Review

Continuing Medical EducationNature Clinical Practice Oncology (2005) 2, 298-304
doi:10.1038/ncponc0196  
Received 6 February 2005 | Accepted 3 May 2005

Current challenges in Wilms' tumor management

Lyndon M Gommersall, Manit Arya*, Imran Mushtaq and Patrick Duffy  About the authors

Correspondence *Great Ormond Street Hospital for Children, London WC1N 3JH, UK

Email manit_arya@hotmail.com

Summary

Wilms' tumor is a renal cancer that predominantly affects children during the first 2 years of life. The continuing success of clinical trials in Wilms' tumor patients over the past 30 years has led to an overall survival of 85%, and treatment-related morbidity has been reduced. Less-aggressive chemotherapeutic regimes are available for patients with validated good prognostic factors, such as low stage and favorable histology. It is becoming increasingly apparent that treatment can be optimized through stratification of patients according to tumor stage and histology. Established treatments for Wilms' tumor include perioperative vincristine and actinomycin, with or without doxorubicin or radiotherapy. Relapsed patients have the option of salvage chemotherapy with ifosfamide, carboplatin and etoposide, as well as high-dose chemotherapy regimes and autologous hemopoietic stem-cell rescue. Further research is required to refine these regimes and identify further the role of additional prognostic factors in this childhood disease. In this article we discuss the most-debated issues and advances that have been made in the management of Wilms' tumor.

Review criteria

Information for this review article was identified by searching the PubMed database for papers published between January 2000 and December 2004. The search terms used were "Wilms tumor" and "nephroblastoma". Associated references from these articles were also included to represent the most important achievements of the past 30 years.

Keywords:

chemotherapy, management, nephroblastoma, radiotherapy, Wilms' tumor

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Introduction

Renal cancers represent 6.3% of cancer diagnoses in individuals under the age of 20. This translates to around 550 new cases of renal tumors in children and adolescents each year in the US, of which approximately 500 are Wilms' tumors (also known as nephroblastoma).

Wilms' tumor predominantly affects children under 5 years of age, most commonly during the first 2 years of life.1 Contemporary treatment of Wilms' tumor has led to an overall survival of over 85%, and the emphasis is now shifting from successful treatment to reducing treatment-associated morbidity without loss of efficacy. Therefore, stratification of patients into low-risk disease with low-intensity treatments, versus high-risk disease and high-intensity treatments has become the main goal. In recent years, improvements in surgical and anesthetic techniques, along with the introduction of radiotherapy-based treatments,2 have decreased the morbidity and mortality associated with treatment.

Large randomized controlled trials have been designed, managed and published by various collaborative groups, including the National Wilms' Tumour Study Group (NWTSG), The International Society of Paediatric Oncology (SIOP) and the United Kingdom Children's Cancer Study Group (UKCCSG). Collectively, these studies have enabled Wilms' tumor treatment to be modified to minimize morbidity for low-risk disease and to maximize the prognosis for high-stage, high-risk patients.

In this article we discuss the most-debated issues and advances that have been made in the management of Wilms' tumor.

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Risk factors for Wilms' tumor

Wilms' tumor normally develops in otherwise healthy children, but about 10% of cases occur in individuals with recognized malformations, which can be classified as overgrowth or non-overgrowth syndromes (Table 1). These associations highlight the importance of screening for renal lesions in 'at-risk' groups of patients.3, 4

Table 1 Almost 10% of children with Wilms' tumor will have recognized malformations, which can be categorized as overgrowth or non-overgrowth syndromes.
Table 1 - Almost 10% of children with Wilms' tumor will have recognized malformations, which can be categorized as overgrowth or non-overgrowth syndromes.
Full tableFigures & Tables indexDownload PowerPoint slide (242K)

Although Wilms' tumor is predominantly a sporadic disease there is a genetic predisposition in a small number of individuals. Several genes have been implicated in the etiology of these lesions. Specific germ-line mutations in one of these genes—the Wilms' tumor 1 (WT1) gene, which is located on the short arm of chromosome 11 (11p13)—have also been implicated in associated genitourinary abnormalities, such as CRYPTORCHIDISM and hypospadias.5 A gene that is implicated in ANIRIDIA is also located adjacent to the WT1 gene, and children with the Wilms' tumor, aniridia, genitourinary abnormalities and (mental) retardation syndrome require close surveillance as they have an increased risk of developing bilateral Wilms' tumors.

A second Wilms' tumor susceptibility gene was identified at or near the BECKWITH–WIEDEMANN SYNDROME (BWS) gene locus on chromosome 11p15.6 Approximately one fifth of patients with BWS develop bilateral tumors, which are primarily observed at the time of initial diagnosis, although metachronous occurrence (i.e. development of a second Wilms' tumor in the contralateral kidney at a later stage), has also been observed.7

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Diagnosis

Most patients with Wilms' tumor present with a palpable abdominal mass, but some children present instead with hematuria, fever or abdominal pain. In rare cases, where patients have renal vein or caval extension, development of varicocele, hepatomegaly, ascites or congestive heart failure can lead to the diagnosis. Associated features, such as aniridia, hemihypertrophy or urogenital anomalies, have been documented.8 Imaging is vital for planning major surgery and ensuring normal function of the contralateral kidney, although different histologic types of renal tumor have common radiographic characteristics.9 Ultrasound in conjunction with a CT scan can help to diagnose renal vein and vena caval involvement, and MRI has been advocated as an alternative to CT to map intravascular extensions of the neoplasm.10 In addition, chest imaging with CT is commonly performed, although the prognostic significance of CT findings is equivocal.11

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Synchronous and metachronous tumors

Approximately 5% of Wilms' tumor cases present with bilateral lesions at the time of diagnosis (synchronous bilateral tumor),12 but a metachronous bilateral tumor develops in approximately 1.5% of children under 1 year old who initially present with a unilateral tumor that is successfully treated. This is especially true in children whose resected kidney contains perilobar nephrogenic rests,13 and periodic abdominal ultrasound is recommended for early detection of metachronous Wilms' tumors if the resected histology shows this characteristic. In 95% of patients, the time to diagnosis of a second tumor is less than 5 years, thereby placing a limit on the period of follow-up surveillance.14

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Staging of Wilms' tumors

Histologic features provide important prognostic information that allow clinicians to ascertain the requirements for treatment following nephrectomy. Nuclear atypia, focal or diffuse anaplasia and sarcomatous tumors are all considered to be unfavourable histologic features. Unfavorable histology accounts for only 10% of all Wilms' tumor patients, but these patients account for 50% of the mortality.15

Favorable histologic features include the formation of a pseudocapsule composed of compressed atrophic renal tissues. In addition, diverse structures of developing renal tissue are often seen, as well as skeletal muscle, cartilage and squamous epithelium. Epithelial differentiated tumors are mainly stage I (Table 2), but tend to be unresponsive to chemotherapy if they are advanced.14 By contrast, blastema-differentiated tumors are highly aggressive, but seem to respond well to chemotherapy.16 In the SIOP-93-01 study, the Stockholm working classification of renal tumors was used to stratify patients who had preoperative chemotherapy into low-risk, intermediate-risk and high-risk histology, on the basis of their nephrectomy pathology reports.17 This classification has recently been revised.18 This is different to the NWTSG classification (Table 2) that represents chemotherapy-naive nephrectomy histology.

Table 2 Staging system of the National Wilms' Tumour Study.
Table 2 - Staging system of the National Wilms' Tumour Study.
Full tableFigures & Tables indexDownload PowerPoint slide (301K)

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Current management of Wilms' tumor

Surgery

The mainstay of initial treatment for most patients with Wilms' tumor is a transperitoneal radical nephrectomy. Intraoperative staging must include examination of the contralateral kidney for tumor or nephrogenic rests, and inspection for evidence of local tumor extension, liver and nodal metastases, and peritoneal seeding. However, as spiral CT now provides sufficient sensitivity and definition in excluding tumor in the contralateral kidney, we at Great Ormond Street Hospital (GOSH) do not examine the opposite kidney intraoperatively. The presence or absence of palpable tumor in the renal vein must also be ascertained before vessel ligation. Tumors extend into the renal vein in 6% of patients, and this is clinically asymptomatic in 50% of cases.19 Careful operative removal is essential, as tumor spillage, incomplete tumor removal, absence of lymph-node sampling and unfavorable histology are all risk factors for abdominal recurrence.20 The incidence of surgical morbidity was reported at 12.7% for the NWTS-4 study, the most common complications being small-bowel obstruction (5.1%), hemorrhage (1.9%) and wound infection (1.9%). This is considerably lower than the surgical complication rate of 19.8% for the NWTS-3 study.

Currently, the role of partial nephrectomy for Wilms' tumor is controversial, as few patients have suitably small peripherally located tumors. Furthermore, other important histologic risk-stratification features, such as nephrogenic rests, cannot be determined from normal resected renal tissue. Therefore, at GOSH, partial nephrectomy is only considered for patients with a solitary kidney, bilateral lesions or renal insufficiency, or in children who are likely to develop multiple neoplasms. Laparoscopic nephrectomy with lymph-node sampling is possible, especially following preoperative chemotherapy,21 but long-term experience with this technique is lacking.

Chemotherapy

Current efficacious treatment regimes for Wilms' tumor are a consequence of several decades of investigation by dedicated research groups, including SIOP, UKCCSG and NWTSG. Current treatment is based on dactinomycin, vincristine and doxorubicin as first-line chemotherapy, with cyclophosphamide, ifosfamide, carboplatin and etoposide being used in patients who have relapsed or who have a poor response. Treatment algorithms depend on the stage and grade of the tumor and are discussed later in this article. Each agent has specific attributes and complications, such as the cardiac toxicity that has been observed with doxorubicin.22

The SIOP and UKW3 trials have favored the use of preoperative chemotherapy to attempt to downstage tumors before nephrectomy, whereas in the NWTSG trials immediate surgery is undertaken without neoadjuvant therapy in order to precisely identify tumor stage. The former approach also leads to a low incidence of perioperative tumor rupture (7%),23 and histologic response to chemotherapy can be assessed postoperatively. However, in the SIOP studies, neoadjuvant chemotherapy was commenced without histologic proof, on biopsy, that the neoplasm had the typical clinical and radiologic features of Wilms' tumor. This approach is controversial, because in the UKW3 study, which involved confirmatory tumor biopsy before the commencement of chemotherapy, 1% of patients had a non-malignant lesion and 12% of lesions that seemed radiographically to be Wilms' tumors were shown to be non-Wilms' tumors on prechemotherapy biopsy.24 The UKW3 trial provided no evidence that percutaneous biopsy led to an increased risk of tumor recurrence of the flank.24

Radiotherapy

Radiotherapy has an important role in the management of Wilms' tumors in the adjuvant setting, based on tumor stage and histology. Recent advances in three-dimensional treatment-planning software, as well as conformal and intensity-modulated radiotherapy, have enabled dose escalation with limited increase in toxicity to adjacent organs. Several authors have reported using intraoperative high-dose-rate radiotherapy for solid malignancies in children with some success,25, 26 but to date, no randomized trials have been undertaken that compare conventional radiotherapy with intraoperative high-dose-rate radiotherapy. Perhaps owing to lack of validation, interest in this technique seems to be diminishing.

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Tumor staging and therapy

The most important determinant of outcome in Wilms' tumor is the histologic grade and stage of the tumor (see Table 2 for the NWTSG staging system), and accurate intraoperative staging is required to assess the requirements for postoperative intervention with chemotherapy or radiotherapy.

Stage I

Stage I patients in whom the tumor has favorable histology and is confined to an intact kidney have an excellent prognosis. The NWTS-1 trial used single-agent chemotherapy, and the NWTS-2 and NWTS-3 trials used combination-agent chemotherapy for the treatment of children under 2 years of age who had favorable histology Wilms' tumors weighing less than 550 g. No significant improvement in recurrence-free survival was observed if chemotherapy was administered postsurgery, supporting the use of nephrectomy alone in this group of patients.27 Conversely, the NWTS-5 trial showed recurrence-free survival of less than 90% for nephrectomy alone, closing the trial and supporting the use of postnephrectomy chemotherapy; however, relapses were treated more successfully in NWTS-5, probably because the patients had not previously been exposed to radiation or chemotherapy.28

NWTS-2 reported that patients with stage I tumors with favorable histology, who were randomly assigned to treatment with vincristine and dactinomycin for either 6 months or 15 months,29 showed 16-year relapse-free survival of 98.9% and 90.5% (P = 0.02) respectively,30 supporting the shorter chemotherapy regime. NWTS-3 reported that for similar patients randomly assigned to vincristine and dactinomycin for 10 weeks or 6 months,31 the 16-year relapse-free survival was 88.9% and 92.5%, respectively (P = 0.08).30

The recently reported SIOP 93-01 trial investigated patients with intermediate-risk and anaplastic tumors. They compared limited-duration postoperative chemotherapy (vincristine and dactinomycin) of 4 weeks with the more standard 18 week regime. The shorter regime produced fewer acute (e.g. bone-marrow toxicity, fever) and late (e.g. neurologic) side effects while maintaining treatment effectiveness. All children received prenephrectomy chemotherapy (vincristine and dactinomycin). In this study, event-free survival was 91.4% for 4 weeks of chemotherapy and 88.8% for 18 weeks of chemotherapy (P = 0.008), supporting the rationale for using shorter regimens since it reduces toxicity while maintaining efficacy.32

Stage II/III

Stage II tumors extend through the perirenal capsule, but can be completely excised. There may be local spillage of tumor confined to the flank, or the tumor may have been biopsied. Extrarenal vessels may contain tumor thrombus or be infiltrated by tumor. With tumor extending into the renal vein, cardiopulmonary bypass facilities and a cardiothoracic surgeon should be available on standby, whereas with neoplastic extension into the inferior vena cava, a joint procedure with the cardiothoracic team is a necessity. The NWTS-1 trial compared children with favorable-histology stage I Wilms' tumor and those with favorable-histology stage II–III tumor, treated with radiotherapy and a combination of vincristine and dactinomycin. The stage II–III disease was shown to have a worse prognosis than stage I. In the NWTS-2 and NWTS-3 trials, a more intensive three-agent chemotherapy regime (vincristine, dactinomycin and doxorubicin) was compared with the standard two-agent regime (vincristine and dactinomycin). In NWTS-3, radiotherapy was administered to randomly selected groups of stage II and stage III patients. In stage II disease, the addition of radiotherapy (20 Gy) produced no statistical improvement in 4-year recurrence-free or overall survival.27 There was no difference between two-agent or three-agent chemotherapy regimes in terms of overall survival for stage II/III patients, but a subset analysis of stage III disease did show a survival benefit for children treated with three-agent chemotherapy instead of two-agent chemotherapy (P = 0.04),27 as well as a decrease in abdominal relapses. High-dose radiotherapy (20 Gy) also had a significant impact on survival, although it raised additional concerns about long-term toxicity.

Therefore, for stage III favorable-histology tumors, low-dose 10 Gy radiotherapy and three-agent chemotherapy have been adopted as the preferred treatment. This regime is supported by the sixth SIOP trial (with additional prenephrectomy two-agent chemotherapy) which studied stage II (lymph-node-positive) and stage III tumors, and reported recurrence-free survival of 49% for postnephrectomy two-agent chemotherapy compared with 74% for three-agent chemotherapy (P = 0.029).23 Any increase in therapeutic intervention, whether with high-dose radiotherapy or addition of doxorubicin, leads to an increase in morbidity. The use of anthracyclins can increase the risk of a second malignant neoplasm and heart failure many years after the completion of treatment.33, 22

Stage IV

Stage IV patients with lung metastases represent a unique group of patients who require lung irradiation in conjunction with vincristine, dactinomycin and doxorubicin to improve survival.27 In the NWTS-3 trial, these patients had a greater than 80% survival rate at 4 years.27 In NWTS-2, three-agent chemotherapy produced no improvement in survival compared with two-agent chemotherapy.25 Therefore, for patients with unfavorable histology, more aggressive chemotherapy was initiated by adding cyclophosphamide to the three-agent regime. However, this produced no additional increase in recurrence-free or overall survival, and increased toxicity without improving outcome.27

Children entered into the UKCCSG Nephroblastoma Study 2 received three-agent chemotherapy, delayed nephrectomy and 12 Gy of whole-lung irradiation. The 4-year event-free and overall survival was 70% and 75%, respectively.34 SIOP studies in stage IV disease use prenephrectomy three-agent chemotherapy without initial lung irradiation. These children are then closely followed, and lung irradiation is delivered if required. This approach limits the number of children who are exposed to whole-lung irradiation, with its inherent immediate and late toxicity.35

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Bilateral Wilms' tumor

Patients with stage V disease (bilateral Wilms' tumor) survive in about 70% of cases, but have a high incidence of renal failure.12, 36 Therefore, prior to surgical intervention, both kidneys should be biopsied to ensure an accurate diagnosis, followed by 6–8 weeks of preoperative chemotherapy. Each kidney can then be reassessed to determine the feasibility of renal-sparing resection. At GOSH, in cases of bilateral disease, we now use positron-emission tomography scanning to detect viable tumor tissue postchemotherapy prior to surgery. This imaging modality is particularly useful in these cases, providing a guide as to the extent and resectability of the tumor (i.e. whether partial or total nephrectomy will be necessary). Any intervention should be monitored closely, and nephron-sparing surgery should be performed in patients who are likely to require renal replacement therapy in the future. In the NWTS-4 study, the rate of renal failure was only 3.8% in unilateral Wilms' tumor patients, so nephron-sparing surgery is probably unnecessary with unilateral disease.36 It is very important in stage V disease that the patient is well hydrated intravenously both preoperatively and postoperatively in order to provide optimum renal perfusion. Additionally, in cases of bilateral neoplasm, one should operate initially on the tumor that is more amenable to partial nephrectomy, and if successful, one can perform a complete nephrectomy on the opposite side if this becomes necessary.

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Relapsed Wilms' tumor

Favorable prognostic factors for relapsed Wilms' tumor include an initial diagnosis of stage I or II, initial two-agent treatment, no radiotherapy, favorable histology and longer time from diagnosis to relapse. Historically, the prognosis for patients with relapsed Wilms' tumor has been poor, although some reports indicate that reintroduction of combination therapy with ifosfamide, carboplatin and etoposide has some efficacy. Abu-Ghosh et al. reported that in a small group of 11 patients, ifosfamide, carboplatin and etoposide chemotherapy produced an overall response rate of 82%. The 3-year event-free survival and overall survival rates were 63.6 plusminus 14.5%,37 but the success of this regime comes at the expense of high-grade hematologic toxicity.38 High-dose chemotherapy combined with autologous hemopoietic stem-cell rescue has been shown to produce a 4-year overall survival of 73% in a small group of 13 patients.39

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Conclusion

Wilms' tumor therapeutic regimes are based predominantly on stage and histologic features. Treatment strategies differ between the US, favoring immediate nephrectomy, and Europe, favoring preoperative chemotherapy. The UK treatment strategy also differs slightly from European strategies, favoring prenephrectomy chemotherapy only after initial tumor biopsy to exclude the small percentage of children who have benign pathology or non-Wilms' tumors, which require different treatment modalities. These approaches have the definitive advantages of a decrease in intraoperative tumor rupture and down-staging for the European approach, and definitive histologic diagnosis and chemotherapy-naive tumor for the US approach. The UK strategy reaps the benefits of histologic diagnosis as well as preoperative chemotherapy prior to nephrectomy.

These differing approaches subtly alter treatment strategies depending on the use of neoadjuvant chemotherapy. However, stage II/III disease in either setting requires further adjuvant treatment with two-agent or three-agent chemotherapy, as well as radiotherapy in some cases. Stage IV patients require three-agent chemotherapy and additional lung irradiation, either immediately or if radiographic evidence of disease develops. Preoperative chemotherapy is universally administered in bilateral tumors, with reassessment and nephron-sparing surgery utilized, when appropriate, to diminish the high incidence of renal replacement therapy in this group. Relapsed Wilms' tumor can be treated with a combination of ifosfamide, carboplatin and etoposide, at the expense of severe bone-marrow toxicity—the latter may be managed by autologous hemopoietic stem-cell rescue.

The last few decades of the 20th century have seen significant refinements in the management of Wilms' tumor patients, with a considerable reduction in treatment-associated morbidity. The management of most patients with two-agent chemotherapy, with no harmful anthracycline or radiotherapy toxicity, is evidence-based and represents curative treatment. However, several areas require further investigation. Relapsed Wilms' tumor patients are currently exposed to high-dose treatment regimes, which need to be optimized. Also, autologous hemopoietic stem-cell rescue requires further evaluation in many nonhematologic malignancies. Further definition of the biologic pathways involved in Wilms' tumor and the discovery of novel therapeutic targets should aid the generation of additional therapies. These therapies will require further evaluation in randomized controlled trials, thereby continuing the excellent progress that has been made in the past few decades.

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Competing interests

The authors declared no competing interests.

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Subject areas under which this article appears: Pediatric Oncology