What are the adjuvant systemic therapy options for a patient with resected metastatic renal cell carcinoma (RCC) and small volume lung metastases (mets)?

Adjuvant Systemic Therapy for Resected Metastatic RCC with Small Volume Lung Metastases

Observation without adjuvant systemic therapy is the standard of care after complete resection of metastatic renal cell carcinoma, including lung metastases, based on the absence of evidence supporting systemic treatment in this setting. 1, 2

Primary Recommendation: Observation

• No systemic therapy should be administered after complete metastasectomy of oligometastatic disease in the absence of residual disease. 1, 2
• The ESMO guidelines explicitly state that observation without adjuvant systemic therapy is the guideline-recommended approach after complete metastasectomy of solitary or oligometastatic lesions. 2
• This recommendation applies regardless of the metastatic site (including lung), as long as complete resection with negative margins was achieved. 2
• A systematic review of 16 studies including 2,350 patients demonstrated consistent benefit of complete metastasectomy for overall survival and cancer-specific survival, supporting the role of surgery followed by observation. 2

Evidence Against Adjuvant Therapy in This Setting

• There is an ongoing cooperative group clinical trial (E2810, NCT01575948) evaluating pazopanib versus placebo in the setting of resected metastatic disease, but results are not yet available and this remains investigational. 1
• Systemic therapy is not indicated after metastasectomy in the absence of residual disease except as part of a research study. 1
• Historical adjuvant trials with cytokines (interferon-α and high-dose IL-2) showed no benefit in survival or recurrence-free survival after complete resection. 1
• The ASSURE trial demonstrated no difference in recurrence-free survival comparing sunitinib or sorafenib to placebo in the adjuvant setting. 1

Distinction from Primary Adjuvant Setting

This scenario differs critically from the adjuvant pembrolizumab indication, which applies only to:

• Patients with high-risk primary RCC after nephrectomy (pT2 grade 4, pT3-4, N+, or M1 with no evidence of disease ≤1 year from nephrectomy). 3
• Pembrolizumab adjuvant therapy is NOT indicated for patients who have undergone metastasectomy years after initial nephrectomy. 2, 3

Surveillance Strategy After Metastasectomy

• Close follow-up is essential to detect early recurrence. 2
• Abdominal and chest CT scans should be performed approximately 4-6 months after metastasectomy to serve as baseline, then as clinically indicated. 1, 2
• Patients should be seen every 6 months for the first 2 years, then annually thereafter. 2
• Each visit should include history, physical examination, and comprehensive metabolic panel (including calcium, LDH, liver function tests). 1, 2

Favorable Prognostic Indicators Supporting Observation

• Metachronous disease with disease-free interval >2 years is associated with better outcomes. 2
• Lung-only metastases, good performance status, and favorable prognostic features predict better outcomes. 1
• Complete resection with negative margins is essential and associated with favorable prognosis. 2
• Absence of progression on any prior systemic therapy is a favorable indicator. 2

When Systemic Therapy IS Indicated

Systemic therapy should be initiated in the following scenarios:

• If metastasectomy was incomplete or margins were positive, treat according to metastatic RCC treatment algorithms with ICI-based combination therapy. 2
• If recurrence develops within 1 year of metastasectomy, PD-1-based combination therapy is the standard of care. 1, 2
• If multiple unresectable metastases are present, first-line ICI combination therapy (axitinib/pembrolizumab, cabozantinib/nivolumab, lenvatinib/pembrolizumab, or nivolumab/ipilimumab) is preferred. 4

Critical Pitfalls to Avoid

• The most important pitfall is initiating systemic therapy after complete metastasectomy when observation is appropriate. 2
• There is no evidence supporting routine adjuvant systemic therapy after complete metastasectomy in this setting. 1, 2
• Do not confuse this scenario with the primary adjuvant setting where pembrolizumab has demonstrated benefit. 1, 3
• Always verify pathology confirms negative margins before committing to observation alone. 2
• Do not use adjuvant sunitinib, as it showed no overall survival benefit despite FDA approval in the primary adjuvant setting. 1, 3