What is the next step after radical nephrectomy for Grade 4 PT3a (pathological tumor stage 3a) clear cell renal cell carcinoma (RCC)?

Next Step After Radical Nephrectomy for Grade 4 pT3a Clear Cell RCC

For patients with Grade 4 pT3a clear cell renal cell carcinoma after radical nephrectomy, surveillance is the standard of care, with consideration of adjuvant pembrolizumab for those at high risk of recurrence. 1

Risk Assessment

The patient's tumor characteristics place them at high risk for recurrence:

• Grade 4 histology (highest grade) 1
• pT3a stage (tumor extends into perinephric tissues) 1
• Clear cell histology 1

Using the SSIGN (Stage, Size, Grade, and Necrosis) scoring system, this patient would accumulate significant risk points:

• pT3a = 4 points
• Grade 4 = 3 points
• Additional points may apply based on tumor size and presence of necrosis 1

This places the patient in a high-risk category with approximately 30-70% risk of recurrence after surgery 1.

Surveillance Protocol

For high-risk patients, the recommended surveillance protocol includes:

• Baseline chest and abdominal CT or MRI within 3-6 months after surgery 1
• Continued imaging every 6 months for at least 3 years 1
• Annual imaging for years 4-5 1
• Consideration for imaging beyond 5 years based on individual risk factors 1
• Regular clinical follow-up with history, physical examination, and comprehensive metabolic panel (including blood urea nitrogen, serum creatinine, calcium, LDH, and liver function tests) every 3-6 months for 3 years, then annually up to 5 years 1

Adjuvant Therapy Considerations

Pembrolizumab (Recommended)

• The KEYNOTE-564 trial demonstrated improved overall survival (HR 0.62) and disease-free survival (HR 0.72) with adjuvant pembrolizumab versus placebo in high-risk ccRCC patients 1, 2
• This is the first adjuvant therapy with proven survival benefit in operable RCC 1, 3
• Recommended for patients with high-risk disease following nephrectomy 1, 2

Sunitinib (Alternative Option)

• FDA-approved for adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy 4
• However, evidence for overall survival benefit is less robust than pembrolizumab 3, 5
• The recommended dosage is 50 mg orally once daily for the first 4 weeks of a 6-week cycle for a maximum of 9 cycles 4

Not Recommended

• Adjuvant radiation therapy has not shown benefit in RCC and is not recommended, even in patients with nodal involvement or incomplete tumor resection 1, 6
• Earlier trials of adjuvant interferon-α or high-dose interleukin-2 showed no delay in time to relapse or improvement in survival 1

Clinical Pearls and Pitfalls

• Most relapses occur within the first 3 years after surgery, with lung being the most common site of distant recurrence (50-60% of patients) 1
• The median time to relapse after surgery is 1-2 years 1
• Longer disease-free intervals between diagnosis and recognition of metastatic disease are associated with longer projected survival 1
• No single follow-up plan is appropriate for all patients; individual follow-up plans should consider tumor size, extent of extrarenal spread, tumor histology, and relative risk of relapse 1
• Patients with neurological symptoms should undergo prompt neurological cross-sectional CT or MRI scanning of the head or spine 1
• Molecular markers such as Ki-67, p-53, and VEGF are not recommended for routine use as benefits remain unproven 1