Hematol Oncol Stem Cell Ther (2016) 9, 20–25

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ORIGINAL RESEARCH REPORT

Wilms tumor: Successes and challenges inmanagement outside of cooperative clinicaltrials

http://dx.doi.org/10.1016/j.hemonc.2015.12.0061658-3876/� 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author at: American University of Beirut Medical Center, Riad El Solh Street, Beirut 1107 2020, Lebanon.E-mail address: rs88@aub.edu.lb (R. Saab).

Wissam Rabeh a, Samir Akel b, Toufic Eid c, Samar Muwakkit a,Miguel Abboud a, Hassan El Solh a, Raya Saab a,*

aChildren’s Cancer Institute, American University of Beirut Medical Center, Beirut, LebanonbDepartment of Surgery, American University of Beirut Medical Center, Beirut, LebanoncDepartment of Radiation Oncology, American University of Beirut Medical Center, Beirut, Lebanon

Received 3 November 2015; accepted 1 December 2015Available online 18 January 2016

KEYWORDSPediatric cancer;Wilms tumor;Nephroblastoma

Abstract

Objective/background: Management of Wilms tumor (WT) in children depends on a multidisci-plinary approach to treatment, and outcomes have significantly improved as reported by coop-erative group clinical trials. Here, we review the clinical outcomes of patients with WT andidentify challenges and barriers encountered in multidisciplinary management outside of coop-erative clinical trials.Methods: We retrospectively reviewed the clinical records of 35 children with WT treatedbetween April 2002 and June 2013 at the Children’s Cancer Institute in Lebanon.Results: Upfront resection was performed in 23 cases. Biopsies were performed for Stage Vtumors (n = 4), those with unresectable tumors or inferior vena caval thrombus (n = 5), andpatients who had partial surgery performed elsewhere prior to presentation (n = 2). One patientdied due to toxicity prior to surgery. The tumor was Stage I in eight patients, Stage II in fivepatients, Stages III and IV in nine patients each, and bilateral (Stage V) in four patients. Adher-ence to The National Wilms Tumor Study-5 recommendations was adequate. At the time ofanalysis, 30 patients were free of disease and four patients had relapse—all having metastaticdisease initially.Conclusion: The National Wilms Tumor Study-5 therapy resulted in favorable outcomes in chil-dren with nonmetastatic Wilms tumor in the setting of a multidisciplinary approach to therapyand resolution of financial barriers to medical care. Upstaging due to prior intervention andlung radiation therapy to all those with computed tomography-detected lung nodules may both

Wilms tumor management and outcome 21

have resulted in overtreatment of a subset of patients. Finally, the relatively high incidence ofbilateral tumors suggests the need for further genetic and molecular studies in this patientpopulation.

� 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is anopen access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-

nd/4.0/).

Introduction

Nephroblastoma (Wilms tumor; WT) is the most commonpediatric renal tumor [1], thought to arise from foci ofpersistent metanephric cells referred to as nephrogenicrests or nephroblastomatosis [2]. The outcome of WT hasimproved significantly over the past few decades; the5-year survival rate has improved from 20% in the 1960sto over 90% in the current decade [3–5]. This improvementis due primarily to a multidisciplinary approach to treat-ment, and to a series of cooperative clinical trials aimingat optimizing therapy and risk stratification, led by twolarge study groups: the North American Children’s Oncol-ogy Group via The National Wilms Tumor Study (NWTS)group, and the European Societe Internationale D’oncolo-gie Pediatrique (SIOP) group. However, despite the impres-sive improvements in outcome, retrospective reviews ofoutcomes from developing countries have shown poorerresults [6–19]. Factors that are thought to contribute tothis disparity include late presentation, malnutrition, pov-erty leading to abandonment of treatment, and lack ofmultidisciplinary collaboration [6–19]. In this study weaimed to determine the characteristics and outcomes ofpatients with WT treated at a multidisciplinary center inLebanon, and to identify successes and barriers in imple-menting established treatment protocols and risk stratifi-cation for this disease when applied in a multidisciplinarysetting outside of a cooperative clinical trial, and afterfinancial barriers to therapy are overcome by a localfundraising body.

Materials and methods

This retrospective study was approved by the InstitutionalReview Board at the American University of Beirut MedicalCenter, Beirut, Lebanon. All patients with Wilms tumortreated at the Children’s Cancer Institute at the AmericanUniversity of Beirut Medical Center between April 2002and June 2013 were identified, and the medical recordswere retrospectively reviewed. Data collected includedthe age at diagnosis, sex, tumor site, size, extent, stage,treatment received, complications, and outcome. The ini-tial workup for all patients included history, physical exam-ination, and laboratory blood tests including kidney functiontests. Staging studies included computed tomography (CT)scans of the chest, abdomen, and pelvis, with oral and intra-venous contrast administration, and in some cases plainX-ray of the chest. Nephrectomy and complete tumor resec-tion was performed upfront whenever feasible; upfronttumor biopsy was restricted to patients with bilateraltumors or those who had extensive regional disease preclud-ing attempts at complete resection. Patients with upfront

biopsy received neo-adjuvant chemotherapy, with delayedsurgical resection.

Risk stratification and treatment planning were unifiedand based on the NWTS-5 protocol. Per this plan, patientswith Stage I and favorable histology Stage II tumors receiveregimen EE4A consisting of vincristine and actinomycin-Dfor 18 weeks [20]; those with unfavorable histology StageII tumors or favorable histology Stage III and IV tumorsreceive regimen DD4A consisting of vincristine,actinomycin-D, and doxorubicin for 24 weeks [20]; andthose with Stage II–IV tumors with diffuse anaplasiareceived regimen I which includes vincristine, cyclophos-phamide, etoposide, and doxorubicin for 24 weeks [21].Patients received radiation therapy (flank, whole abdomen,lung, metastatic sites) as per the NWTS-5 protocol; specifi-cally, patients with Stage III focal tumor received focalabdominal radiation to 10.8 Gy; those with tumor spill, pos-itive peritoneal cytology, or extensive lymphadenopathyreceived whole abdomen radiation to 10.8 Gy; patients withlung metastases received radiation to the lungs to 12 Gy,and those with bulky extra-abdominal metastases receivedradiation to that site, as needed. After finishing treatment,all patients were followed up regularly with physical exam-ination, imaging with ultrasonography of the abdomen, CTof the chest for those with initial Stage IV disease, and chestX-ray for patients with Stage I–III disease, as well as urineanalysis and serum blood urea nitrogen and creatininelevels.

Data was analyzed using the SPSS software version 22(SPSS Inc., Chicago, IL, USA). Kaplan–Meier survival curveswere generated to estimate overall survival (OS), event freesurvival (EFS), and Stage specific survival estimates. OS wasdefined as time from initial diagnosis to time of death fromany cause or to most recent follow-up. EFS was defined astime from initial diagnosis to first relapse, death from anycause, or most recent follow-up, whichever occurred first.

Results

Thirty-five children were diagnosed with nephroblastomaand represented 4% of all patients diagnosed with cancerduring the study period. Patient characteristics are shownin Table 1. Male to female ratio was 1:1.7, and the meanage at diagnosis was 3.9 ± 3.1 years (median 3 years, range,0.6–16 years). Stage distribution is shown in Table 1; localStage III disease was due to positive abdominal lymph nodesby histology in six patients (3 of whom also had metastaticdisease), intra-operative tumor spillage in two patients,nonresectable tumor in five patients, pre-operative tumorrupture due to trauma in one patient, and upstaging dueto incomplete operation prior to referral in two patients.Three patients had tumor thrombus involving the inferior

22 W. Rabeh et al.

vena cava at diagnosis, and one patient had thrombusreaching renal vein but with patent inferior vena cava.

Twenty-three patients (66%) had an upfront nephrec-tomy followed by Stage specific chemotherapy and radio-therapy as per the North American NWTS-5 protocol.Eleven patients (31%) had an upfront biopsy followed bydefinitive surgery at a median time of 6 weeks after initia-tion of chemotherapy (range, 2–15 weeks). One patientdied due to disseminated intravascular coagulation priorto timing of surgery. All remaining patients underwent suc-cessful tumor resection. Thirty patients underwent unilat-eral nephrectomy, and two of them also required partialdiaphragmatic resection to achieve negative margins. Forthe four patients with bilateral tumors, two underwentbilateral partial nephrectomies, and two required unilateralradical nephrectomy and partial nephrectomy on the otherside. One patient had diffuse anaplasia; all others had favor-able histology tumors. Eight patients received wholeabdominal radiation therapy, and six received flank/tumorbed radiation. Five patients received radiation therapy tothe lungs, and one received additional radiation therapyto liver metastases. Planned chemotherapy was adminis-tered successfully, with minimal delays in schedule. Compli-cations of chemotherapy are shown in Table 2. Surgicalcomplications were infrequent: two patients developedfunctional intestinal obstruction, which was managed con-servatively and resolved without long-term sequelae. Ingeneral, patients were observed in the pediatric intensive

Table 1 Patient characteristics

Variable

Sex Male

Kidney site RightLeftBilateral

Tumor histology FavorableAnaplastic

Local lymph nodes Positive

Metastasis LungsMultiple organs (liver,Distant lymph nodes

Stage IIIIIIIVV

Nephrectomy UpfrontDelayed (initial biopsy)Nonea

Radiotherapy (local) Stage IIIStage IVStage V

Note. Data are presented as n (%).a One patient died of disseminated intravascular coagulation prior t

care unit for at least 2 days after nephrectomy. Of note,one patient developed chronic renal failure during treat-ment, due to focal segmental glomerulosclerosis occurringin the remaining noninvolved kidney. This child was foundto have Denys-Drash syndrome using WT1 gene mutationanalysis, and is currently on chronic dialysis awaiting renaltransplantation.

The treatment outcomes are shown in Table 2. At thetime of analysis, 30 patients (86%) were alive; all were freeof disease at a median follow-up time of 58 months fromdiagnosis (range, 23–134 months). Four patients had dis-ease relapse at a median time of 8.8 months (range, 7.1–12.2 months) from initial diagnosis. Notably, all fourpatients who had relapse had initial metastatic (Stage IV)disease. Relapse occurred in the lungs in all four patients;two patients also had synchronous liver metastases andone had synchronous metastasis to the uterus. All fourpatients who relapsed died due to disease progressiondespite second-line therapy. The 3-year OS and EFS esti-mates for all analyzed patients were 88.6% and 85.7%,respectively (Figure 1A and B). When analyzed by Stage,patients with Stage I, II, and V disease had 100% 3-year OS,whereas patients with Stage III disease had a 3-year OS of90%, and those with Stage IV disease had a 3-year OS of67% (Figure 1C). EFS rates followed a similar pattern,with 3-year EFS for patients with Stages I, II, and V diseaseat 100%, Stage III disease at 90%, and Stage IV disease at55.6%.

No. of patients (N = 35)

13 (37)

19 (54)12 (34)4 (12)

34 (97)1 (3)

11 (31)

7 (20)bone, and lung) 1 (3)

1 (3)

8 (23)5 (14)9 (26)9 (26)4 (11)

23 (66)11 (31)1 (3)

8 (23)7 (20)0 (0)

o surgery.

Table 2 Complications and outcomes

No. (N = 35)

Treatment complications Neutropenic fever 4 (12)Severe diarrhea 5 (14)Febrile urinary tract infection 5 (14)Varicella infection 4 (12)Disseminated intravascular coagulation 1 (3)Functional intestinal obstruction 2 (6)

Outcome Continued complete remission 30 (86)Relapse 4 (12)Deatha 5 (14)

Note. Data are presented as n (%).a All patients who relapsed died of disease progression.

Wilms tumor management and outcome 23

Discussion

The NWTS studies have shown 2-year EFS of 94.9% and an OSof 98.7% for Stage I disease, 8-year EFS of 83.6% and an OS of93.8% for Stage II disease, 8-year EFS of 88.9% and an OS of93% for Stage III disease, and a 2-year EFS of 80.6% and an OSof 89.5% for Stage IV disease [22,23]. Similarly, the SIOPstudy group has shown a 5-year EFS of 92% for Stage I andnode-negative Stage II disease, with an EFS of 82% fornode-positive Stage II and III tumors, and a 5-year EFS of72.3% with an OS of 83.3% for Stage IV disease [24–26].Other developed countries have shown similar results[27–32]. In our series, the 3-year EFS and OS were 85.7%and 88.6% respectively. Although we describe a small

Figure 1 (A) Overall survival estimate; (B) event-free survival estievent-free survival estimate stratified by tumor stage. Note. St = st

number of patients limiting statistical comparisons, it seemsthat our experience shows similar outcome rates forpatients with Stage I, II, III, and V disease, while patientswith metastatic disease fared worse than published resultsfrom cooperative group trials. In general, patient character-istics at presentation did not differ from those publishedfrom other centers, taking the variable sample sizes intoaccount. We observed a female preponderance, similar towhat has been observed in the NWTS and SIOP studies[24,26]. The median age at presentation was 36 months,which is comparable to what has been observed in otherstudies [9,11–13,15–18,33,34]. The right kidney was morecommonly affected than the left in our study. In our cohortof patients, treatment was not interrupted and there was noabandonment—a very important consideration that affects

mate for the entire group; (C) overall survival estimate; and (D)age.

24 W. Rabeh et al.

outcome in developing and middle-income countries [6–19]. This is likely due to the fact that all financial barrierswere resolved by complete financial coverage of treatmentcosts by a local fundraising body, which allowed patientswith poor socioeconomic status and lack of third-partyinsurance to continue therapy without major interruptions.While the apparently worse outcome of children with StageIV disease in our study could be due to a difference in tumorbiology, it should be kept in mind that the small number ofpatients analyzed limits the significance of this observeddifference.

Other issues in treatment allocation and delivery werenoted that deserve mentioning. Firstly, upstaging was nec-essary in two of 35 patients (6%) due to inappropriate sur-gery before patient referral to the oncologist. Thisupstaging resulted in treatment as Stage III disease, withmore intensive chemotherapy (DD4A regimen) and wholeabdomen radiation therapy. Even after accounting forpatients who had their disease upstaged due to inadequateor unclear surgical details prior to referral, we still had ahigh rate of patients who presented with late Stage disease(III and IV), compared with developed countries[17,26,27,29]. This is in fact similar to what has beenobserved in most low- and middle-income countries[7,9,11,12,14,16,33,35]. Whether this is an indication ofdelayed presentation or more aggressive tumor biology, stillneeds to be determined.

We also noted that all patients in our series had diseasestaging based on chest CT and not chest X-ray, and all thosewith lung nodules detected with CT scan received Stage IV-directed therapy (DD-4A) as well as radiation therapy to thelungs. While one study showed that three-drug regimen forCT-only metastases can improve EFS but not OS [36], inother studies patients with CT-only lung metastases in thesetting of low-stage primary tumors were shown to be ade-quately treated with a two-drug regimen [37,38]. Mostpatients with metastases, however, had local Stage IIIdisease, and therefore treatment regimen included anthra-cyclines. The benefit of lung radiation in patients withCT-only lung metastases is still unclear [36,38] and may con-tribute to significant long-term side effects [39–41]. Thus,further efforts should be made to ensure discussion of suchissues in multidisciplinary meetings when individualizedtherapy decisions are made.

Finally, the rate of bilateral tumors (11% of our patients)seems higher than that observed in the NWTS and SIOPcohorts, as well as other reported series [7,9,12–14,16,19,29,3,32,34–36,42]. While the reasons for this finding areunclear, and taking into consideration the limitation ofour small number of patients, it does raise questions regard-ing possible predisposition conditions to bilateral tumors inthis population and warrants further future assessment. Inour series, patients with Stage V tumors did very well, whichcompares favorably to published results [12,13,16,29,31,32,34,42–44]. Three of these patients received DD4A regi-men and one received EE-4A regimen. All had completetumor resection consisting of either bilateral partialnephrectomies or nephrectomy on one side and partialnephrectomy on the other. None received radiationtherapy, and all four are in continued Complete Remission(CR) with normal renal function.

Conclusion

Although similar to other developing countries, more thanhalf of our patients presented with late Stage disease (IIIand IV) and the outcome of patients in this studyapproached that reported in cooperative trials in developedcountries. This likely represents the effects of a multidisci-plinary approach to management, availability of a special-ized pediatric oncology surgeon, availability of promptsupportive care measures, and financial coverage of treat-ment contributing to low abandonment rates. Earlier refer-ral of patients to a tertiary care setting, prior to attemptedsurgery, would be expected to further improve outcome andminimize over-staging of such patients.

Conflicts of interest

The authors have no conflict of interests related to thissubject.

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