What is the recommended treatment strategy for renal cell carcinoma, including localized, locally advanced, and metastatic disease?

Treatment of Renal Cell Carcinoma

For localized cT1 RCC, perform partial nephrectomy as the primary curative treatment; for metastatic clear cell RCC, initiate first-line therapy with either dual immunotherapy (nivolumab-ipilimumab) or immunotherapy combined with anti-VEGF TKI (such as pembrolizumab-lenvatinib or nivolumab-cabozantinib). 1, 2

Localized Disease (cT1-T2)

Surgical Management

Partial nephrectomy (PN) is the preferred surgical approach for cT1 tumors over radical nephrectomy (RN), regardless of surgical technique used. 1 This recommendation is based on:

• Superior renal function preservation compared to RN, reducing cardiovascular and metabolic complications
• Non-inferior cancer-specific survival demonstrated in prospective RCT data (HR 2.06,95% CI 0.62-6.84)
• Equivalent oncological outcomes in retrospective studies for pT1b tumors

For cT2 and T3a tumors, PN remains an option when technically feasible. Meta-analysis of 3,391 patients showed no differences in cancer-specific survival, overall survival, or recurrence-free survival between PN and RN for pT3a disease, supporting PN for functional benefits. 1

Surgical Approach Selection

Laparoscopic or robot-assisted RN demonstrates less morbidity and shorter hospital stays compared to open RN, with similar oncological outcomes. 1 The choice between retroperitoneal versus transperioneal approaches shows equivalent perioperative outcomes.

Alternative Management for Small Renal Masses

For tumors <4 cm in frail patients with high surgical risk, consider:

• Active surveillance for indolent disease
• Ablative therapies (radiofrequency, thermoablation) 3
• Stereotactic body radiation therapy (SBRT) as an emerging noninvasive option 4

Locally Advanced Disease

For lymph node-positive RCC with bulky or multiple nodal metastases, patients often behave like metastatic disease and may benefit more from upfront systemic therapy than surgery alone. 5 Cytoreductive nephrectomy should be reserved for intermediate-risk disease; avoid surgery in poor-risk patients. 2

Metastatic Clear Cell RCC

First-Line Therapy

Two combination strategies are standard of care, both demonstrating superior survival compared to sunitinib monotherapy:

1. Dual immunotherapy: Nivolumab-ipilimumab
2. ICI-TKI combinations:
   • Pembrolizumab-lenvatinib
   • Nivolumab-cabozantinib
   • Pembrolizumab-axitinib

2, 6, 7

Treatment selection criteria:

• Tumor burden and location of metastases
• Threatening metastases requiring rapid response
• Speed of progression
• Patient comorbidities and tolerance for specific toxicity profiles
• Histology confirmation (clear cell vs non-clear cell)

Subsequent-Line Therapy

After progression on first-line ICI-based therapy:

• TKIs (cabozantinib, lenvatinib-everolimus)
• mTOR inhibitors (everolimus)
• HIF2α inhibitor (belzutifan) 7

Role of Local Therapies in Metastatic Disease

For oligometastatic or oligoprogressive disease, consider:

• Metastasectomy for isolated progression sites
• SBRT for oligometastases or oligoprogression in combination with systemic therapy 4, 7
• Active surveillance in indolent oligometastatic setting with local treatment for localized progression 6

Non-Clear Cell RCC

Papillary RCC (pRCC)

Cabozantinib monotherapy is the preferred first-line treatment for advanced pRCC, demonstrating PFS advantage over sunitinib. 2 Alternative options include:

• Sunitinib
• Pembrolizumab
• Lenvatinib-pembrolizumab (ORR 49% in prospective trial)
• Cabozantinib-nivolumab (ORR 48% in prospective trial)

For MET-altered pRCC, savolitinib (MET inhibitor) shows activity in small randomized studies. 2

Other Non-Clear Cell Histologies

Sunitinib has demonstrated activity in non-clear cell histologies with improved PFS compared to everolimus. 2

Specific histology-directed therapy:

• Sarcomatoid differentiation: PD-1-targeted combinations are standard of care
• Chromophobe RCC: Consider mTOR inhibitors (chromosome 17 mutation leads to FLCN gene loss and mTOR upregulation)
• Collecting duct carcinoma: Platinum-based chemotherapy or cabozantinib monotherapy
• FH-deficient RCC/HLRCC: Bevacizumab-erlotinib combination based on phase II data
• SMARCB1-deficient RCC: Platinum-based chemotherapy

2

Critical Considerations

Shared Decision-Making

43% of patients at diagnosis have no understanding of their RCC subtype, and 29% report no involvement in treatment decisions. 1 Engage patients actively in treatment selection, discussing:

• Disease characteristics and prognosis
• Treatment options with expected outcomes
• Potential side effects and quality of life impact
• Patient preferences and values

Adjuvant Therapy

Adjuvant pembrolizumab has proven efficacy to reduce RCC recurrence risk after nephrectomy in high-risk disease. 4 KIM-1 is emerging as a potential prognostic and predictive biomarker for identifying patients likely to benefit from adjuvant therapy. 1

Common Pitfalls

• Avoid surgery in poor-risk metastatic disease without considering upfront systemic therapy
• Do not rely solely on TNM staging for treatment decisions; incorporate patient condition, comorbidities, and tumor biology
• Recognize geographic variations in patient education and access to care that may impact treatment delivery
• Monitor for immunotherapy-related toxicities with ICI-based combinations, requiring different management than traditional TKI toxicities