What is the recommended treatment for a patient with stage 4 bilateral renal cell carcinoma (RCC)?

Treatment for Stage 4 Bilateral Renal Cell Carcinoma

For patients with stage 4 bilateral renal cell carcinoma, systemic therapy is the preferred initial treatment option rather than cytoreductive nephrectomy, especially for those with poor-risk features, clear cell histology, and high-volume distant metastases. 1

Patient Stratification and Initial Assessment

First, determine the patient's risk category using the International Metastatic RCC Database Consortium (IMDC) criteria:

• Risk factors:

  • Time from diagnosis to treatment < 1 year
  • Karnofsky performance status < 80%
  • Hemoglobin < lower limit of normal
  • Calcium > upper limit of normal
  • Neutrophil count > upper limit of normal
  • Platelet count > upper limit of normal

• Risk stratification:

  • Favorable risk: No risk factors
  • Intermediate risk: 1-2 risk factors
  • Poor risk: ≥3 risk factors

Treatment Algorithm Based on Histology and Risk Category

For Clear Cell RCC (70-80% of cases):

Poor-risk patients:

1. First-line options:
   • Nivolumab + ipilimumab (preferred) 1
   • Cabozantinib + nivolumab 1
   • Pembrolizumab + axitinib 1
   • Avelumab + axitinib 1

Intermediate-risk patients:

1. First-line options:
   • Nivolumab + ipilimumab (preferred) 1
   • Pembrolizumab + axitinib 1
   • Cabozantinib + nivolumab 1
   • Avelumab + axitinib 1

Favorable-risk patients:

1. First-line options:
   • Pembrolizumab + axitinib (preferred) 1
   • Cabozantinib + nivolumab 1
   • Avelumab + axitinib 1
   • Single-agent TKIs (sunitinib, pazopanib) 1, 2

For Non-Clear Cell RCC:

1. First-line options:
   • Cabozantinib (preferred for papillary RCC) 1
   • Sunitinib 2
   • Pembrolizumab 1

Role of Surgery in Stage 4 Bilateral RCC

The CARMENA trial demonstrated that sunitinib alone was non-inferior to cytoreductive nephrectomy followed by sunitinib in intermediate and poor-risk patients with metastatic RCC 1. This has changed the treatment paradigm:

• Surgery is NOT recommended for:

  • Patients with poor-risk features
  • High volume metastatic disease
  • Brain metastases

• Surgery may be considered for:

  • Patients with excellent performance status
  • Small-volume distant metastases
  • Oligometastatic disease amenable to metastasectomy or ablative techniques

Second-line Treatment Options

After progression on first-line therapy:

1. After immunotherapy combinations:

   • Cabozantinib (preferred) 1
   • VEGFR TKIs (if not received previously) 1

2. After TKI failure:

   • Nivolumab 1
   • Cabozantinib 1
   • Belzutifan (for subsequent lines) 1

Important Considerations and Pitfalls

• Bilateral RCC presents unique challenges: Preserving renal function is critical when considering any surgical approach to avoid dialysis dependency.

• Tissue sampling is essential: For patients with surgically unresectable tumors, biopsy to determine histology should guide subsequent management 1.

• Monitor for treatment-specific toxicities:

  • Immune-related adverse events with checkpoint inhibitors
  • Cardiovascular and hepatic toxicities with TKIs like sunitinib 2

• Common pitfall: Assuming all patients need cytoreductive nephrectomy. The CARMENA trial showed that upfront systemic therapy is appropriate for many patients with metastatic disease 1, 3.

• Avoid delay in systemic therapy: For patients with symptomatic metastases or rapidly progressive disease, starting systemic therapy promptly is critical for survival outcomes.

The treatment landscape for stage 4 RCC has evolved significantly, with immunotherapy combinations showing superior outcomes compared to traditional TKI monotherapy, particularly for intermediate and poor-risk patients 1. The 5-year survival rate for stage 4 kidney cancer has improved from less than 10% to approximately 20-23% with modern therapies 3.