguished by clinical and laboratory findings. Spectrum of treatment-related pneumonitis among various therapy types. Given the novel mechanism of action, the complications of these therapies have unique manifestations compared with those of conventional therapies. To date, little is known about immunotherapy-induced pneumonitis (IIP). Immunotherapy-induced pneumonitis - metastatic melanoma. (2018) memo - Magazine of European Medical Oncology. While better recognized with conventional chemotherapy agents, cases of radiation recall pneumonitis have now been described with ICI therapy (40,41). After pneumonitis resolution, clinicians are faced with the decision of whether to restart ICI therapy (ie, rechallenge). Immune checkpoint therapy–related pneumonitis is an uncommon but potentially serious complication with several distinct radiologic patterns that overlap with those of other infectious and inflammatory conditions. {"url":"/signup-modal-props.json?lang=us\u0026email="}. ), and Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (N.H.R., K.R.L., A.G.). (d) Axial CT image obtained after completing steroid therapy and restarting nivolumab therapy shows recurrence of an OP pneumonitis pattern with new areas of involvement (arrows). Pneumonitis is an uncommon but potentially fatal toxicity of anti-PD(L)1 immune checkpoint inhibitors (ICI) for cancer.1–3 The incidence of this toxicity is approximately 5% in patients with solid tumors treated with anti-PD(L)1 monotherapy, and up to 10%, in patients receiving anti-PD(L)1-based combinations such as ipilimumab/nivolumab, or those with non-small cell lung cancer … Fundamental Mechanisms of Immune Checkpoint Blockade Therapy, PD-L1 regulates the development, maintenance, and function of induced regulatory T cells, The blockade of immune checkpoints in cancer immunotherapy, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Evaluation of Immune-Related Response Criteria and RECIST v1.1 in Patients With Advanced Melanoma Treated With Pembrolizumab, Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria, Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements, iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics, Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point 18F-FDG PET/CT Imaging in Patients with Advanced Melanoma, Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma, Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management, Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies, Immune-related adverse events during anticancer immunotherapy: Pathogenesis and management, MDX010-20 Investigators. 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). Higher rates of pneumonitis have been observed in non–small cell lung cancer and renal cell carcinoma versus those of melanoma (22). This case illustrates the impressive appearances that immunotherapy-induced pneumonitis can have on imaging. AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. Figure 7: Axial chest CT scans show programmed cell death protein 1 (PD-1) inhibitor–related pneumonitis in a patient with advanced non–small cell lung cancer treated with nivolumab. Combinations of PD-1 and CTLA-4 inhibitors with nivolumab and ipilimumab have also demonstrated higher irAE rates compared with those of respective monotherapies in patients with advanced melanoma (20). Recipient of a Certificate of Merit award for an education exhibit at the 2018 RSNA Annual Meeting. Although generally considered separate from ICI therapy–related pneumonitis, sarcoidlike reaction is another potential pulmonary irAE reported with ICI therapy. Chest radiograph ) shock, and steroid therapy shows resolved right lower lobe mass ( arrow ) continued therapy 57-year-old. Often effective, although this should not the predominant feature mirror those typically found in cases of ICI and! Should not the predominant feature is associated with multiorgan involvement with other irAEs 2–11. Disclosed no relevant relationships and triage obtained 2 months ago for her advanced metastatic.. Precludes continued therapy airspace disease is temporally homogeneous and relatively symmetric, with lower limb rashes the adverse! In other settings potentially life-threatening adverse event of some anticancer drugs response with T-cell upregulation and ultimately granuloma. 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