Wilms tumor (WT), or nephroblastoma, is the most common renal tumor in children, with approximately 500 new cases diagnosed in the United States every year. Advances in multimodal therapy including surgery, chemotherapy, and radiation therapy given according to risk stratification have allowed most patients to achieve survival rates in excess of 90%. Hence, current cooperative protocols are focused on achieving outstanding oncological outcomes as well as minimizing treatment-related toxicity when feasible.¹

Although 75% of WT cases are diagnosed before age 5 years, it remains the most common malignancy affecting the kidney until around age 13, when it is surpassed by renal cell carcinoma;² moreover, WT cases are consistently reported in adolescents and young adults (AYA). Given the significant therapeutic discrepancies between WT and renal cell carcinoma, urologists should be aware of WT in the differential diagnosis of AYA with renal masses, particularly when they present as large tumors at diagnosis. In this article, the current standard of care for the management of WT will be summarized.

Surgery

In North America, most patients are treated following Children’s Oncology Group (COG) protocols. COG recommends up-front radical nephrectomy when feasible based on the criteria outlined in the Figure. European (Societé Internationale d’Oncologie Pédiatric) protocols recommend neoadjuvant chemotherapy without a biopsy followed by delayed nephrectomy in every patient 6 months to 10 years of age.³

Figure 1. Criteria that must be fulfilled for consideration of upront nephrectomy in children with renal tumors.

The lack of lymph node sampling during nephrectomy is the most common protocol violation in WT treatment (10% to 18% of cases).^4,5 It has huge implications for staging and treatment decision making (see below). Hence, it is paramount that urologists treating children and AYA with renal tumors sample nodes; sampling should include the hilar, paraaortic, and interaortocaval windows for left-sided tumors and hilar, pericaval, and interaortocaval areas for right-sided ones.⁶ The exact number of lymph nodes to be sampled remains debatable, but most authors would agree that surgeons should aim to sample at least 5 to 7 nodes to increase the chances of finding a positive one and conversely reduce the chances of a false-negative sampling.⁷

Patients with bilateral tumors, unilateral tumors in the setting of a predisposition syndrome, and tumors in a solitary kidney should be treated with neoadjuvant chemotherapy with assessment of response at 6 and 12 weeks followed by nephron-sparing surgery (NSS) if feasible. Continuation of chemotherapy for longer than 12 weeks is discouraged in such cases.⁸ The current role of NSS and minimally invasive modalities in the management of unilateral WT is limited due to tumor size and risk of upstaging.

Histology and Risk Stratification

About 90% of WTs are classified as favorable histology (FHWT), while 10% comprise the more aggressive anaplastic histology, which is inherently deemed as high-risk disease requiring intense systemic therapy.

Up-front nephrectomy allows patients with FHWT to be further stratified based on stage and biology. Preoperative tumor rupture or intraoperative tumor spill, percutaneous or open biopsy, positive margins, and positive lymph nodes lead to a stage III designation, which will require adjuvant radiation therapy.

In terms of biology, presence of loss of heterozygosity (LOH) of 1p and 16q has been shown to be associated with worse outcomes.⁹ In the last generation of COG studies, patients with LOH 1p and 16q received more intensive therapy with improved outcomes. Gain of chromosome 1q is also associated with worse prognosis;¹⁰ it will be factored in the risk stratification process and treatment decisions in the next generation of COG studies.

Chemotherapy

The most commonly used agents in the treatment of FHWT are vincristine, dactinomycin, and doxorubicin. Reducing or omitting exposure to doxorubicin and its cardiotoxic side effects is an important goal of cooperative trials in the WT literature.

In the last few years, results from the last generation of COG studies (AREN0532, AREN0533, and AREN0534) have become available and serve as a helpful guide to the current standard of care. Patients with stage I FHWT stratified as very low risk (younger than 2 years of age and tumor weighing less than 550 gm) who had nodes sampled, which were negative, are candidates for surgical treatment alone, with excellent results (event-free survival of 89.7% and overall survival 100%).¹¹

Patients with stage I and II standard risk disease (no LOH 1p and 16q) are treated with the 2-drug chemotherapy regimen known as EE-4A (vincristine and dactinomycin). In cases of stage I or II disease with unfavorable biology (LOH 1p and 16q) and stage III disease without LOH 1p and 16q, adjuvant treatment includes 3 drugs and is known as DD-4A (vincristine, dactinomycin, and doxorubicin). This approach resulted in improved outcomes on AREN0532 compared to historical controls in the National Wilms Tumor Study 5.

Stage III and IV patients with LOH 1p and 16q are treated with a 5-drug regimen known as regimen M, which consists of vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide. Of note, all patients with local stage III disease also receive abdominal radiation.

FHWT Stage IV patients with lung metastases only are a good example of the paradigm of maximizing oncological outcomes while minimizing treatment-related morbidity. If there is no evidence of adverse biology features (LOH 1p and 16q), they are treated with 3-drug chemotherapy (DD-4A). If complete response to chemotherapy is observed in the lungs at week 6 of DD-4A, they remain on this regimen. If the lung response is incomplete, they are switched to 5-drug chemotherapy (regimen M), as well as whole lung irradiation.

The approach described for patients with stages III and IV disease also showed improved outcomes compared to historical controls on the COG study AREN0533.^12,13

Future Directions

The next generation of COG studies will continue to focus on the dichotomy of improving outcomes for patients at increased risk of relapse and decreasing therapy for patients expected to experience excellent results based on risk stratification. From a surgical standpoint, targeting lymph node sampling, both in terms of location as well as ideal number of nodes to be sampled, will be a major area of study.

The ability to obtain detailed information about tumor histology and biology without having to sample renal tissue, using tools such as circulating tumor DNA and liquid biopsy,¹⁴ may change the initial surgical approach to pediatric renal tumors and allow NSS and minimally invasive surgery to have a more prominent role in the future.