Renal cell carcinoma (RCC), a common malignant tumor in the urinary system, has a high incidence rate. The clear cell renal cell carcinoma (ccRCC) is the most prevalent pathological subtype. In 2022, the United States reported 79,000 new cases of RCC, with 13,920 deaths attributed to this disease.

Historically, treatment options for metastatic RCC have been limited, leading to poor patient outcomes and short survival periods. However, recent advancements in molecular targeted drugs, such as vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs), and novel immunotherapies, represented by immune checkpoint inhibitors (ICIs), have significantly improved the treatment landscape for metastatic RCC.

The American Society of Clinical Oncology (ASCO) has released guidelines for treating metastatic ccRCC, focusing on five key clinical issues: 1) diagnosis of metastatic ccRCC; 2) the role of cytoreductive nephrectomy; 3) first-line systemic treatment options; 4) second-line and alternative treatment strategies; and 5) local treatment of metastatic lesions, including bone and brain metastases.

For diagnosing metastatic ccRCC, the guidelines recommend comparing the histology of metastatic lesions with that of the primary tumor (strong recommendation). This evaluation should include common ccRCC markers, such as paired box gene 8 (PAX8) and carbonic anhydrase IX (CAIX). In cases where obtaining tissue from metastatic lesions is challenging or when measurable solid metastases are detected within a year of RCC diagnosis, imaging-based diagnosis can be used.

Cytoreductive nephrectomy is recommended for patients with only one International Metastatic RCC Database Consortium (IMDC) risk factor and a significant reduction in tumor burden following surgery (strong recommendation).

The choice of first-line systemic treatment depends on the IMDC risk stratification. High-risk and intermediate-risk patients are recommended to receive combination therapy with two ICIs or one ICI and one VEGFR TKI. Low-risk patients may receive combination therapy with one ICI and one VEGFR TKI or monotherapy with either an ICI or a VEGFR TKI.

For second-line and subsequent systemic treatments, patients who progress on VEGFR TKI monotherapy can switch to nivolumab or cabozantinib. Patients who progress on combination therapy with an ICI and a VEGFR TKI can switch to another VEGFR TKI monotherapy.

Local treatment, such as surgery, ablation, or radiation therapy, is recommended for patients with low tumor burden and metastatic lesions that can be completely resected. Symptomatic bone metastases should be treated with radiation therapy, and patients at risk of skeletal-related events should receive bone-targeted agents, such as bisphosphonates or denosumab. Brain metastases should be treated with surgery or radiation therapy.