What is the recommended treatment approach for a patient with renal cell carcinoma?

Treatment of Renal Cell Carcinoma

The treatment approach for renal cell carcinoma depends critically on disease stage: for localized disease (T1 tumors <7 cm), partial nephrectomy is the preferred surgical approach; for metastatic clear cell RCC, immune checkpoint inhibitor-based combination therapy is now the standard first-line treatment for intermediate- and poor-risk patients, while favorable-risk patients may receive VEGFR tyrosine kinase inhibitor monotherapy. 1, 2, 3

Localized and Locoregional Disease (Stages I-III)

Surgical Management by Tumor Stage

For T1 tumors (<7 cm):

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

For T2 tumors (>7 cm):

• Laparoscopic radical nephrectomy is the preferred surgical option 1

For T3 and T4 tumors (locally advanced):

• Open radical nephrectomy with negative margins remains the standard of care, though laparoscopic approach may be considered in select cases 1, 2

Alternative Approaches for Special Populations

Ablative therapies (radiofrequency ablation, microwave ablation, cryoablation):

• Appropriate for patients with small cortical tumors ≤3 cm, frail patients, high surgical risk, solitary kidney, compromised renal function, hereditary RCC, or bilateral tumors 1
• Renal biopsy is recommended before ablative treatment to confirm malignancy and subtype 1

Active surveillance:

• Consider for elderly patients (≥75 years) with significant comorbidities or short life expectancy and solid renal tumors <40 mm 1
• Renal biopsy is recommended to select appropriate candidates 1

What NOT to Do Routinely

• Routine adrenalectomy is NOT required unless imaging shows abnormal adrenal glands or tumor involves the upper pole 1, 2
• Routine lymph node dissection is NOT required unless nodes are palpable or enlarged on imaging 1, 2

Adjuvant Therapy

• No adjuvant therapy is currently recommended as standard of care for localized RCC after complete surgical resection 1
• The ASSURE trial showed no significant differences in disease-free survival or overall survival with adjuvant sunitinib or sorafenib versus placebo 1

Metastatic Disease Management

Critical First Step: Risk Stratification

Before selecting any systemic therapy, patients MUST be stratified using the International Metastatic RCC Database Consortium (IMDC) criteria: 2, 3, 5

• Favorable risk: 0 risk factors
• Intermediate risk: 1-2 risk factors
• Poor risk: 3+ risk factors

Risk factors include: poor performance status, time from diagnosis to treatment <1 year, low hemoglobin, elevated corrected calcium, elevated neutrophils, and elevated platelets 2, 3

This is the most common pitfall—failing to risk-stratify before selecting therapy fundamentally compromises treatment optimization. 2

First-Line Systemic Therapy for Metastatic Clear Cell RCC

For intermediate- and poor-risk patients, immune checkpoint inhibitor-based combination therapy is strongly preferred: 1, 2, 3

• Nivolumab plus ipilimumab [I, A; ESMO-MCBS score: 3] 1, 3, 6
• Pembrolizumab plus axitinib 2, 3
• Pembrolizumab plus lenvatinib 2, 3
• Nivolumab plus cabozantinib 2, 3, 6
• Avelumab plus axitinib 2

These combination regimens achieve tumor response rates of 42-71% with median overall survival of 46-56 months 4

For favorable-risk patients:

• VEGFR tyrosine kinase inhibitor monotherapy remains acceptable 2, 3
• Options include sunitinib, pazopanib, cabozantinib, or tivozanib 1, 2
• Nivolumab plus ipilimumab is NOT recommended for good-risk patients 1

Critical caveat for performance status 2 patients:

• Even with PS 2, combination therapy is preferred over monotherapy 3
• Single-agent therapy should only be reserved for highly select patients who absolutely cannot tolerate combination regimens 3
• Do NOT use single-agent nivolumab as first-line therapy—this represents suboptimal treatment that may compromise survival 3

Second-Line Systemic Therapy

After VEGFR-targeted therapy:

• Nivolumab [I, A; ESMO-MCBS score: 5] is recommended 1, 3
• Cabozantinib [I, A; ESMO-MCBS score: 3] is recommended 1
• Lenvatinib plus everolimus [II, B; ESMO-MCBS score: 4] is FDA- and EMA-approved 1

After immune checkpoint inhibitor-based combination therapy:

• VEGFR tyrosine kinase inhibitors are the preferred approach 2
• Lenvatinib plus everolimus is recommended after nivolumab/ipilimumab [IV, C; ESMO-MCBS score: 3] 1

After two prior TKIs:

• Nivolumab [I, A; ESMO-MCBS score: 5] or cabozantinib is recommended 1

Role of Cytoreductive Nephrectomy

Cytoreductive nephrectomy is recommended for patients with: 1, 2, 5

• Good performance status [I, A]
• Large primary tumors with limited volumes of metastatic disease
• Symptomatic primary lesions

Cytoreductive nephrectomy is NOT recommended for: 1, 2

• Patients with poor performance status [III, B]
• Intermediate- and poor-risk patients with asymptomatic primary tumors when immediate medical treatment is required [I, A]

This represents a major shift from the immunotherapy era when cytoreductive nephrectomy was routinely recommended for good PS patients 1

Metastasectomy and Local Therapies

Metastasectomy may provide survival benefit for highly selected patients with: 1, 2

• 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

No systemic treatment is recommended after complete metastasectomy 1

Local treatment strategies (SBRT, SRS, conventional radiotherapy) should be considered after multidisciplinary review for: 1, 2

• Oligometastatic disease
• Limited disease progression on immunotherapy (allowing continuation of systemic therapy)
• Symptomatic bone metastases

Special Clinical Situations

Brain metastases:

• Brain-directed local therapy with radiation and/or surgery is essential 2, 3
• ICI-based combination first-line treatment is preferred 2, 3
• For single unresectable brain metastasis in good-prognosis patients, stereotactic radiosurgery with or without whole brain radiotherapy should be considered [II, A] 1
• Whole brain radiotherapy 20-30 Gy in 4-10 fractions provides effective symptom control [II, B] 1

Bone metastases:

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

Sarcomatoid features:

• ICI-based combination therapy is recommended 3

Non-Clear Cell Histology

• Enrollment in specifically designed clinical trials is strongly recommended 3
• In the absence of trials, sunitinib, sorafenib, or temsirolimus may provide benefit 3
• Temsirolimus has level 1 evidence of activity in poor-risk patients 1, 3

Treatment Duration and Monitoring

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

Follow-Up Recommendations

For high-risk patients after surgery:

• CT scans of thorax and abdomen every 3-6 months for the first 2 years 1

For low-risk patients:

• Annual CT scan is recommended 1

For metastatic patients during systemic therapy:

• 2- to 4-month follow-up with CT scan is advised 1
• RECIST criteria should be used to assess drug efficacy 1

Critical Pitfalls to Avoid

• Failing to risk-stratify metastatic patients before selecting therapy—this is the critical first step 2
• Performing upfront cytoreductive nephrectomy in intermediate/poor-risk patients with high metastatic burden requiring immediate systemic therapy 2
• Using single-agent nivolumab as first-line therapy instead of combination regimens 3
• Treating non-clear cell histology the same as clear cell without considering clinical trial enrollment 2
• Discontinuing effective immunotherapy 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 2
• 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 2, 3