Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature

Abstract

BackgroundRadiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP.Case PresentationOur first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy.ConclusionsImmunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.

Radiation Recall Pneumonitis Anticipates Bilateral Immune-Induced Pneumonitis in Non-Small Cell Lung Cancer

“…ICIs enhance the local immune response in lung parenchyma, promoting inflammation in previously injured areas, thus triggering RRP [ 28 ]. RT promotes inflammation in the lung parenchyma through several mechanisms ( Figure 2 ) [ 29 ]. A case series suggested that RRP might be associated with IIP, as in the case we are presenting [ 27 ].…”

“…In addition, withdrawal of the suspected triggering drug is recommended [ 23 ]. In some case reports of ICI-triggered RRP, ICI treatment was resumed following the resolution of the RRP, and no toxicity recurrences were reported [ 29 ].…”

Radiation Recall Pneumonitis: The Open Challenge in Differential Diagnosis of Pneumonia Induced by Oncological Treatments

“…Radiation recall, on the other hand, is the reactivation of the damage at the level of the previously treated site, at a distance of several times from the radiotherapy treatment, following the administration of a drug. The phenomenon can occur following the administration of chemotherapy [ 40 , 41 ], target therapy [ 42 , 43 ], immunotherapies [ 44 , 45 ] or vaccinations [ 46 , 47 ], and it is not radiation dose-related. Radiation recall reactions were first described in 1959 by D’Angio et al who described the onset of dermatitis in patients treated with actinomycin D, after having previously undergone radiotherapy treatments, demonstrating the absence of such reactions after only treatment with actinomycin and the significant increase of the same in patients treated with the combination of actinomycin and radiotherapy compared to those treated exclusively with radiotherapy [ 48 ].…”

Avoiding Toxicity With Lung Radiation Therapy: An IASLC Perspective

“…53 Other rare toxicities including the radiation recall phenomenon can occur in all patients receiving systemic therapies including immunotherapy. 54 Typically the most common type of recall reaction after thoracic treatment is radiation pneumonitis, although rare conditions such as recall myelopathy may also occur. 16 The use of RT in patients who have received surgical management has recently been explored in the lung ART trial in which patients with resected stage III lung cancer were randomized to receive postoperative RT or observation.…”