Management of brain metastases from renal cell carcinoma

Abstract

The most common primary tumors associated with brain metastases are lung (20-56%), melanoma (6-11%), breast (5-30%), and renal cell carcinoma (RCC) (2-7%) (1,2). However, the true incidence is likely higher than these estimates because most guidelines for solid tumors do not recommend routine brain magnetic resonance imaging (MRI) screening in patients without neurological symptoms. Recent clinical trial enrolments often involve a concomitant requirement for brain MRI screening. Unfortunately, the safety and activity of immune checkpoint inhibitors (ICIs), which are already recommended for patients with metastatic clear cell RCC (mccRCC), have not been revealed in those with brain metastases because they were included in the exclusion criteria of crucial trials (3,4). The current study, the GETUG-AFU 26 NIVOREN trial, prospectively assessed clinical outcome of nivolumab in mccRCC patients with asymptomatic brain metastases who progressed after molecular targeted therapies. This study considered two important issues, (I) brain imaging before ICIs treatment and (II) focal therapy prior to ICIs for asymptomatic brain metastases from RCC, which are discussed as below. Various factors are linked with brain metastases including sex, age, ethnicity, tumor type, and molecular subtype. In the Metropolitan Detroit Cancer Surveillance System, the incidence of brain metastases in lung cancer (21.4% vs. 19.4%), melanoma (11.7% vs. 7.1%) and breast cancer (7.4% vs. 4.6%) were higher in African Americans than other ethnic groups, however, the incidence of those in RCC was not (5.3% vs. 6.8%) (2). Focusing on the molecular signatures of brain metastases, the whole-exome sequencing of matched primary tumors (lung, breast, and RCCs) and brain metastases revealed that, although primary tumor and brain metastases clonally originated from a shared precursor, a diverse evolutionary pattern occurred at each site of metastases, suggesting that sequencing of primary biopsies alone may miss the opportunity for the optimal therapy (5). Although the tumor suppressor gene VHL is well-known as a mutational driver for clear cell RCC, brain metastases from RCC revealed mutations in the genes PTEN, CDKN2A, and PIK3CA that were not detected in the corresponding primary tumors (5). Above all, the present study showed that more than 10% of patients with mRCC had unexpectedly asymptomatic brain metastases before nivolumab treatment. Based on these findings that it is difficult to predict the presence of brain metastasis, we recommend performing brain imaging at the initial diagnosis of mRCC, even if the patient does not have neurological symptoms. Radiographically, brain MRI irrespective of intravenous gadolinium contrast is recommended for the evaluation of brain metastases and has a higher sensitivity compared to contrast enhanced CT. Additionally, diffusion-weighted (DW)-MRI, which differentiates abscesses or high-grade gliomas, and fluid-attenuated inversion recovery (FLAIR) MRI, which shows vasogenic edema as areas of increased signal intensity, can be helpful in the clinical evaluation of brain metastases (6). 18 F-fluorodeoxyglucose (FDG)-PET may provide sufficient information to differentiate between brain metastases and lymphoma, but not glioma, when differential diagnoses are difficult using MRI alone (7). Shirotake. Brain metastases from RCC