What are the treatment options for a patient with symptomatic renal cell carcinoma?

Treatment of Symptomatic Metastatic Renal Cell Carcinoma

For patients with symptomatic metastatic renal cell carcinoma, radiotherapy is the most effective immediate intervention for palliation of symptoms in critical sites (bone, brain), while systemic therapy selection depends on risk stratification and prior treatment history.

Immediate Symptom Management

Bone Metastases

• Local radiotherapy provides symptom relief in up to two-thirds of patients with symptomatic bone metastases, with complete symptomatic responses in 20-25% of cases 1, 2
• Single fraction or fractionated radiotherapy courses are both effective options 1
• Modern image-guided techniques (VMAT or SBRT) enable high-dose delivery and overcome the apparent radioresistance of RCC 1, 2

Spinal Cord Compression

• Surgery combined with radiotherapy improves survival and maintains ambulation compared to radiation alone in ambulatory patients with limited metastatic disease 1, 2
• Ambulatory status at diagnosis is a critical favorable prognostic factor 1

Brain Metastases

• Corticosteroids provide temporary relief of cerebral symptoms and should be initiated immediately 1
• Whole-brain radiotherapy (20-30 Gy in 4-10 fractions) is recommended for effective symptom control 1, 3
• For good-prognosis patients with a single unresectable brain metastasis, stereotactic radiosurgery (SRS) with or without WBRT should be considered 1

Bone Health Support

• Bisphosphonate therapy with zoledronic acid reduces skeletal-related events in patients with bone metastases, based on assessment of expected survival time and probability of symptomatic benefit 1

Systemic Treatment Selection

First-Line Treatment by Risk Group

Intermediate and Poor-Risk Patients:

• Nivolumab plus ipilimumab is the recommended first-line treatment 1, 4, 5
• This combination has Level I evidence with an ESMO-MCBS score of 3 1
• Cabozantinib monotherapy is also approved for intermediate-risk (Level II, A) and poor-risk groups (Level II, B) 1, 6

Good and Intermediate-Risk Patients:

• VEGF-targeted agents and TKIs are recommended options, including sunitinib, pazopanib, or bevacizumab plus interferon 1, 4
• Tivozanib is EMA-approved specifically for good-risk patients 1

Second-Line Treatment

Following TKI Therapy:

• Nivolumab (Level I, A; ESMO-MCBS score: 5) or cabozantinib (Level I, A; ESMO-MCBS score: 3) are the recommended second-line options 1, 3, 6, 5
• Lenvatinib plus everolimus is FDA- and EMA-approved following TKIs (Level II, B; ESMO-MCBS score: 4) 1

Following Two TKIs:

• Either nivolumab (Level I, A) or cabozantinib is recommended 1

Following Nivolumab/Ipilimumab:

• Lenvatinib plus everolimus is recommended (Level IV, C; ESMO-MCBS score: 3) 1

Role of Cytoreductive Nephrectomy

• Cytoreductive nephrectomy is recommended in patients with good performance status 1, 3
• Exception: Do NOT perform cytoreductive nephrectomy in intermediate- and poor-risk patients with asymptomatic primary tumors when immediate medical treatment is required 1, 3

Critical Pitfalls to Avoid

• Never use radiotherapy in the neoadjuvant or adjuvant setting for primary RCC—four negative trials have demonstrated no benefit 1, 2
• Do not delay palliative radiotherapy for symptomatic metastases while awaiting systemic therapy initiation 1, 2
• Avoid using nivolumab/ipilimumab in good-risk patients, as it is not recommended for this group 1
• When combining cabozantinib with nivolumab, monitor for higher frequencies of Grade 3-4 hepatotoxicity and consider dose modifications 6, 5

Monitoring During Treatment

• CT scans every 2-4 months are advised during systemic therapy to determine response and resistance 1, 3, 4
• RECIST criteria remain the best method to assess drug efficacy 1, 3, 4
• When using nivolumab with cabozantinib or ipilimumab, monitor liver enzymes periodically and assess for adrenal insufficiency 6, 5