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

Treatment Options for Renal Cell Carcinoma

Treatment for renal cell carcinoma is determined by stage at diagnosis: partial nephrectomy is the definitive treatment for localized disease (T1 tumors <7 cm), while combination immunotherapy with nivolumab plus ipilimumab is the preferred first-line treatment for intermediate- and poor-risk metastatic disease. 1, 2

Localized/Locoregional Disease (Stages I-III)

T1 Tumors (<7 cm, Organ-Confined)

• Partial nephrectomy is the first-choice treatment, preserving renal function with equivalent oncological outcomes to radical nephrectomy, achieving >94% 5-year cancer-specific survival 1, 2, 3
• Laparoscopic radical nephrectomy is recommended if partial nephrectomy is not technically feasible 1
• For patients with compromised renal function, solitary kidney, or bilateral tumors, partial nephrectomy is recommended regardless of tumor size 1

Ablative Therapies for Selected Patients

• Radiofrequency ablation (RFA), microwave ablation (MWA), or cryoablation are appropriate options for small cortical tumors ≤3 cm in frail patients, those with high surgical risk, compromised renal function, hereditary RCC, or bilateral tumors 1, 2
• Renal biopsy is mandatory before ablative therapy to confirm malignancy and histologic subtype 1, 2

Active Surveillance

• Recommended for elderly patients with significant comorbidities, short life expectancy, and solid renal tumors <40 mm 1, 2
• Renal biopsy is recommended to appropriately select these patients 1

T2 Tumors (>7 cm)

• Laparoscopic radical nephrectomy is the preferred option 1, 2

T3 and T4 Tumors (Locally Advanced)

• Open radical nephrectomy is the standard of care, though laparoscopic approach can be considered in selected cases 1, 2

Critical Pitfall: Adjuvant Therapy

• Adjuvant therapy is NOT routinely recommended after nephrectomy 2
• While sunitinib showed disease-free survival benefit in the S-TRAC trial, it demonstrated no overall survival benefit and is not EMA-approved for adjuvant use 2

Advanced/Metastatic Disease (Stage IV)

Cytoreductive Nephrectomy

• Recommended in patients with good performance status 1, 2
• Should NOT be performed in intermediate- and poor-risk patients with asymptomatic primary tumors when immediate medical treatment is required 1, 2
• This is a critical decision point that directly impacts mortality outcomes

First-Line Systemic Treatment

For Intermediate- and Poor-Risk Patients:

• Nivolumab plus ipilimumab is the recommended first-line treatment, achieving tumor response rates of 42-71% with median overall survival of 46-56 months 1, 2, 4, 3
• This combination is NOT recommended for good-risk patients 1
• Cabozantinib is EMA-approved for intermediate-risk (ESMO-MCBS score: 3) and poor-risk groups (ESMO-MCBS score: 3) 1, 5

For Good- and Intermediate-Risk Patients:

• VEGF-targeted agents and tyrosine kinase inhibitors (TKIs) are recommended options 1
• Options include sunitinib, bevacizumab plus interferon-α, pazopanib, and tivozanib (EMA-approved for good-risk patients) 1

Alternative First-Line Combination:

• Nivolumab plus cabozantinib is FDA-approved for first-line treatment of advanced RCC 5, 4
• Nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks combined with cabozantinib 40 mg orally once daily 5, 4

Second-Line Systemic Treatment

Following TKI Failure:

• Nivolumab (Level I, A evidence; ESMO-MCBS score: 5) or cabozantinib (Level I, A evidence; ESMO-MCBS score: 3) are the recommended second-line options 1, 2, 5, 4
• Lenvatinib plus everolimus is FDA- and EMA-approved (ESMO-MCBS score: 4) and is recommended after nivolumab/ipilimumab combination 1
• If these drugs are unavailable, either everolimus or axitinib can be used 1

Following Two TKIs:

• Either nivolumab or cabozantinib is recommended 1

Palliative Radiotherapy

For Symptomatic Metastases:

• Radiotherapy is effective for palliation of symptomatic metastatic disease and prevention of progression in critical sites such as bone or brain (Level I, A evidence) 1, 2
• Image-guided RT techniques such as VMAT or SBRT enable high-dose delivery 1

For Brain Metastases:

• Corticosteroids provide temporary relief of cerebral symptoms 1
• Whole-brain radiotherapy (WBRT) 20-30 Gy in 4-10 fractions is recommended for effective symptom control (Level II, B evidence) 1, 2
• For good-prognosis patients with single unresectable brain metastasis, stereotactic radiosurgery (SRS) with or without WBRT should be considered (Level II, A evidence) 1

For Spinal Cord Compression:

• Initial surgery followed by postoperative RT improves survival and maintenance of ambulation compared with irradiation alone (Level I, A evidence) 1

Metastasectomy

• May be an option, particularly in patients presenting with solitary metastasis 1

Diagnostic Requirements Before Treatment

Mandatory Laboratory Tests

• Serum creatinine, hemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio, lactate dehydrogenase (LDH), C-reactive protein (CRP), and serum-corrected calcium 1, 2
• These tests are both prognostic and required for risk stratification 2

Imaging for Staging

• Contrast-enhanced CT of chest, abdomen, and pelvis is mandatory for accurate staging 1, 2, 6
• MRI provides additional information for assessing local advancement and venous tumor thrombus involvement 2
• FDG-PET is NOT standard and should not be used for diagnosis or staging of clear cell RCC 2, 6

Tissue Diagnosis

• Renal biopsy is recommended before ablative therapies and before starting systemic treatment in metastatic disease 1, 2
• Biopsy confirms malignancy, determines histologic subtype, and guides treatment selection 2
• Biopsy provides high diagnostic accuracy with rare complications 2

Follow-Up Protocol

After Curative Treatment

• High-risk patients: CT scans of thorax and abdomen every 3-6 months for the first 2 years 1, 2
• Low-risk patients: Annual CT scan 1, 2

During Systemic Therapy for Metastatic Disease

• 2-4 month follow-up intervals with CT scan 1, 2
• RECIST is the most frequently used method to assess drug efficacy 1

Critical Surgical Considerations

Timing of Surgery

• Stop treatment with cabozantinib at least 3 weeks prior to scheduled surgery, including dental surgery 5
• Withhold cabozantinib for at least 3 weeks prior to invasive dental procedures to prevent osteonecrosis of the jaw 5

Key Warnings for Systemic Therapy

Cabozantinib-Specific Warnings

• Do not administer if recent history of hemorrhage 5
• Monitor for perforations and fistulas; discontinue for Grade 4 events 5
• Discontinue for myocardial infarction or serious venous or arterial thromboembolic events 5
• Monitor blood pressure regularly; interrupt for uncontrolled hypertension 5
• Monitor for severe diarrhea; interrupt until resolution, resume at reduced dose 5
• Monitor urine protein; interrupt until proteinuria resolves to ≤Grade 1, discontinue for nephrotic syndrome 5

Nivolumab Plus Cabozantinib Combination Warnings

• When used in combination with nivolumab, higher frequencies of Grade 3 and 4 ALT and AST elevation may occur 5
• Monitor liver enzymes before initiation and periodically throughout treatment 5
• Primary or secondary adrenal insufficiency may occur; for Grade 2 or higher, initiate hormone replacement as clinically indicated 5