Wilms’ tumor, neuroblastoma, rhabdomyosarcoma (RMS), and testis tumors are treated by pediatric urologists and pediatric surgeons in conjunction with trials sponsored by the Children’s Oncology Group (COG) of the National Cancer Institute (NCI). COG has assumed responsibility for trials formerly run by the National Wilms’ Tumor Study (NWTS) group and Intergroup Rhabdomyosarcoma Study (IRS) group. The multimodal approach of combining surgery, radiotherapy (RT), and chemotherapy has resulted in significant improvements in survival while reducing treatment-related morbidity. The next generation of studies is being designed using risk stratification systems based on clinical and molecular criteria. As more children survive treatment, long- term concerns including secondary malignancy, bone deformity, and genitourinary dysfunction are being addressed by COG.

Wilms’ Tumor

Wilms’ tumor is the most common pediatric urologic tumor—75% of patients present between one and five years of age, with an equal incidence between boys and girls. Patients present with an abdominal mass, which rarely crosses the midline. Contrast computed tomography (CT) of the chest, abdomen, and pelvis is obtained to evaluate both the mass and possible metastatic disease. Surgical exploration is performed through a subcostal transverse incision. Classically, the recommendation has been that in cases of unilateral disease, the contralateral kidney must be explored due to 7% of patients having false negative pre-operative studies.¹ This recommendation may be changing because it appears that patients with missed small contralateral lesions progressed well with post- operative chemotherapy.² In cases of bilateral disease, an open biopsy of the tumor is performed, chemotherapy is given, and delayed bilateral nephron- sparing surgery is performed.The next generation of studies may use upfront chemotherapy for bilateral tumors without biopsy, as recommended by the International Society of Paediatric Oncology (SIOP).

The patient’s prognosis is dependent on the tumor histology and stage. Chemotherapy with dactinomycin and vincristine results in a 90% overall cure rate for low-stage tumors. For favorable histology tumors, stage I–II (completely resected) have a 92–97% survival, stage III (lymph node positive or intra-operative spill) 84%, and stage IV (distant lymph nodes or lung involvement) 83%. RT and doxorubicin are added for stage III disease and metastatic sites (stage IV).3 Long-term survival for children with bilateral disease (stage V) is 70%.⁴

The NWTS approach in the US is different from that of SIOP. The NWTS asks for open biopsy and, if possible, resection before chemotherapy. This avoids giving chemotherapy for a non-Wilms’ tumor, but at the expense of a higher rate of intra-operative spill, and more children receiving RT for stage III tumors.

The SIOP approach of pre-operative chemotherapy allows for safer surgery, but gives more chemotherapy.

One key problem with the SIOP approach is the possibility of downstaging tumors, and undertreating patients. The trade-off is that patients with stage II tumors receive doxorubicin on SIOP protocols, but not on NWTS protocols. Overall survival is essentially the same between the latest NWTS and SIOP protocols, so the argument over which approach is better for a given child depends on the skill of the physicians treating the child.⁵ In NWTS V, selected good risk patients (stage I disease, less than two years of age, tumor <550g) were managed without chemotherapy, but it became apparent due to a high number of relapses that all patients with Wilms’ tumor require chemotherapy.6 This point will likely be revisited in upcoming studies, as many of these children were rescued by chemotherapy. Other aspects of NWTS V included investigation of chromosome 16q and 1p loss of heterozygosity as markers of poor prognosis. New chemotherapeutic regimens for rhabdoid tumor (carboplatin, etoposide, and cyclophosphamide) as well as diffuse anaplasia and clear cell sarcoma (etoposide and cyclophosphamide) were studied.

Long-term complications are most easily assessed in patients with bilateral Wilms’ tumor. Maintaining renal function in the face of surgery, chemotherapy, and radiation is the primary reason why nephron-sparing surgery is performed. In NWTS ^2–4, 35% of patients Pediatric Urologic Oncology 1 B USINESS BRIEFING: US ONCOLOGY REVIEW 2006 Hsi-Yang Wu, MD Fernando A Ferrer, MD Hsi-Yang Wu, MD, is Director of Pediatric Urology Research at the Children’s Hospital of Pittsburgh and Assistant Professor of Urology at the University of Pittsburgh. His clinical interests include pediatric urologic oncology, cryptorchidism, and voiding dysfunction. His National Institutes of Health (NIH)- supported laboratory studies neural and smooth muscle maturation in pediatric bladder function, with an aim to develop new treatments for pediatric urinary incontinence.

Fernando A Ferrer, MD, is Director of Pediatric Urology at Connecticut Children’s Medical Center and Assistant Professor of Surgery (Urology), Pediatrics, and Oncology at the University of Connecticut. His clinical interests include pediatric urologic oncology and major reconstructive surgery for urinary continence. He serves on the Children’s Oncology Group (COG) committees that study Wilms’ tumor (Renal Tumor Committee) and late complications (Late Effects Committee), and is involved in developing new protocols for tumor treatment.

who underwent renal-sparing surgery and radiation for bilateral Wilms’ tumor developed an elevation in blood urea nitrogen (BUN) >25 or creatinine >1.5 at a median follow-up of 27 months.⁷ At 15 years post- treatment for bilateral Wilms’, the incidence of ESRD approaches 15%.⁶ The use of nephron-sparing surgery in cases of unilateral disease has been studied in Europe in patients who had received pre-operative chemotherapy. Outcomes for favorable histology patients were equivalent to those undergoing total nephrectomy.⁸ The use of nephron-sparing surgery must balance the very low risk of end-stage renal disease (ESRD) from a total nephrectomy (0.25%) with the risk of local recurrence.9 Future studies for Wilms’ tumor will likely focus on understanding the molecular biologic characteristics of the tumors.The association of p53 abnormalities with anaplasia, integrase interactor-¹ (INI1) abnormalities in rhabdoid tumors, and chromosomal translocation in children with renal cell carcinoma are examples.^10–12 From a therapeutic perspective, the use of new chemotherapeutic agents, such as topoisomerase inhibitors (irinotecan),¹³ and changes in protocol such as omitting biopsy before treatment in bilateral tumors and revisiting omitting chemotherapy in select cases can be expected.