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 shows the lungs after completion of radiation therapy. 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). OP pattern in a 51-year-old man undergoing nivolumab therapy for stage IV gastric adenocarcinoma. While chest radiography may be used as an initial screening tool, chest CT can better depict even subtle changes of pneumonitis and help differentiate among subtypes, which are more completely described in the following section. 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. Intravenous steroid therapy with intravenous methylprednisolone along with empirical antibiotic therapy should be administered. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. (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). Spectrum of treatment-related pneumonitis among various therapy types. 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). (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. (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. June 15, 2020 Within a few months, coronavirus disease 2019 (COVID-19) has become a pandemic with more than 2 million patients infected and a high mortality rate. Moreover, the administration of immunotherapy (durvalumab) after chemoradiation in patients with locally advanced NSCLC was related to an acceptable rate of lung toxicity (3.4% grade 3/4 versus 2.6% in the placebo arm) [ 10 , 11 ]. A smaller series by Nishino et al (31) with 20 pneumonitis cases described similar patterns as well as acute interstitial pneumonia (AIP)–acute respiratory distress syndrome (ARDS) occurring in 10% of patients. Table 2: National Cancer Institute CTCAE Pneumonitis Grading System. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. (2018) memo - Magazine of European Medical Oncology. Enter your email address below and we will send you the reset instructions. (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. PNEUMONITIS DURING mTOR INHIBITOR THERAPY mTOR is a serine/threonine protein kinase that plays a key role in the phosphatidylinositol 3-kinase/Akt/mTOR pathway, which is an established oncogenic driver in human cancers. Her previous chest imaging was normal (following study - chest radiograph). ICI therapies are increasingly being used as first- and second-line agents in the treatment of a growing number of malignancies. Abstract. To standardize terminology regarding treatment-related adverse events, pneumonitis symptoms are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (26). The mechanism of radiation recall reactions remains unclear, although possibilities include changes in the function of stem cells in the irradiated field versus idiosyncratic drug hypersensitivity reactions (39). The patient was receiving anti-PD1 (nivolumab) to treat her advanced metastatic melanoma. During PET/CT surveillance, ... delaying nivolumab for grade 2 & discontinuation of immunotherapy for grade 3 & 4 pneumonitis 2. (b) Axial chest CT image shows new multifocal ground-glass opacities (black arrows), with interval enlargement of several pulmonary masses (white arrows). Pneumonitis is a potential consequence of both lung-directed radiation and immune checkpoint blockade (ICB), particularly treatment with PD-1/PD-L1 inhibitors. A bronchiolitis pattern may be difficult to distinguish from aspiration or infection. Given the novel mechanism of action, the complications of these therapies have unique manifestations compared with those of conventional therapies. 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. (b) Axial CT image in a 63-year-old woman undergoing gemcitabine therapy for pancreatic cancer shows bilateral subpleural reticular opacities, with background faint ground-glass and interstitial opacities (arrows) that are more pronounced in the left lower lobe. Aspiration is typically found in the dependent lungs, with accompanying fluid or debris-filled airways, and esophagus, while infection can often be delineated clinically. 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 . ADVERTISEMENT: Radiopaedia is free thanks to our supporters and advertisers. Treatment typically includes administering corticosteroids and/or discontinuing therapy (42). Figure 9c. Also, tumors may increasingly express PD-L1 receptors causing decreased T-cell activity and tumor proliferation (7). 2017 and had a recorded diagnosis of pneumonitis related to immunotherapy. Patients with grade 1 or 2 pneumonitis have no or milder symptoms and are typically managed as outpatients, while patients with grade 3 or higher require more intensive management. Figure 4c. Significant morbidity and mortality can result, and severe pneumonitis attributed to ICB precludes continued therapy. 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). Furthermore, basilar predominance and subpleural sparing in the NSIP pattern are less typical findings of infection. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. No pleural effusion. (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. Immunotherapy was subsequently held, and steroid therapy was administered. However, in certain conditions such as leflunomide-induced acute interstitial pneumonia, patients have pre-existing lung disease. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. A complete response was achieved following treatment with pembrolizumab, with lower limb rashes the only adverse events occurring during therapy. Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. Immunotherapy was subsequently held, and steroid therapy was administered. This patient was not clinically septic and the pattern of consolidation/groundglass is relatively symmetrical. Background: Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non-small-cell lung cancer (NSCLC). Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. 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). GI = gastrointestinal. (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. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. In the setting of a requisite costimulatory interaction such as the CD28 receptor, T-cells become activated and further activate a cascade of antitumor activity (3,4). Illustration shows the global effect of irAEs with associated manifestations. There are two tiny subcutaneous nodules in the medial aspect of the right breast. 33 Everolimus and temsirolimus are specific inhibitors of mTOR and are used as anticancer therapeutic agents. 4, Respiratory Investigation, Vol. Patients with suspected pneumonitis should undergo initial clinical assessment with physical examination and pulse oximetry. Check for errors and try again. Currently in its fifth version, the CTCAE categorizes symptoms on a five-point grading scale according to increasing severity (Table 2). After pneumonitis resolution, clinicians are faced with the decision of whether to restart ICI therapy (ie, rechallenge). Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. In the melanoma cohort, the development of a sarcoidlike reaction has been associated with an eventual therapeutic response (43). AIP–ARDS pattern of pneumonitis in a 57-year-old man undergoing nivolumab therapy for stage IV lung adenocarcinoma. 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. Six weeks after starting nivolumab therapy, the patient presented with severely worsening dyspnea. 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. Sarcoidlike reactions demonstrate identical histopathologic features to those of sarcoidosis, namely noncaseating granuloma formation. 93, No. 18 (1): 42-53. Described findings of HP pattern mirror those typically found in cases of subacute HP depicted in other settings. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. 5, No. Lucian Beer, Maximilian Hochmair, Helmut Prosch. Figure 10b. Also, ICI therapy–related pneumonitis is more commonly associated with multiorgan involvement with other irAEs. Associated focal ground-glass and consolidative opacities may be visualized, although this should not the predominant feature. ■ Illustrate the imaging patterns of ICI therapy–related pneumonitis and related clinical classification schemes. To date, little is known about immunotherapy-induced pneumonitis (IIP). Adjacent bronchial wall thickening is also frequently depicted (Fig 7). Because of the greater experience with larger clinical trials involving ICI therapies and emerging toxicity profiles, different patterns with respect to presentation, imaging findings, and management have become apparent between ICI therapy–related and conventional chemotherapy-related pneumonitis. 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. Figure 1b. 1. COVID-19 Pneumonia Mimicking Immunotherapy-Induced Pneumonitis on 18F-FDG PET/CT in a Patient Under Treatment With Nivolumab. 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 … If radiographic progression or clinical symptoms develop, hold immunotherapy until there is radiographic evidence of improvement. Previous history of metastatic melanoma. While better recognized with conventional chemotherapy agents, cases of radiation recall pneumonitis have now been described with ICI therapy (40,41). No fevers or raised septic markers. If the address matches an existing account you will receive an email with instructions to reset your password. The left lower lobe mass also increased in size (white arrow). Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. Recurrent pneumonitis cases were further subcategorized as either provoked by treatment renewal or unprovoked. Overall, the incidence of ICI therapy–related pneumonitis is estimated to be between 3% and 6% (21). (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). Imaging features are similar to those of sarcoidosis and include mediastinal and hilar lymphadenopathy and pulmonary nodules in a perilymphatic distribution, with upper lung predominance (42). (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. 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