Dramatic Radiation Recall Pneumonitis Induced by Osimertinib after Palliative Thoracic Radiotherapy for Lung Cancer

The risk of radiation recall pneumonitis (RRP) has been reported in patients exposed to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs),1Chiang C.-L. Chen Y.-W. Wu M.-H. Huang H.-C. Tsai C.-M. Chiu C.-H. Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer.J Chin Med Assoc. 2016; 79: 248-255Crossref PubMed Scopus (22) Google Scholar whereas no such case of RRP has been reported with osimertinib until now. A right inferior lobe lung adenocarcinoma with metastatic pleural effusion was diagnosed in a 58-year-old male nonsmoker in June 2014. After first-line treatment with cisplatin and gemcitabin chemotherapy resulted in a partial tumoral response, the patient was referred to our institution in December 2014. Molecular analysis identified an EGFR exon 21 L858R mutation, and fludeoxyglucose F 18 positron emission tomography coupled to thomodensitometry showed a local lung progression that was treated with gefinitib, 250 mg/d. Local progression occurred in September 2015. A T790M resistance mutation was identified in a tissue biopsy specimen and treated with osimertinib, 80 mg/d. In October 2016, a new local progression was treated with carboplatin paclitaxel doublet with bevacizumab. Again, there was a new local progression in July 2017, and after osimertinib rechallenge for 4 months, the multidisciplinary tumor board proposed pursuing osimertinib and performing hypofractionated mediastinopulmonary radiation therapy (RT) (55 Gy in 20 fractions) in December 2017; osimertinib was withheld 7 days before the RT. In February 2018, a positron emission tomography/computed tomography (CT) scan showed a partial mediastinal response with fibrotic radiation pneumonitis (RP) in the right upper lobe and no new lesions (Fig. 1B). Osimertinib was resumed, and 2 weeks later the patient was hospitalized for dyspnea with a score of 4 on the Modified Medical Research Council dyspnea scale with a worsening of general condition and fever (body temperature 38.4°C). A CT scan revealed peribronchial consolidation and ground glass opacities predominating in the right lung (Fig. 1C). Bronchoalveolar lavage in the right lower lobe displayed major lymphocytic alveolitis (1,200,000 elements/mL with 27% macrophages and 71% lymphocytes, among which 50.6% of CD4-positive cells); the microbiological analysis results were negative. On the basis of the clinical, radiological, and cytological findings, the diagnosis of acute RRP favored by the osimertinib reintroduction was retained. Osimertinib was discontinued, and administration of prednisolone, 0.5 mg/kg/d, was started. The patient's respiratory symptoms improved quickly and a CT scan assessment 1 week later showed an important regression of the pulmonary consolidation in the right upper lobe and in the left lower lobe, without, however, a complete resolution (Fig. 1D). In February 2019, the patient was still alive without any cancer treatment. The lung cancer is in remission and the RP has not recurred, although administration of prednisolone was stopped after 8 months. Combining conventionally fractionated thoracic RT and an EGFR TKI is a debated strategy in patients with oligoprogression.2Campo M. Al-Halabi H. Khandekar M. Shaw A.T. Sequist L.V. Willers H. Integration of stereotactic body radiation therapy with tyrosine kinase inhibitors in stage IV oncogene-driven lung cancer.Oncologist. 2016; 21: 964-973Crossref PubMed Scopus (39) Google Scholar Serious pulmonary toxicity can be observed when these treatment modalities are combined, with a 37.5% rate of grade 3 to 5 RP in one study with erlotinib.3Zhuang H. Yuan Z. Chang J.Y. et al.Radiation pneumonitis in patients with non–small-cell lung cancer treated with erlotinib concurrent with thoracic radiotherapy.J Thorac Oncol. 2014; 9: 882-885Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar EGFR TKIs have been reported as potent radiation sensitizers,4Prakash Chinnaiyan Shyhmin Huang Geetha Vallabhaneni et al.Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva).Cancer Res. 2005; 65: 3328-3335Google Scholar but the correct timing to withhold them is subject to debate. Most TKIs have a half-life longer than 30 hours, so withholding the drug for 1 to 3 days before the beginning of RT seems to be a reasonable precaution.2Campo M. Al-Halabi H. Khandekar M. Shaw A.T. Sequist L.V. Willers H. Integration of stereotactic body radiation therapy with tyrosine kinase inhibitors in stage IV oncogene-driven lung cancer.Oncologist. 2016; 21: 964-973Crossref PubMed Scopus (39) Google Scholar RRP is a special form of RP, which is an inflammatory reaction in a previously irradiated area of lung tissue after application of a pharmacologic agent. When RT is followed by an EGFR TKI, subclinical damage from irradiation may be uncovered and manifested clinically and on a CT scan as RRP.1Chiang C.-L. Chen Y.-W. Wu M.-H. Huang H.-C. Tsai C.-M. Chiu C.-H. Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer.J Chin Med Assoc. 2016; 79: 248-255Crossref PubMed Scopus (22) Google Scholar In our patient who was previously exposed to osimertinib without side effects, resumption of administration of osimertinib after thoracic RT (which proved effective in locoregional control of his disease) was followed by severe interstitial lung disease not only in the irradiated area but also in the contralateral lung. This inflammatory pneumonitis proved to be quickly responsive to corticosteroids, which is a strong argument for an RRP. We are reporting a case of acute RRP that was probably induced by osimertinib. Physicians must be aware of the potential toxicities and their different forms brought about by these novel combinations even when third-generation EGFR TKIs are used.