What is the recommended adjuvant therapy for pediatric patients with lymph node positive or metastatic renal cancer?

Adjuvant Therapy for Lymph Node Positive or Metastatic Renal Cancer in Pediatric Patients

Pediatric patients with completely resected renal cell carcinoma, including those with lymph node-positive (N1M0) disease, should NOT receive adjuvant therapy and should be managed with observation alone. 1, 2, 3

Key Evidence Supporting Observation Over Adjuvant Therapy

The most compelling evidence comes from the Children's Oncology Group AREN0321 prospective study, which demonstrated that pediatric patients with N1M0 disease achieved excellent outcomes without any adjuvant therapy: 4-year event-free survival of 87.5% and overall survival of 87.1% after complete surgical resection alone. 2 This represents the highest quality pediatric-specific data available and directly contradicts the need for adjuvant treatment in this population.

The biological behavior of pediatric RCC fundamentally differs from adult disease, making adult treatment paradigms inappropriate for children. 1 Multiple retrospective analyses support this observation:

• A systematic literature review of 243 pediatric RCC patients found that among 58 children with N+M0 disease, 72.4% were alive without disease at last follow-up. 3
• Patients receiving no adjuvant therapy fared equally well (15 of 16 alive) compared to those receiving various adjuvant treatments (22 of 31 alive). 3
• The survival rate for pediatric N+M0 RCC is nearly triple that of adult historical controls. 3

Why Adult Adjuvant Therapies Are Not Recommended

Adult adjuvant therapy data—including cytokines, VEGF inhibitors, and mTOR inhibitors—showed no benefit even in adults and cannot be extrapolated to pediatric patients. 1 Specifically:

• Interferon-alpha has been used in isolated pediatric cases but causes significant side effects (fever, bone marrow suppression, decreased liver function) without proven survival benefit in children. 1, 4
• Tyrosine kinase inhibitors (like sunitinib) lack prospective evidence in pediatric populations and are not recommended as adjuvant therapy despite limited use in metastatic disease. 5
• Radiotherapy has no role in the adjuvant setting for RCC based on four negative randomized trials in adults. 6, 7

Surgical Management Principles

Complete surgical resection remains the cornerstone and only curative treatment for pediatric RCC. 4, 5 The surgical approach should include:

• Radical nephrectomy (performed in 81.5% of AREN0321 patients) or partial nephrectomy when feasible (18.5% of cases). 2
• Regional lymphadenectomy is recommended for staging purposes, though its therapeutic benefit remains controversial. 5, 8
• Complete resection of all known disease sites, including metastatic lesions when technically feasible. 2

Management of Metastatic Disease (M1)

Pediatric patients presenting with metastatic RCC have poor outcomes regardless of treatment approach. 2, 5 In the AREN0321 study, only 2 of 8 patients with M1 disease were alive at last follow-up. 2

For metastatic disease:

• Surgical resection of primary tumor and metastatic sites should be attempted when complete resection is achievable. 4, 2
• No standard adjuvant therapy exists with proven efficacy. 5
• Enrollment in clinical trials is strongly preferred over empiric systemic therapy. 5
• Sunitinib may be considered for unresectable metastatic disease despite limited pediatric evidence. 5

High-Risk Histologic Subtypes

Translocation-associated RCC (tRCC) and renal medullary carcinoma (RMC) are the predominant subtypes associated with mortality in pediatric patients. 2 These subtypes warrant:

• Close surveillance after complete resection
• Strong consideration for clinical trial enrollment if metastatic or recurrent disease develops
• No routine adjuvant therapy for completely resected disease 2

Critical Pitfalls to Avoid

Do not expose pediatric patients with completely resected RCC to adjuvant therapies based on adult treatment paradigms. 1, 3 The key errors include:

• Applying adult risk stratification systems (SSIGN score, UISS) to pediatric patients—these are not validated in children. 9
• Using pembrolizumab or other immune checkpoint inhibitors, which are only studied and approved for adult clear cell RCC. 9
• Administering adjuvant radiotherapy, which has no proven benefit and exposes children to long-term toxicity. 6, 7
• Initiating cytotoxic chemotherapy, which has not proven effective in large pediatric cohorts. 5

Surveillance Strategy

After complete surgical resection, implement active surveillance with:

• Regular clinical examinations and imaging to detect recurrence early
• No specific pediatric surveillance protocol is established, but monitoring should be more intensive in the first 2-3 years when most recurrences occur
• Long-term follow-up is warranted given the potential for late relapses 6