Journal of Pediatric Surgery (2013) 48, 1419

www.elsevier.com/locate/jpedsurg

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 381052794, USA
Received 19 September 2012; accepted 13 October 2012

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 of advances in surgical techniques, anesthesia, and supportive care. During the last three decades, the National 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 of treatments for children with WT. The National Wilms Study Group demonstrated that radiation therapy is not necessary for those with Stage I and II, favorable histology Wilms tumor, and that the dose necessary for local control for those with local Stage III disease is 1050 to 1080 cGy. Administration of actinomycin D and doxorubicin using a single dose rather than divided dose schedule produced less myelosuppression and equivalent outcomes. Loss of heterozygosity for chromosomes 1p and 16q was associated with an inferior outcome. Areas for future investigation include the role of whole lung irradiation in the treatment of those with pulmonary metastases, the use of parenchymal sparing surgical techniques for removal of Wilms tumors, and identification of minimal necessary therapy. 2013 Elsevier Inc. All rights reserved.

Daniel M. Green, MD

I am honored to be given the opportunity to present the 2012 Robert E. Gross Memorial Lecture. I never knew Dr.
This work was supported in part by United States Public Health Service grants no. CA-42326 and CA-054498 from the National Institutes of Health, Bethesda, MD. We thank investigators of the Children's Oncology Group and the health professionals who managed the care of children entered in the National Wilms Tumor Studies. Tel.: +1 901 595 5915; fax: +1 901 595 5845. E-mail address: daniel.green@stjude.org. 0022-3468/$ see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpedsurg.2012.10.012

Gross personally but am impressed by the fact that a man with monocular vision was able to become a world renowned pediatric surgeon [1]. Although Wilms' name is associated with the most frequent renal tumor of children, others described the tumor prior to his monograph [2] and Beckwith credited John Hunter with preparing perhaps the earliest specimen between 1763 and 1793, now in the collection of the Hunterian Museum of the Royal College of Surgeons in London [3]. The successful treatment of children with Wilms tumor began with the development of appropriate anesthetic and surgical techniques, and careful pre- and post-operative management. The trans-abdominal approach for removal of a Wilms tumor was described by Mixter in 1931 and used routinely by Ladd and his colleagues [4,5]. Radiation therapy was administered post operatively to children with Wilms tumor at Children's Hospital Boston for the first time in 1935, and the results of such therapy, a doubling of the survival rate of unstaged children with Wilms' tumor who were more than 12 months of age at

The evolution of treatment for Wilms tumor diagnosis, were initially reported in 1949 by Gross and Neuhauser. They stated, Therapy in all instances should include trans-abdominal nephrectomy and postoperative roentgen irradiation to the area [6]. However a subsequent report from the Urology Section of the American Academy of Pediatrics showed no improvement in survival for 24 months after diagnosis from postoperative irradiation [7]. The use of chemotherapy for the treatment of children with Wilms tumor began with the demonstration of the activity of actinomycin D in 1958 [8] and vincristine in 1963 [9]. The administration of adjuvant chemotherapy to children with Wilms tumor was initiated by Farber in 1966 [8,10]. A subsequent randomized study by the Children's Cancer Study Group A demonstrated improved relapse-free survival (RFS) when patients received postoperative radiation therapy followed by multiple courses, compared to a single course, of post-nephrectomy actinomycin D [11,12]. In 1968, the major questions in the management of children with Wilms tumor were the role of postnephrectomy radiation therapy and the benefit, if any, from the use of adjuvant combination chemotherapy. There were strong opinions available, but little scientifically valid data. Because Wilms tumor is rare, these questions could only be addressed through multi-institutional randomized clinical trials. In what I believe to have been a pivotal decision, 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 group have informed our current management of children with Wilms tumor, leading to decreased tumor related mortality, decreased morbidity and improved quality of life.

15 Children with stage I/FH WT on NWTS-1 who were younger than 24 months of age at diagnosis had an excellent outcome [17]. There was not a significant improvement in the RFS for children younger than 24 months with tumors that weighed less than 550 g treated with a single agent (NWTS-1) or combination chemotherapy (NWTS-2 and NWTS-3) [18]. These analyses, and the results of a successful pilot study conducted at Boston Children's Hospital [19], supported treatment of this group of children with nephrectomy only. This study (NWTS-5) was designed with a stringent stopping rule to ensured closure of the study, with high probability, if, based on interim analysis, the true RFS rate was 90% or less. The study was closed because this boundary was exceeded, but the two-year overall survival (OS) rate was 100% [20,21]. These children were more successfully retreated than prior stage I/FH children, probably because they were naive to both radiation therapy and chemotherapy. Nephrectomy only is being re-evaluated for the treatment of children younger than 24 months with a stage I/FH WT weighing less than 550 g.

2. Stage IIIII/favorable histology

The prognosis for children with groups IIIII/FH WT treated on NWTS-1 with radiation therapy and the combination of vincristine and actinomycin D (regimen C) was not as good as that for children with group I WT [13]. The investigators of the NWTSG developed a new chemotherapy regimen that included vincristine, actinomycin D, and doxorubicin (regimen D) based on the reported response rate of WT to doxorubicin of 60% (31 of 52 patients, with 8 complete responses and 23 partial responses) [22]. In NWTS-2 children in groups IIIV were randomly assigned between regimens C and D. The 16-year RFS percentages of children in group IIIII/FH for regimens C and D were 72.4% and 86.4%, respectively (P=0.05) [16]. The RFS percentages were approximately 70% for regimen C and 88% for regimen D when these results were reported in 1981 (P=0.004) [14]. The 16-year OS percentages were 80.4% for those treated with two drugs and 86.7% for those treated with three drugs (P=0.58) [16]. Neither the original report nor these updated results demonstrated a statistically significant difference in survival percentages between those treated with two, compared with three drugs [14,16]. Children were randomly assigned in NWTS-3, using a 22 factorial design, to treatment with (DD) or without (K) doxorubicin, and with radiation doses of 10 (K1 or DD1) or 20 Gy (K2 or DD2) (stage III) or 0 (K or DD) or 20 Gy (DD or DD2) (stage II). The 16-year RFS percentages of children with stage II or III/FH WT were 85.4% for those treated with three drugs and 82.6% for those treated with two drugs (P= 0.30) [16]. The 16-year OS percentages were 88.1% for those treated with two drugs and 88.8% for those treated with three

1. Stage I/favorable histology

The NWTS demonstrated that abdominal radiation therapy was not necessary for children with stage I/favorable histology (FH) WT who received postoperative chemotherapy with vincristine and actinomycin D [1315]. The postnephrectomy administration of this combination of agents was shown in NWTS-1 to significantly improve the RFS percentage of children with group II/III tumors compared to treatment with either single agent [13]. Children with group I/FH WT were randomly assigned in NWTS-2 to treatment with vincristine and actinomycin D for either 6 (regimen E) or 15 (regimen F) months [14]. The 16-year RFS percentage was 98.9% for those treated for 6 months and 90.5% for those treated for 15 months (P=0.02) [16]. These children were randomly assigned in NWTS-3 to treatment with vincristine and actinomycin D for 10 weeks (regimen L) or 6 months (regimen EE) [15]. The 16-year RFS percentage was 88.9% for those treated for 10 weeks and 92.5% for those treated for 6 months (P=0.08) [16].

16 drugs (P=0.68) [16]. These results are not different from those originally reported [15]. Overall stratified analyses restricted to children with stage III/FH WT demonstrated that the addition of doxorubicin improved the 16-year RFS percentages (83.7%) compared with those for patients treated with two drugs (74.2%) (P= 0.05) [16]. There was no significant difference between the 16-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 between patients with stage II/FH WT who received 20 Gy compared with 0 Gy [15]. A subset analysis demonstrated a benefit for those stage III/FH children treated with three drugs compared with two drugs (P=0.04) [15]. Fewer abdominal relapses occurred among those with stage III/FH WT treated with three (3%; four of 134) compared to two (7.8%; 11 of 141 patients) drugs [15]. The data suggested that either a three-drug chemotherapy regimen or a higher radiation therapy dose (20 Gy) was necessary to successfully treat children with stage III/FH tumors. Concern about the late effects of the higher radiation therapy dose and the absence of data regarding the long-term effects of treatment with doxorubicin resulted in the selection of the three-drug regimen with the lower radiation therapy dose (10 Gy) as the standard for this group of children.

D.M. Green with vincristine and actinomycin D. Those with stages III/FH or IV/FH were treated with vincristine, actinomycin D and doxorubicin. The two-year relapse-free survival percentages for those with stage I/FH were 92.5% (divided dose) and 94.9% (single dose) and for those with stage II/FH were 89.7% (standard dose) and 85.9% (single dose) (p=0.89). The fouryear relapse-free survival percentages for those with stage III/ FH were 95.3% (divided dose) and 91.1% (single dose) and for those with stage IV/FH were 81.3% (standard dose) and 80.6% (single dose) [24]. Patients with stages IIIV/FH were randomized in National Wilms Tumor Study-4 to short (approximately six months) versus long (approximately fifteen months) of treatment. The four-year, relapse-free survival percentages were 83.7% (short) versus 88.2% (long) (P=0.107) for those with stage II/FH, 92.2% (short) versus 90.8% (long) (P= 0.682) for those with stage III/FH, and 82.4% (short) versus 84.5% (long) (P=0.613) for those with stage IV/FH [25]. As the result of NWTS-4, treatment for six months with single dose (pulse-intensive) was adopted as the standard of treatment for North American children with Wilms tumor.

5. Loss of heterozygosity
Historically the prognosis of children with Wilms tumor was determined by surgical and pathological findings. Grundy et al. identified a novel determinant of prognosis, loss of markers of heterozygosity (LOH) for chromosomes 1 p or 16q. LOH for 1p was more frequent among those with stages III or IV Wilms tumor and that for 16q was more frequent among those with stages II, III and IV Wilms tumor. The presence of LOH for 16q was associated with poorer RFS (no LOH: 88% versus LOH: 75%, P=0.02) [26]. These results were the basis for the design of National Wilms Tumor Study-5, in which treatment was not randomized so that the relationship between LOH and prognosis could be more completely evaluated. The effect of LOH on outcome in NWTS-5 was most apparent among those who had LOH for both 1p and 16q. Compared to the four-year relapse-free survival percentage for those with stages I/FH or II/FH with no LOH (85.7%), the four-year relapse-free survival percentages were 84.4% (LOH 1p only), 82.2% (LOH 16q only) (P=0.01) and 68.7% (LOH 1p and 16q) (P=0.001). Compared to the fouryear relapse-free survival percentage for those with stages III/FH or IV/FH no LOH (85.7%), the four-year relapse-free survival percentages were 84.4% (LOH 1p only) (P=0.02), 82.2% (LOH 16q only) (P=0.01) and 68.7% (LOH 1p and 16q) (P=0.001) [27].

3. Stage IV/favorable histology

Children with stage IV/FH WT were randomly assigned in NWTS-2 to treatment with regimen C or D (vide supra). All received abdominal and whole-lung irradiation [14]. The four-year RFS percentages were 53.3% for those on regimen C and 57.7% for those on regimen D (P=0.63) [23]. The four-year OS rates were 53.3% for those on regimen C and 61.5% for those on regimen D (P=0.62) [23]. The results for NWTS-3 children with stage IV/FH tumors demonstrated no statistically significant improvement in four-year RFS or OS from the addition of cyclophosphamide to the three-drug regimen. The 16-year RFS percentages were 76.5% for the three-drug regimen (regimen DD) and 77.6% for the fourdrug regimen (regimen J) (P=0.65) [16]. The 16-year OS percentages were 79.5% for the three-drug regimen and 80.1% for the four-drug regimen (P=0.65) [16].

4. National Wilms Tumor Study-4

National Wilms Tumor Study-4 was designed to determine if administration of actinomycin D and doxorubicin as single doses was associated with improved EFS, decreased acute and/ or long term morbidity and lower cost, and to determine if those with stages II through IV Wilms tumor could be treated successfully with only six, rather than fifteen, months of chemotherapy. Those with stage I/FH or II/FH were treated

6. Long-term outcomes
Wilms tumor patients have an increased risk of death compared to the general population. The standardized

The 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, but remains increased more than twenty years after diagnosis (SMR 4.3, 95% CI, 2.7 to 6.5). The primary cause of death during the first five years after diagnosis is the original cancer. Although this remains the most frequent cause of death more than five years after diagnosis, second malignant neoplasms, cardiac disease and end-stage renal disease are also significant causes of mortality [28]. The cumulative risk of a second malignant neoplasm among participants in the National Wilms Tumor Studies was 1.6% fifteen years after diagnosis [29]. The prevalence of serious adverse health events is 24.2% at twenty-five years after diagnosis among five-year survivors of Wilms tumor. The hazard ratio (HR) for a grade 3 to 4 serious adverse outcome is 4.7 (95% CI, 3.6 to 6.1) among five-year Wilms 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 renal failure (50.7, 95% CI, 14.5 to 177.4) are all increased among five-year survivors of Wilms tumor [30]. The cumulative incidence of congestive heart failure was 4.4% twenty years after diagnosis among National Wilms Tumor Study participants who received doxorubicin as part of their initial therapy and was 17.4% among those who received doxorubicin for an initial or subsequent relapse. Female sex, cumulative doxorubicin dose and left flank radiation therapy were each significant risk factors for congestive heart failure [31,32].

17 than Wilms' tumor. Recent data suggest that, even with the use of modern imaging techniques, an incorrect diagnosis will be made in 4.8% of patients [39]. A major concern regarding the management of children who receive pre-nephrectomy chemotherapy is the potential for loss of important staging information. The experience reported by the investigators in the International Society of Pediatric Oncology who designed a clinical trial in which those patients who were treated with pre-nephrectomy combination chemotherapy and were subsequently diagnosed as stage II Wilms tumor without regional lymph node involvement were randomized either to receive no irradiation or abdominal irradiation post-nephrectomy suggested that pre-nephrectomy chemotherapy produced sufficient tumor response to destroy perinephric tumor extensions and/or tumor deposits which were present in regional lymph nodes [40]. All received post-nephrectomy adjuvant chemotherapy which included vincristine and actinomycin D. This trial was discontinued when an unexpected, statistically significant excess of intra-abdominal recurrences occurred in the non-irradiated patients [41].

8. Nephron sparing surgery

Nephron sparing surgery has been advocated to decrease the risk of hyperfiltration injury and thus the risk of late renal failure in successfully treated Wilms tumor patients. The risk of end-stage renal disease in children with unilateral, nonsyndromic Wilms tumor treated on the National Wilms Tumor Study Group protocols is 0.7% [42]. The frequency of nephrogenic rests in nephrectomy specimens from children with non-syndromic unilateral Wilms tumor is 36% [43]. These rests may not be included in a partial nephrectomy specimen, potentially increasing the risk of local recurrence of tumor. In addition partial nephrectomy may increase the risk of tumor spill and/or a positive surgical margin, necessitating abdominal irradiation and the use of doxorubicin in addition to vincristine and actinomycin D. Currently a minority of children with unilateral Wilms tumor (only stage III) receive abdominal irradiation and doxorubicin. Those with small tumors, who might be candidates for partial nephrectomy, are those with small, early stage tumors whose post-nephrectomy treatment would include only two drugs, vincristine and actinomycin D, and would not include abdominal irradiation. Partial nephrectomy has been suggested for children with syndromic, unilateral Wilms tumor, including those with DenysDrash syndrome (DDS), Wilms tumor, aniridia, genitourinary malformation and mental retardation syndrome (WAGR) and BeckwithWiedemann syndrome [44]. Although an argument can be made that this is justified in those with DDS or WAGR as the result of their dramatic risk of late renal failure [45,46], such an argument cannot be made for children with BeckwithWiedemann syndrome. All of these children with syndromic Wilms tumor harbor

7. Pre-nephrectomy chemotherapy
Pre-nephrectomy chemotherapy is recommended to decrease the risk of intra-operative tumor rupture, the risk of intra-operative hemorrhage and increase the percentage of patients with low stage tumors. The International Society of Pediatric Oncology reported that the risk of tumor rupture decreased in sequential studies from 33.3% to 6.0% to 8.0% when pre-operative radiation therapy or chemotherapy was administered [33,34]. These percentages can be compared to those reported from the National Wilms Tumor Studies in which the rates were 21.5% (NWTS-1) [17], 12.1% (NWTS2) [35] and 13.3% (NWTS-3) [36]. The National Wilms Tumor Study Group reported that extensive hemorrhage occurred less frequently among patients who had a tumor thrombus in the inferior vena cava when pre-nephrectomy chemotherapy was administered (17.8%) [37] compared to when immediate nephrectomy was performed (32.5%) [38]. The potential disadvantages of pre-nephrectomy chemotherapy include loss of staging information, treatment of a benign condition with chemotherapy and treatment of a different malignant disease with the wrong chemotherapy. The results of both the National Wilms Tumor Study and the International Society of Pediatric Oncology nephroblastoma trials demonstrated that 7.6% (40/522) [13] to 9.9% (44/442) [33] of patients with the pre-nephrectomy diagnosis of Wilms' tumor have a benign or malignant condition other

18 kidneys greater than 80% of which have one or more associated nephrogenic rests [43]. Partial nephrectomy in this setting may increase the risk of recurrence in the kidney remnant in children already known to be at risk for the occurrence of new disease in the contralateral kidney [43]. However it is important to remember that, even though the risk of contralateral relapse is increased among those with BeckwithWiedemann syndrome and a unilateral renal tumor compared to those with non-syndromic unilateral Wilms tumor, the absolute risk remains low, with more than 90% of BeckwithWiedemann syndrome patients who present with a unilateral tumor never developing Wilms tumor in the contralateral kidney [47].

D.M. Green
[11] Wolff JA, D'Angio G, Hartmann J, et al. Long term evaluation of single versus multiple courses of actinomycin D therapy of Wilms' tumor. New Engl J Med 1974;290:84-6. [12] Wolff JA, Krivit W, Newton WAJ, et al. Single versus multiple dose dactinomycin therapy of Wilms' tumor. New Engl J Med 1968;279:290-4. [13] D'Angio GJ, Evans AE, Breslow N, et al. The treatment of Wilms' tumor: results of the National Wilms' Tumor Study. Cancer 1976;38: 633-46. [14] D'Angio GJ, Evans A, Breslow N, et al. The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study. Cancer 1981;47:2302-11. [15] D'Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer 1989;64:349-60. [16] Green DM. The treatment of stages IIV favorable histology Wilms' tumor. J Clin Oncol 2004;22:1366-72. [17] Breslow NE, Palmer NF, Hill LR, et al. Wilms' tumor: prognostic factors for patients without metastases at diagnosis: results of the National Wilms' Tumor Study. Cancer 1978;41:1577-89. [18] Green DM, Breslow NE, Beckwith JB, et al. Treatment outcomes in patients less than 2 years of age with small, stage I, favorable-histology Wilms' tumors: a report from the National Wilms' Tumor Study. J Clin Oncol 1993;11:91-5. [19] Larsen E, Perez-Atayde A, Green DM, et al. Surgery only for the treatment of patients with stage I (Cassady) Wilms' tumor. Cancer 1990;66:264-6. [20] Green DM, Breslow NE, Beckwith JB, et al. Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 2001;19:3719-24. [21] Shamberger RC, Anderson JR, Breslow NE, et al. Long-term outcomes for infants with very low risk Wilms tumor treated with surgery alone in National Wilms Tumor Study-5. Ann Surg 2010;251: 555-8. [22] Green DM. Diagnosis and management of malignant solid tumors in infants and children. Boston: Martinus Nijhoff; 1985. [23] Green DM, Breslow NE, Evans I, et al. Treatment of children with stage IV favorable histology Wilms tumor: a report from the National Wilms Tumor Study Group. Med Pediatr Oncol 1996;26: 147-52. [24] Green DM, Breslow NE, Beckwith JB, et al. Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 1998;16:237-45. [25] Green DM, Breslow NE, Beckwith JB, et al. Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 1998;16:3744-51. [26] Grundy PE, Telzerow PE, Breslow N, et al. Loss of heterozygosity for chromosomes 16q and 1p in Wilms' tumors predicts an adverse outcome. Cancer Res 1994;54:2331-3. [27] Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorablehistology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 2005;23:7312-21. [28] Cotton CA, Peterson S, Norkool PA, et al. Early and late mortality after diagnosis of Wilms tumor. J Clin Oncol 2009;27:1304-9. [29] Breslow NE, Takashima JR, Whitton JA, et al. Second malignant neoplasms following treatment for Wilm's tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 1995;13: 1851-9. [30] Termuhlen AM, Tersak JM, Liu Q, et al. Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2011;57:1210-6. [31] Green DM, Grigoriev YA, Nan B, et al. Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 2001;19:1926-34.

9. Discussion
The survival rate of children with Wilms' tumor has improved dramatically since the inception of the prospective randomized trials conducted by various multi-institutional cooperative groups. Future research must address the several important remaining questions including treatment of young children with small, stage I/FH WT using nephrectomy only, the role of doxorubicin in combination with abdominal irradiation for the management of children with stage III/FH WT, the need for whole-lung radiation therapy for the management of children with stage IV/FH WT, and the identification and utilization of biologic features of the excised tumor for treatment stratification. Answers to these questions will continue the progress that has been achieved improving the survival rate and minimizing the adverse acute and late effects of therapy.

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