What are the treatment options for Renal Cell Carcinoma (RCC)?

Treatment of Renal Cell Carcinoma

For localized RCC (T1 tumors ≤7 cm), partial nephrectomy is the preferred treatment to preserve renal function while achieving complete tumor removal, and for metastatic clear cell RCC, immune checkpoint inhibitor (ICI) combination therapy with either a VEGFR tyrosine kinase inhibitor or dual ICI therapy is the first-line standard of care, stratified by IMDC risk criteria. 1, 2, 3

Localized Disease (Stages I-III)

Small Renal Masses (T1, ≤7 cm)

• Partial nephrectomy is the recommended surgical approach for all T1 tumors when negative margins can be obtained and morbidity risk is acceptable 4, 1, 2
• This nephron-sparing approach preserves renal function and achieves 5-year cancer-specific survival exceeding 94% for tumors <4 cm 5
• Laparoscopic radical nephrectomy is the preferred alternative when partial nephrectomy is not feasible for organ-confined RCC (T1-T2N0M0) 4, 2

Larger Tumors (>7 cm) and Locally Advanced Disease (T3-T4)

• Open radical nephrectomy with negative margins remains the standard of care for locally advanced RCC 4, 2
• Laparoscopic approach can be considered for select cases 4
• Routine adrenalectomy is NOT required unless imaging shows abnormal adrenal glands or the tumor involves the upper pole 4
• Routine lymph node dissection is NOT required unless nodes are palpable or enlarged on CT imaging 4

Alternative Approaches for Select Patients

• Ablative treatments (cryoablation, radiofrequency ablation) are options for patients with small cortical tumors (≤3 cm), age >70 years, high surgical risk, solitary kidney, compromised renal function, hereditary RCC, or multiple bilateral tumors 4, 2
• Active surveillance is appropriate for patients ≥75 years with substantial comorbidities and solid renal tumors <4 cm 4, 2

Adjuvant Therapy

• No adjuvant therapy is currently recommended as standard of care for localized disease 4
• The S-TRAC trial showed benefit for adjuvant sunitinib in high-risk patients, but this remains controversial and enrollment in clinical trials is preferred 4
• Neoadjuvant approaches remain experimental and should not be used outside clinical trials 4

Metastatic Disease Management

Risk Stratification (Critical First Step)

Before selecting any systemic therapy, stratify patients using IMDC criteria into risk groups: 2, 3

• Favorable risk: 0 risk factors (5-year metastasis-free survival 97.1%) 4
• Intermediate risk: 1-2 risk factors (5-year metastasis-free survival 73.8%) 4
• Poor risk: 3+ risk factors (5-year metastasis-free survival 31.2%) 4

Risk factors include: poor performance status, time from diagnosis to treatment <1 year, low hemoglobin, elevated calcium, elevated neutrophils, and elevated platelets 3

Role of Cytoreductive Nephrectomy

• Cytoreductive nephrectomy is NO LONGER standard of care for IMDC intermediate and poor-risk patients with asymptomatic primary tumors requiring immediate systemic therapy 3
• Cytoreductive nephrectomy IS appropriate for patients with good performance status, large primary tumors, limited metastatic burden, and symptomatic primary lesions 4, 2, 3
• Cytoreductive nephrectomy is NOT recommended in patients with poor performance status 4

First-Line Systemic Therapy for Clear Cell RCC

Intermediate and Poor-Risk Patients

ICI combination therapy is strongly preferred: 2, 3

• Nivolumab plus ipilimumab (demonstrated superior overall survival vs sunitinib with 9.4% complete response rate) 3
• Axitinib plus pembrolizumab 3
• Axitinib plus avelumab 3
• Lenvatinib plus pembrolizumab 3
• Cabozantinib plus nivolumab 3

Favorable-Risk Patients

VEGFR TKI monotherapy remains acceptable: 3

• Sunitinib 50 mg daily (4 weeks on/2 weeks off) - FDA-approved with demonstrated superiority over interferon-alpha 3, 6
• Pazopanib 4, 3
• Cabozantinib 3
• ICI-based combinations may also be used, though data are less robust in this subgroup 3

Poor-Risk Patients (Alternative)

• Temsirolimus as monotherapy has level 1 evidence demonstrating overall survival improvement when ICI combinations cannot be given 2, 3

Second-Line Systemic Therapy

After VEGF-targeted therapy: 3

• Axitinib is the preferred option (level IA evidence) 3
• Nivolumab is recommended given overall survival benefit and tolerability 4, 2, 3
• Everolimus (level IIA evidence) 3
• Sorafenib (level IA evidence) 3
• Pazopanib (level IIA evidence) 3

After two TKIs: 2

• Everolimus is recommended 2

Special Clinical Situations

Metastasectomy and Local Therapies

Metastasectomy may provide survival benefit for highly selected patients with: 4, 3

• Solitary or easily accessible pulmonary metastases
• Long metachronous disease-free interval (≥2 years)
• Response to immunotherapy/targeted therapy before resection
• Good performance status
• Low or intermediate Fuhrmann grade
• Complete resection achievable

Local treatment strategies (SBRT, SRS, conventional radiotherapy) should be considered after multidisciplinary review for oligometastatic disease 4, 3

Bone Metastases

• Bone-directed radiation therapy for symptomatic lesions 2, 3
• Bone resorption inhibitors (zoledronic acid or denosumab) when clinical concern for fracture or skeletal-related events exists 3
• Cabozantinib-containing regimens may be preferred based on expert opinion 2, 3

Brain Metastases

• Brain-directed local therapy with radiation therapy and/or surgery is essential 2, 3
• ICI-based combination first-line treatment is preferred (ipilimumab plus nivolumab, or ICI plus TKI) 2, 3

Sarcomatoid Features

• ICI-based combination therapy is strongly recommended 2, 3

Non-Clear Cell Histology

• Enrollment in specifically designed clinical trials is the preferred approach 2, 3
• In the absence of trials, sunitinib, sorafenib, or temsirolimus may provide benefit based on expanded access programs and retrospective data 2, 3

Common Pitfalls to Avoid

• Failing to risk-stratify metastatic patients before selecting therapy - this is the critical first step that determines optimal treatment 3
• Performing upfront cytoreductive nephrectomy in intermediate/poor-risk patients with high metastatic burden requiring immediate systemic therapy 3
• Treating non-clear cell histology the same as clear cell without considering clinical trial enrollment 3
• Discontinuing effective therapy for limited progression when local therapy could be applied 2
• Not considering bone-directed therapy in patients with bone metastases at risk for skeletal complications 3
• Using high-dose IL-2 outside experienced high-volume centers 2, 3
• Routine adrenalectomy or lymph node dissection when imaging shows no evidence of involvement 4

Treatment Duration and Monitoring

• All targeted agents are given continuously until disease progression in the absence of major toxicity 3
• Average duration of disease control is 8-9 months in first-line setting and 5-6 months in second-line setting 3
• For patients on immunotherapy who experience limited disease progression, local therapy may be offered and immunotherapy may be continued 2