What is the recommended work-up and treatment plan for renal cell carcinoma?

Renal Cell Carcinoma Work-Up and Treatment

Initial Diagnostic Work-Up

For suspected RCC, obtain contrast-enhanced CT of chest, abdomen, and pelvis as the mandatory staging study, combined with specific laboratory tests including serum creatinine, hemoglobin, lactate dehydrogenase, C-reactive protein, and corrected calcium. 1

Imaging Protocol

• Contrast-enhanced CT of chest, abdomen, and pelvis is mandatory for accurate staging 1
• MRI provides additional information for assessing local advancement and venous tumor thrombus involvement 1
• In patients with CT contrast allergy or renal insufficiency, use high-resolution non-contrast chest CT plus abdominal MRI 1
• Do not routinely perform bone scan or brain imaging unless clinical signs or symptoms are present 1
• FDG-PET is not standard and should not be used for diagnosis or staging of clear cell RCC 1

Laboratory Assessment

The following tests are both prognostic and required for risk stratification 1:

• Serum creatinine
• Hemoglobin
• Leukocyte and platelet counts
• Lymphocyte to neutrophil ratio
• Lactate dehydrogenase (LDH)
• C-reactive protein (CRP)
• Serum-corrected calcium

Tissue Diagnosis

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

Staging System

Use UICC TNM 8 staging system 1:

• T1: Tumor ≤7 cm, limited to kidney
• T2: Tumor >7 cm, limited to kidney
• T3: Extends to major veins or perinephric tissues but not beyond Gerota fascia
• T4: Invades beyond Gerota fascia

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Treatment Algorithm by Stage

T1 Tumors (<7 cm)

Partial nephrectomy is the recommended first-line treatment for organ-confined T1 tumors, preserving renal function with equivalent oncological outcomes to radical nephrectomy. 1

Surgical Options

• Partial nephrectomy (PN) is preferred via open, laparoscopic, or robot-assisted approaches 1
• Laparoscopic radical nephrectomy if PN is not technically feasible 1
• In patients with compromised renal function, solitary kidney, or bilateral tumors, PN is mandatory with no tumor size limitation 1

Alternative Approaches for Small Tumors (≤3 cm)

• Radiofrequency ablation (RFA), microwave ablation (MWA), or cryoablation (CA) are options for small cortical tumors ≤3 cm 1
• These are particularly appropriate for frail patients, high surgical risk, solitary kidney, compromised renal function, hereditary RCC, or bilateral tumors 1
• Renal biopsy must be performed before ablation to confirm malignancy and subtype 1
• Ablation has slightly higher local recurrence rates compared to PN but similar long-term cancer-specific survival 1

Active Surveillance

• Consider for elderly patients with significant comorbidities or short life expectancy with solid renal tumors <40 mm 1
• Renal tumors grow slowly (mean 3 mm/year) with 1-2% progression to metastatic disease 1
• Renal biopsy is recommended to select appropriate patients for active surveillance 1

T2 Tumors (>7 cm)

Laparoscopic radical nephrectomy is the preferred option for T2 tumors. 1

T3 and T4 Tumors (Locally Advanced)

Open radical nephrectomy remains the standard of care for locally advanced RCC, though laparoscopic approach can be considered. 1

• Do not perform systematic adrenalectomy or extensive lymph node dissection unless CT shows evidence of involvement 1
• Resection of venous tumor thrombi should be considered but is technically challenging with high complication risk 1

Adjuvant Therapy

Adjuvant therapy is not routinely recommended after nephrectomy. 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 1.

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Treatment of Advanced/Metastatic Disease

Cytoreductive Nephrectomy

Cytoreductive nephrectomy is recommended in patients with good performance status, except in intermediate- and poor-risk patients with asymptomatic primary tumors when medical treatment is required. 1

First-Line Systemic Therapy

The treatment selection depends on MSKCC/IMDC risk stratification (based on Karnofsky performance status, LDH, hemoglobin, corrected calcium, and time from diagnosis) 2:

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, and tivozanib 1, 2

For Intermediate and Poor-Risk Patients

The combination of nivolumab plus ipilimumab is the recommended first-line treatment 1, 3

• This combination is FDA and EMA-approved for intermediate and poor-risk advanced RCC 3
• Do not use nivolumab/ipilimumab for good-risk patients 1
• Cabozantinib is an alternative for intermediate and poor-risk groups 1

Second-Line Systemic Therapy

After TKI Failure

Nivolumab or cabozantinib are the recommended second-line options following TKI therapy. 1

• Nivolumab has the highest ESMO-MCBS score (5) with improved toxicity profile and quality of life compared to everolimus 1
• Cabozantinib is also highly effective (ESMO-MCBS score: 3) 1

After Nivolumab/Ipilimumab

• Lenvatinib plus everolimus is recommended after nivolumab/ipilimumab combination 1

After Two TKIs

• Either nivolumab or cabozantinib is recommended 1

If Preferred Agents Unavailable

• Everolimus or axitinib can be used 1

Radiation Therapy for Metastatic Disease

Radiation therapy is effective for palliation of symptomatic metastatic disease and prevention of progression in critical sites such as bone or brain. 1

Brain Metastases

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

Local/Unresectable Disease

• Stereotactic body radiotherapy (SBRT) or volumetric-modulated arc therapy (VMAT) for unresectable local or recurrent disease 1
• RT is an alternative when radioablation is not appropriate 1

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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
• Low-risk patients: Annual CT scan 1

During Systemic Therapy for Metastatic Disease

• 2-4 month follow-up intervals with CT scan 1
• Use RECIST criteria to assess drug efficacy 1

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Critical Pitfalls to Avoid

• Do not use FDG-PET for routine staging - it is not validated for clear cell RCC 1
• Do not perform routine bone scan or brain imaging unless symptomatic 1
• Do not skip renal biopsy before ablative therapy - confirmation of malignancy and subtype is essential 1
• Do not use nivolumab/ipilimumab in good-risk patients - it is only indicated for intermediate and poor-risk groups 1
• Do not perform systematic lymph node dissection or adrenalectomy unless imaging shows involvement 1
• Do not assume small renal masses are benign - even tumors <2 cm require proper evaluation and often biopsy 4