Symptomatic pneumonitis in the irradiated lung after nivolumab: Three case studies

Abstract

Background: Nivolumab is a feasible therapy option in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line conventional treatment, including chemoradiotherapy (CRT). There is limited information about an overlapping toxicity of nivolumab when applied after primary multimodality treatment. Here, we describe symptomatic grade 2 pneumonitis in the irradiated lung in patients undergoing second- or third-line nivolumab therapy. Patients: Nivolumab as second or third-line therapy was applied in patients with advanced NSCLC after initial treatment with sequential CRT. Case 1: A 66-year-old female patient who presented with squamous NSCLC stage ypT2a pN2 cM0 R0 underwent adjuvant thoracic irradiation after induction chemotherapy and radical surgery. Nivolumab was started 6 months post-radiotherapy when recurrent disease was detected on restaging CT. twelve days after the first nivolumab treatment, the patient developed grade 2 dyspnea and cough. Case 2: A 76-year-old male patient with non-squamous NSCLC stage cT1a cN2 cM1b (single metastatic brain tumor) received intracranial stereotactic radiosurgery followed by chemotherapy with Cisplatin/ Pemetrexed and thoracic radiotherapy to a total dose of 66Gy delivered to the PET-positive tumor and mediastinal lymph nodes. Second-line nivolumab was started 6 months later and after the fourth cycle (70 days after the first nivolumab treatment), the patient developed grade 2 dyspnea and cough requiring immediate hospitalization. Case 3: A 56-year-old female patient was diagnosed with metastatic non-squamous NSCLC, including metastasis to the brain. She was treated with Cisplatin/Pemetrexed followed by consolidative irradiation to the brain and thorax after good systemic remission. Due to systemic progression including metastasis the the adrenal gland, second-line chemotherapy with docetaxel and nintedanib followed by local radiotherapy was applied. Six months after thoracic irradiation, new pulmonary lesions were detected and the patient was started on third-line therapy with nivolumab. After 6 cycles (10 months following thoracic radiotherapy and 77 days after the first cycle of nivolumab), the patient required hospitalization because of grade 2 coughing and dyspnea. In all three patients comprehensive radiological and functional diagnostic as well as bronchoscopy were performed after onset of respiratory symptoms. The PET/CT scans revealed a broad pattern of lung parenchyma changes (from ground-glass opacification/opacities and recurring consolidations) with diffuse increased metabolic activity. Imaging analysis was strongly consistent with parenchyma changes in the irradiated lung volume receiving 15 to 20 Gy. No pathological endobronchial findings were observed on bronchoscopy. Nivolumab treatment was interrupted and patients were treated with systemic corticoids for the following one to two months with rash alleviation of symptoms. Imaging analysis was strongly consistent with parenchyma changes in the irradiated lung volume receiving 15 to 20 Gy. Conclusion: Three cases of symptomatic pneumonitis in the irradiated lung in patients with advanced NSCLC treated with nivolumab in the second- or third-line setting were described. Interruption of immunotherapy and systemic corticoid therapy for several weeks was necessary in all three cases. Future prospective investigation of the described phenomenon is urgently indicated.