An Overview of Systemic Targeted Therapy in Renal Cell Carcinoma, with a Focus on Metastatic Renal Cell Carcinoma and Brain Metastases

Abstract

The most commonly diagnosed malignancy of the urinary system is represented by renal cell carcinoma. Various subvariants of RCC were described, with a clear-cell type prevailing in about 85% of all RCC tumors. Patients with metastases from renal cell carcinoma did not have many effective therapies until the end of the 1980s, as long as hormonal therapy and chemotherapy were the only options available. The outcomes were unsatisfactory due to the poor effectiveness of the available therapeutic options, but then interferon-alpha and interleukin-2 showed treatment effectiveness, providing benefits but only for less than half of the patients. However, it was not until 2004 that targeted therapies emerged, prolonging the survival rate. Currently, new technologies and strategies are being developed to improve the actual efficacy of available treatments and their prognostic aspects. This article summarizes the mechanisms of action, importance, benefits, adverse events of special interest, and efficacy of immunotherapy in metastatic renal cell carcinoma, with a focus on brain metastases.

Keywords: brain metastases; immune checkpoint inhibitors; immunotherapy; neuro-oncology; renal cell carcinoma; systemic therapy; targeted therapy.

Figure 1

Mechanism of action of cabozantinib (also known as XL-184 or BMS-907351), a micromolecule that inhibits multiple receptor tyrosine kinases implicated in tumor growth, angiogenesis, drug resistance, and metastatic progression of cancer. VEGFR—vascular endothelial growth factor receptor; AXL—the gene AXL, located at chromosome 19q13.2 (originating from the Greek word “anexelekto”, translated as “uncontrolled”), is encoding a protein called AXL; RET—rearranged during transfection (a protooncogene responsible for encoding a receptor TK; this receptor plays a critical role in the formation of neural crest-derived cell lineages and genitourinary tract; MET—mesenchymal-epithelial transition factor (a type of receptor TK, usually revealed on the surface of several types of epithelial cells; 1—intracellular space; 2—cellular membrane; 3—extracellular space; A—angiogenesis; B—lymphangiogenesis; C—tumoral growth, metastatic invasion; D—indirectly stimulates the tumoral growth, invasion, and metastatic evolution; pro-inflammatory role in the tumor microenvironment.

Figure 2

Summary of recommended systemic therapy in mRCC.