www.elsevier.com/locate/jpedsurg

Journal of Pediatric Surgery (2013) 48, 14–19

Robert E. Gross Lecture

The evolution of treatment for Wilms tumor☆

Daniel M. Green MD⁎

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, 262 Danny Thomas Place,Mail Stop 735, Memphis, Tennessee 38105–2794, USA

Received 19 September 2012; accepted 13 October 2012

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Key words:Wilms tumor;Nephrectomy;Actinomycin D;Doxorubicin;Radiation therapy

Abstract The prognosis for children with Wilms tumor (WT) has improved dramatically as the result ofadvances in surgical techniques, anesthesia, and supportive care. During the last three decades, theNational Wilms Tumor Study Group (NWTSG), the International Society of Pediatric Oncology (SIOP),and the United Kingdom Children's Cancer Study Group (UKCCSG) conducted sequential studies oftreatments for children with WT. The National Wilms Study Group demonstrated that radiation therapy isnot necessary for those with Stage I and II, favorable histology Wilms tumor, and that the dose necessaryfor local control for those with local Stage III disease is 1050 to 1080cGy. Administration of actinomycinD and doxorubicin using a single dose rather than divided dose schedule produced less myelosuppressionand equivalent outcomes. Loss of heterozygosity for chromosomes 1p and 16q was associated with aninferior outcome. Areas for future investigation include the role of whole lung irradiation in the treatmentof those with pulmonary metastases, the use of parenchymal sparing surgical techniques for removal ofWilms tumors, and identification of minimal necessary therapy.© 2013 Elsevier Inc. All rights reserved.

Gross personally but am impressed by the fact that a manwith monocular vision was able to become a world renowned

Daniel M. Green, MD

I am honored to be given the opportunity to present the2012 Robert E. Gross Memorial Lecture. I never knew Dr.

☆ This work was supported in part by United States Public Healthervice grants no. CA-42326 and CA-054498 from the National Institutes ofealth, Bethesda, MD. We thank investigators of the Children's Oncologyroup and the health professionals who managed the care of childrenntered in the National Wilms Tumor Studies.⁎ Tel.: +1 901 595 5915; fax: +1 901 595 5845.E-mail address: daniel.green@stjude.org.

022-3468/$ – see front matter © 2013 Elsevier Inc. All rights reserved.ttp://dx.doi.org/10.1016/j.jpedsurg.2012.10.012

pediatric surgeon [1].Although Wilms' name is associated with the most

frequent renal tumor of children, others described the tumorprior to his monograph [2] and Beckwith credited JohnHunter with preparing perhaps the earliest specimen between1763 and 1793, now in the collection of the HunterianMuseum of the Royal College of Surgeons in London [3].

The successful treatment of children with Wilms tumorbegan with the development of appropriate anesthetic andsurgical techniques, and careful pre- and post-operativemanagement. The trans-abdominal approach for removal of aWilms tumor was described by Mixter in 1931 and usedroutinely by Ladd and his colleagues [4,5].

Radiation therapy was administered post operatively tochildren with Wilms tumor at Children's Hospital Bostonfor the first time in 1935, and the results of such therapy,a doubling of the survival rate of unstaged children withWilms' tumor who were more than 12months of age at

15The evolution of treatment for Wilms tumor

diagnosis, were initially reported in 1949 by Gross andNeuhauser. They stated, “Therapy in all instances shouldinclude trans-abdominal nephrectomy and postoperativeroentgen irradiation to the area” [6]. However a subse-quent report from the Urology Section of the AmericanAcademy of Pediatrics showed no improvement in sur-vival for 24months after diagnosis from postoperativeirradiation [7].

The use of chemotherapy for the treatment of childrenwith Wilms tumor began with the demonstration of theactivity of actinomycin D in 1958 [8] and vincristine in1963 [9]. The administration of adjuvant chemotherapy tochildren with Wilms tumor was initiated by Farber in1966 [8,10]. A subsequent randomized study by theChildren's Cancer Study Group A demonstrated improvedrelapse-free survival (RFS) when patients received post-operative radiation therapy followed by multiple courses,compared to a single course, of post-nephrectomyactinomycin D [11,12].

In 1968, the major questions in the management ofchildren with Wilms tumor were the role of post-nephrectomy radiation therapy and the benefit, if any,from the use of adjuvant combination chemotherapy. Therewere strong opinions available, but little scientifically validdata. Because Wilms tumor is rare, these questions couldonly be addressed through multi-institutional randomizedclinical trials. In what I believe to have been a pivotaldecision, Giulio J. D'Angio, M.D., a radiation oncologist,was asked to form the National Wilms Tumor Study(NWTS) Group in 1968. The sequential studies of this grouphave informed our current management of children withWilms tumor, leading to decreased tumor related mortality,decreased morbidity and improved quality of life.

1. Stage I/favorable histology

The NWTS demonstrated that abdominal radiationtherapy was not necessary for children with stage I/favorablehistology (FH) WT who received postoperative chemother-apy with vincristine and actinomycin D [13–15]. The post-nephrectomy administration of this combination of agentswas shown in NWTS-1 to significantly improve the RFSpercentage of children with group II/III tumors compared totreatment with either single agent [13]. Children with groupI/FH WT were randomly assigned in NWTS-2 to treatmentwith vincristine and actinomycin D for either 6 (regimen E)or 15 (regimen F) months [14]. The 16-year RFS percentagewas 98.9% for those treated for 6months and 90.5% forthose treated for 15months (P=0.02) [16]. These childrenwere randomly assigned in NWTS-3 to treatment withvincristine and actinomycin D for 10weeks (regimen L) or6months (regimen EE) [15]. The 16-year RFS percentagewas 88.9% for those treated for 10weeks and 92.5% forthose treated for 6months (P=0.08) [16].

Children with stage I/FH WT on NWTS-1 who wereyounger than 24months of age at diagnosis had an excellentoutcome [17]. There was not a significant improvement inthe RFS for children younger than 24months with tumorsthat weighed less than 550g treated with a single agent(NWTS-1) or combination chemotherapy (NWTS-2 andNWTS-3) [18]. These analyses, and the results of a suc-cessful pilot study conducted at Boston Children's Hospital[19], supported treatment of this group of children withnephrectomy only. This study (NWTS-5) was designedwith a stringent stopping rule to ensured closure of the study,with high probability, if, based on interim analysis, the trueRFS rate was 90% or less. The study was closed because thisboundary was exceeded, but the two-year overall survival(OS) rate was 100% [20,21]. These children were moresuccessfully retreated than prior stage I/FH children,probably because they were naive to both radiation therapyand chemotherapy. Nephrectomy only is being re-evaluatedfor the treatment of children younger than 24months with astage I/FH WT weighing less than 550g.

2. Stage II–III/favorable histology

The prognosis for children with groups II–III/FH WTtreated on NWTS-1 with radiation therapy and the combi-nation of vincristine and actinomycin D (regimen C) wasnot as good as that for children with group I WT [13]. Theinvestigators of the NWTSG developed a new chemother-apy regimen that included vincristine, actinomycin D, anddoxorubicin (regimen D) based on the reported responserate of WT to doxorubicin of 60% (31 of 52 patients, with8 complete responses and 23 partial responses) [22].

In NWTS-2 children in groups II–IV were randomlyassigned between regimens C and D. The 16-year RFSpercentages of children in group II–III/FH for regimens Cand D were 72.4% and 86.4%, respectively (P=0.05) [16].The RFS percentages were approximately 70% for regimenC and 88% for regimen D when these results were re-ported in 1981 (P=0.004) [14]. The 16-year OS percent-ages were 80.4% for those treated with two drugs and86.7% for those treated with three drugs (P=0.58) [16].Neither the original report nor these updated results dem-onstrated a statistically significant difference in survivalpercentages between those treated with two, compared withthree drugs [14,16].

Children were randomly assigned in NWTS-3, using a2×2 factorial design, to treatment with (DD) or without (K)doxorubicin, and with radiation doses of 10 (K1 or DD1) or20Gy (K2 or DD2) (stage III) or 0 (K or DD) or 20Gy (DDor DD2) (stage II). The 16-year RFS percentages of childrenwith stage II or III/FH WT were 85.4% for those treated withthree drugs and 82.6% for those treated with two drugs (P=0.30) [16]. The 16-year OS percentages were 88.1% for thosetreated with two drugs and 88.8% for those treated with three

16 D.M. Green

drugs (P=0.68) [16]. These results are not different fromthose originally reported [15].

Overall stratified analyses restricted to children with stageIII/FH WT demonstrated that the addition of doxorubicinimproved the 16-year RFS percentages (83.7%) comparedwith those for patients treated with two drugs (74.2%) (P=0.05) [16]. There was no significant difference between the16-year OS percentage for those treated with three (87.0%),compared to two (82.4%) drugs (P=0.26) [16].

The four-year RFS and OS rates did not differ betweenpatients with stage II/FH WT who received 20Gy comparedwith 0Gy [15]. A subset analysis demonstrated a benefit forthose stage III/FH children treated with three drugs com-pared with two drugs (P=0.04) [15]. Fewer abdominal re-lapses occurred among those with stage III/FH WT treatedwith three (3%; four of 134) compared to two (7.8%; 11 of141 patients) drugs [15]. The data suggested that either athree-drug chemotherapy regimen or a higher radiation ther-apy dose (20Gy) was necessary to successfully treat childrenwith stage III/FH tumors. Concern about the late effects ofthe higher radiation therapy dose and the absence of dataregarding the long-term effects of treatment with doxorubi-cin resulted in the selection of the three-drug regimen withthe lower radiation therapy dose (10Gy) as the standard forthis group of children.

3. Stage IV/favorable histology

Children with stage IV/FH WT were randomly assignedin NWTS-2 to treatment with regimen C or D (vide supra).All received abdominal and whole-lung irradiation [14]. Thefour-year RFS percentages were 53.3% for those on regimenC and 57.7% for those on regimen D (P=0.63) [23]. Thefour-year OS rates were 53.3% for those on regimen C and61.5% for those on regimen D (P=0.62) [23]. The results forNWTS-3 children with stage IV/FH tumors demonstrated nostatistically significant improvement in four-year RFS or OSfrom the addition of cyclophosphamide to the three-drugregimen. The 16-year RFS percentages were 76.5% for thethree-drug regimen (regimen DD) and 77.6% for the four-drug regimen (regimen J) (P=0.65) [16]. The 16-year OSpercentages were 79.5% for the three-drug regimen and80.1% for the four-drug regimen (P=0.65) [16].

4. National Wilms Tumor Study-4

National Wilms Tumor Study-4 was designed to determineif administration of actinomycin D and doxorubicin as singledoses was associatedwith improved EFS, decreased acute and/or long term morbidity and lower cost, and to determine ifthose with stages II through IV Wilms tumor could be treatedsuccessfully with only six, rather than fifteen, months ofchemotherapy. Those with stage I/FH or II/FH were treated

with vincristine and actinomycin D. Those with stages III/FHor IV/FH were treated with vincristine, actinomycin D anddoxorubicin. The two-year relapse-free survival percentagesfor those with stage I/FH were 92.5% (divided dose) and94.9% (single dose) and for those with stage II/FHwere 89.7%(standard dose) and 85.9% (single dose) (p=0.89). The four-year relapse-free survival percentages for those with stage III/FHwere 95.3% (divided dose) and 91.1% (single dose) and forthose with stage IV/FHwere 81.3% (standard dose) and 80.6%(single dose) [24].

Patients with stages II–IV/FH were randomized inNational Wilms Tumor Study-4 to short (approximately sixmonths) versus long (approximately fifteen months) oftreatment. The four-year, relapse-free survival percentageswere 83.7% (short) versus 88.2% (long) (P=0.107) for thosewith stage II/FH, 92.2% (short) versus 90.8% (long) (P=0.682) for those with stage III/FH, and 82.4% (short) versus84.5% (long) (P=0.613) for those with stage IV/FH [25]. Asthe result of NWTS-4, treatment for six months with singledose (pulse-intensive) was adopted as the standard of treat-ment for North American children with Wilms tumor.

5. Loss of heterozygosity

Historically the prognosis of children withWilms tumor wasdetermined by surgical and pathological findings. Grundy et al.identified a novel determinant of prognosis, loss of markers ofheterozygosity (LOH) for chromosomes 1 p or 16q. LOH for 1pwas more frequent among those with stages III or IV Wilmstumor and that for 16q was more frequent among those withstages II, III and IVWilms tumor. The presence of LOH for 16qwas associated with poorer RFS (no LOH: 88% versus LOH:75%, P=0.02) [26]. These results were the basis for the designof National Wilms Tumor Study-5, in which treatment was notrandomized so that the relationship between LOH andprognosis could be more completely evaluated.

The effect of LOH on outcome in NWTS-5 was mostapparent among those who had LOH for both 1p and 16q.Compared to the four-year relapse-free survival percentagefor those with stages I/FH or II/FH with no LOH (85.7%), thefour-year relapse-free survival percentages were 84.4%(LOH 1p only), 82.2% (LOH 16q only) (P=0.01) and68.7% (LOH 1p and 16q) (P=0.001). Compared to the four-year relapse-free survival percentage for those with stagesIII/FH or IV/FH no LOH (85.7%), the four-year relapse-freesurvival percentages were 84.4% (LOH 1p only) (P=0.02),82.2% (LOH 16q only) (P=0.01) and 68.7% (LOH 1p and16q) (P=0.001) [27].

6. Long-term outcomes

Wilms tumor patients have an increased risk of deathcompared to the general population. The standardized

17The evolution of treatment for Wilms tumor

mortality ratio (SMR) is 24.3 (95% Confidence Interval (CI)I,22.6 to 26.0) during the first five years after diagnosis, butremains increased more than twenty years after diagnosis(SMR 4.3, 95% CI, 2.7 to 6.5). The primary cause of deathduring the first five years after diagnosis is the original cancer.Although this remains the most frequent cause of death morethan five years after diagnosis, second malignant neoplasms,cardiac disease and end-stage renal disease are also significantcauses of mortality [28]. The cumulative risk of a secondmalignant neoplasm among participants in the National WilmsTumor Studies was 1.6% fifteen years after diagnosis [29].

The prevalence of serious adverse health events is 24.2% attwenty-five years after diagnosis among five-year survivors ofWilms tumor. The hazard ratio (HR) for a grade 3 to 4 seriousadverse outcome is 4.7 (95% CI, 3.6 to 6.1) among five-yearWilms tumor survivors compared to a sibling control group.The HRs for hypertension (8.2, 95% CI, 6.4 to 10.5),congestive heart failure (23.6, 95% CI, 10.8 to 51.5) and renalfailure (50.7, 95% CI, 14.5 to 177.4) are all increased amongfive-year survivors of Wilms tumor [30]. The cumulativeincidence of congestive heart failure was 4.4% twenty yearsafter diagnosis among National Wilms Tumor Study partic-ipants who received doxorubicin as part of their initial therapyand was 17.4% among those who received doxorubicin foran initial or subsequent relapse. Female sex, cumulativedoxorubicin dose and left flank radiation therapy were eachsignificant risk factors for congestive heart failure [31,32].

7. Pre-nephrectomy chemotherapy

Pre-nephrectomy chemotherapy is recommended todecrease the risk of intra-operative tumor rupture, the riskof intra-operative hemorrhage and increase the percentage ofpatients with low stage tumors. The International Society ofPediatric Oncology reported that the risk of tumor rupturedecreased in sequential studies from 33.3% to 6.0% to 8.0%when pre-operative radiation therapy or chemotherapy wasadministered [33,34]. These percentages can be compared tothose reported from the National Wilms Tumor Studies inwhich the rates were 21.5% (NWTS-1) [17], 12.1% (NWTS-2) [35] and 13.3% (NWTS-3) [36]. The National WilmsTumor Study Group reported that extensive hemorrhageoccurred less frequently among patients who had a tumorthrombus in the inferior vena cava when pre-nephrectomychemotherapy was administered (17.8%) [37] compared towhen immediate nephrectomy was performed (32.5%) [38].

The potential disadvantages of pre-nephrectomy chemo-therapy include loss of staging information, treatment of abenign condition with chemotherapy and treatment of adifferent malignant disease with the wrong chemotherapy.The results of both the National Wilms Tumor Study and theInternational Society of Pediatric Oncology nephroblastomatrials demonstrated that 7.6% (40/522) [13] to 9.9% (44/442)[33] of patients with the pre-nephrectomy diagnosis ofWilms' tumor have a benign or malignant condition other

than Wilms' tumor. Recent data suggest that, even with theuse of modern imaging techniques, an incorrect diagnosiswill be made in 4.8% of patients [39].

A major concern regarding the management of childrenwho receive pre-nephrectomy chemotherapy is the potentialfor loss of important staging information. The experiencereported by the investigators in the International Society ofPediatric Oncology who designed a clinical trial in whichthose patients who were treated with pre-nephrectomy com-bination chemotherapy and were subsequently diagnosed asstage II Wilms tumor without regional lymph node in-volvement were randomized either to receive no irradiationor abdominal irradiation post-nephrectomy suggested thatpre-nephrectomy chemotherapy produced sufficient tumorresponse to destroy perinephric tumor extensions and/ortumor deposits which were present in regional lymph nodes[40]. All received post-nephrectomy adjuvant chemotherapywhich included vincristine and actinomycin D. This trialwas discontinued when an unexpected, statistically signif-icant excess of intra-abdominal recurrences occurred in thenon-irradiated patients [41].

8. Nephron sparing surgery

Nephron sparing surgery has been advocated to decreasethe risk of hyperfiltration injury and thus the risk of late renalfailure in successfully treated Wilms tumor patients. The riskof end-stage renal disease in children with unilateral, non-syndromic Wilms tumor treated on the National WilmsTumor Study Group protocols is 0.7% [42].

The frequency of nephrogenic rests in nephrectomyspecimens from children with non-syndromic unilateralWilms tumor is 36% [43]. These rests may not be includedin a partial nephrectomy specimen, potentially increasing therisk of local recurrence of tumor. In addition partialnephrectomy may increase the risk of tumor spill and/or apositive surgical margin, necessitating abdominal irradiationand the use of doxorubicin in addition to vincristine andactinomycin D. Currently a minority of children withunilateral Wilms tumor (only stage III) receive abdominalirradiation and doxorubicin. Those with small tumors, whomight be candidates for partial nephrectomy, are those withsmall, early stage tumors whose post-nephrectomy treatmentwould include only two drugs, vincristine and actinomycinD, and would not include abdominal irradiation.

Partial nephrectomy has been suggested for children withsyndromic, unilateral Wilms tumor, including those withDenys–Drash syndrome (DDS), Wilms tumor, aniridia,genitourinary malformation and mental retardation syn-drome (WAGR) and Beckwith–Wiedemann syndrome[44]. Although an argument can be made that this is justifiedin those with DDS or WAGR as the result of their dramaticrisk of late renal failure [45,46], such an argument cannot bemade for children with Beckwith–Wiedemann syndrome.All of these children with syndromic Wilms tumor harbor

18 D.M. Green

kidneys greater than 80% of which have one or moreassociated nephrogenic rests [43]. Partial nephrectomy inthis setting may increase the risk of recurrence in the kidneyremnant in children already known to be at risk for theoccurrence of new disease in the contralateral kidney [43].However it is important to remember that, even though therisk of contralateral relapse is increased among those withBeckwith–Wiedemann syndrome and a unilateral renaltumor compared to those with non-syndromic unilateralWilms tumor, the absolute risk remains low, with more than90% of Beckwith–Wiedemann syndrome patients whopresent with a unilateral tumor never developing Wilmstumor in the contralateral kidney [47].

9. Discussion

The survival rate of children with Wilms' tumor hasimproved dramatically since the inception of the prospectiverandomized trials conducted by various multi-institutionalcooperative groups. Future research must address the severalimportant remaining questions including treatment of youngchildren with small, stage I/FH WT using nephrectomy only,the role of doxorubicin in combination with abdominalirradiation for the management of children with stage III/FHWT, the need for whole-lung radiation therapy for themanagement of children with stage IV/FH WT, and theidentification and utilization of biologic features of the excisedtumor for treatment stratification. Answers to these questionswill continue the progress that has been achieved —improving the survival rate and minimizing the adverseacute and late effects of therapy.

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19The evolution of treatment for Wilms tumor

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