Radiation recall pneumonitis from immune checkpoint inhibitors after extra pulmonary radiation.

Radiation recall is an unpredictable, poorly understood inflammatory reaction within the confines of previously irradiated tissue that occurs following exposure to a systemic agent. In this article, we will focus on a subcategory of radiation recall, called radiation recall pneumonitis (RRP), precipitated by immune checkpoint inhibitors (ICI). Historically, RRP can develop weeks to years after radiation treatment to the lung, most commonly after receiving certain chemotherapeutic agents, but more recently has been recognized in association with immunotherapy agents (ICIs). Up until now, RRP following exposure to ICIs has been described in patients who have received radiation to the lung itself. Here we present three cases of RRP in patients who received radiation to areas adjacent to the lung parenchyma, and developed pulmonary infiltrates in an area adjacent to the radiation field while on ICI therapy. Since ICI induced RRP is treatable and steroid sensitive, early recognition and treatment are important.

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.

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.

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

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.

What Is Different in Acute Hematologic Malignancy-Associated ARDS? An Overview of the Literature.

Background and Objectives: Acute hematologic malignancies are a group of heterogeneous blood diseases with a high mortality rate, mostly due to acute respiratory failure (ARF). Acute respiratory distress syndrome (ARDS) is one form of ARF which represents a challenging clinical condition. The paper aims to review current knowledge regarding the variable pathogenic mechanisms, as well as therapeutic options for ARDS in acute hematologic malignancy patients. Data collection: We provide an overview of ARDS in patients with acute hematologic malignancy, from an etiologic perspective. We searched databases such as PubMed or Google Scholar, including articles published until June 2022, using the following keywords: ARDS in hematologic malignancy, pneumonia in hematologic malignancy, drug-induced ARDS, leukostasis, pulmonary leukemic infiltration, pulmonary lysis syndrome, engraftment syndrome, diffuse alveolar hemorrhage, TRALI in hematologic malignancy, hematopoietic stem cell transplant ARDS, radiation pneumonitis. We included relevant research articles, case reports, and reviews published in the last 18 years. Results: The main causes of ARDS in acute hematologic malignancy are: pneumonia-associated ARDS, leukostasis, leukemic infiltration of the lung, pulmonary lysis syndrome, drug-induced ARDS, radiotherapy-induced ARDS, diffuse alveolar hemorrhage, peri-engraftment respiratory distress syndrome, hematopoietic stem cell transplantation-related ARDS, transfusion-related acute lung injury. Conclusions: The short-term prognosis of ARDS in acute hematologic malignancy relies on prompt diagnosis and treatment. Due to its etiological heterogeneity, precision-based strategies should be used to improve overall survival. Future studies should focus on identifying the relevance of such etiologic-based diagnostic strategies in ARDS secondary to acute hematologic malignancy.

Imaging features of toxicities associated with immune checkpoint inhibitors.

The past decade has witnessed a change in landscape of cancer management with the advent of precision oncology. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and have played an important role in improving patient survival. While the patients are living longer, treatment with ICIs are sometimes associated with adverse effects, some of which could be fatal. Radiologists can play a crucial role by early identification of some of these adverse effects during restaging scans. Our paper focuses on the imaging features of commonly occurring ICI toxicities based on organ system.

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

Purpose: Whilst 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 Materials: From 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. Results: With 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). Conclusions: Treatment-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 Induced by Sintilimab: A Case Report and Literature Review.

Radiation recall pneumonitis (RRP) is described as an unpredictable acute inflammatory reaction within the previously irradiated lung site during the administration of systematic therapy after radiotherapy. Here, we reported a case of a 54-year-old woman with non-small lung cancer (NSCLC), who had pneumonitis at 3 and 10 months after radiotherapy regarded as radiation pneumonitis (RP) and RRP induced by anti-PD-1 sintilimab, respectively. This unique patient with double pneumonitis (RP and RRP) has drawn attention to the identification of immune or radiation pneumonitis, its potential mechanism, and further treatment strategy after the emergence of RRP.

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

BACKGROUND: Radiation 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 PRESENTATION: A 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. CONCLUSIONS: RRP is a rare occurrence. Patients undergoing immunotherapy after prior irradiation may be at increased risk of this rare radiation pneumonitis.

Rapid Development of Clinically Symptomatic Radiation Recall Pneumonitis Immediately Following COVID-19 Vaccination.

In this report, we present the case of a 66-year-old man who received local consolidation radiotherapy to the right lung and mediastinum for oligometastatic non-small cell lung cancer (NSCLC) following partial response to upfront chemoimmunotherapy. He continued with maintenance immunotherapy and was asymptomatic for eight months after completing radiation therapy. He then developed symptoms consistent with pneumonitis within three to five days of his first administration of the coronavirus disease 2019 (COVID-19) vaccine injection. He reported that these symptoms significantly intensified within three to five days of receiving his second dose of the vaccine. The clinical time frame and radiographic evidence raised suspicion for radiation recall pneumonitis (RRP). Patients undergoing maintenance immunotherapy after prior irradiation may be at increased risk of this phenomenon that may be triggered by the administration of the COVID-19 vaccine.

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

BACKGROUND AND PURPOSE: Radiation 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 METHODS: Medical 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. RESULTS: Among 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 %. CONCLUSION: We 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.

Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications.

BACKGROUND: The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. 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. Thus far, the underlying mechanism of this toxicity remains largely unknown. MAIN TEXT: In this review, we discuss the unique pattern of radiation recall pneumonitis (RRP) induced by PD-1 blockade. The clinical presentation is different from common radiation pneumonitis (RP) or RRP induced by cytotoxic drugs. The immune checkpoint inhibitors may evoke an inflammatory reaction in patients' previously irradiated fields, with infiltrating lymphocytes and potential involvement of related cytokines. All RRP patients have showed durable response to anti-PD-1/PD-L1. RRP is manageable; however, interruption of checkpoint blockades is necessary and immunosuppressive treatment should be started immediately. Further analyses of the predictive factors, including RT dosimetric parameters, tumor-infiltrating lymphocytes (TILs), and PD-L1 expression, are needed given the wide use of immune checkpoint inhibitors and high mortality from lung toxicity with the combination treatment. CONCLUSION: Immune checkpoint inhibitors may evoke an RRP in the patients' previously irradiated fields. Interactions between immune checkpoint inhibitors and radiotherapy should be studied further.

Radiation Recall Pneumonitis Induced by Anti-PD-1 Blockade: A Case Report and Review of the Literature.

Background: Radiation recall pneumonitis (RRP) is an unpredictable but relatively severe subclinical radiation damage which occurs in the previously irradiated fields of pulmonary tissue after administration of a systemic agent. Previous reports of RRP were mainly attributed to chemotherapy and molecular-target agents. RRP induced by immunotherapy has been rarely reported. Here we describe a case of a novel pattern of RRP induced by anti-PD-1 blockade Camrelizumab 2 years after radiotherapy, with some focus on further understanding of this phenomenon. Case Report: A 64-year-old man with non-small cell lung cancer (NSCLC) received two cycles of chemotherapy with cisplatin and pemetrexed first. Subsequently, he underwent concomitant chemoradiotherapy with cisplatin and pemetrexed to simultaneous integrated boost (SIB) radiotherapy. After 15 months, due to tumor progression and brain metastasis, he started with administration of anti-PD-1 blockade Camrelizumab (200 mg q2w) and stereotactic radiosurgery (SRS). The patient developed fever, dyspnea and cough after the eighth administration of Camrelizumab. Meanwhile, his chest CT revealed patchy consolidation and ground-glass opacities localized within the previously irradiated area. Subsequent treatment regimen was adjusted to 80 mg q12h prednisolone with discontinuation of Camrelizumab. Then the symptoms gradually eased and reexamination of CT showed significant improvement in RRP after 2 weeks. Conclusion: Our case report presents a novel pattern of RRP induced by anti-PD-1 blockade Camrelizumab 2 years after radiotherapy. This indicates that previous radiotherapy combined with subsequent anti-PD-1 blockade has a potential to cause overlapping damage to lung, suggesting that intensive attention might be needed for patients who are treated with anti-PD-1 blockade in conjunction with a prior history of thoracic radiation.

Interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy: a case report.

BACKGROUND: Interstitial pneumonitis is a rare reaction in a previously irradiated area of pulmonary or thoracic lesion after treatment with anticancer drugs such as taxanes. CASE PRESENTATION: A 66-year-old man presented with a fever and dyspnea after treatment with cabazitaxel for castration-resistant prostate cancer. He was treated with an intravenous broad-spectrum antimicrobial agent, however he complained of dyspnea and had a pulse oximetric saturation of 80% while breathing room air. The patients had been treated for bone metastases with 37.5 Gy to the thoracic spine (Th 7) as a local radiotherapy. Radiological images showed pulmonary interstitial opacities in the irradiated field of the both lungs. The steroid pulse therapy was started. The patient's dyspnea disappeared and the interstitial opacities had also improved. CONCLUSIONS: This report is a case of interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy.

Radiation recall pneumonitis in the setting of immunotherapy and radiation: a focused review.

Radiation recall pneumonitis (RRP) is an entity described as pneumonitis localized to a previously irradiated field after exposure to a systemic agent. It has previously been described in the literature in the context of chemotherapeutic agents as well as certain biologics. With immunotherapy taking a more prominent role in the treatment of several different malignancies and its own baseline risk of pneumonitis, it is important to explore the likelihood of RRP, specifically in those patients who have been previously treated with radiation therapy. The current literature regarding RRP with checkpoint inhibitors is reviewed in this article. Alongside this review, we report a case of RRP after pembrolizumab initiation in a patient in our practice.

Radiation recall pneumonitis induced by ifosfamide for malignant soft tissue tumor arising from the chest wall: A case report.

The present study reports a rare case of radiation recall pneumonitis attributed to ifosfamide that was used as a single antitumor agent for a recurrent malignant soft tissue tumor, arising from the chest wall. A 74-year-old man, who had a mass in his right upper chest wall, underwent surgical excision under the diagnosis of chronic expanding hematoma. He was referred to the present hospital with a recurrent tumor as the excised tumor was diagnosed as undifferentiated high-grade sarcoma. The extension of the tumor following previous surgery was aggressive and the tumor margins were unclear on magnetic resonance imaging. Wide excision was done with adequate margins for the new recurrent tumor as it was difficult to set sufficient tumor margins following the previous surgery. Radiotherapy (60 Gy) on his right subclavicular area and chemotherapy with ifosfamide (3.5 g × 4 days/cycle) was started 1 month following surgery to control the growth of residual tumors and to prevent metastases. The third cycle of chemotherapy with ifosfamide (3 g × 4 days) was started 80 days following the final surgery and 15 days following termination of radiotherapy. Following administration, he felt short of breath and dyspnea gradually increased. This condition was diagnosed as interstitial pneumonitis induced by ifosfamide following radiotherapy. Although corticosteroid pulse therapy was performed, he died due to respiratory failure. To the best of the author's knowledge, this is the first case report of radiation recall pneumonitis induced by ifosfamide used as a single anti-tumor agent. Caution is needed when ifosfamide is planned for patients who have undergone previous radiotherapy to the chest.

Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer.

BACKGROUND: Radiation recall pneumonitis (RRP) is a special form of radiation pneumonitis precipitated by certain pharmacological agents. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is an effective treatment for advanced nonsmall-cell lung cancer (NSCLC) and has been reported as a potent radiation sensitizer. The incidence and general characteristics of EGFR-TKI-related RRP in patients with NSCLC remain unclear. METHODS: Clinical records and serial chest images of consecutive patients with advanced NSCLC who had received thoracic radiotherapy (TRT) and EGFR-TKI treatment were retrospectively reviewed. EGFR-TKI-related RRP was diagnosed according to history, clinical manifestations, and radiographic characteristics. Potential risk factors were analyzed. RESULTS: In total, 160 patients with NSCLC who received EGFR-TKI after TRT were identified. Of these patients, seven (4.4%) developed EGFR-TKI-related RRP. The median time interval between the end of radiotherapy and RRP was 124 days (range, 80-635 days) and that between the initiation of EGFR-TKI and RRP was 43 days (range, 18-65 days). No risk factor for the development of RRP was identified except that patients in whom EGFR-TKI was initiated within 90 days after the completion of radiotherapy had significantly higher rates of RRP than those of patients who began receiving EGFR-TKI treatment after 90 days (21% vs. 2.1%, p = 0.005). CONCLUSION: In patients with NSCLC who have a history of TRT, treatment with EGFR-TKI may induce not only interstitial lung disease but also RRP. Physicians should be aware of both unexpected adverse events when using EGFR-TKI.

Radiation recall pneumonitis induced by erlotinib after palliative thoracic radiotherapy for lung cancer: Case report and literature review.

Radiation lung injury usually develops 1-6 months after cessation of radiation therapy to the lung. Acute change in the previously irradiated lung after administration of antineoplastic agent is known as radiation recall pneumonitis. Erlotinib is a reversible epidemal growth factor receptor tyrosine kinase inhibitor, which is effective for patients with advanced lung cancer with epidermal growth factor receptor mutations. Here we report a rare case of radiation recall pneumonitis following treatment with erlotinib 4 months after palliative radiotherapy to the lung. A 76-year-old man with non-small cell lung cancer was treated with polychemotherapy, palliative thoracic irradiation (30 Gy in 12 fractions) and erlotinib thereafter. Two months after administration of erlotinib he developed of severe dyspnea, cough, anorexia and lack of energy. CT chest revealed extensive radiation pneumonitis. Erlotinib was ceased and high-dose steroids were started. The symptoms ultimately resolved and erlotinib was resumed cautiously after 11 weeks. On dosimetric analysis, lung V20 and the mean lung dose were 20.33% and 10.7 Gy, respectively, and hence, the risk of radiation pneumonitis is very low. These data indicate that systemic administration of erlotinib after low-dose palliative radiation therapy can be associated with unexpected toxicity when visceral organs are within the radiation field.