Pazopanib-associated interstitial lung disease in a patient with renal cell carcinoma

Background

Pazopanib is a multi-targeted tyrosine kinase inhibitor, which is currently used to treat advanced renal cell carcinoma and advanced soft-tissue sarcomas.1 2 While pneumothorax has been characterised as among the adverse events associated with pazopanib, there are only rare reports of interstitial lung disease, notably in cases of soft-tissue sarcoma.2 3 However, several recent reports describe pazopanib-associated interstitial lung disease in patients with lung metastasis from primary renal cell carcinoma or leiomyosarcoma.4 5 Herein, we report a case of pazopanib-associated interstitial lung disease in a patient with metastatic renal cell carcinoma.

Case presentation

A man in his 70s presented to our hospital with chief problem of 7 days of dry cough and fatigue and spontaneous haematochezia. His past medical history was significant for renal cell carcinoma in his left kidney that was treated with radical nephrectomy 18 years prior to presentation. Since 15 months prior to presentation, the patient had been treated with sunitinib and followed with nivolumab for multiple lung, pancreas and liver metastatic lesions of renal cell carcinoma; these drugs were discontinued, as they did not halt the progression of metastatic disease. Three months prior to presentation, pazopanib was introduced. He also underwent gamma knife radiosurgery to eliminate a right anterior lobe metastatic lesion. He developed dry cough and fatigue for 7 days prior to presentation and haematochezia on the day of presentation. He reported no odynophagia, nausea, myalgia or arthralgia. Additional medical history included hypothyroidism, chronic gastritis, gastro-oesophageal reflux disorder, irritable bowel syndrome, benign prostate hyperplasia, insomnia and anxiety disorder. His current medications included levothyroxine, rebamipide (gastroprotective drug work by stimulating prostaglandin generation in gastric mucosa, approved for the treatment of peptic ulcer disease and gastritis in Japan),6 silodosin, candesartan, zolpidem, vonoprazan (potassium-competitive acid inhibitors work by competing for potassium on the luminal side of the parietal cell, and cause rapid and reversible inhibition of pumps,7 approved for the prevention of nonsteroidal anti-inflammatory drug-induced ulcers and treatment of peptic ulcer disease in Japan), mosapride (gastrointestinal prokinetic drug work by facilitating acetylcholine release from the enteric cholinergic neurons through a selective 5-HT4 receptor agonistic action,8 approved for the treatment of heartburn, nausea and vomiting due to gastritis in Japan) and diazepam as needed. He reported no known allergies and no relevant family history. He lived independently with his spouse. He did not drink or smoke.

Investigations

On physical examination, he was alert and oriented, with a blood pressure of 154/84 mm Hg, pulse of 75 beats/min, respiratory rate of 24 breaths/min, body temperature was 37.5°C and oxygen saturation in ambient air was 86%; his oxygen saturation improved to 98% on oxygen at 3 L/min. There was a non-tender palpable mass on the right lobe of the thyroid. Heart examination was normal. Fine crackles were heard in the left posterior lower lung field. The abdominal examination was unremarkable with no signs of hepatomegaly, and there was no peripheral oedema or rash.

Complete blood count revealed slightly elevated neutrophils (white cell count of 7.4x10⁹/L with neutrophils at 79.9%) without anaemia or thrombocytopenia. Blood chemistry panel revealed hypoalbuminemia (2.4 g/dL), mildly elevated serum aspartate aminotransferase (71 U/L), moderately elevated serum lactate dehydrogenase (433 U/L) and alkaline phosphatase (630 U/L) and significant elevation of serum C-reactive protein (29.58 mg/dL). Chest CT without contrast revealed ground-glass opacities and consolidation of both lower lobes of the lung and mediastinal lymphadenopathy; these findings were not detected on a chest CT at 5 months prior to presentation (figure 1A,B). Blood cultures and urine cultures were both sterile. Sputum could not be obtained.

Differential diagnosis

The patient was admitted to the hospital with an initial diagnosis of bacterial pneumonia and was treated with piperacillin/tazobactam. Given that interstitial lung disease was also in the differential diagnosis, pazopanib was discontinued. His fatigue and cough slightly diminished in response to antibiotics; however, on hospital day 3, moderate hypoxemia and tachypnoea occurred. On day 4, chest CT without contrast revealed further deterioration, with ground-glass opacities and consolidation of both lungs (figure 1C). Bronchoscopy with bronchoalveolar lavage was planned but not performed as the patient chose to decline the procedure. A test for serum antinuclear antibody and antineutrophil cytoplasmic antibody were negative, as well as tests for serum antibodies against the citrullinated peptide, aminoacyl tRNA synthetase, melanoma differentiation-associated gene 5, transcriptional intermediary factor 1-γ, cytomegalovirus, Aspergillus spp and beta-d-glucan (table 1). Interestingly, the drug-induced lymphocyte stimulation test (DLST) to pazopanib was strongly positive (Stimulation Index 314%). Based on these results, the clinical diagnosis was pazopanib-associate interstitial lung disease with or without community-acquired pneumonia; fungal infection, vasculitis and collagen vascular disease-related interstitial lung disease were ruled out.

Treatment

Piperacillin/tazobactam was continued together with one dose of azithromycin (2000 mg) and methylprednisolone (1000 mg) for 3 days, followed by 40 mg of intravenous prednisolone for the treatment of interstitial lung disease. The dose of steroid was along with the consensus statement for the treatment of drug-induced lung injuries by the Japanese Respiratory Society.9 As his oxygenation status deteriorated, non-invasive positive pressure ventilation was provided starting on hospital day 5. His worst P/F ratio was 150 mm Hg with positive end-expiratory pressure of 5–7 cmH₂O, and echocardiography showed normal ejection fraction without any signs of volume overload; however, considering the timing of deteriorating respiratory condition, he did not meet the Berlin definition of acute respiratory distress syndrome.10 His condition gradually improved, and piperacillin/tazobactam and non-invasive positive pressure ventilation were discontinued on hospital day 8. Prednisolone was discontinued on hospital day 15 due to the development of acute delirium although a more prolonged course of treatment with corticosteroids (1–2 months) was recommended.9

Outcome and follow-up

His respiratory condition remained stable on oxygen at <2 L/min. A slight cough remained. On hospital day 20, a follow-up chest CT revealed that ground-glass opacities and consolidations had diminished slightly, while bilateral pleural effusions had developed (figure 1D). After discussion between the patient and his urologist, who followed him for renal cell carcinoma, the patient decided to stop antitumor treatment, and he declined any additional follow-up tests. After completing the rehabilitation programme, he was discharged on hospital day 36 and has been treated with palliative home medical care for the past 2 months.