Management of Wilms’ tumour: current practice and future goals...successful cancer therapy. Now that overall good outcomes have been achieved, the primary objective of clinical trials

For personal use. Only reproduce with permission from The Lancet.

THE LANCET Oncology Vol 5 January 2004 http://oncology.thelancet.com 37

Most patients with Wilms’ tumour in Europe and NorthAmerica can be cured with treatment and subsequently leada normal adulthood. However, for some, therapy as appliedtoday results in long-term side-effects and creates asubstantial burden on quality of life. Therefore, investigatorsinvolved in the management of patients with Wilms’ tumourare increasingly focusing their efforts on curtailing the long-term sequelae of therapy. This aim has been achieved bylowering the total amount of chemotherapy, radiotherapy, orboth administered to patients who have characteristicsassociated with favourable outcome. Although excellentsurvival has been maintained, many patients receive lesstherapy today than patients with similar characteristics did adecade or two ago. Better understanding of the biologicalprocesses that lead to this childhood cancer will allowfurther improvements in its management.

Lancet Oncol 2004; 5: 37–46

Wilms’ tumour is the most common childhood renaltumour (figure 1), accounting for about 6% of all paediatricmalignant disease. With an overall annual incidence of 8·1per million children, about 650 new cases can be expectedeach year in North America.1 The multidisciplinarymanagement of Wilms’ tumour has resulted in a strikingimprovement in survival from 30% in the 1930s to morethan 85% nowadays and has become a paradigm forsuccessful cancer therapy. Now that overall good outcomeshave been achieved, the primary objective of clinical trials onWilms’ tumour has shifted towards refinement of therapy forchildren with low-risk tumours so that they can be sparedfrom modalities resulting in unwanted long-term side-effectswithout compromising the excellent cure rates. At the sametime, investigators continue to look for novel strategies,including treatment intensification, for patients with high-risk tumours for whom outcome might be further improved.We review the progress that has been achieved in themanagement of Wilms’ tumour, current understanding of itsbiology, and the future goals for research on this disorder.

DiagnosisClinical presentationA functional review of patients with Wilms’ tumour does notshow any tumour-specific symptoms. The most commonpresentation is with a symptomless abdominal mass, althoughabout a third of patients present with abdominal pain,anorexia, vomiting, malaise, or a combination of thesesymptoms. Physical examination reveals hypertension inabout 25% of patients and congenital anomalies (aniridia,

genitourinary malformations, hemihypertrophy, or signs ofovergrowth) in 13–28% of children, depending on whetherthey have unilateral or bilateral disease.2 The syndromesassociated with the highest risk of developing Wilms’ tumourinclude the syndrome of aniridia, genitourinary malforma-tion, mental retardation (generally referred to as WAGRsyndrome), the Beckwith-Wiedemann syndrome, and theDenys-Drash syndrome. Other syndromes that have beenassociated with Wilms’ tumour are shown in table 1. Up to30% of patients have haematuria and less than 10% havecoagulopathy.

ReviewManagement of Wilms’ tumour

JAK is at the Department of Radiation Oncology, and EJP is at theDepartment of Pathology, Children’s Memorial Hospital,Northwestern University, Chicago, IL, USA. JSD is at theDepartment of Hematology/Oncology, St Jude Children’s ResearchHospital, Memphis, TN. MM is at the Department of Pediatrics,Division of Hematology-Oncology, University of Southern California,Los Angeles, CA, USA. GMH is at the Department of PediatricSurgery, Denver Children’s Hospital, Denver, CO, USA. PG is at theDepartments of Pediatrics and Oncology, University of Alberta,Edmonton, Canada. MJC is at the Departments of Oncology andPediatrics, University of Calgary, Alberta, Canada.Correspondence: Prof Max J Coppes, Children's Cancer Program,Alberta Children's Hospital, 1820 Richmond Road SW, Calgary,Alberta, T2T 5C7, Canada, Tel: +1 (403) 943 7396. Fax: +1 (403) 228 4196. Email: [email protected]

Management of Wilms’ tumour: current practiceand future goals

John A Kalapurakal, Jeffrey S Dome, Elizabeth J Perlman, Marcio Malogolowkin, Gerald M Haase, Paul Grundy, Max J Coppes

Figure 1. Wilms’ tumour consists of varying proportions of three celltypes: tubular (a), blastemal (b), and stromal (c) components. Stained withhaematoxylin and eosin.


THE LANCET Oncology Vol 5 January 2004 http://oncology.thelancet.com38

ImagingMost patients with Wilms’ tumour undergo abdominalultrasonography and CT at diagnosis. In addition, eitherradiography or CT of the chest is done to seek lungmetastases. The clinical significance of tumours noted on CTbut not visualised on a chest radiograph remains unclear.3,4

The value of MRI in this disorder has yet to be established,but two recent reports have indicated that MRI can help todistinguish between nephrogenic rests (see below) andWilms’ tumour.5,6

StagingWilms’ tumours are staged on the basis of anatomical tumourextent, and therapy is currently based on stage and histology.However, genetic markers are expected be included in riskassessment and therapy in the future. Classifications based ontumour extent have evolved over the years. For example, aftercareful analysis of the prognostic significance of severalclinicopathological factors documented during the first twotrials by the North American National Wilms’ Tumor StudyGroup (NWTSG), NWTS-1 and NWTS-2, use of a groupingsystem was abandoned in favour of a staging system, whichhas been used from NWTS-3 onwards. Patients with lymph-node involvement, previously included in group II disease,are now classified as having stage III disease, and those withlocal tumour spill were moved from group III to stage IIdisease. Refinements to the inclusion criteria for stages I andstage II disease (see panel) were introduced in the currentNWTS-5 study. Previously, one of the criteria for stage IIdisease was either renal-capsular penetration or extension ofthe tumour past the hilar plane, an imaginary boundarymarked by the medial border of the renal sinus. The hilar-plane criterion was replaced with renal sinus vascularinvasion.

HistopathologyNon-Wilms’ tumoursInitially most paediatric renal tumours were classified asWilms’ tumour, with either favourable or unfavourablehistology. After careful histopathological examination of allunfavourable-histology tumours registered in the first two

NWTSG studies, pathologists from the study grouprecognised that certain tumours represented separate diseaseentities. Therefore from NWTS-3 onwards, clear-cellsarcoma of the kidney and rhabdoid tumour of the kidneywere excluded from trials on Wilms’ tumour, although theNWTSG continues to organise separate therapeutic trials forthese disease entities. These two types of renal tumour arenot discussed further in this review.

Favourable histology in untreated Wilms’tumourMost Wilms’ tumours are solitary lesions, although asubstantial proportion are multifocal, with 6% involvingboth kidneys, and another 12% arising multifocally within asingle kidney.7 The classic untreated Wilms’ tumour consistsof varying proportions of three (triphasic) cell types:blastemal, stromal, and epithelial, commonly recapitulatingvarious stages of normal renal development (figure 1). Lesscommonly, heterologous epithelial or stromal componentsare identified, including mucinous or squamous epithelium,skeletal muscle, cartilage, osteoid, or fat.8 Not all specimensare triphasic; biphasic and monophasic patterns arefrequently encountered. Many monophasic blastemalWilms’ tumours are highly invasive and may raise thedifferential diagnosis of other small round blue-celltumours, such as primitive neuroectodermal tumour,neuroblastoma, and lymphoma. Similarly, monophasicundifferentiated stromal Wilms’ tumour can mimic primarysarcomas such as clear-cell sarcoma of the kidney, congenitalmesoblastic nephroma, or synovial sarcoma. Otherdifferentiated stromal Wilms’ tumours show a predom-inance of skeletal-muscle differentiation, varying from well-differentiated (rhabdomyomatous) to poorly differentiated(rhabdomyoblastic) skeletal muscle. Lastly, purely tubularand papillary Wilms’ tumour can be difficult to distinguishfrom papillary renal-cell carcinoma.8

Review Management of Wilms’ tumour

Table 1. Syndromes and genetic loci associated withWilms’ tumour

Syndrome Locus Implicated genes

WAGR 11p13 WT1

Denys-Drash 11p13 WT1

Beckwith-Wiedemann 11p15 IGF2, H19, p57Kip2

Simpson-Golabi-Behmel Xq26 GPC3

Li-Fraumeni 17p13 p53

Hyperparathyroid jaw tumour 1q21–q31 HRPT2

Neurofibromatosis 17q11 NF1

Sotos 5q35 NSD1

Bloom 15q26 BLM

Perlman ? ?

Mosaic variegated aneuploidy ? ?

Trisomy 18 18 ?

NWTSG staging system for renal tumours

Stage ITumour confined to the kidney and completely resected; no penetrationof the renal capsule or involvement of renal sinus vessels.

Stage IITumour extends beyond the kidney but is completely resected (negativemargins and lymph nodes); at least one of the following has occurred:

● penetration of the renal capsule

● invasion of the renal sinus vessels

● biopsy of tumour before removal

● spillage of tumour locally during removal

Stage IIIGross or microscopic residual tumour remains postoperatively including:inoperable tumour, positive surgical margins, tumour spillage involvingperitoneal surfaces, regional lymph-node metastases, or transectedtumour thrombus.

Stage IVHaematogenous metastases or lymph-node metastases outside theabdomen (eg, lung, liver, bone, brain).

Stage VBilateral renal Wilms’ tumours.



Anaplastic untreated Wilms’ tumourThe histological feature of greatest clinical significance inuntreated Wilms’ tumour is anaplasia, which is defined bythe presence of greatly enlarged polyploid nuclei (figure 2).The frequency of anaplasia is about 5% and is correlatedwith patients’ age. It is rare in the first 2 years of life, then thefrequency increases to about 13% in patients older than 5 years. It is far more frequent in African-American than inwhite patients9 and has been strongly linked with thepresence of p53 mutations.10

Anaplasia is judged to be a marker of resistance tochemotherapy,11 but whether it also confers increasedaggressiveness or tendency to disseminate still remainsunclear. This recognition has resulted in a distinctionbetween tumours showing anaplastic changes that are focalfrom those that are diffuse.12 The diagnosis of focal anaplasiarequires that cells with anaplastic nuclear changes areconfined to sharply circumscribed regions within theprimary tumour and surrounded on all sides by non-anaplastic tissue. The diagnostic criteria for diffuse anaplasiainclude any of the following: presence of anaplasia in anyextrarenal site; its presence in a random biopsy specimen;unequivocal anaplasia in one region of the tumour coupledwith extreme nuclear pleiomorphism approaching thecriteria of anaplasia (extreme nuclear unrest) elsewhere inthe tumour; anaplasia that has not been documented to besurrounded by non-anaplastic tissue. The distinctionbetween focal and diffuse anaplasia is prognosticallysignificant.12

Further links between the histological pattern and theclinical behaviour of Wilms’ tumour have long been sought.Blastemal-rich tumours tend to be extremely invasive andpresent at an advanced stage, although many respond well tochemotherapy. By contrast, predominantly epithelial andrhabdomyomatous Wilms’ tumours are more likely to presentat a low stage, reflecting less aggressiveness, yet many areresistant to chemotherapy.13 Although the small number of

high-stage epithelial-predominant tumours limits theanalysis, these results suggest a better outcome for advanced-stage diffuse blastemal Wilms’ tumour than for advanced-stage epithelial-predominant Wilms’ tumour.14 More recently,preliminary analysis of the group assigned no adjuvantchemotherapy in a trial of young children with small stage Itumours provides further support for the excellent prognosisof confined epithelial differentiated Wilms’ tumours, and theincreased risk of relapse and subsequent responsiveness ofblastemal-predominant Wilms’ tumours.15 Future therapeuticprotocols will probably continue to define a subset of tumoursthat can be treated with surgery alone. These include cysticpartially differentiated nephroblastoma among others.Although much of the past success of the NWTSG has reliedon the accurate histological subclassification of Wilms’tumours into high-risk and low-risk types, further riskclassification will probably depend on molecular geneticfeatures.

Histology of previously treated Wilms’ tumourTumours that have been subjected to chemotherapy beforenephrectomy differ in histopathological findings from thoseresected at diagnosis. Most notably, about 6% of suchtumours show massive necrosis, a feature rarely seen inspecimens obtained at diagnosis.16 A comparison of thehistopathological subtypes noted in untreated andpretreated Wilms’ tumours is given in table 2.

Nephrogenic restsThe existence of precursor lesions to Wilms’ tumour hasbeen recognised for many years.17 These lesions consist ofabnormally persistent embryonal nephroblastic tissue withsmall clusters of blastemal cells, tubules, or stromal cells(figure 3). Nephrogenic rests can be subclassified by theirposition within the renal lobe and histological appearance(table 3): perilobar nephrogenic rests are limited to theperiphery of the renal cortex and intralobar nephrogenicrests occur randomly throughout the renal lobe. Thedifferent types of nephrogenic rests are associated withvarius clinical and histological tumour features (table 3).The term nephroblastomatosis is used to refer to thepresence of multiple nephrogenic rests. There are severalpossible fates for nephrogenic rests. Only a small numberdevelop a clonal transformation into Wilms’ tumour. Somebecome hyperplastic, with striking enlargement thatpreserves the rectangular shape of the preceding rest, yetlacks the peritumoral pseudocapsule characteristic of Wilms’tumour. Most nephrogenic rests become dormant orinvolute spontaneously. The presence of nephrogenic restswithin a kidney resected for a Wilms’ tumour indicates theneed for monitoring the contralateral kidney for tumourdevelopment, particularly in young infants.18

BiologyThe biological characterisation of Wilms’ tumour hasprovided the foundation for our understanding of keyconcepts in cancer genetics, including the roles of tumoursuppressor genes and relaxation of genomic imprinting intumorigenesis. Although Wilms’ tumour was one of the


Figure 2. Anaplasia. The criteria for diagnosis of anaplasia are: nuclei withdiameters at least three times those of adjacent tumour cells;hyperchromasia of the enlarged cells providing evidence for increasedchromatin content; and the presence of multipolar or otherwiserecognisably polyploid mitotic figures.9 All of these features must beidentified for the diagnosis of anaplasia, although the presence of a singlemultipolar mitotic figure, or an unequivocally gigantic tumour-cellnucleus, may be sufficient to establish the diagnosis in small biopsyspecimens. Stained with haematoxylin and eosin.



original examples in Knudson’s two-hit model of cancerdevelopment, subsequent research has shown that multiplegenes and several genetic events contribute to the formationof this malignant disorder (figure 4).19 The molecularchanges that have been described in Wilms’ tumour can beclassified as primary events predisposing to the tumour orsecondary events associated with malignant progression.

WT1Initial insights into the molecular biology of Wilms’ tumourwere derived from the observation that in patients withaniridia, genitourinary malformations, and mentalretardation (WAGR syndrome), the risk of developing thetumour is more than 30%. Cytogenetic analysis of individualswith this syndrome showed deletions at chromosome 11p13,which was later found to be the locus of a contiguous set ofgenes including PAX6, the gene causing aniridia, and WT1,one of the Wilms’ tumour genes. The WT1 gene encodes atranscription factor that is crucial to normal kidney andgonadal development.20 Although several target genes of WT1have been identified, its precise role in tumour suppressionremains to be elucidated. The Denys-Drash syndrome, whichis characterised by pseudohermaphroditism, glomerulopathy,renal failure, and a 95% chance of Wilms’ tumourdevelopment, is caused by point mutations in the zinc-fingerDNA-binding region of the WT1 gene, resulting in a proteinwith a dominant-negative effect.21 Although WT1 has a clearrole in tumorigenesis of Wilms’ tumour in patients with theWAGR and Denys-Drash syndromes, only a minority ofpatients with sporadic Wilms’ tumour carry WT1 mutationsin the germline (<5%) or in tumour tissue (6–18%).20 These

observations indicate that other genesare involved in Wilms’ tumourdevelopment.

WT2The Beckwith-Wiedemann syndromeis an overgrowth disorder manifestedby large birthweight, macroglossia,organomegaly, hemihypertrophy, neo-natal hypoglycaemia, abdominal-walldefects, ear abnormalities, and pre-disposition to Wilms’ tumour andother malignant disorders. About 5%of individuals with this syndromedevelop Wilms’ tumour. Beckwith-Wiedemann syndrome maps tochromosome 11p15, a locus sometimescalled WT2, because loss of hetero-zygosity at this locus has been detectedin Wilms’ tumour.22,23 Although theprecise WT2 gene remains undefined,there is a cluster of genomicallyimprinted candidate genes, includinginsulin-like growth factor 2, H19, andp57Kip2 at this locus.

FWT1 and FWT2Familial predisposition to Wilms’

tumour is rare, affecting only 1·5% of patients with thetumour. Analysis of families has revealed familial Wilms’tumour predisposition at FWT1 (17q) and FWT2 (19q)loci.20

Other potential Wilms’ tumour susceptibilitygenesIn addition to its well-established association with theWAGR, Beckwith-Wiedemann, and Denys-Drashsyndromes, Wilms’ tumour has been reported in rareindividuals with other genetic disorders (table 1). The genescausing most of these disorders have been cloned, but theirrole in Wilms’ tumorigenesis is unknown. Secondary geneticchanges in Wilms’ tumour have been reported in the p53gene24 and at chromosomes 1p and 16q.25,26 A primaryobjective of the NWTS-5 trial was to assess prospectively theprognostic significance of loss of heterozygosity at the 16qand 1p loci in a large cohort of patients.


Table 2. Histological subtypes in favourable-histologyWilms tumour that did or did not receive preoperativechemotherapy16

Histology subtype Immediate Preoperativesurgery chemotherapy

Epithelial predominant 15·5% 3·1%

Stromal predominant 0 14·0%

Blastemal predominant 39·4% 9·3%

Mixed 45·1% 29·4%

Regressive predominant 0 37·6%

Completely necrotic 0 6·6%

Figure 3. Nephrogenic rests are classified by their position within the kidney. (a) Intralobarnephrogenic rests (A) are randomly distributed but tend to be situated deep within the renal lobe,probably reflecting an earlier developmental insult to the kidney. Many of these lesions are stroma-rich and intermingle with the adjacent renal parenchyma. (b) Perilobar nephrogenic rests (B) aremostly subcapsular and sharply demarcated and contain predominantly blastema and tubules.These presumably reflect later developmental disturbances in nephrogenesis. Stained withhaematoxylin and eosin.



TreatmentSurgeryPrimary surgical resection of Wilms’ tumour remains thestandard initial therapy undertaken in North America afterappropriate clinical and imaging assessment. Someinvestigators have argued that “the resolution ofcontemporary ultrasound, CT, and MR imaging equipmentallows discrimination of intrarenal masses severalmillimeters in size”.27 The most recent NWTSG studyrecommended a transperitoneal approach to provideadequate exposure for complete local-regional staging.28 Thisprocedure includes mobilisation and inspection of thecontralateral kidney to exclude bilateral disease beforenephrectomy if possible. It also permits inspection of hilarand regional nodes, which remain a crucial factor in staging.Although suspicious lymph nodes are excised irrespective oflocation, a formal lymph-node dissection is not beneficial orrecommended.

Most Wilms’ tumours that appear to involve contiguousstructures actually only compress or adhere to the adjacentorgan without invasion. Therefore, radical en-bloc resectionin these tumours, which is associated with increased surgicalcomplications, can be avoided. However, wedge resection ofinfiltrated structures such as the diaphragm, liver, or psoasmuscle can be undertaken if all disease can be completelyremoved with little operative morbidity. This procedure isadvantageous because the tumour can be downstaged tostage II and subsequent therapy reduced. Tumour extensioninto the renal vein and proximate inferior vena cava can inmost cases be removed en-bloc with the kidney. However,primary resection of extension into the inferior vena cava tothe hepatic level or into the atrium is associated with higheroperative morbidity. In these circumstances, preoperativechemotherapy decreases the size and extent of the tumourthrombus without increasing its adherence to the vascularwall, thereby facilitating subsequent excision.

Tumour spillage remains an important concept in thesurgery of Wilms’ tumour. Surgeons must be aware of anytumour-capsule violation with contamination of theperitoneal cavity during attempt at local tumour control.This event can happen by accident (ie, during operativeremoval), may be unavoidable (ie, preoperative rupture), orcan occur by design (ie, planned biopsy). The accurateassessment of a local spill (stage II) from diffusecontamination (stage III) is difficult; therefore, treatmentassignment may be altered. Nevertheless, peritoneal soilagedefinitely increases the risk of local and abdominal

recurrence, although current datasuggest that overall survival is notadversely affected.29

Some tumours are initially judgedto be unresectable or to pose too greata surgical risk because of massive size.The surgeon is best suited to make thisdecision, and initial exploration toassess operability and obtain adequatebiopsy material from the tumour isrecommended. The error rate of

imaging in the preoperative diagnosis of renal masses is5–10%,30 and the histological diagnosis based on needlebiopsy material is similarly inaccurate.31 In the trulyinoperable cases, preoperative chemotherapy is successful indecreasing the primary tumour mass and generally renders itresectable.

Partial nephrectomy as a primary tumour resectionstrategy remains controversial and is probably not indicatedin routine treatment of Wilms’ tumour. A recent review ofpatients with unilateral tumours showed a low incidence ofrenal failure after 6 years of follow-up, and most of thesepatients had intrinsic renal diseases not related to theirtumour.32 In fact, most Wilms’ tumours are too large orcentrally located for partial nephrectomy to be considered atinitial presentation. If strict surgical criteria were applied, suchthat the lesion was limited to one pole of the kidney withoutcollecting-system involvement and with separation betweenthe tumour and kidney to allow clear resection margins, less


Normaldevelopment

Normalkidney

?

?

Embryonickidney

(with NR)

WT1inactivation

WT2 LOIothers? p53

inactivationLOH 16q, 1p

others?PersistentNRs

Wilmstumour

Malignantprogression/

anaplasia

Figure 4. Model of tumorigenesis of Wilms’ tumour. Inactivatingmutations of the WT1 gene or loss of imprinting (LOI) of genes at theWT2 locus predispose to the abnormal persistence of nephrogenic rests(NR). NR can sustain additional genetic events, still to be identified, andconvert to Wilms’ tumour. True Wilms’ tumours can undergo subsequentgenetic events, such as p53 mutation and loss of heterozygosity atchromosomes 16q or 1p, which affect their biological behaviour. Whetherall Wilms’ tumours arise from nephrogenic rests is not certain; somegenetic mutations may permit this phase of tumorigenesis to bebypassed.19

Table 3. Nephrogenic rests: perilobar versus intralobar

Feature Intralobar Perilobar

Location within renal lobe Random; many central PeripheralAssociated syndromes WAGR, Denys-Drash syndrome Beckwith-Wiedemann syndrome,

Perlman syndrome, trisomy 13, hemihypertrophy, trisomy 18

Interface with kidney Intermingling Distinct

Dominant histological Triphasic, prominent stroma Blastemal, epithelialcomponent

Number Single in most cases Multiple in many cases

© L

ippi

ncot

t W

illia

ms

& W

ilkin

s



than 5% of patients would be eligible for partial nephrectomyat the time of diagnosis.33 Even after preoperativechemotherapy only about 10% of patients would be suitablefor a renal-parenchyma-sparing procedure.34 Furthermore,the use of partial nephrectomy carries other risks includingunique surgical complications and failure to identify andinclude nephrogenic rests in the surgical specimen. Therefore,at present, renal-sparing procedures for patients withunilateral Wilms’ tumour are suitable only for those with asolitary kidney, synchronous or metachronous bilateraldisease, renal insufficiency of any aetiology, and children atrisk of multiple neoplasms such as in Beckwith-Wiedemannsyndrome.

ChemotherapyThree highly effective drugs are used in the first-line therapyof Wilms’ tumours: dactinomycin, vincristine, anddoxorubicin. Four other drugs are used in patients whoexperience relapse or do not respond to the combination ofdactinomycin, vincristine, and doxorubicin. These includecyclophosphamide, ifosfamide, carboplatin, and etoposide.

The best combination of agents and duration of therapyhas been developed by several cooperative clinical-trialgroups worldwide, including the Société Internationald’Oncologie Pédiatrique (SIOP), the UK Children’s CancerStudy Group (UKCCSG), the German Pediatric Oncology(GPO) group, the Brazilian Pediatric Oncology Group, theFrench Société d’Oncologie Pédiatrique (SFOP), and theNWTSG. Through successive clinical trials these groupshave continued to refine therapy and decrease the acute andlong-term morbidity associated with the treatment ofWilms’ tumour.

SIOP studiesIn the SIOP studies, the therapeutic approach has beenfocused on developing stage-specific strategies afterprenephrectomy therapy. Stage classification and histo-pathological diagnosis are delayed until surgery, which occursseveral weeks after clinical and imaging diagnosis. The use ofprenephrectomy therapy facilitates surgery in most tumours,because they shrink after the administration of radiotherapyor chemotherapy. This approach reduces the incidence ofperioperative tumour rupture,35,36 chemotherapy being aseffective as radiotherapy.37 In addition, chemotherapy-inducedtumour shrinkage results in a different stage distribution ofpatients who undergo immediate nephrectomy to that ofpatients who receive prenephrectomy chemotherapy by theNWTSG surgical pathological staging system.38 Moreover, itallows assessment of whether the histopathological featuresthat characterise Wilms’ tumours after chemotherapy (eg,epithelial predominant, stromal predominant, blastemalpredominant, mixed) are associated with tumour shrinkage,stage, or outcome.16,39 Finally, this approach establishes in vivothe efficacy of the chemotherapeutic agents used, allowingconsideration of other chemotherapeutic agents after surgeryfor patients whose tumours did not show signs of response. A drawback of administering prenephrectomy chemotherapyis that treatment is initiated without histopathological tissueconfirmation.

The first and second SIOP trials showed that preoperativeirradiation reduces the incidence of tumour rupture andrecurrence-free survival but not overall survival.35,40 SIOP-5showed that preoperative chemotherapy with vincristine anddactinomycin is as effective as preoperative irradiation plusdactinomycin in preventing tumour rupture.37 SIOP-6showed that there was no difference in survival when childrenwith SIOP stage I disease were randomly assigned either 17weeks or 38 weeks of postoperative chemotherapy withvincristine and dactinomycin. Among SIOP stage II patientswith negative lymph nodes who were randomly assigned noradiotherapy, there was a higher recurrence rate.36 In SIOP-9,the main objective was to find the optimum duration ofpreoperative chemotherapy (4 weeks or 8 weeks), to increasefurther the rate of SIOP stage I tumours and reduce thenumber of SIOP stage II and III tumours requiring moreaggressive therapy. No advantage was noted for 8 weeks oftherapy. Among SIOP stage II patients with negative lymphnodes, the rate of abdominal relapse was reduced by theaddition of epirubicin without radiotherapy.38 In SIOP-93-01,postoperative therapy was based on stage and pathologicalresponse to chemotherapy. From postoperative histology,tumours were classified as low, intermediate, or high riskaccording to the Stockholm working classification of renaltumours.41 The final results of that study have not yet beenpublished.

Since therapy is initiated without histopathological tissueconfirmation, the approach advocated by SIOP must bebalanced against the risks involved with the administrationof chemotherapy without tissue diagnosis, the modificationof tumour histology, and the loss of accurate staginginformation.

UKCCSGLike the NWTSG, the UKCCSG initially used postoperativetreatment regimens stratified by stage and histology afterprimary nephrectomy. Their first study (UKW1) showedthat vincristine alone for 6 months was as effective asvincristine and dactinomycin for patients with stage Ifavourable-histology Wilms’ tumour. The results for stageIII favourable-histology patients were similar to thosereported by NWTSG investigators, but the 6-year survivalfor stage IV patients with lung metastases (65%) wassignificantly worse than the 4-year survival (82%) reportedby the NWTSG.42 This discrepancy was attributed to theroutine inclusion of lung irradiation in all lung stage IVpatients on NWTSG treatments.42 In UKW2, patients withstage I favourable-histology Wilms’ tumour treated with tenweekly doses of vincristine had similar outcome (95% 4-yearsurvival rate) to that noted for comparable patientsregistered on the NWTSG trials. However, more carefulanalysis suggested that the excellent outcome in stage Ifavourable-histology Wilms’ tumour does not apply forchildren aged four years or older.43 For these children, theUKCCSG does not recommend a 10-week course ofpostoperative vincristine monotherapy. Finally, althoughbetter than that reported for UKW1, the 4-year overallsurvival for stage IV patients in UKW2 (75%)44 remainedinferior to that reported by the NWTSG.42




NWTSGThe first three NWTSG trials30,45,46 showed that postoperativeabdominal radiotherapy was unnecessary for patients withstage I favourable histology or anaplastic histology or for thosewith stage II favourable histology, when treated withvincristine and dactinomycin after nephrectomy. Theaddition of doxorubicin to the combination chemotherapydecreased the risk of relapse but did not improve overallsurvival for children with stage III favourable-histologyWilms’ tumour. Moreover, the dose of abdominal irradiationcould be decreased to 10·8 Gy for stage III favourable-histology patients receiving the three-drug regimen. Theaddition of cyclophosphamide to the combination ofvincristine, dactinomycin, and doxorubicin did not improvethe outcome for patients with stage IV favourable-histologyWilms’ tumour, but it did improve relapse-free and overallsurvival in patients with stage II to IV anaplastic-histologyWilms’ tumour. The fourth NWTSG study investigated theefficacy, toxicity, and cost of different schedules of dactino-mycin and doxorubicin administration, finding thatdactinomycin could be given safely in 1 day rather than over 5days and doxorubicin in 1 day rather than over 3 days.47 Theseso-called pulse-intensive regimens were as effective as thestandard courses but were accompanied by less severehaematological toxicity and fewer health-care encounters.48 Asa consequence pulse-intensive therapy (table 4) has becomethe standard of care for treatment of Wilms’ tumour in NorthAmerica.

Having almost reached cure for most patients, NWTSGinvestigators have felt the need to refine risk categoriesfurther before embarking on new treatment strategies. Themajor aim of the just closed non-randomised NWTS-5 trialtherefore was to assess the prognostic value of loss ofheterozygosity at chromosomes 1p and 16q and DNAploidy. Data from NWTS-5 are currently being analysed.

Synchronous bilateral Wilms’ tumourAbout 6% of all children with Wilms’ tumour present withsimultaneous bilateral tumours (stage V) at the time ofdiagnosis. Although more than 70% survive, these childrenare at high risk of renal failure.32 This risk has led to therecommendation that such patients undergo bilateral renalbiopsy with staging of each kidney followed by chemotherapyto shrink the tumour and facilitate renal-sparing procedures.Primary excision of the tumour masses is not recommended.

After 6–8 weeks of chemotherapy, thepatient is reassessed and the feasibilityof resection assessed. A second-look procedure may be indicated.Additional chemotherapy or radio-therapy may be needed, but surgeryshould not be delayed indefinitely. Ingeneral, definitive surgery should bedone within 12–16 weeks of diagnosisto limit the risk of chemoresistantclonal expansion.

Relapsed Wilms’ tumourThe historical long-term survival for

patients with recurrent Wilms’ tumour is less than 30%,49

but this survival does not reflect the use of agents such ascyclophosphamide, ifosfamide, carboplatin, and etoposide,which have shown substantial activity against the tumour.50–53

The use of modern multiagent intensive salvage regimenshas improved survival to the 50–60% range.54 Favourableprognostic factors include initial stages I or II, treatmentwith vincristine and dactinomycin only, no previousradiotherapy, favourable histology, and relapse longer than 6 months after initial diagnosis. All other patients have ahigh risk of treatment failure. Recent studies with high-dosechemotherapy followed by autologous stem-cell rescue havealso shown encouraging results.55,56 However, an adequatelypowered randomised trial of conventional chemotherapyversus high-dose chemotherapy followed by autologousbone-marrow rescue is needed to investigate whether thisapproach offers any advantages over conventional second-line therapies.

RadiotherapyTreatment with radiation continues to have an importantrole in the management of Wilms’ tumour. The past decadehas witnessed remarkable technical innovations in radiationdelivery systems and treatment planning software. The useof three-dimensional treatment planning systems based onCT and MRI will enable accurate tumour targeting andsuperior protection of adjacent normal structures. Thistechnology could be used to deliver conformal radiotherapyfor abdominal tumour recurrences and for metastatic sites inthe brain, lung, and liver.

Flank/abdominal irradiationSuccessive NWTSG trials have refined the indications forradiotherapy. The first study of Wilms’ tumour showed thatradiotherapy conferred no advantage in children youngerthan 24 months with group I tumours who also received 15 months of dactinomycin.30 That study also showed that ingroup III tumours, with local tumour spill or previousbiopsy, there was no need for irradiation of the wholeabdomen, thus sparing them the toxicity associated with suchirradiation.57 NWTS-2 showed that radiotherapy could beavoided in all children with group I Wilms’ tumour if theyreceived vincristine and dactinomycin.58 In NWTS-1 andNWTS-2, an age-adjusted dose schedule was used for flankirradiation: 18–24 Gy for children younger than 8 months;


Table 4. Treatment regimens used in NWTS-5

Stage Histology Radiotherapy Chemotherapy regimen Duration (weeks)

I–II Favourable No EE4A 18

I Anaplastic No EE4A 18

III–IV Favourable Yes DD4A 24

II–IV Focal anaplasia Yes DD4A 24

II–IV Anaplastic Yes I 24

I–IV CCSK Yes I 24

I–IV RTK Yes RTK 24

CCSK=clear-cell sarcoma of the kidney; RTK=rhabdoid tumour of the kidney. EE4A=vincristine plus pulse-intensivedactinomycin; DD4A=vincristine plus pulse-intensive dactinomycin and doxorubicin; I=vincristine, doxorubicin,cyclophosphamide, and etoposide; RTK=carboplatin, etoposide, and cyclophosphamide.



24–30 Gy for those aged 19–30 months; 30–35 Gy for thoseaged 31–40 months; and 35–40 Gy for children older than 40months. The abdominal relapse rate was 3–5% in group IIand III tumours, and there was no dose-response relationacross these dose ranges. The third NWTSG study provedthat radiotherapy could be avoided in children with stage IItumours if vincristine and dactinomycin were given. Thisstudy also showed that children with stage III favourable-histology tumours who received 10·8 Gy radiotherapy andvincristine, dactinomycin, and doxorubicin had similartumour control to those who received 20 Gy with vincristineand dactinomycin. This was an important finding because iteliminated the need for an age-adjusted dose schedule andsignificantly reduced the recommended dose of radiation.59

In NWTS-2, the predisposing factors for local tumourrecurrence were unfavourable histology, delay of 10 days orlonger before starting radiotherapy, and small radiation-field size.58 The issue of whether timing of irradiation affectsoutcome was reanalysed recently. NWTSG investigatorsshowed that a delay of 10 days or longer did not significantlyinfluence flank or abdominal tumour recurrences amongchildren with favourable-histology tumours treated onNWTS-3 and NWTS-4.60 However, owing to the rathernarrow range of 8–12 days after nephrectomy by which timeradiotherapy was administered, the possibility of detecting ameaningful difference in recurrence was limited. Childrenwith abdominal tumour relapse fared poorly; in NWTS-3,87% of children with a local tumour recurrence died of thedisease.59

In NWTS-4, the frequency of abdominal tumourrecurrence in children with local tumour spill and stage IItumours of all histologies was 16·5%.29 These children didnot receive flank irradiation according to the revisedguidelines in NWTS-4. Survival after local recurrence waspoor, with only 43% surviving at 2 years. The incidence oftumour recurrence for patients with stage III tumours withlocal spill after irradiation was only 7·8%.29

Although diffuse anaplastic tumours are resistant tochemotherapy, and presumably radiotherapy, these tumourshave not shown a radiation dose response between 10·8 Gyand 40 Gy.61 The optimum radiation dose for anaplasticWilms’ tumour remains unknown.

The current standard of care includes flank/abdominalirradiation (10·8 Gy in six fractions) for stage III favourable-histology tumours and stage II–III diffuse anaplastic Wilms’tumours.

Whole lung irradiationIn children with lung metastases detected on chestradiograph, whole lung irradiation (12 Gy in eight fractions)continues to be administered, leading to high cure rates. InNWTS-3, the 4-year relapse-free survival was 71·9%, and the4-year survival was 78·4% in children with favourable-histology Wilms’ tumour and lung metastases.46 These resultsare slightly superior to those reported by investigators fromthe UKCCSG.44 In their report, the UKCCSG investigatorsnoted that only 37 of 59 patients with pulmonary metastasesreceived radiotherapy as prescribed by the protocol andquestioned whether omission of whole lung irradiation had

affected outcome in this group of patients.44 SIOPinvestigators continue to advocate the omission ofradiotherapy for patients whose lung metastases disappearcompletely after 6 weeks of prenephrectomy chemotherapywith vincristine, dactinomycin, and doxorubicin. TheUKCCSG experience showed overall 6-year survival of only65% for such patients.42 Given the superior survival obtainedwith pulmonary radiotherapy, we agree with the UKCCSGinvestigators who suggested that the omission ofradiotherapy is probably not warranted given the negligibleexpected long-term side-effects of 12 Gy to the lungs.

In children with pulmonary metastases visible on CT butnot chest radiograph, the role of pulmonary irradiation isunclear. In such patients treated on NWTS-3 and NWTS-4,the 4-year event-free survival was 89% with irradiation and80% with chemotherapy alone, a difference that was notsignificant.62 The pulmonary relapse rate was 4% (two of 53)after irradiation compared with 16% (six of 37) withchemotherapy alone. Although there are genuine concernsabout radiation toxicity, the poor outcome in children whorelapse after initial treatment necessitates a critical assessmentof the role of pulmonary irradiation in these patients.

Long-term sequelaeAs the follow-up of successfully treated children increases,data are emerging on the late consequences of treatment. Thetype of late sequelae and their severity depends on the ageand sex of the child, extent of surgery, chemotherapy drugs,and radiation-related factors. Several organ systems shouldbe considered, including the kidneys, heart, and gonads. Themost common cause for renal failure in patients with Wilms’tumour is bilateral nephrectomy, and the second leadingcause of renal insufficiency is radiation-induced damage andsurgical complications involving the remaining kidney. Thefrequency of renal failure in bilateral Wilms’ tumour was16·4% for NWTS-1 and NWTS-2, 9·9% for NWTS-3, and3·8% for NWTS-4.32 The frequency of renal failure inunilateral Wilms’ tumour remained stable. Congestive heartfailure is a well-known complication after the administrationof anthracyclines and the risk is further increased whenassociated with whole-lung irradiation. Consequently,patients with advanced-stage Wilms’ tumour who arereceiving doxorubicin should be monitored for cardiacdysfunction.63 Pulmonary function can be affected in thosereceiving radiotherapy to the lungs, particularly those treatedbilaterally. In these patients, total lung capacity and vitalcapacity can be expected to decrease by 50–70% of predicted.Gonadal function can be endangered in women who havereceived abdominal radiotherapy for Wilms’ tumour. TheNWTSG has clearly shown that such women are at high riskof adverse pregnancy outcomes.64 Finally, some childrentreated for Wilms’ tumour are at increased risk of developinga second malignant neoplasm, whether solely as a result oftheir carcinogenic treatment or as a result of an inheritedpredisposition to cancer, or both. Most second tumours haveoccurred in irradiated areas. The risk factors for secondneoplasms include radiation exposure, radiation doses,organs at risk (sensitivity of breast and thyroid gland beingthe highest), and the use of chemotherapy agents especially




alkylating agents or doxorubicin. The frequency of radiation-related complications has been significantly reduced with themodern use of megavoltage X-rays and lower total doses ofirradiation.65–67

Conclusions and future goalsAt present, more than 85% of children with Wilms’ tumourare being cured and in our current treatments about 75% donot require radiotherapy or doxorubicin chemotherapy.Despite this success, several challenges remain. For patientswith low-risk disease, acute and long-term toxicities oftreatment must be limited. For patients with high-riskdisease, such as tumours with anaplastic histology, noveltherapies must be identified to improve survival. The role ofhigh-dose chemotherapy in children with recurrent tumoursneeds to be defined. The biological characterisation of Wilms’tumour will also enable clinicians to define more accurately apatient’s risk of recurrence and to select the best therapy.Future clinical trials will use genetic markers in addition toclinical staging and pathological classification for treatmentstratification. As the pathways of Wilms’ tumorigenesis areelucidated, novel molecular therapeutic targets are likely tobe identified. The progress of research endeavours in thedifferent disciplines, coupled with a critical analysis of theever-growing body of evidence accumulated by the clinicalcooperative groups, promises a future of hope and optimismfor the affected children and treating physicians alike.

Conflicts of interestNone declared.

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Management of Wilms’ tumour: current practice and future goals...successful cancer therapy. Now that overall good outcomes have been achieved, the primary objective of clinical trials