Current Multimodality Treatments against Brain Metastases from Renal Cell Carcinoma

Abstract

In patients with renal cell carcinoma, brain metastasis is generally one of the poor prognostic factors. However, the recent introduction of molecular target therapy and immune checkpoint inhibitor has remarkably advanced the systemic treatment of metastatic renal cell carcinoma and prolonged the patients’ survival. The pivotal clinical trials of those agents usually excluded patients with brain metastasis. The incidence of brain metastasis has been increasing in the actual clinical setting because of longer control of extra-cranial disease. Brain metastasis subgroup data from the prospective and retrospective series have been gradually accumulated about the risk classification of brain metastasis and the efficacy and safety of those new agents for brain metastasis. While the local treatment against brain metastasis includes neurosurgery, stereotactic radiosurgery, and conventional whole brain radiation therapy, the technology of stereotactic radiosurgery has been especially advanced, and the combination with systemic therapy such as molecular target therapy and immune checkpoint inhibitor is considered promising. This review summarizes recent progression of multimodality treatment of brain metastasis of renal cell carcinoma from literature data and explores the future direction of the treatment.

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…Brain metastases (BM) is generally associated with a very poor prognosis and high degree of morbidity, requiring urgent multidisciplinary care, and is relatively unresponsive to conventional systemic therapy [11,[16][17][18][19][20][21][22][23][24][25]. BM is also a serious condition that causes headaches, focal neurological deficits, altered mental status or gradual cognitive impairment, epileptic seizures driven by increased intracranial pressure by vasogenic edema, or alterations in cerebrospinal fluid (CSF) flow, thereby impairing the quality of life (QOL) [11,[17][18][19][25][26][27]. Unfortunately, BM is not a rare finding in mRCC (8%-15%), and its prevalence has increased in the past two decades [16][17][18][19][20][21][22].…”

“…The median OS of RCC patients with BM (RCC-BM) is only 5-8 months [16][17][18][19][20][21][22]. Therefore, early detection and effective treatment of BM is an unmet medical need for mRCC [11,17,19,25]. Improved clinical outcomes of extracranial metastases by the introduction of TKIs and immune checkpoint inhibitors (ICIs) has led to the adoption of improved imaging techniques for BM, thereby increasing awareness of the benefit of brain screening [11,[17][18][19][20]27].…”

“…As advances in both local and systemic therapies provide better survival outcomes, mRCC patients with solitary BM and good performance status (PS) can benefit from early detection of asymptomatic BM [11,19,25,28]. Nevertheless, current surveillance guidelines for patients with RCC do not recommend brain imaging, unless BM is clinically suspected [11,29,30]. A large mRCC cohort study to investigate the rate of incidental BM highlighted that a relevant proportion of patients with mRCC (4.3%) may harbor occult BM through brain imaging as a part of eligibility assessments for clinical trial [16].…”

“…Systemic therapy against mRCC has evolved significantly over the past two decades [11][12][13][14]. Vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitors (TKIs) (e.g., sunitinib, pazopanib, axitinib, tivozanib, lenvatinib, and cabozantinib) or mammalian target of rapamycin (mTOR) pathway inhibitors (e.g., everolimus and temsirolimus) were used in the 2000s for mRCC, either combined or as a monotherapy [11][12][13][14]. A validation study of the International Metastatic RCC Database Consortium (IMDC) system revealed that the median overall survival (OS) significantly improved in the 2000s as compared to that observed in the cytokine era (favorable risk: 43.2 months, intermediate risk: 22.5 months, and poor risk: 7.8 months) [15].…”

“…A validation study of the International Metastatic RCC Database Consortium (IMDC) system revealed that the median overall survival (OS) significantly improved in the 2000s as compared to that observed in the cytokine era (favorable risk: 43.2 months, intermediate risk: 22.5 months, and poor risk: 7.8 months) [15]. Unfortunately, the 5-year OS rate for mRCC remains under 30% despite the TKI-based approach [11][12][13][14].…”