Epidemiology

Wilms tumor accounts for 6% of all childhood cancers in the United States, where the estimated incidence is 470 cases per year,³ or 8 per million children younger than the age of 16 years.^2,4 In the United States, the disease is slightly more prevalent among girls than boys (1 : .92 for unilateral tumors, 1 : .6 for bilateral tumors). This disparity is not maintained worldwide; the global incidence is 1 in 10,000 children with no gender predilection noted.⁴ The incidence of Wilms is three times higher among Africans and African Americans than among East Asians, with the incidence among the European and American white population falling between these two extremes.⁵

Age at presentation depends on gender and laterality. Males tend to present earlier than females, and bilateral tumors earlier than unilateral tumors. The median age at diagnosis of bilateral disease is 30 months, whereas for unilateral disease it is 40 months.⁶ Seventy-five percent of all patients present before 5 years of age.⁷ Bilateral disease is noted in 4% to 8% of patients at presentation^8–10; 7% to 12% of patients with unilateral Wilms demonstrate multifocal disease in the affected kidney.¹¹

The majority of cases are sporadic, but Wilms tumor is thought to have a hereditary basis in 15% to 20% of affected patients.¹² Approximately 1.5% of patients have familial Wilms, wherein one or more family members has the disease (usually siblings or cousins, rarely parents); in these cases, the mode of inheritance is generally thought to be autosomal dominant with variable penetrance.¹³

Etiology, Genetics, and Cytogenetic Abnormalities

Investigation of the role of parental environmental exposures as a causal factor of Wilms tumor has yielded inconsistent findings. Case-control studies have suggested that paternal exposure to lead and hydrocarbons increases the incidence of Wilms tumor in offspring, and that fathers employed as auto mechanics, welders, and machinists demonstrate an increased odds ratio for Wilms tumor among their offspring.^14–17 However, other studies have failed to find any such correlation with paternal exposure or occupation.^18–20 Previously reported maternal associations (smoking during pregnancy, hypertension of pregnancy, tea consumption) were not confirmed in a large case-control study.^16,21

Genetic explanations of the causal factors of Wilms tumor originated with Knudson’s “two-hit hypothesis,” originally developed for retinoblastoma.^22,23 Briefly, the two-hit hypothesis proposes that tumors develop as a consequence of two mutational events in a single cell. If the first mutational event is prezygotic (or germ line), the tumor is potentially hereditary and affected individuals are at risk of developing multiple tumors. Conversely, sporadic cases occur as a result of two postzygotic (or somatic) mutations in a single cell; because two postzygotic events are unlikely to occur in more than one cell, these patients are unlikely to present with multiple tumors.²¹ This hypothesis explains the earlier age of onset and bilateral presentation of familial Wilms compared with sporadic cases.^13,24

Whereas the two-hit hypothesis has been confirmed in retinoblastoma to occur via inactivation of both alleles of a tumor-suppressor gene on 13q, the genetic events that lead to the development of Wilms tumor are less well-defined and appear to be more complex. Multiple genetic loci appear to play a role in the development of Wilms. The best known of these are located on the short arm of chromosome 11.²⁵ Designated Wilms Tumor-1 (WT-1, at 11p13) and WT-2 (at 11p15) mutations in these putative tumor suppressor genes are found in 30% to 40% of Wilms tumors²¹ and are associated with three well-described congenital anomaly syndromes:

Although evidence for the role of these genetic loci in the development of Wilms is compelling, studies of affected pedigrees have failed to confirm either 11p13 or 11p15 as the location of the familial Wilms tumor gene.²⁸ Based on epidemiologic and clinicopathologic analyses, NWTS group investigators have suggested that mechanisms other than germ line mutations (e.g., somatic mosaicism) are responsible for some bilateral and multicentric tumors.^6,29

Other genetic mutations appear to contribute to adverse outcomes in children with Wilms tumor, although they are not clearly causative of the disease. Alterations in chromosomes 1p and 16q are associated with poor prognosis in children with Wilms tumor, implying that these genes are involved with tumor progression rather than tumor initiation²¹; hence they are referred to as Wilms tumor progressor genes, to distinguish them from WT-1 and WT-2. In a study of 232 children registered on NWTS-3 and NWTS-4, loss of heterozygosity (LOH) at either locus was associated with a poorer 2-year relapse-free and overall survival (OS), even with adjustment for stage and histologic subgroup.³⁰

Heterozygous mutations in p53 are strongly associated with the anaplastic phenotype as compared with FH findings,³¹ suggesting that p53 abnormalities result in more aggressive histologic features. Overall, however, the incidence of p53 mutations in Wilms tumor is relatively low.^32,33

Anatomy

Wilms tumors can arise in any area of the renal parenchyma. There is no predilection for either side. Extrarenal Wilms tumors are rare but can occur in the retroperitoneum, usually in the vicinity of the kidney. The tumor has occasionally been known to occur in the pelvis, inguinal region, or thorax, arising from displaced metanephric elements or teratomas.³⁴

Pathologic Conditions

Childhood kidney tumors are organized according to the NWTS pathologic classification system (Table 57-1), which includes favorable as well as focal and diffuse anaplastic Wilms tumors, as well as clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney. Although these are histologically distinct from Wilms tumor, children with these diseases are included in NWTS trials because of the rarity of their occurrence, and treatment recommendations are based on NWTS findings.

Table 57-1 National Wilms’ Tumor Study Pathologic Classification System of Pediatric Renal Tumors

Congenital mesoblastic nephroma Classical Cellular or atypical Wilms’ tumor Favorable histology Anaplastic Focal anaplasia Diffuse anaplasia Clear cell sarcoma Rhabdoid tumor

Congenital mesoblastic nephroma, which is included in the NWTS classification system, falls at the benign end of the spectrum of pediatric renal tumors. It is the most common renal tumor of infancy,²⁴ presenting at a median age of 2 to 3 months and occurring predominantly in males.³⁵ It is characterized by bundles of spindle cells resembling fibroblasts or smooth muscle; cells at the periphery frequently extend deeply into the parenchyma or perirenal tissues. Despite its tendency for local extension, local recurrence or distant metastasis is highly uncommon, and the tumor may be curable by surgery alone (radical nephrectomy with wide margins). The cellular (or atypical) subclass of mesoblastic nephroma demonstrates increased cellularity and high mitotic rates. In older infants, this has been occasionally associated with local recurrence or the development of distant metastases.³⁶ However, in infants younger than 3 months, cellular congenital mesoblastic nephroma is not associated with a poorer prognosis.³⁷ Because there is no established role for radiation therapy in the management of mesoblastic nephroma, the subject is not discussed further in this chapter.

Wilms tumor is derived from primitive metanephric blastema and is classically triphasic in composition, consisting of varying proportions of blastemic, stromal, and epithelial elements.² These elements appear to recapitulate normal renal embryogenesis. At the same time, Wilms tumors often contain tissues not found in the kidney, such as skeletal muscle, cartilage, and squamous epithelium, reflecting the pluripotent nature of primitive metanephric cells.²¹ Although triphasic composition is typical, Wilms tumor is characterized by tremendous structural and histologic diversity. Biphasic patterns are common, and tumors expressing predominantly or exclusively one element can still be categorized as Wilms tumor.³⁸ Mixed composition is most common (41% of tumors), followed by blastemal predominant (39%) and epithelial predominant (18%); stromal predominant tumors are rare (1%). Although blastemal predominant tumors appear to be clinically more aggressive, these tumors are still classified as FH unless diffuse anaplasia is noted.³⁹

Wilms tumors are classified as FH unless they meet clearly defined criteria for anaplasia. These criteria were established by Beckwith and Palmer⁴⁰ following analysis of NWTS-1, and were refined by Faria and coworkers after analysis of NWTS-3 and 4 (Table 57-2). The original criteria did not account for location or multicentricity of anaplastic nests, and the distinction between focal and diffuse anaplasia lacked prognostic significance. In contrast, when Faria and colleagues’ strict criteria were applied in a review of NWTS-3 and four cases, patients with focal anaplasia were found to have a significantly superior 4-year survival as compared with patients with diffuse anaplasia; this difference was maintained stage for stage except for stage I tumors, in which survival was 100% for both focal and diffuse anaplasia.⁴¹ This prognostic significance highlights the importance of thorough sampling of the gross specimen during pathologic evaluation, as well as meticulous documentation of the exact specimen site from which each slide is obtained.

Table 57-2 Anaplastic Wilms’ Tumor:

Definitions and Criteria

Definition of anaplasia	1 Nuclei with major diameters at least 3 times those of adjacent cells AND 2 Hyperchromatism of the enlarged nuclei AND 3 Multipolar or otherwise recognizably polypoid mitotic figures
Focal anaplasia: criteria	Anaplasia confined to a single region of the kidney
Diffuse anaplasia: criteria	Anaplasia present in more than one region of the kidney OR anaplasia in any extrarenal site (including vessels of the renal sinus, extracapsular infiltrates, or nodal or distant metastases) OR anaplasia in a random biopsy specimen

Modified from the National Wilms’ Tumor Study-5: Therapeutic Trial and Biology Study. Unpublished. Activated June 16, 1995; last revised June 1998.

Eighty-nine percent of Wilms tumor cases in NWTS-3 were categorized as FH; 5% were anaplastic. The likelihood of anaplasia increased with age in NWTS-3; it was noted in only 2% of children younger than age 2 but increased to 13% in children ages 5 and older. Anaplastic tumors are significantly more frequent in black children than white children.⁴²

Clear cell sarcomas and rhabdoid tumors of the kidney were originally believed to be monophasic variants of Wilms tumor; however, NWTS pathologists established both as unique tumors in 1978.^40,43 They have since been analyzed separately but remain within the NWTS trials. Both entities are associated with strikingly poorer outcomes than Wilms tumor. CCSK is a primitive mesenchymal neoplasm distinguished by cells with poorly stained cytoplasm, prominent cytoplasmic vacuolation, and indistinct cell borders; groups of cells are often separated from one another by an arborizing network of thin-walled capillary vessels.^24,39 CCSK accounts for 4% of all childhood renal tumors. Like Wilms, its most common site of distant spread is to the lungs; however, CCSK is distinguished by its propensity for bone and brain metastases as well. Twenty-three percent of children with CCSK in NWTS-3 developed bone metastases, as compared with 0.3% of all other children entered in the study.^44,45

Rhabdoid tumor of the kidney, in contrast to CCSK, is marked by strongly acidophilic cytoplasmic staining. The tumor cells thus resemble myoblasts, but skeletal muscle markers are negative and the cell of origin is unknown.^46,47 Like CCSK, rhabdoid tumors have a propensity for brain metastases; in addition, they can arise as primary CNS neoplasms,⁴⁸ particularly primitive neuroectodermal tumors; this finding suggests a possible neural crest origin for rhabdoid tumors, a hypothesis that has been supported by histochemical analysis.^47,49,50 Rhabdoid tumor occurs most commonly in male infants; median age at diagnosis is 13 months, and most cases are diagnosed in the first 2 years of life. In children older than 5 years diagnosed with rhabdoid tumor, pseudorhabdoid lesions (carcinomas, melanomas, histiocytic tumors, or myosarcomas) should be suspected.⁵¹ Rhabdoid tumors carry the poorest prognosis of all childhood renal tumors because of propensity for both local relapse and distant metastases.

Clinical Presentation

Eighty-three percent of children with Wilms tumor present with a painless abdominal mass.⁵² Other common presenting signs and symptoms include abdominal pain (37%), hypertension secondary to increased renin activity (25%), fever (23%), and hematuria (21%).⁵³ Abdominal pain resulting from any cause (local distention, intralesional hemorrhage, peritoneal rupture) has been correlated with poorer 5-year survival.⁵⁴ Acute subcapsular hemorrhage into the tumor results in a distinctive constellation of symptoms, including rapid abdominal enlargement, anemia, hypertension, and sometimes fever; plain radiographs of the abdomen may demonstrate a thin rim of eggshell-like calcification.⁵⁵

Less commonly, children may present with varicocele, enlarged testicle, hernia, pleural effusion, congestive heart failure, or hydrocephalus.⁵⁶ Several paraneoplastic syndromes have been reported in association with Wilms tumor, including Cushing syndrome, erythrocytosis, hypercalcemia, and acquired von Willebrand disease.⁵⁷

Screening for children with known phenotypic or genotypic risk factors for the development of Wilms tumor is controversial. No randomized trials have been performed to address this question. Retrospective analyses of the NWTS registry and the National Childhood Cancer Registry of the United Kingdom failed to demonstrate a benefit to screening in children with aniridia, hemihypertrophy, or BWS.^58,59 However, these studies were limited by the variation in incidence and time intervals of screening, as well as the methods used. In contrast, a case series analysis of children with BWS or hemihypertrophy, in which the case group had undergone systematic ultrasound screening at intervals of 4 months or less, suggested that screening sonograms every 4 months decreased the incidence of late-stage disease in these children (42% stage III to IV disease in unscreened children versus 0% in screened children, P < 0.003).⁶⁰ A simulation model of sonogram screening three times yearly for children with BWS suggested that such a program would be comparably cost-effective to mammographic screening if applied from birth to age 4, largely because detection of earlier-stage disease would obviate the expense associated with radiation therapy.⁶¹ This hypothesis is supported by the finding that children with BWS in NWTS-3 and 4 were more likely to present with lower-stage tumors, although this may be a reflection of low biologic potential of Wilms tumor in these children in addition to the effect of increased surveillance screening.²⁷

Routes of Spread

The most common location of local spread in Wilms is to the vessels of the renal sinus, which may be distended by tumor or demonstrate tumor thrombus. Penetration through the renal capsule is the second most common site of extrarenal spread. Not uncommonly, inflammation of the perirenal tissues can result in the formation of an inflammatory pseudocapsule, which may cause adhesions to adjacent organs such as the liver; yet on pathologic analysis, penetration of the true capsule by tumor is not demonstrated. Such cases are classified as stage I (limited to kidney, and completely resected, with negative margins).²¹ Even when tumor is adherent to or directly invades the liver, analysis of FH NWTS-3 cases demonstrated no detrimental effect on prognosis stage for stage.⁶² Conversely, patients with renal vein involvement were much more likely to have metastatic disease at diagnosis.⁶³

Metastatic spread occurs most commonly in the regional (renal hilar and para-aortic) lymph nodes, lung, and liver. Other metastatic sites are uncommon in Wilms tumor. Bone metastases are a hallmark of CCSK, and both CCSK and rhabdoid tumor are associated with brain metastases.

Diagnostic and Staging Studies

The primary differential diagnosis of a pediatric abdominal mass is Wilms tumor versus neuroblastoma; these can generally be distinguished on computed tomography (CT) or magnetic resonance imaging (MRI). Neuroblastoma arises from the adrenal gland or paravertebral sympathetic ganglia; as such, it compresses but does not distort the renal parenchyma. Conversely, Wilms is an intrarenal tumor, and therefore is marked by distortion of kidney architecture. Furthermore, tumor calcification is more common in neuroblastoma (>50%) than in Wilms (<10% to 15%). Ultimately, the determination of neuroblastoma versus Wilms is based on pathologic findings.

The purpose of radiographic imaging in the workup of Wilms tumor is to establish the presence of a functioning, normal contralateral kidney; identify tumor thrombus in the renal vein and inferior vena cava (IVC); and establish the presence or absence of pulmonary metastases. A CT scan of the chest and abdomen as well as abdominal sonogram are recommended.

Abdominal ultrasound can fulfill several functions. It can establish the renal origin of the mass; demonstrate whether the mass is solid or cystic; and identify the presence and extent of tumor thrombus in the renal vein and IVC.³⁴ Evaluation of the contralateral kidney is also possible, although this function is largely supplanted by CT. Contrast-enhanced CT imaging of the abdomen is recommended for further evaluation of the mass and adjacent viscera. CT can provide additional information on renal function, retroperitoneal lymphadenopathy, and extension to or invasion of adjacent organs, particularly hepatic metastases. Of note, however, in most cases in which CT identifies hepatic invasion, subsequent surgical exploration reveals only compression by tumor.⁶⁴

The use of preoperative CT or MRI to evaluate for tumor in the contralateral kidney has been advocated in some surgical literature. However, others believe that imaging cannot replace intraoperative exploration.²⁴ The NWTS protocols require surgical exploration to rule out contralateral disease. Debate also exists concerning the use of abdominal CT versus abdominal MRI in diagnosis of children with suspected Wilms tumor because of concern regarding radiation exposure.⁶⁵

In the past, there has been controversy over whether lung metastases detected by CT scan but not chest radiograph warrant whole lung radiotherapy. This question was addressed by Meisel et al.⁶⁶ in an analysis of NWTS-3 and 4 data. The authors found no significant differences in event-free survival (EFS) or OS among chest x-ray–positive, CT-negative children who received intensive doxorubicin-containing chemotherapy and whole-lung irradiation (WLI) versus multidrug chemotherapy (with or without doxorubicin) and no WLI. Although WLI resulted in fewer pulmonary relapses, a greater number of deaths were attributed to pulmonary toxicity. The authors concluded that WLI was not clearly necessary in treatment of children with discordant chest x-ray, CT findings,⁶⁶ noting, however, that the small study numbers prevented a definitive recommendation.

Additional radiographic studies are required for children with CCSK or rhabdoid tumor of the kidney. MRI scan of the brain is required in both cases to rule out brain metastases and, in children with rhabdoid tumor, associated primary neuroectodermal tumors. Children with CCSK should also undergo skeletal survey and radionuclide bone scan to rule out bone metastases.

Laboratory studies should be obtained in all children with suspected Wilms tumor, including urinalysis, complete blood count, blood chemistries, liver function tests, and alkaline phosphatase. Children with CCSK should also undergo bone marrow aspiration and biopsy.

Stage III Stage IV Hematogenous metastases (lung, liver, bone, brain, etc.), or lymph node metastases outside the abdominopelvic region are present. (The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present). Stage V Bilateral renal involvement by tumor is present at diagnosis. An attempt should be made to stage each side according to the previously discussed criteria on the basis of the extent of disease.

Standard Therapeutic Approaches

The treatment approach advocated by the NWTS involves upfront surgery consisting of a modified radical nephrectomy and selective lymph node sampling. Exceptions to this rule include cases with intravascular tumor thrombus above the level of the hepatic vein, tumor contiguous with other abdominal structures, or bilateral renal involvement. In these situations, initial surgical exploration is still recommended for accurate staging and to obtain biopsies (in these situations biopsy will not result in further upstaging), but definitive surgical resection is postponed until after the administration of preoperative chemotherapy.⁶⁷ Preoperative biopsy is not encouraged and results in automatic upstaging unless performed via fine-needle aspiration.

Preoperative sonography is strongly recommended to identify extensive intravascular thrombus, which can extend into the IVC to the right atrium, or in the case of left-sided tumors, down the gonadal vein. IVC extension occurs in only 6% of cases, and is usually asymptomatic. Attempts at primary excision of tumor and thrombus were associated with excessive surgical morbidity in NWTS-4⁶⁸; however, if appropriate presurgical chemotherapy is given, even extensive intravascular thrombus does not adversely affect prognosis.^21,69,70

Diagnostic imaging studies may reveal contiguity of tumor to adjacent structures such as the liver, spleen, or pancreas. If the surgeon is sure that all disease can be completely removed, radical en bloc resection of the affected kidney and adjacent nonessential structures is acceptable. However, if complete en bloc resection cannot be performed, the tumor will be considered spilled.^21,67,71

Patients with bilateral Wilms tumor have a good survival prognosis but increased risk of renal failure. This risk can be decreased through the use of preoperative chemotherapy and renal parenchymal-sparing surgical procedures. Upfront surgery is still recommended, at which time bilateral renal biopsies should be obtained, suspicious lymph nodes sampled, and a surgical stage assigned to each side. Radical excision should not be performed at the initial operation. Partial nephrectomy or wedge resection can be used only if all tumor can be removed with preservation of the majority of the renal parenchyma on both sides.

Preoperative chemotherapy is recommended by the COG in three distinct circumstances: tumors deemed unresectable at initial surgical exploration,⁷² bilateral tumors at presentation,⁶⁷ and tumor extension into the IVC above the level of the hepatic veins.⁷⁰ Preoperative chemotherapy almost always reduces tumor bulk, which can facilitate complete removal of the tumor and decrease surgical complications. However, it has not been shown to improve OS and is not generally advocated by the COG because it results in loss of important staging information. Even in the circumstances outlined earlier in which upfront chemotherapy is recommended, the COG strongly encourages surgical exploration for diagnosis and staging before chemotherapy.^73,74

The evolution of Wilms tumor management in North America is outlined in the following discussion of the NWTS trials. The International Society of Pediatric Oncology has also conducted successive clinical trials of Wilms tumor management in Europe. This approach differs from that in the United States primarily in its use of routine preoperative chemotherapy and radiation therapy. These trials are not discussed in this chapter.

NATIONAL WILMS TUMOR STUDY–1

NWTS-1 (1969 to 1974) asked three major treatment questions: whether postoperative radiation therapy could be eliminated in children with stage I disease, whether actinomycin D or vincristine or the combination of both was superior in treatment of children with stage II and III disease, and whether preoperative vincristine was beneficial in the management of children with stage IV disease.⁷⁵

The radiation dose was determined on an age-dependent scale, ranging from 18 Gy for children younger than 18 months to 40 Gy for children older than 40 months. Stage I and II patients received radiation to the site of the kidney and associated tumor as visualized on preoperative imaging. The field extended across the midline to encompass the vertebral bodies and minimize asymmetric growth deformities. Group III patients received either flank or whole-abdomen radiation based on the extent of residual disease or tumor spillage at surgery. Patients with pulmonary metastases received WLI to 14 Gy. Other sites of metastatic disease received higher doses, to a minimum of 30 Gy.

The results of NWTS-1 led to the following treatment recommendations. First, postoperative radiation could be eliminated in children younger than age 2 with stage I disease; among older children, radiation appeared to decrease the rate of abdominal recurrences. Second, combination chemotherapy with actinomycin-D and vincristine was preferred for children with stage II or III disease, rather than monotherapy with either agent alone. Lastly, preoperative vincristine was of no benefit to children with metastatic disease.⁷⁵

Retrospective analyses of the NWTS-1 data demonstrated that initiation of radiation later than postoperative day 10 was associated with adverse outcomes,⁷⁶ a finding that was confirmed in NWTS-2 and NWTS-3.⁷¹ Retrospective review also suggested that local spillage at surgery required flank irradiation only, rather than whole-abdomen irradiation.⁷⁷

It should be noted that 3% of the 358 children randomized (10 patients) died of complications of treatment; 5 of these children were disease free at the time of death. This highlights the importance of refining and minimizing therapeutic interventions, a major goal of subsequent studies.

NATIONAL WILMS TUMOR STUDY–2

NWTS-2 asked three major chemotherapeutic questions. First, could multiagent chemotherapy replace radiation in older children with stage I disease? Second, did stage I children require the protracted postoperative chemotherapy specified in NWTS-1? Third, did the addition of doxorubicin to actinomycin D and vincristine benefit children with stages II to IV disease?

Radiation therapy was eliminated for all stage I children. Flank irradiation was given to all stage II to IV children according to the same age-dependent scale used in NWTS-1; whole-abdomen irradiation was reserved for children with diffuse peritoneal seeding. Children with lung metastases were initially treated with WLI to 14 Gy, but the dose was scaled back to 12 Gy after a 10% incidence of pneumonitis was noted. No randomization was performed with regard to radiation. Comparison of stage I outcomes with those recorded in NWTS-1 suggested that elimination of radiation in children age 2 and older did not adversely affect outcomes.⁷⁸ Data analysis showed no statistically significant difference in 3-year survival between children receiving 6 months of chemotherapy (97%) and children receiving 15 months of chemotherapy (92%). Addition of doxorubicin was shown to benefit children with stages II to IV disease. When analyzed by histologic examination, this benefit was significant for FH patients. Patients with UH showed a trend toward improved survival with the addition of doxorubicin, but this did not reach statistical significance.⁷⁸

NATIONAL WILMS TUMOR STUDY–3

NWTS-3 (1979 to 1985) was the first of the trials in which histologic anatomy was used to stratify patients into treatment arms. Results of randomization of stage I FH patients confirmed that these children could be successfully treated with surgery followed by an abbreviated course of chemotherapy (10 weeks versus 6 months). The 4-year recurrence-free survival (RFS) and OS for children treated with short-course chemotherapy was 89% and 96%, respectively; this did not differ significantly from the outcomes of children treated with long-course chemotherapy.⁹

Regarding stage II FH patients, NWTS-3 asked two questions: (1) whether flank irradiation could be safely eliminated, and (2) whether addition of doxorubicin to the standard regimen (actinomycin and vincristine) was beneficial. Children treated on the least intensive arm (actinomycin plus vincristine, without radiotherapy) demonstrated outcomes (87% 4-year RFS and 91% 4-year OS) that were statistically equivalent to those seen in the other three arms. Both doxorubicin and flank irradiation were thus shown to be unnecessary for children with stage II FH disease.⁹

Children with stage III FH disease were similarly randomized in a two-step fashion, to irradiation to 10 or 20 Gy and to chemotherapy with or without doxorubicin. In these children, addition of doxorubicin resulted in superior outcomes. There was no significant difference in rates of abdominal relapse between patients receiving 10 versus 20 Gy. However, a trend toward inferior outcomes was noted among patients receiving 10 Gy in the absence of doxorubicin. This suggested the necessity of including either doxorubicin or full dose (20 Gy) irradiation in the treatment of stage III FH patients⁹; NWTS-4 subsequently prescribed doxorubicin plus 10 Gy for all stage III FH patients.

Patients with UH (any stage) or stage IV FH all underwent nephrectomy followed by tumor bed irradiation and radiotherapy to sites of metastatic disease. They were then randomized to receive actinomycin, vincristine, and doxorubicin with or without cyclophosphamide. Addition of cyclophosphamide did not result in a statistically significant improvement in RFS or OS.⁹ However, subset analysis later suggested that when UH patients were further categorized as having either focal or diffuse anaplasia, those with stages II to IV diffuse anaplasia or CCSK (but not rhabdoid tumor) did benefit from the addition of cyclophosphamide.⁷⁹ For NWTS-4, the term favorable histology was thus amended to include focal anaplasia, and unfavorable histology was more strictly defined as diffuse anaplasia. Furthermore, stage I patients were grouped together in NWTS-4 regardless of histologic findings, as neither focal nor diffuse anaplasia had a negative prognostic effect in the earliest stage of the disease.

NATIONAL WILMS TUMOR STUDY–4

The primary intent of NWTS-4 (1986 to 1994) was to ascertain whether cost- and time-saving measures could be safely incorporated into the treatment regimens. To this end, 1687 patients across all stages were randomized to pulse-intensive (PI) versus standard-dose chemotherapy; for children with stages II to IV FH disease, a second randomization to 6 versus 15 months of chemotherapy was performed. As predicted, PI chemotherapy was both cost- and time-effective, resulting in fewer clinic visits and lower treatment costs. The 2-year RFS was equivalent between the PI and standard-dose arms (91.3% and 91.4%, respectively). Interestingly, the PI regimen also resulted in less hematologic toxicity.⁸⁰ Analysis of short- versus long-course chemotherapy in stages II to IV FH patients similarly demonstrated no significant difference in 4-year RFS. The cost of treatment for patients treated with PI short-course chemotherapy was approximately one-half that of patients treated on the standard-dose, long-course regimen.⁸¹

The focus on socioeconomic effects in NWTS-4 was made possible by the excellent treatment outcomes achieved in previous trials for children with FH disease. However, outcomes for patients with stages II to IV diffuse anaplasia and children with CCSK remained relatively poor. Therefore, these children were also randomized to receive cyclophosphamide (in addition to actinomycin D, vincristine, and doxorubicin), in an attempt to improve outcomes and clarify the suggestion of benefit to cyclophosphamide, which was retrospectively noted in NWTS-3. Cyclophosphamide was shown to improve both RFS and OS for patients with stages II to IV diffuse anaplastic disease. The combined NWTS-3 and NWTS-4 results for this group of children revealed a 55% 4-year RFS and 52% 4-year OS for patients who received cyclophosphamide, approximately twice that of patients who did not receive the drug (27% 4-year RFS and OS) (P = 0.02).² However, even the improved outcomes noted in the cyclophosphamide group compared poorly with those of patients with FH disease.

Patients with CCSK (all stages) were randomized to PI versus standard-dose chemotherapy, followed by a second randomization to short (24 to 26 weeks) versus long (54 to 65 weeks) courses of chemotherapy. There was no statistically significant difference in outcomes between randomization arms, leading to the conclusion that PI short-course chemotherapy was also acceptable for children with CCSK.⁸⁰

NATIONAL WILMS TUMOR STUDY–5

The primary intent of NWTS-5 was to identify genetic prognostic factors (specifically, deoxyribonucleic acid [DNA] ploidy and LOH at 16q or 1p) that predict for adverse outcomes, with the goal of targeting intensified therapies to patients at risk for relapse and minimizing treatment for the remainder of patients. Urine, blood, and tumor tissue samples of enrolled patients were obtained for analysis, and blood samples were also obtained from both biologic parents of each child.⁶⁷

The results of NWTS-5 have not yet been published, but outside of a current protocol, the NWTS-5 management guidelines by stage and histologic findings represent the current standard of care in the United States (Table 57-4). Treatment recommendations were modified from NWTS-4 for children with UH in an attempt to improve their historically poor outcomes. For children with stages II to IV diffuse anaplasia or CCSK, actinomycin was replaced by etoposide, and cyclophosphamide has been dose-intensified. Children with rhabdoid tumors were treated with a combination of cyclophosphamide, etoposide, and carboplatin, given that a neural crest origin has been postulated for rhabdoid tumor and that these agents have been previously employed for treatment of primitive neurogenic tumors.^67,81

Another goal of NWTS-5 was to minimize therapy (and thus decrease toxicity) for infants younger than 24 months with stage I FH disease. Such patients were initially treated with surgery alone, provided that their tumors were less than 550 grams in weight. However, the protocol was revised to include postoperative chemotherapy in 1998, after increased pulmonary relapses were noted. NWTS-5 continues to advise that infants younger than 18 months with pulmonary metastases at presentation receive a trial of chemotherapy alone, with reservation of WLI for persistent disease 4 weeks after initiation of chemotherapy.

CURRENT CHILDREN’S ONCOLOGY GROUP PROTOCOLS

The most recent generation of Wilms tumor protocols were activated in 2008 and 2009. They comprise five protocols of, which one is a tumor biology and banking study (AREN03B2).⁸² The other four are experimental therapeutic trials designated as follows: high-risk renal tumors (AREN0321)⁸³; very low- and standard-risk FH Wilms tumor (AREN 0532)⁸⁴; treatment of newly diagnosed higher-risk FH Wilms tumors (AREN0533)⁸⁵; treatment for patients with bilateral, multicentric, or bilaterally predisposed unilateral Wilms tumor (AREN0534).⁸⁶

AREN0321 for high-risk tumors aims to enroll patients with diagnoses of anaplastic Wilms tumor, CCSK, and malignant rhabdoid tumor. Primary objectives are to evaluate whether a treatment regimen containing cyclophosphamide, carboplatin, and etoposide alternating with vincristine, doxorubicin, and cyclophosphamide improves the EFS and OS of patients with diffuse anaplastic Wilms tumor and malignant rhabdoid tumor as compared with historical controls. The study will also evaluate, in a phase II “window” study, the antitumor activity of a combination of vincristine and protracted-schedule irinotecan against metastatic diffuse anaplastic Wilms tumor.

All patients will receive abdominal radiotherapy except those with stage I CCSK. Patients with anaplastic Wilms tumor and clear cell sarcoma shall receive 10.8 Gy to the flank, except in the case of stage 3 diffuse anaplasia in which the dose will be increased to 19.8 Gy. The radiotherapy dose for rhabdoid tumors is also 19.8 Gy, except in the case of infants younger than 12 months for whom a dose of 10.8 Gy is recommended. Adjustments in doses and fields are recommended for various scenarios when whole-abdominal radiotherapy is indicated. High-risk patients will receive radiotherapy to metastatic sites including lungs, lymph nodes, liver, brain, and bone with doses and fields outlined in the protocol. When indicated, radiation therapy shall begin concurrent with the initiation of chemotherapy after surgery. This should take place by postoperative day 10 and no later than day 14.

AREN0532 is a low-risk protocol for Stage I through III FH Wilms tumor stratified by clinical and biological risk factors. LOH for chromosome 1p and 16q in stage I and II FH Wilms tumor has been shown to be associated with a poorer prognosis. These patients will be moved from being treated with low-risk chemotherapy while being observed on AREN03B2 to a standard-risk arm and treated with the same chemotherapy as patients with stage III Wilms tumor without LOH 1p and 16q. This study has three strata: (1) very low–risk patients younger than 2 years old with tumors smaller than 550 g treated with surgery alone; (2) stage I and II standard-risk patients with LOH treated with dactinomycin, doxorubicin and vincristine; and (3) stage III standard-risk patients treated with dactinomycin, vincristine, and doxorubicin and radiotherapy. Radiotherapy is to begin concurrent with chemotherapy, after surgery, as discussed previously.

AREN0533 seeks to investigate two separate strategies for patients with higher-risk stage III and IV FH Wilms tumor. The first is to eliminate pulmonary radiotherapy for patients with lung metastases who have a favorable early response to chemotherapy. This is based on reports from European investigators who have had success with this approach, sparing 75% of patients with lung metastases from radiotherapy. In the current protocol, patients will receive 6 weeks of chemotherapy consisting of vincristine, dactinomycin, and doxorubicin followed by restaging. Only those patients who do not have complete resolution of pulmonary nodules by chest CT scan will undergo pulmonary irradiation. They will also receive intensified chemotherapy. It is imperative that this approach only be used for patients who have properly consented and enrolled in this investigational trial. A recent report from the English UKW trials have shown that omission of protocol-recommended pulmonary radiotherapy significantly decreased EFS for patients with metastatic Wilms tumor.⁸⁷ Outside of a clinical trial, whole-lung radiotherapy to 12 Gy remains the standard of care for patients with pulmonary metastases.

The second risk stratification variable in AREN0533 is the allelic loss of 1p and 16q. Patients with stage III and IV FH Wilms tumor with LOH of both 1p and 16q will be assigned to an intensified chemotherapy regimen of vincristine, dactinomycin, doxorubicin, etoposide, and cyclophosphamide in an attempt to improve on their historical 4-year EFS of 65%. All such patients will also receive standard whole-lung radiotherapy for pulmonary metastases regardless of their response at week 6.

AREN0534 is the first cooperative trial to formally study patients with bilateral Wilms tumor or a propensity for development of bilateral Wilms tumor. Eligible patients include (1) synchronous or metachronous bilateral Wilms tumors; (2) unilateral Wilms tumor and aniridia, BWS, idiopathic hemihypertrophy, Simpson-Golabi-Behmel syndrome, Denys-Drash syndrome, or other associated genitourinary anomalies; (3) multicentric Wilms tumor or unilateral Wilms tumor with contralateral nephrogenic rests in a child younger than 1 year of age; (4) diffuse hyperplastic perilobar nephroblastomatosis; or (5) Wilms tumor arising in a solitary kidney. Because of the increased risk for renal failure, patients with these presentations are treated with preoperative chemotherapy including vincristine, dactinomycin, and doxorubicin to preserve renal parenchyma. Based on restaging partial nephrectomies are recommended at week 6 or at week 12. Standard postoperative radiotherapy is indicated for all abdominal stage III tumors. All patients with lung metastases will receive whole-lung radiotherapy on this protocol. Patients with abdominal stage I through III UHs will receive radiotherapy according to the guidelines in the high-risk protocol AREN0321.

Techniques of Radiotherapy

Indications and doses for flank–versus–whole abdomen irradiation are outlined in Table 57-5. Both regimens are delivered in an anterior-posterior fashion and are prescribed to midplane. For flank irradiation, the medial field border is extended across the midline to completely include the vertebral bodies at the levels concerned, but not far enough to overlap any portion of the contralateral kidney.⁶⁷ The other borders are defined as the preoperative outline of the kidney and tumor, plus a 1-cm margin. Using this technique, the superior border should rarely approach the diaphragmatic dome.

Table 57-5 Abdominal Radiation: Fields and Doses

Extent of Disease	Radiotherapy Field	Dose
Renal hilar nodes	Flank, crossing midline to include entire vertebral bodies	1.8 Gy × 6 = 10.8 Gy
Microscopic residuum confined to flank
Positive para-aortic nodes	Include entire length of bilateral para-aortic chains	1.8 Gy × 6 = 10.8 Gy
Peritoneal seeding	Whole abdomen	1.8 Gy × 6 = 10.8 Gy or 1.5 Gy × 7 = 10.5 Gy
Preoperative intraperitoneal rupture
Diffuse operative spill
Gross residual disease >3 cm	Disease + 1 cm margin	10.8 Gy boost

Adapted from Grundy PE, Green DM, Coppes MJ, et al: In Pizzo PA, Poplack DG, eds: Principles and practice of pediatric oncology, ed 4, Philadelphia, 2002, Lippincott Williams & Wilkins, p 865; and National Wilms’ tumor study-5: therapeutic trial and biology study. Unpublished. Activated June 16, 1995; last revised June 1998.

In the case of whole-abdomen irradiation, the portal extends from the diaphragmatic domes superiorly and to the bottom of the obturator foramina inferiorly, with shielding of the femoral heads.

Abdominal irradiation should be initiated no later than 10 days postoperatively, provided the patient is stable, free of ileus or diarrhea, and has an absolute neutrophil count of at least 1000 and hemoglobin of at least 10.5. Rhabdoid tumor is the exception to this rule with abdominal irradiation delayed until week 6 of chemotherapy. The recommended schedule for flank irradiation is 1.8 Gy daily to 10.8 Gy; higher doses may be employed for CCSK and rhabdoid tumor. (Note that this represents a significant modification from all prior NWTS protocols, in which patients with UH received higher-dose radiotherapy [up to 40 Gy] on an age-dependent scale.) This recommendation is based in part on retrospective analysis of prior NWTS studies, which failed to show a dose-response relationship for anaplastic Wilms tumor.⁷⁹ However, doses as low as 10.8 Gy have never been studied in this subgroup; the prior minimum dose was 18 Gy, for children 18 months or younger. An additional 10.8 Gy should be delivered to regions of gross (>3 cm) residual disease, with a 1-cm margin.

The treatment schedule may be modified to 1.5 Gy daily to 10.5 Gy in whole-abdomen irradiation if the treating clinician is concerned about large-volume fields. This modification can also be used in either flank or whole-abdomen therapy when simultaneous WLI is required, to avoid disparate fractionation schedules to the two regions. Fig. 57-2 displays an example of such a modification.

Whole-lung radiotherapy is delivered via anterior-posterior portals and is prescribed to midplane. The superior border extends above the clavicles to encompass the apices; the inferior border includes the posterior inferior portions of the lung. The humeral heads and extrathoracic scapulae and clavicles are shielded. No other shielding is employed. The recommended schedule is 1.5 Gy daily to 12 Gy. Localized foci of lung disease persisting 2 weeks after radiation may be either excised or treated with an additional 7.5 Gy (1.5 Gy/day × 5),⁶⁷ although caution is advised given the potentially fatal risk of pulmonary toxicity in patients receiving combined modality therapy. Initial reports show promise of significant cardiac sparing when intensity-modulated radiation therapy is used to deliver whole-lung radiotherapy.⁸⁸

If liver metastases are completely resected, hepatic irradiation is unnecessary. Treatment of residual or unresectable disease varies based on histologic findings. For patients with FH or focal anaplasia, focal unresectable liver metastases are treated with a 2-cm margin in 1.8-Gy daily fractions to 19.8 Gy. If diffuse liver involvement is known or suspected, the entire organ should receive 19.8 Gy. Additional boosting to focal regions (5.4 to 10.8 Gy) is at the discretion of the treating clinician, with the caveat that 75% of the whole liver should not receive more than 30.6 Gy as a result of all radiotherapy, including whole-organ irradiation and overlap from abdominal or lung fields, or both. For patients with diffuse anaplasia, CCSK, or rhabdoid tumor, focal liver metastases are treated to 30.6 Gy. Whole-liver irradiation for diffuse disease also requires a dose of 30.6 Gy, and supplemental boosting (5.4 to 10.8 Gy) to focal areas is permissible. In these children, the dose to the whole liver should not exceed 30.6 Gy.

Other metastatic sites requiring radiation include lymph nodes outside of the abdomen or pelvis, bone, and brain. Metastatic nodes receive 19.8 Gy; bone metastases are treated with at least a 3-cm margin to a dose of 30.6 Gy. Cerebral metastases are treated with whole-brain irradiation to 30.6 Gy.⁶⁷

Radiotherapeutic management of metastatic Wilms tumor is outlined in Table 57-6. In all cases, care must be taken to limit the dose received by the normal kidney. NWTS-5 specifies that the dose to more than one-third of the contralateral kidney (or to the residual normal kidney in children with bilateral Wilms) should not exceed 14.4 Gy. Use of brachytherapy in the management of Wilms tumor has been anecdotally reported in fewer than 20 patients,^89–92 all of whom had either recurrent disease or residual tumor after standard therapy.

Table 57-6 Radiotherapy for Metastatic Disease

Disease Site	Radiotherapy Field	Dose
Lung
Age 18 mo or older	WLI ± boost to residual foci post-RT	WLI: 1.5 Gy × 8 = 12 Gy Boost: 1.5 Gy × 5 = 7.5 Gy

Age younger than 18 mo WLI if disease persists after week 4 of chemotherapy ± boost to residual foci post-RT Liver FH or focal anaplasia     Focal metastases Disease + 2 cm margin 1.8 Gy × 11 = 19.8 Gy Diffuse involvement Whole liver Diffuse anaplasia, CCSK, or rhabdoid tumor     Focal metastases Disease + 2 cm margin 1.8 Gy × 18 = 30.6 Gy Diffuse involvement Whole liver Lumph nodes outside the abdomen or pelvis   Involved nodes 1.8 Gy × 11 = 19.8 Gy Bone Lesion + 3 cm margin 1.8 Gy × 18 = 30.6 Gy Brain Whole brain 1.8 Gy × 18 = 30.6 Gy

CCSK, Clear cell sarcoma of the kidney; FH, favorable histology; WLI, whole lung irradiation.

From Grundy PE, Green DM, Coppes MJ, et al: In Pizzo PA, Poplack DG, eds: Principles and practice of pediatric oncology, ed 4, Philadelphia, 2002, Lippincott Williams & Wilkins, p 865; and National Wilms’ tumor study-5: therapeutic trial and biology study. Unpublished. Activated June 16, 1995; last revised June 1998.

Management of Inoperable Disease

As previously described, patients with unresectable disease should undergo surgical exploration and biopsies for diagnosis and staging, followed by chemotherapy with vincristine, actinomycin, and doxorubicin. Radiographic re-evaluation should be performed at week 5, with surgery performed shortly thereafter. If a persistent inadequate response is noted, preoperative irradiation with concurrent vincristine may be considered. The suggested dose is 12 to 12.6 Gy in 1.5- to 1.8-Gy daily fractions. Postoperative radiotherapy should be administered to all children who did not receive it preoperatively. After completion of radiotherapy, the chemotherapy regimen for stage III disease should be completed.³⁴

Management of Synchronous Bilateral Disease

After surgical exploration, bilateral biopsies, and staging of each kidney, children with bilateral Wilms tumor should receive preoperative chemotherapy according to the highest stage of disease identified. Radiographic evaluation of response to therapy should begin at week 5, followed by a second-look procedure when the disease appears resectable; if serial imaging studies fail to show reduction in tumor, second-look surgery should still be performed to distinguish between persistent viable tumor and residual benign tissue. At that time, bilateral partial nephrectomies or wedge excisions should be performed only if negative margins can be obtained.⁹³ If one kidney has extensive tumor precluding partial resection, complete excision of tumor from the least involved kidney is performed; if this procedure leaves the partially resected kidney viable and functioning, the extensively involved kidney can be removed by radical nephrectomy.⁶⁷

Postoperatively, patients in whom complete resection was achieved should complete the chemotherapy regimen that corresponds to the highest stage of disease identified either initially or at second-look surgery. Radiotherapy is not indicated in the management of these patients.⁶⁷

Patients with persistent gross disease after a second-look procedure should be considered for reoperation after further chemotherapy. If repeat abdominal explorations (the number and extent of which are at the discretion of the treating surgeon) fail to eradicate gross disease, patients should receive radiation to the involved kidney and tumor bed in the manner described earlier.⁶⁷

CRITICAL NORMAL TISSUES—RADIATION INJURY

In the past when higher radiation doses were used, musculoskeletal late effects in patients with Wilms tumor could be directly attributed to radiation therapy.^94,95 These included scoliosis, kyphosis, muscular hypoplasia, and iliac wing hypoplasia in patients who received flank or whole-abdomen irradiation. Severe musculoskeletal complications are unlikely when doses less than 24 Gy are used. Even in the setting of lower doses, however, radiation fields should be designed to minimize asymmetric development (e.g., treating the entire vertebral bodies in flank irradiation to avoid scoliosis).

Females who receive whole abdominal irradiation are at increased risk of late reproductive sequelae including ovarian failure⁹⁶ and adverse pregnancy outcomes such as fetal loss, premature delivery, and possibly birth defects.^96–98 In the largest series to date, Li and coworkers reported an excess risk of low birth weight (relative risk 4.0) and perinatal mortality (relative risk 7.9) in females who had received abdominal irradiation, as compared with white women in the United States.⁹⁸

Radiation pneumonitis can be a life-threatening consequence of WLI, and is potentiated by concurrent chemotherapies. Twelve percent of patients on NWTS-3 who received pulmonary irradiation developed pneumonitis not caused by Pneumocystis carinii, with an associated 75% mortality.⁹⁹ Reduction of the dose of concurrently administered doxorubicin and actinomycin-D has reduced the current incidence of radiation pneumonitis, although the risk of fatal pulmonary complications remains a major concern for children who receive supplemental radiation for residual lung disease after the standard 12 Gy.⁶⁷

Chronic renal failure can occur as a consequence of radiation nephritis, but the reported incidence is less than 0.25% among children with unilateral disease and an apparently normal contralateral kidney at the time of diagnosis.¹⁰⁰ The risk of renal failure is higher in patients with bilateral disease, although the incidence has decreased over the span of the NWTS trials from 9.9% in NWTS-1 to 3.8% in NWTS-4. Most cases of renal failure in children with bilateral Wilms are caused by either surgery or the sequelae of the Denys-Drash syndrome.

Second malignancies are a potential complication of both chemotherapy and radiation therapy. The cumulative incidence of second malignancies among children followed by the NWTS is 1.6% at 15 years, and the risk appears to continuously increase.^101,102 Reviewers of the International Society of Pediatric Oncology experience reported a 0.65% cumulative incidence of second cancer at 15 years, with all second cancers occurring in the first 10 years after treatment. No excess risk was observed after 10 years, but this may have been a function of the length of follow-up.¹⁰³ The single most important risk factor appears to be radiation with doxorubicin potentiating the radiation-associated risk. Notably, however, even patients who received only vincristine and actinomycin-D, without doxorubicin or radiation therapy, have an increased risk of second cancers as compared with the U.S. population when adjusted for age, sex, and race.¹⁰² Furthermore, inherited predisposition to multiple cancers may contribute to the excess risk of second malignancies among children treated for Wilms tumor.

Although late congestive heart failure is primarily due to doxorubicin toxicity, the risk of congestive heart failure is increased from 1% to 5.4% in patients receiving WLI¹⁰³ and has been anecdotally reported in patients whose left ventricles received radiation during the course of left-sided abdominal therapy.¹⁰⁴

Small-bowel obstruction occurred in 6.9% of children enrolled in NWTS-3, primarily as a result of bowel adhesions after surgery. This incidence is comparable to that of other children undergoing major abdominal operations. A review of the NWTS-3 experience found that the incidence of small bowel obstruction was not increased by postoperative abdominal radiation therapy.¹⁰⁵

Acknowledgment

The authors wish to express their gratitude to Eve S. Ferdman for her editorial assistance in the preparation of this chapter.