Curr Urol Rep (2010) 11:5865 DOI 10.

1007/s11934-009-0082-z

Current Management of Wilms Tumor

Leah Nakamura & Michael Ritchey

Published online: 22 January 2010 # Springer Science+Business Media, LLC 2010

Abstract Wilms tumor is the most common malignant renal tumor in children. Survival has improved dramatically over time as a result of prospective randomized clinical trials conducted by the pediatric cooperative cancer groups. Current research is directed toward identifying low-risk patients for whom a reduction in treatment intensity would decrease longterm morbidity. This article reviews the most recent advances in the biology and treatment of children with Wilms tumor. Keywords Wilms . Nephroblastoma . Oncology

Introduction Nephroblastoma, or Wilms tumor (WT), is the most common solid renal malignancy in children, accounting for 6% to 7% of all childhood cancers. Survival now approaches 90% for most children. Current management strategies focus on reducing morbidity, especially among those with a good prognosis. This article reviews recent advances in the molecular biology, as well as treatment of children with WT.

Genetics The genetic basis for development of WT remains an area of intense investigation for researchers. Two familial WT genes have been localized: FWT1 at 17q12-q21 and FWT2
L. Nakamura : M. Ritchey (*) Department of Urology, Mayo Clinic Arizona, 5777 E Mayo Blvd, Phoenix, AZ 85054, USA e-mail: michaelritchey@yahoo.com

at 19q13 [1]. Familial cases have an earlier age of onset and an increased frequency of bilateral disease. Approximately 10% of children with WT have congenital anomalies and syndromes, and the latter can be classified into overgrowth and non-overgrowth. One well-known example of a nonovergrowth syndrome is WAGR (Wilms tumor, Aniridia, Genital anomalies, mental Retardation). These children were noted to have heterozygous germline deletions of chromosome 11p13 that led to the cloning of the first Wilms tumor gene, WT1 [2]. WT1 is important for normal renal and gonadal development, and mutations of this gene can lead to both renal tumors and glomerular disease. Denys-Drash syndrome (DDS), another well-recognized non-overgrowth syndrome with the specific association of male pseudohermaphroditism, renal mesangial sclerosis, and nephroblastoma, is caused by point mutations in the zinc-finger DNA-binding region of WT1 [3]. The incidence of WT1 mutations in patients with WT not associated with any syndrome is approximately 2% [4]. WAGR and DDS patients are more likely to have bilateral tumors and are diagnosed at a younger age [5]. Both have a higher risk of renal insufficiency, and recent evidence suggests this is due to the WT1 mutation [6]. A number of nephrotic conditions associated with mesangial sclerosis are believed to be due to abnormalities of WT1 [7]. Recent studies have shown that both DDS and WAGR patients have smaller glomeruli than normal, and that this may predispose these patients to renal failure [8]. Aniridia is caused by a defect in the PAX6 gene that is located adjacent to WT1. It is present in 1.1% of WT patients. About 40% to 70% of aniridia patients with deletions of WT1 will develop WT as opposed to those patients with normal WT1 who do not develop WT [9]. The Wnt/beta-catenin signaling pathway is likely involved in tumorigenesis because activating mutations of the beta-

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catenin gene (CTNNB1) are found in more than half of the WTs with WT1 mutation. A number of overgrowth syndromes are at risk for the development of WT, including hemihypertrophy, BeckwithWiedemann syndrome (BWS), Perlman, Sotos, and the Simpson-Golabi-Behmel syndromes. WT develops in BWS and hemihypertrophy in about 4% to 10% of cases, and 21% present with bilateral disease [10]. Those with nephromegaly are at the greatest risk [11]. The WT2 gene has been linked to BWS, identified at 11p15 and associated with a loss of heterozygosity at this site. The WT2 locus has been extensively studied, and a number of genes have been identified, including H19 and IGF2 [12]. IGF2 induces cell growth, and overexpression of this gene could lead to WT and BWS. This can be caused by a duplication of the paternal allele or loss of imprinting (LOI) of the maternal allele. Tumors secondary to this genetic alteration have been linked to presentation at an older age [12]. The WT gene on the X chromosome, or WTX at Xq11.1, is inactivated in up to one third of WTs [13]. WTX targets the active X in women and single X in men and is inactivated by a single hit event, which is thought to play a role in the Wnt/beta-catenin signaling pathway. Mutations in WT1, WTX, and CTNNB1 provide the genetic basis for about one third of WTs [2]. Other chromosomal abnormalities involved with WT include loss of the long arm of chromosome 16 in 20% of tumors, loss of the short arm of chromosome 1p in 10%, and loss of heterozygosity at 11q in 20%. Loss of heterozygosity (LOH) at 1p and 16q is associated with an increased risk of tumor relapse [14, 15]. LOH of 11q is three to four times more frequent in anaplastic tumors [14]. One of the objectives of the National Wilms Tumor Study (NWTS-5) was to confirm prognostic utility of LOH at 1p or 16q. Stage I-II tumors with LOH at either locus had increased risk of relapse and death, whereas those with stage III-IV tumors had increased risk only with LOH at both regions [15]. These findings contributed to the decisionmaking process in treatment protocols (Table 1). Increased risk of relapse and death with LOH at 16q was confirmed in the UKW1-3 clinical trial that proved it an adverse risk factor regardless of initial approach to therapy (preoperative chemotherapy vs immediate nephrectomy) [16]. A number of other markers have been examined to predict tumor relapse and poor outcome in children with WT. One potential marker is telomerase, a reverse transcriptase that maintains chromosome ends, compensating for the loss of DNA that occurs in replication. High telomerase activity has been found to be an unfavorable prognostic feature for several types of cancers. A case cohort study involving 291 patients showed a correlation between telomerase RNA expression and recurrence, independent of tumor stage [17]. Tissue factor, an initiator

of the coagulation pathway, has been shown to be expressed in a number of tumor types and may be involved in tumor angiogenesis. Tissue factor expression was shown to be associated with tumor recurrence and survival in a small group of patients with WT [18]. Gene expression analysis has shown potential in predicting tumor relapse in children with stage III favorable histology (FH) WTs [19].

Screening Screening with serial renal ultrasounds at 3- to 4-month intervals has been recommended in children at high risk for development of WT. The Wilms Tumor Surveillance Working Group from the United Kingdom recommended conducting screening when a condition has a WT incidence of greater than 5% [20]. Although screening usually detects tumors at a lower stage, no studies have shown improved patient survival [21]. Early detection can lead to opportunity for nephron-sparing surgery. After removal of a WT, monitoring of the contralateral kidney for development of metachronous tumor is recommended, particularly in those patients with nephrogenic rests identified in the kidney. Infants with nephrogenic rests in the resected kidney are at greatest risk for metachronous tumors and should have ultrasound surveillance every 3 to 4 months until 5 years of age [22]. Those that have BWS, SimpsonGolabi-Behmel, and familial Wilms histories should continue surveillance until 7 years of age [20].

Pathology Histology is the most important prognostic factor in WT and is characterized by tremendous histologic diversity. Classic WT is characterized by three components: blastemal, epithelial, and stromal [23]. Those with predominant epithelial components usually are stage I with low aggressiveness but may be resistant to therapy if presenting at an advanced stage. Those with a blastemal component are aggressive but usually responsive to chemotherapy [23]. An unfavorable histologic feature is anaplasia that is associated with resistance to chemotherapy and carries a poor prognosis [24]. It is also seen with an increased frequency after preoperative chemotherapy [25, 26]. The pathologic findings of WT will be different following preoperative chemotherapy and reflect the response to treatment [27]. The International Society of Pediatric Oncology (SIOP) classifies tumors with complete tumor necrosis following preoperative chemotherapy as low risk. Children with stage I low-risk tumors following postchemotherapy nephrectomy receive no further chemotherapy [28]. Stromal and epithelial predominant tumors are found

60 Table 1 Summary of current childrens oncology group renal tumor studies

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AREN 0532: Very low/standard risk FH WT 1. Very low-risk patients (stage I FH tumors <550 g; <2 years of age) will be treated by nephrectomy alone. The goal is to achieve a 4-year EFS 85% and 4-year OS 95%. 2. Low-risk patients that do not qualify for surgery alone (stage I or II FH tumors >550 g; >2 years of age will be treated with 18 weeks of dactinomycin and vincristine (regimen EE-4A). 3. Patients with stage III FH WT without LOH of 1p and 16q will be treated with vincristine, dactinomycin, doxorubicin (regimen DD-4A), and radiotherapy. The goal is to achieve a 4-year EFS of 85% and 4-year OS 95%. 4. Patients with stage I and II FH WT with LOH of 1p and 16q will be treated with regimen DD-4A but not radiotherapy. The goal is to improve the current 4-year EFS. AREN 0533: Higher risk FH WT 1. Patients with stage IV FH WT will be treated with regimen DD-4A. Those that have complete resolution of the pulmonary lesions after 6 weeks will not receive radiation therapy. The goal is to achieve a 4-year EFS of 85% without whole lung irradiation. 2. Patients with stage IV FH WT who do not have resolution of pulmonary metastases after 6 weeks of therapy will receive cyclophosphamide and etoposide in addition to regimen DD-4A. The goal is to achieve a 4-year EFS of 85%. 3. Patients with stage III or IV FH WT with loss of LOH for 1p and 16q will receive cyclophosphamide and etoposide in addition to regimen DD-4A (regimen M) and radiotherapy. The goal is to improve the 4-year EFS to 75%. AREN 0321: High-risk renal tumors 1. Patients with stage I diffuse anaplasia and IIII focal anaplasia WT will be treated with regimen DD-4A and radiotherapy. 2. Patients with stage I CCSK will be treated with vincristine, dactinomycin, doxorubicin (regimen DD-4A), but not radiotherapy. 3. Patients with stage IV focal anaplasia, diffuse anaplasia stage II-III WT, stage IV CCSK, or stage IIV malignant rhabdoid tumor of the kidney will be treated with new chemotherapy protocols to try and improve survival. AREN 0534: Bilateral, multicentric, or susceptible to developing bilateral WT 1. Patients with bilateral WT will be given 6 to 12 weeks of vincristine, dactinomycin, and doxorubicin. Surgery is to be performed no later than week 12. The goal is to improve the 4-year EFS to 73%. 2. Patients with DHPLNR will be treated with 18 weeks of vincristine and dactinomycin. The goal is to evaluate the efficacy of chemotherapy in preserving renal units in children with WT and preventing WT development. 3. Patients with unilateral tumors and aniridia, BWS, hemihypertrophy, or other overgrowth syndromes will be receive pre-nephrectomy chemotherapy for 6 weeks with vincristine and dactinomycin. The goal is to facilitate partial nephrectomy in 25% of children. BWS Beckwith-Wiedemann syndrome, CCSK clear cell sarcoma of the kidney, DHPLNR diffuse hyperplastic perilobar nephrogenic rests, EFS event-free survival, FH favorable histology, LOH loss of heterozygosity, OS overall survival, WT Wilms tumor

more often after chemotherapy. These histologic subtypes may demonstrate a poor clinical response to therapy but have an excellent prognosis if completely excised. The proportion of blastemal predominant tumors is decreased after chemotherapy, indicating some response of this tumor type to the preoperative chemotherapy. However, patients with blastemal predominant tumors after chemotherapy have a high relapse rate [29]. Tumors with diffuse anaplasia and blastemal predominance after chemotherapy are classified as high risk by SIOP. WT is thought to arise from nephrogenic rests, precursor lesions present in more than one third of kidneys with WT [30]. There are two categories: perilobar nephrogenic rests (PLNRs) and intralobar nephrogenic rests (ILNRs). As their names imply, they are differentiated by location within the renal lobe. ILNRs are associated with WT1 and CTNNB1 mutations and are frequently found in patients with aniridia, WAGR, DDS, and WT1 [31]. Tumors arising from ILNRs have a distinct histology that is stromal predominant with varying degrees of rhabdomyogenesis. PLNRs have been linked to 11p15 and IGF2 LOI and frequently noted in patients with BWS. Tumors associated with PLNRs often have a blastemal-predominant histology.

Nephroblastomatosis refers to the presence of multiple nephrogenic rests. Diffuse hyperplastic perilobar nephrogenic rests appear as a thick rind compressing the normal kidney parenchyma. These patients are prone to developing WT, often with bilateral lesions and anaplasia noted after chemotherapy [25].

Diagnosis and Staging Most cases of WT are found incidentally with a palpable smooth abdominal mass. Abdominal pain and gross hematuria are less frequent findings at diagnosis. The presence of gross hematuria could indicate tumor extension into the collecting system [32]. About 25% of patients present with hypertension secondary to elevated plasma renin levels that resolves after removal of the tumor [33]. Although WT is the most common solid renal tumor in children, there are no specific features on imaging that can confirm the diagnosis of WT. In the United Kingdom Childrens Cancer Study Group (UKCCSG), 12% of renal tumors consistent with Wilms had a different diagnosis on

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biopsy [34]. In the SIOP-9 study, 5.4% of patients were misdiagnosed as WT prior to nephrectomy [35]. Imaging is more important to establish the presence of a solid renal mass, plan out surgery, and confirm a normal contralateral kidney. Ultrasound is usually the first study done in children with an abdominal mass. Doppler ultrasound can help to exclude intracaval tumor extension [36]. MRI is done if ultrasound is inconclusive in this regard [37]. CT and MRI can help define the extent of the lesion, but there are caveats. Inoperability of a tumor should only be determined at the time of exploration because apparent extension of the tumor is usually secondary to compression by the tumor and not frank invasion. Exploration of the contralateral kidney is no longer recommended if the preoperative CT or MRI is normal [38]. The most common site for metastases is the lung, and CT of the chest is recommended before surgery. Tumor stage is another important prognosticator, and two staging systems are available (Table 2). The current staging system used by the Childrens Oncology Group (COG) is based primarily on the surgical and histopathological findings. The system used by SIOP is performed after preoperative chemotherapy.

Surgery A transperitoneal approach is recommended for removal of the tumor. This allows thorough abdominal exploration to exclude tumor extension, metastases, or peritoneal seeding. Selective sampling of suspicious nodes is needed for accurate tumor staging. A formal retroperitoneal lymph node dissection is not recommended [39]. Avoiding tumor rupture and spillage is important due to a sixfold increased risk of local relapse [39, 40]. Other risk factors for local tumor recurrence include unfavorable histology, incomplete tumor removal, and absence of any lymph node sampling. There have been several reports of laparoscopic nephrectomy for WT. This is usually done in conjunction with preoperative chemotherapy and is likely more feasible after the tumor is reduced in size [41]. Experience with open nephrectomy after chemotherapy has shown that these tumors are less prone to tumor spillage [42]. Although prechemotherapy laparoscopic nephrectomy has been reported [43], many more cases will need to be performed to determine if there is any increased risk of tumor spillage, residual disease, or surgical complications.

Cooperative Group Studies Multiple clinical trials have been conducted by the National Wilms Tumor Study Group (NWTSG; now incorporated into the COG), SIOP, and UKCCSG to determine the

appropriate role for each of the therapeutic modalities available. NWTSG and COG primarily recommend initial nephrectomy followed by adjuvant therapy. Exceptions include patients with bilateral disease or those prone to development of bilateral disease. COG also recommends preoperative therapy for patients found to have inoperable tumors and those with extensive involvement of the inferior vena cava. SIOP and UKCCSG advocate chemotherapy before surgery is performed except in the case of very young infants. NWTS-5 completed enrollment in 2003. Children less than 2 years of age with stage I FH tumors weighing less than 550 grams did not receive chemotherapy after nephrectomy, but this was stopped early due to excessive tumor recurrences [44]. More recently, Green et al. [44] conducted a long-term review of this cohort and found no difference in overall survival between the two groups after 5 years, and event-free survival in the surgery-only group was 84%. This concept is being examined again in the current COG trials (Table 1). A new intensified chemotherapy regimen for anaplastic WT was evaluated in NWTS-5, but this did not enhance survival [24]. Treatment of tumor relapse was prospectively studied in NWTS-5. Relapse rates are less than 15% for children with WT, and most occur within the first 2 years after diagnosis. Patients whose initial treatment consisted of dactinomycin and vincristine only had an overall 81% survival at 4 years, whereas those treated with dactinomycin, vincristine, doxorubicin, and radiation had an overall survival of 48% at 4 years [45]. Adult patients in the NWTS studies were noted to have similar outcomes to children and should be treated with the same protocols [46]. Table 1 lists the current COG renal tumor protocols and their major objectives. As previously noted, almost all children treated on SIOP trials receive preoperative chemotherapy. SIOP-9 demonstrated that treatment with vincristine and dactinomycin for 4 weeks versus 8 weeks had comparable rates of stage distribution and tumor shrinkage in patients with stage IIII disease [35]. These studies have yielded interesting information regarding the histologic changes to the chemotherapy and its impact on survival (see pathology discussion above). SIOP 93-01 demonstrated that survival can be maintained with a reduction of postoperative chemotherapy (dactinomycin and vincristine) from 18 to 4 weeks for patients with stage I intermediate-risk and anaplastic histology [47]. The ongoing SIOP 2001 study will address the question whether patients with stage II and III intermediate-risk tumors can be safely treated without an anthracycline. Data from SIOP 93-01 have suggested that survival was not adversely affected when nonviable tumor was identified in the renal sinus and/or perirenal fat after preoperative chemotherapy [47].

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Table 2 Staging systems used by the Childrens Oncology Group and International Society of Pediatric Oncology Childrens Oncology Group Stage I: Tumor confined to the kidney and completely resected. The renal capsule is intact, and the tumor was not ruptured prior to removal. No renal sinus extension. There is no residual tumor. II: Extracapsular penetration, but is completely resected. Renal sinus extension or extrarenal vessels may contain tumor thrombus or may be infiltrated by tumor. III: Residual nonhematogenous tumor confined to the abdomen: lymph node involvement, any tumor spillage, peritoneal implants, tumor beyond surgical margin either grossly or microscopically, or tumor not completely removed. IV: Hematogenous metastases to lung, liver, bone, brain, etc. V: Bilateral renal involvement at diagnosis. International Society of Paediatric Oncology Stage I: Tumor limited to the kidney: fibrous pseudocapsule surrounds tumor if outside of contours of kidney; clear resection margins; no renal sinus vessel involvement. II: Tumor extends beyond kidney into perirenal fat, renal sinus, adjacent organs, or inferior vena cava; complete resection with clear margins. III: Incomplete excision of tumor; positive abdominopelvic lymph nodes; tumor penetration through peritoneal surface; tumor thrombi at vascular resection margins. IV: Hematogenous metastases; extra-abdominopelvic lymph node metastases. V: Bilateral tumors at diagnosis.

The UKCCSG trials also use preoperative chemotherapy but recommend biopsy prior to treatment [48]. This is done to avoid giving inappropriate chemotherapy to benign or non-Wilms tumors. The UKW1 and UKW2 studies evaluated using single-agent vincristine for treatment of stage I FH tumors and found a comparable survival of 96% with two-drug chemotherapy [49]. The UKW3 trial randomly assigned patients to either immediate surgery or to 6 weeks preoperative chemotherapy and then delayed surgery [50]. Event-free and overall survival at 5 years was similar between the two groups. They concluded that all children with nonmetastatic WT should receive chemotherapy prior to tumor resection.

Renal-Sparing Surgery Synchronous bilateral Wilms tumors (BWTs) occur in 5% to 7% of children with WT, and these patients should receive preoperative chemotherapy in hopes of reducing tumor size to allow renal-sparing surgical procedures. Renal failure rates approach 15% at 15 years posttreatment in these patients, making renal-sparing treatment important [51]. The most common etiology for renal failure was the need for bilateral nephrectomy for persistent or recurrent tumor in the remaining kidney. The current COG protocol for patients with BWT recommends 6 weeks of chemotherapy prior to surgery. Tumor response is assessed after 6 weeks with imaging to determine its amenability to partial resection. If partial resection is feasible, surgery is performed. Some tumors may have a complete response to therapy and not require surgical

resection of the primary tumor [52]. Tumors not responding to therapy require bilateral open biopsy to determine histology. Failure to achieve a reduction in volume is likely due to tumor differentiation but may indicate anaplasia [53]. Additional chemotherapy is given based on the biopsy findings, and regardless of response, all patients should undergo surgical resection within 12 weeks of starting therapy. For those large, centrally located tumors or difficult resections secondary to potential vascular compromise of the kidney, tumor enucleation may be considered [54]. There have been a number of reports on the use of partial nephrectomy for unilateral WT [55, 56]. The main rationale is to preserve renal tissue to prevent later development of renal insufficiency. The incidence of renal failure following nephrectomy for most children with unilateral WT is 0.6% at 20 years [51]. The risk of renal failure is higher for patients with genitourinary anomalies, DDS, and WAGR, secondary to a WT1 mutation. Most WTs are too large at diagnosis to allow for partial nephrectomy, but after preoperative chemotherapy, partial nephrectomy can be performed in 10% to 15% of patients. There are concerns of increased risk of local recurrence after partial nephrectomy; therefore, one should follow strict surgical guidelines to reduce the risk of residual tumor [54, 56]. If anaplasia is present, complete resection is mandatory. COG has proposed a renal-sparing protocol for select patients at high risk for bilateral disease or increased risk of renal failure. Lesions should be completely excised with adequate margins and only undergo partial nephrectomy if the tumor can be removed as stage I. Patients with high-risk histologic patterns after chemotherapy should be treated with complete nephrectomy.

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63 patients: a UK Childrens Cancer Study Group Study. J Clin Oncol 2004, 22:41404106. Breslow NE, Norris R, Norkool PA, et al.: Characteristics and outcomes of children with the Wilms tumor-Aniridia syndrome: a report from the National Wilms Tumor Study Group. J Clin Oncol 2003, 21:45794585. Breslow NE, Takashima JR, Ritchey ML, et al.: Renal failure in the Denys-Drash and Wilms tumor-aniridia syndromes. Cancer Res 2000, 60:40304032. Morrison AA, Viney RL, Saleem MA, Ladomery MR: New insights into the function of the Wilms tumor suppressor gene in podocytes. Am J Physiol Renal Physiol 2008, 295:F12F17. Dahan K, Kamal M, Noel LH, et al.: Small glomeruli in WAGR (Wilms Tumor, Aniridia, Genitourinary Anomalies and Mental Retardation) syndrome. Am J Kidney Dis 2007, 49:793800. van Heyningen V, Hoovers JM, de Kraker J, et al.: Raised risk of Wilms tumour in patients with aniridia and submicroscopic WT1 deletion. J Med Genet 2007, 44:787790. Porteus MH, Narkool P, Neuberg D, et al.: Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms' tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2000, 18:20262031. DeBaun MR, Siegel MJ, Choyke PL: Nephromegaly in infancy and early childhood: a risk factor for Wilms tumor in Beckwith-Wiedemann syndrome. J Pediatr 1998, 132:401404. Ravenel JD, Broman KW, Perlman EJ, et al.: Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. J Natl Cancer Inst 2001, 93:16981703. Rivera MN, Kim WJ, Wells J, et al.: An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 2007, 315:642645. Wittmann S, Zirn B, Alkassar M, et al.: Loss of 11q and 16q in Wilms tumors is associated with anaplasia, tumor recurrence, and poor prognosis. Genes Chromosomes Cancer 2007, 46:163170. Grundy PE, Breslow NE, Li S, et al.: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2005, 23:73127321. Messahel B, Williams R, Ridolfi A, et al.: Allele loss at 16q defines poorer prognosis Wilms tumour irrespective of treatment approach in the UKW1-3 clinical trials: a Childrens Cancer and Leukaemia Group (CCLG) Study. Eur J Cancer 2009, 45:819826. Dome JS, Bockhold CA, Li SM, et al.: High telomerase RNA expression level is an adverse prognostic factor for favorablehistology Wilms tumor. J Clin Oncol 2005, 23:91389145. Maciel EO, Carvalhal GF, da Silva VD, et al.: Increased tissue factor expression and poor nephroblastoma prognosis. J Urol 2009, 182:15941599. Huang CC, Gadd S, Breslow N, et al.: Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Childrens Oncology Group. Clin Cancer Res 2009, 15:17701778. Scott RH, Walker L, Olsen OE, et al.: Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child 2006, 91:995999. This is an excellent review of the role of screening for WT in at-risk children. This article provides evidence-based recommendations for surveillance of these children. Choyke PL, Siegel MJ, Craft AW, et al.: Screening for Wilms tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy. Med Pediatr Oncol 1999, 32:196200.

Late Effects of Treatment WT anti-cancer therapy can cause a number of late sequelae [57]. Clinicians should be aware of these potential problems and monitor children closely as they grow, especially those who were treated at a young age. An increased incidence of second malignant neoplasms has been noted in children treated for WT, including sarcomas, breast cancer, lymphoma, melanoma, and leukemia. There is a 1.6% cumulative incidence at 15 years postdiagnosis in NWTS trials and 0.65% at 15 years in SIOP trials [57]. One of the greatest risk factors is prior irradiation, and most tumors occur in the radiation field. Doxorubicin has been noted to potentiate the effects of radiation. A recent report of mortality rates of the NWTSG cohort found an overall standardized mortality ratio (SMR) for 5year survivors of 6.0. The SMR was 24.3 in the first 5 years, 12.6 for the next 5 years, and over 3.0 after that. Of the 978 deaths that occurred, 8.6% were attributed to late effects of treatment [58].
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Conclusions Improved overall survival of children with WT is the result of prospective randomized clinical trials conducted over the past few decades. Late effects of these successful treatments are now well recognized. The future aims of all clinical trials are reduction of these side effects and long-term sequelae through risk stratification for low-risk groups. Improved treatment for groups with poorer prognosis such as unfavorable histology and recurrent WT is still being investigated.
Disclosure No potential conflicts of interest relevant to this article were reported. 13.

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Curr Urol Rep (2010) 11:5865 and chemotherapy regimens on abdominal recurrence. A report from the National Wilms Tumor Study Group. Int J Radiat Oncol Biol Phys 2009 (in press). Duarte RJ, Denes FT, Cristofani LM, et al.: Laparoscopic nephrectomy for Wilms tumor. Expert Rev Anticancer Ther 2009, 9:753761. Godzinski J, Tournade MF, de Kraker J, et al.: Rarity of surgical complications after postchemotherapy nephrectomy for nephroblastoma. Experience of the International Society of Paediatric Oncology-Trial and Study SIOP-9. International Society of Paediatric Oncology Nephroblastoma Trial and Study Committee. Eur J Pediatr Surg 1998, 8:8386. Barber TD, Wickiser JE, Wilcox DT, et al.: Prechemotherapy laparoscopic nephrectomy for Wilms tumor. J Pediatr Urol 2009, 5:416419. Green DM, Breslow NE, Beckwith JB, et al.: Treatment with nephrectomy only for small, stage I/favorable histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2001, 19:37193724. Malogolowkin M, Cotton CA, Green DM, et al.: Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor Study Group. Pediatr Blood Cancer 2008, 50:236 241. Kalapurakal JA, Nan B, Norkool P, et al.: Treatment outcomes in adults with favorable histologic type Wilms tumor: an update from the National Wilms Tumor Study Group. Int J Radiat Oncol Biol Phys 2004, 60:13791384. de Kraker J, Graf N, van Tinteren H, et al.: Reduction of postoperative chemotherapy in children with stage I intermediaterisk and anaplastic Wilms tumour (SIOP 93-01 trial): a randomised controlled trial. Lancet 2004, 364:12291235. Pritchard-Jones K, Kelsey A, Vujanic G, et al.: Older age is an adverse prognostic factor in stage I, favorable histology Wilms tumor treated with vincristine monochemotherapy: a study by the United Kingdom Children s Cancer Study Group, Wilms Tumor Working Group. J Clin Oncol 2003, 21:32693275. Mitchell C, Jones PM, Kelsey A, et al.: The treatment of Wilms tumour: results of the United Kingdom Childrens cancer study group (UKCCSG) second Wilms tumour study. Br J Cancer 2000, 83:602608. Mitchell C, Pritchard-Jones K, Shannon R, et al.: Immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic Wilms tumour: results of a randomised trial (UKW3) by the UK Childrens Cancer Study Group. Eur J Cancer 2006, 42:25542562. Breslow NE, Collins AJ, Ritchey ML, et al.: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 2005, 174:19721975. This report from the NWTSG discusses the risks of renal failure following the treatment of WT. It provides the best estimates of renal failure risk in this population and identifies groups of patients at significant risk. Hamilton TE, Ritchey ML, Argani P, et al.: Synchronous bilateral Wilms tumor with complete radiographic response managed without surgical resection: a report from the National Wilm s Tumor Study 4. J Pediatr Surg 2008, 43:19821984. Shamberger RC, Haase GM, Argani P, et al.: Bilateral Wilms tumors with progressive or nonresponsive disease. J Pediatr Surg 2006, 41:652657. Davidoff AM, Giel DW, Jones DP, et al.: The feasibility and outcome of nephron-sparing surgery for children with bilateral Wilms tumor. The St Jude Childrens Research Hospital experi-

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Curr Urol Rep (2010) 11:5865 ence: 19992006. Cancer 2008, 112: 20602070. This article should be read by all surgeons treating patients with bilateral WT or considering renal-sparing surgery in children with renal tumor. It shows that preservation of the kidneys is possible even with apparent significant tumor burden on imaging studies. 55. Haecker FM, von Schweinitz D, Harms D, et al.: Partial nephrectomy for unilateral Wilms tumor: results of study SIOP 93-01/GPOH. J Urol 2003, 170:939942.

65 56. Cozzi F, Schiavetti A, Morini F, et al.: Renal function adaptation in children with unilateral renal tumors treated with nephron sparing surgery or nephrectomy. J Urol 2005, 174:14041408. 57. Wright KD, Green DM, Daw NC: Late effects of treatment for Wilms tumor. Pediatr Hematol Oncol 2009, 26:407413. 58. Cotton CA, Peterson S, Norkool PA, et al.: Early and late mortality after diagnosis of Wilms tumor. J Clin Oncol 2009, 27:13041309.