What is the management of renal cell carcinoma?

Management of Renal Cell Carcinoma

For localized RCC, partial nephrectomy is the definitive treatment for tumors <7 cm, while metastatic disease requires risk-stratified systemic therapy with nivolumab plus ipilimumab for intermediate/poor-risk patients or VEGF-targeted agents for good-risk patients, with cytoreductive nephrectomy reserved only for good performance status patients except when immediate systemic therapy is needed. 1

Diagnosis and Staging

Initial workup must include:

• Laboratory tests: serum creatinine, hemoglobin, leukocyte and platelet counts, lymphocyte-to-neutrophil ratio, lactate dehydrogenase, CRP, and serum-corrected calcium 1
• Contrast-enhanced CT of chest, abdomen, and pelvis for accurate staging 1
• Renal tumor core biopsy is mandatory before ablative therapies and in all metastatic patients before starting systemic treatment 1
• Pathology assessment using 2016 WHO classification and ISUP grading 1

Localized Disease (T1-T2)

T1 Tumors (<7 cm)

Partial nephrectomy (PN) is the gold standard for organ-confined tumors up to 7 cm, based on Level I evidence from randomized controlled trials 1. This can be performed via open, laparoscopic, or robot-assisted approaches 1.

If PN is not technically feasible, laparoscopic radical nephrectomy (RN) is recommended 1.

For patients with compromised renal function, solitary kidney, or bilateral tumors, PN is mandatory with no tumor size limitation 1.

Alternative Approaches for Small Renal Masses

For cortical tumors ≤3 cm in frail patients, high surgical risk, solitary kidney, or compromised renal function:

• Radiofrequency ablation (RFA), microwave ablation (MWA), or cryoablation (CA) are acceptable options 1
• Renal biopsy must be performed before ablation to confirm malignancy and subtype 1
• Counsel patients about higher local recurrence rates compared to surgery 1

Active surveillance is appropriate for:

• Elderly patients with significant comorbidities or short life expectancy
• Solid renal tumors <40 mm
• Renal biopsy is required to select appropriate candidates 1
• Mean tumor growth is only 3 mm/year with 1-2% progression to metastatic disease 1

T2 Tumors (>7 cm)

Laparoscopic RN is the preferred option 1.

Locally Advanced Disease (T3-T4)

Open RN remains standard of care, though laparoscopic approach can be considered in selected cases 1.

Do not perform systematic adrenalectomy or extensive lymph node dissection unless CT shows evidence of invasion 1.

For venous tumor thrombus:

• Resection should be considered but is technically challenging with high complication risk 1
• Outcome depends on tumor thrombus level 1

Adjuvant Therapy

Adjuvant therapy is NOT recommended as standard of care 1.

The evidence is conflicting:

• S-TRAC trial showed disease-free survival benefit with sunitinib but no overall survival benefit 1
• FDA approved adjuvant sunitinib (50 mg daily, 4 weeks on/2 weeks off, for nine 6-week cycles) for high-risk RCC following nephrectomy 2
• EMA has not approved adjuvant therapy due to imbalance between risk and clinical benefit 1
• Pooled analysis of S-TRAC, ASSURE, and PROTECT showed no statistically significant DFS or OS improvement 1

Neoadjuvant therapy is experimental and should not be used outside clinical trials 1.

Radiotherapy has NO role in adjuvant or neoadjuvant setting based on four negative randomized trials 1, 3.

Metastatic Disease

Role of Cytoreductive Nephrectomy

The paradigm has shifted based on the CARMENA trial:

Upfront cytoreductive nephrectomy should NO LONGER be considered standard of care for MSKCC intermediate- and poor-risk patients with asymptomatic primary tumors when medical treatment is required 1.

CN is still recommended for:

• Patients with good performance status 1
• Those with local symptoms from the primary tumor 1
• Patients achieving near-complete responses to systemic therapy 1

First-Line Systemic Therapy

Risk stratification using MSKCC or IMDC criteria is essential before selecting therapy 1.

For Intermediate and Poor-Risk Patients:

Nivolumab plus ipilimumab is the recommended first-line option 1, 4:

• Level I evidence with ESMO-MCBS score of 3 1
• NOT recommended for good-risk patients 1

Cabozantinib is EMA-approved alternative:

• Level II, A evidence for intermediate-risk (ESMO-MCBS score: 3) 1
• Level II, B evidence for poor-risk (ESMO-MCBS score: 3) 1

For Good and Intermediate-Risk Patients:

VEGF-targeted agents and TKIs are recommended options:

• Sunitinib, pazopanib, or bevacizumab plus interferon 1
• Tivozanib is EMA-approved specifically for good-risk patients (Level II, A; ESMO-MCBS score: 1) 1

Second-Line Systemic Therapy

Following TKI failure:

• Nivolumab is the preferred option (Level I, A; ESMO-MCBS score: 5) 1
• Cabozantinib is alternative (Level I, A; ESMO-MCBS score: 3) 1

Following nivolumab/ipilimumab combination:

• Lenvatinib plus everolimus (Level IV, C; ESMO-MCBS score: 3) 1

If none of these drugs available:

• Everolimus or axitinib can be used 1

After two TKIs:

• Either nivolumab (Level I, A; ESMO-MCBS score: 5) or cabozantinib 1

Non-Clear Cell Histology

No prospective randomized data exist for non-clear cell RCC 1.

Enrollment in specifically designed clinical trials is strongly recommended 1.

If trials unavailable, consider:

• Sunitinib, sorafenib, or temsirolimus based on expanded access programs and subgroup analyses (Level III, B) 1

Role of Radiotherapy in Metastatic Disease

Radiotherapy is highly effective for palliation but has NO role in primary disease management 1, 3.

Bone Metastases

Local radiotherapy (single fraction or fractionated) provides:

• Symptom relief in up to two-thirds of cases 1, 3
• Complete symptomatic response in 20-25% 1

Zoledronic acid reduces skeletal-related events and should be used based on expected survival and probability of symptomatic benefit (Level II, A) 1.

Spinal Cord Compression

For ambulatory patients with limited metastatic disease:

• Surgery plus radiotherapy improves survival and maintains ambulation compared to radiation alone (Level I, A) 1, 3

Brain Metastases

Corticosteroids provide temporary relief of cerebral symptoms 1.

Whole-brain radiotherapy (WBRT) 20-30 Gy in 4-10 fractions is effective for symptom control (Level II, B) 1, 3.

For good-prognosis patients with single unresectable brain metastasis:

• Stereotactic radiosurgery (SRS) with or without WBRT should be considered (Level II, A) 1, 3
• SRS alone has less late cognitive dysfunction than combination therapy 1

Unresectable Local/Recurrent Disease

Image-guided RT techniques (VMAT or SBRT) can deliver high doses when surgery is not possible due to poor performance status (Level IV, B) 1, 3.

Modern stereotactic radiotherapy overcomes apparent radioresistance of RCC through high-dose-per-fraction mechanisms 3.

Follow-Up

No evidence exists that any particular follow-up protocol influences outcome 1.

For localized RCC after surgery:

• CT scans of thorax and abdomen with intervals dependent on risk factors 1
• Long-term follow-up benefit has never been demonstrated 1

During systemic therapy for metastatic disease:

• 2-4 month follow-up with CT scan to determine response and resistance 1
• RECIST criteria remain the best method to assess drug efficacy 1

Critical Pitfalls to Avoid

• Never use radiotherapy in adjuvant/neoadjuvant setting for primary RCC - four negative trials prove no benefit 1, 3
• Do not perform upfront cytoreductive nephrectomy in intermediate/poor-risk patients with asymptomatic primary tumors requiring immediate systemic therapy - CARMENA trial showed no benefit 1
• Do not assume small renal masses are benign - biopsy confirmation essential before choosing surveillance 1
• Do not use neoadjuvant targeted therapy to downsize tumors before surgery - this is experimental and may compromise surgical outcomes 1
• Ensure adequate brain metastasis control before initiating anti-VEGF therapy 1