(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. HP pattern is an uncommon manifestation of ICI therapy–related pneumonitis. Despite treatment of pneumonitis, approximately one-fourth of patients will develop recurrence (21) (Fig 10). (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. Depending on the severity and initial response, other agents such as infliximab, mycophenolate, or intravenous immunoglobulin may also be added. (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. Outside of the lung, the skin is a common site of involvement. (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. ICI therapy can also be used with nivolumab, a PD-1 inhibitor, and ipilimumab, a combination that has FDA approval for the treatment of colorectal cancer and renal cell carcinoma. As opposed to conventional cytotoxic chemotherapy, which acts by a variety of mechanisms and stages of the cell cycle to directly interfere with cancer cell growth, cancer immunotherapy harnesses the immune system to limit the ability of cancer cells to evade the immune system and combat proliferation. 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. For example, patients receiving ICI therapy have shown greater susceptibility to the development of treatment-related pneumonitis, with increased risk of high-grade pneumonitis (45). Immunotherapy was subsequently held, and steroid therapy was administered. 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. Enter your email address below and we will send you the reset instructions. Grade 1 immune-related pneumonitis is managed with close observation and consideration of holding immunotherapy. The lungs and pleural spaces are clear, the mediastinal contours are within the normal limits. (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. Sarcoidlike reactions demonstrate identical histopathologic features to those of sarcoidosis, namely noncaseating granuloma formation. 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). For patients with grade 2 pneumonitis, diagnostic evaluation to rule out infection may be pursued, which can include nasopharyngeal, sputum, and urine culture and sensitivity tests (27). Although generally considered separate from ICI therapy–related pneumonitis, sarcoidlike reaction is another potential pulmonary irAE reported with ICI therapy. Infection, including atypical and fungal causes such as invasive aspergillosis, should also be considered and often can be distinguished by clinical and laboratory findings. Given the novel mechanism of action, the complications of these therapies have unique manifestations compared with those of conventional therapies. Figure 10c. (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. However, large-scale head-to-head studies comparing various ICI therapies are lacking. NSIP pattern is associated with a lower toxicity grade (median CTCAE grade 1) (31). 2017 and had a recorded diagnosis of pneumonitis related to immunotherapy. Sarcoidlike reaction has been most commonly reported in patients undergoing ipilimumab therapy and in those with melanoma (42). For example, increased CTLA-4 binding in the presence of certain tumors cells leads to competitive inhibition of costimulatory CD28 binding, leading to decreased T-cell activation. 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 … 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. Currently in its fifth version, the CTCAE categorizes symptoms on a five-point grading scale according to increasing severity (Table 2). Significant morbidity and mortality can result, and severe pneumonitis attributed to ICB precludes continued therapy. Immunotherapy was subsequently held, and steroid therapy was administered. Background: Nivolumab is a novel immunotherapy that was recently approved for treatment of advanced non-small-cell lung cancer (NSCLC). Adjacent bronchial wall thickening is also frequently depicted (Fig 7). How Do Cytotoxic Lymphocytes Kill Cancer Cells? Although this occurs through multiple mechanisms, the CTLA-4 and PD-1 pathways play an important role for tumor proliferation. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). (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. Radiation recall pneumonitis (RRP) is a delayed radiation-induced lung toxicity triggered by systemic agents, typically anticancer drugs. Illustration shows the global effect of irAEs with associated manifestations. As the clinical manifestation is often nonspecific, CT plays an important role in diagnosis and triage. In the melanoma cohort, the development of a sarcoidlike reaction has been associated with an eventual therapeutic response (43). Clinically, ICI therapy–related pneumonitis tends to occur with overall higher severity, potentially requiring higher doses of steroid therapy or more potent immunosuppressive therapy compared with that of conventional chemotherapy pneumonitis. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. (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. For example, trimethoprim and sulfamethoxazole may be administered for Pneumocystis jirovecci prophylaxis (47). However, conventional imaging response criteria such as RECIST 1.1 have shortcomings in the evaluation of treatment response for ICI therapy, leading to the potential for premature cessation of therapy in patients who might otherwise show benefit with therapy (9). Immune check… The left lower lobe mass also increased in size (white arrow). The CT appearance of ICI therapy–related pneumonitis generally parallels that visualized in nontreatment-related interstitial lung diseases and is summarized with the main differential considerations in Table 3. 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). 2. (a) Baseline axial chest CT image shows the lungs before starting immunotherapy. Lucian Beer, Maximilian Hochmair, Helmut Prosch. (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). In addition, undergoing combination immunotherapy, concurrent radiation therapy, and previous high-dose chemotherapy are also thought to be risk factors (48). Normally, an important function of T cells is in the cell-mediated clearance of tumor cells. Recipient of a Certificate of Merit award for an education exhibit at the 2018 RSNA Annual Meeting. (c) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. (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. Table 4: American Society of Clinical Oncology Clinical Practice Guideline for the Management of ICI-related Pneumonitis. Figure 9c. Common Terminology Criteria for Adverse Events, Advances in Radiation Oncology, Vol. Chest radiography can be considered to track evolving pneumonitis findings. Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. The symptoms improved on discontinuation of atezolizumab and a course of prednisone. Table 3: ICI Therapy–related Pneumonitis Patterns. APC = antigen-presenting cell, B7-1/2 = ligands B7-1 and B7-2. 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. Immunotherapy was subsequently held, and steroid therapy was administered. (2)Clinical Oncology Department, Virgen Macarena University Hospital, Seville, Spain. 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). (a) Axial chest CT image obtained 5 months after starting nivolumab therapy shows diffuse centrilobular ground-glass nodules (arrows). ICI therapy–related pneumonitis is an uncommon but important complication of ICI therapy, with potential for significant morbidity and mortality. However, there are currently no specific histologic findings for ICI therapy–related pneumonitis. (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). Radiologic response to respective treatments (ie, bronchopulmonary hygiene physical therapy and antibiotic therapy) is also often helpful. However, true progression will often be associated with progressive disease elsewhere and will lack response to immunosuppressive therapy. COVID-19 Pneumonia Mimicking Immunotherapy-Induced Pneumonitis on 18F-FDG PET/CT in a Patient Under Treatment With Nivolumab. 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). (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. Radiation recall pneumonitis in a 65-year-old woman with metastatic breast cancer. (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. However, in some cases, nodules may be nodular and masslike with spiculated margins, simulating findings of malignancy (34). 18 (1): 42-53. 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). Minimal subpleural ground-glass opacities in the right lower lobe were thought to be dependent atelectasis. More severe forms of pulmonary toxicity, such as acute interstitial pneumonia leading to acute respiratory Increased FDG uptake within adenopathy has also been observed at PET/CT (44). 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. The patient previously underwent radiation therapy for multiple left posterior rib metastases. Airspace disease is temporally homogeneous and relatively symmetric, with consolidative opacities uncommon, features that help in distinguishing NSIP from OP patterns. 11 (2): 138. 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). Onset has been shown to occur earlier in patients with lung cancer compared with those with melanoma (2.1 versus 5.2 months, respectively) (25). 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 … 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) Follow-up axial chest CT image obtained 3 months later after withholding ICI therapy and administering steroid therapy shows resolved pneumonitis. A baseline coronal chest CT image obtained before starting immunotherapy (not shown) showed no airspace abnormalities. (a) Baseline axial chest CT image shows the lungs before immunotherapy was initiated. During PET/CT surveillance, ... delaying nivolumab for grade 2 & discontinuation of immunotherapy for grade 3 & 4 pneumonitis 2. Figure 7a. The main differential diagnosis is infection, which does not respect the boundaries and occurs outside of the prior radiation field. (c) Follow-up axial chest CT image shows near-complete resolution of pneumonitis, with several remaining faint subpleural right lower lobe opacities (arrows). 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. 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). ), and Department of Radiology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (N.H.R., K.R.L., A.G.). 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. Pneumonitis is a potentially lethal side effect of immune checkpoint inhibition, occurring in 1–5% of patients enrolled in trials [2–11]. Figure 3a. Furthermore, ICI therapy may also be combined with conventional chemotherapies given the ability of cytotoxic chemotherapy to potentiate the immune response of ICIs (2). Intravenous steroid therapy with intravenous methylprednisolone along with empirical antibiotic therapy should be administered. Figure 3c. Pneumonitis may manifest with other irAEs, such as dermatitis, colitis, and endocrinopathies (21). 3 (10): 1185-92. Pneumonitis Related to Melanoma Immunotherapy. ICI therapy–related pneumonitis is an uncommon although potentially serious complication of ICI therapy. Figure 5b. Recurrent pneumonitis in a 78-year-old patient with small cell lung carcinoma. NSIP pattern in a 67-year-old man undergoing pembrolizumab therapy for stage IV lung adenocarcinoma. With ongoing ICI clinical trials, the number of approvals and combinations and complexity of treatment regimens is expected to grow in the foreseeable future. (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. Figure 10d. 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. 1. Furthermore, basilar predominance and subpleural sparing in the NSIP pattern are less typical findings of infection. (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). INTRODUCTION:There is an increasing usage of immune-checkpoint inhibitors (ICI) including programmed cell death-1 inhibitors for several cancers including melanoma. However, little is known about the clinical and radiological features of checkpoint inhibitor-induced lung disease. On review of her medical history, she has started immunotherapy 2 months ago for her advanced metastatic melanoma. Bronchiolitis pattern of pneumonitis in a 63-year-old woman undergoing nivolumab therapy for lung adenocarcinoma. (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. The patient previously underwent radiation therapy for multiple left posterior rib metastases. Figure 7b. (a) Baseline axial chest CT image obtained before starting immunotherapy shows multiple lung nodules and masses. The diagnosis of immunotherapy-induced pneumonitis was made after careful exclusion of other pulmonary conditions such as infection and malignancy. At imaging, ICI therapy–related pneumonitis tends to be more extensive at patient presentation, with findings likely to be lower lung predominant (Fig 9). 58, No. Overall, the incidence of ICI therapy–related pneumonitis is estimated to be between 3% and 6% (21). Tirumani SH, Ramaiya NH, Keraliya A, Bailey ND, Ott PA, Hodi FS, Nishino M. Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab. The left lower lobe mass also increased in size (white arrow). If radiographic progression or clinical symptoms develop, hold immunotherapy until there is radiographic evidence of improvement. No fevers or raised septic markers. 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