Recurrent intracranial hemorrhage without brain metastasis after VEGFR TKI rechallenge in metastatic renal cell carcinoma: a case report and literature review.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are widely used in the treatment of metastatic renal cell carcinoma (RCC). Although hemorrhagic events are recognized adverse effects of these agents, intracranial hemorrhage is rare, and the safety of re-administration of VEGFR TKIs after central nervous system (CNS) hemorrhage remains unclear. We report a 52-year-old man with metastatic clear cell RCC who initially received first-line immunotherapy with ipilimumab and nivolumab, resulting in disease progression, followed by second-line sunitinib, which achieved a partial response. However, he subsequently developed sudden neurological deterioration, and brain imaging revealed multifocal cerebellar hemorrhages without evidence of brain metastasis; the absence of metastasis was confirmed by surgical and histopathological examination. After surgical management, complete radiologic resolution of the hemorrhage was confirmed 4 weeks postoperatively. Pazopanib was subsequently initiated based on the prior favorable response to VEGFR TKI therapy; however, recurrent cerebellar hemorrhage occurred within 4 weeks of rechallenge, leading to rapid clinical deterioration and death despite supportive care. This case highlights that VEGFR TKI-associated intracranial hemorrhage can occur even in the absence of brain metastases and may recur with fatal consequences upon rechallenge. These findings suggest that early VEGFR TKI rechallenge (<1-2 months) after CNS hemorrhage may be unsafe, and that careful risk-benefit assessment with an adequate waiting period is essential when considering re-administration.