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. 2021 Feb 26;13(5):976. doi: 10.3390/cancers13050976

Outcome of Stage IV Completely Necrotic Wilms Tumour and Local Stage III Treated According to the SIOP 2001 Protocol

Raquel Dávila Fajardo 1,2,*, Rhoikos Furtwängler 3, Martine van Grotel 2, Harm van Tinteren 4, Claudia Pasqualini 5, Kathy Pritchard-Jones 6, Reem Al-Saadi 6, Beatriz de Camargo 7, Gema L Ramírez Villar 8, Norbert Graf 3, Xavier Muracciole 9, Patrick Melchior 10, Daniel Saunders 11, Christian Rübe 10, Marry M van den Heuvel-Eibrink 2, Geert O Janssens 1,2, Arnauld C Verschuur 12
Editor: Takehiko Kamijo
PMCID: PMC7956604  PMID: 33652659

Abstract

Simple Summary

Around 15–20% of all Wilms tumour (WT) patients present with metastatic disease. Approximately 10% of these patients achieve complete necrosis after preoperative chemotherapy, which is associated with a favourable prognosis. The aim of this observational study is to describe the outcome of metastatic patients with completely necrotic (low-risk histology), local stage III WT treated according to the SIOP 2001 protocol, whether or not postoperative radiotherapy was applied.

Abstract

Objective: Wilms tumour (WT) patients with a localised completely necrotic nephroblastoma after preoperative chemotherapy are a favourable outcome group. Since the introduction of the SIOP 2001 protocol, the SIOP– Renal Tumour Study Group (SIOP–RTSG) has omitted radiotherapy for such patients with low-risk, local stage III in an attempt to reduce treatment burden. However, for metastatic patients with local stage III, completely necrotic WT, the recommendations led to ambiguous use. The purpose of this descriptive study is to demonstrate the outcomes of patients with metastatic, completely necrotic and local stage III WT in relation to the application of radiotherapy or not. Methods and materials: all metastatic patients with local stage III, completely necrotic WT after 6 weeks of preoperative chemotherapy who were registered in the SIOP 2001 study were included in this analysis. The pattern of recurrence according to the usage of radiation treatment and 5 year event-free survival (EFS) and overall survival (OS) was analysed. Results: seven hundred and three metastatic WT patients were registered in the SIOP 2001 database. Of them, 47 patients had a completely necrotic, local stage III WT: 45 lung metastases (11 combined localisations), 1 liver/peritoneal, and 1 tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients did not receive radiotherapy. Median follow-up was 6.6 years (range 1–151 months). Two of the 47 patients (4%) developed disease recurrence in the lung (one combined with abdominal relapse) and eventually died of the disease. Both patients had received abdominal radiotherapy, one of them combined with lung irradiation. Five-year EFS and OS were 95% and 95%, respectively. Conclusions: the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent. Our results suggest that abdominal irradiation in this patient category may not be of added value in first-line treatment, consistent with the current recommendation in the SIOP–RTSG 2016 UMBRELLA protocol.

Keywords: Wilms tumour, nephroblastoma, completely necrotic, metastatic disease

1. Introduction

The Wilms tumour (WT), or nephroblastoma, is the most frequent paediatric renal tumour, which accounts for 80–90% of all tumours of the kidney in childhood [1]. Around 15–20% of all WT patients present with stage IV disease. The most frequent metastatic site is the lung, followed by liver, extra-abdominal lymph-node metastasis, and, relatively infrequently, bone or brain metastasis [2,3,4,5]. The usual treatment approach for WT combines the use of chemotherapy and surgery with the addition of radiotherapy based on stage and histology risk group. Over the past decades, the focus on improving risk stratification adapted treatment has resulted in an increased overall survival (OS) for patients with WT. At present, long-term OS exceeds 90% in localised disease and 80% in metastatic patients [4,6,7,8,9]. Achieving completely necrotic WT histology after preoperative chemotherapy is prognostically favourable. In the SIOP 9 study, the OS rate of patients with completely necrotic stage IV disease was 100% [10,11]. Furthermore, patients undergoing resection of lung metastases show high survival rates if no vital tumour cells are found in the specimen [4,8]. Since the introduction of the SIOP 2001 protocol, this excellent outcome has resulted in the omission of abdominal radiotherapy in patients with localised disease, completely necrotic stage III. Whether radiotherapy to the primary tumour area or to the metastatic sites is required in the case of patients with metastatic disease and completely necrotic, local stage III WT has never been assessed.

This report describes the outcomes of metastatic patients with completely necrotic (low-risk (LR) histology, as defined in the revised SIOP working classification of renal tumours of childhood), local stage III WT, treated according to the SIOP 2001 protocol, based on the use or non-use of postoperative radiotherapy (Tables S1 and S2).

2. Materials and Methods

2.1. Treatment Protocol

According to the SIOP 2001 protocol, all newly diagnosed patients with a metastatic intrarenal tumour received 6 weeks of preoperative chemotherapy (weekly intravenous (i.v.) vincristine (1.5 mg/m2) combined with actinomycin D (45 µg/kg) (every 2 weeks), and doxorubicin (50 mg/m2; weeks 1 and 5) (VAD)), followed by tumour nephrectomy and standard lymph node sampling [4,12]. Reference pathology assessment was performed in all cases. Postoperative treatment was determined by the local stage of the abdominal tumour, its histologic subtype, and the result of the radiological re-evaluation of the metastatic site at the time of surgery.

Patients with metastatic WT, local stage III and LR or intermediate-risk (IR) histology received postoperative VAD chemotherapy for 27 weeks (weekly i.v. vincristine combined with actinomycin D every 3 weeks and doxorubicin every 6 weeks, total cumulative dose not exceeding 300 mg/m2) if the metastatic lesions were absent or completely resected at time of nephrectomy, and no radiotherapy to the metastatic site was applied. In the presence of multiple, non-resectable, or incompletely resected metastasis, postoperative treatment consisted of four drugs: CDCV chemotherapy (high-risk regimen) continued for 34 weeks with etoposide (150 mg/m2) and carboplatin (200 mg/m2) for three consecutive days in weeks 4, 10, 13, 16, 22, 25, 28, and 34 (24 doses in total) combined with cyclophosphamide (450 mg/m2) for three consecutive days in weeks 1, 7, 19, and 31 (12 doses in total) and doxorubicin (50 mg/m2, total cumulative dose not exceeding 300 mg/m2) for one day only in weeks 1, 7, 19, and 31 (4 doses in total) (Figure S1). Flank/abdominal irradiation was indicated for local stage III IR, but not for LR histology (14.4 Gy in 8 fractions of 1.8 Gy, +/− a boost of 10.8 Gy in 6 fractions of 1.8 Gy to areas of macroscopic tumour rest). Radiotherapy to the metastases was indicated if persistent at re-evaluation in week 9 (15 Gy in 10 fractions of 1.5 Gy to both lungs, with optional boost of 10–15 Gy in 1.5 Gy per fraction to areas of gross residual disease after surgery; Figures S1 and S2). For LR stage IV patients, VAD postoperative chemotherapy could be considered as alternative to the four-drug regimen according to the decision of the local multidisciplinary tumour board. Abdominal radiotherapy was started at week 2 to 4 of postoperative chemotherapy for patients with metastatic complete remission at the time of tumour nephrectomy. If not, radiotherapy could be delayed until week 10 in an attempt to avoid overlap between the lung and abdominal fields. No specific recommendations regarding radiotherapy to the persistent metastases were made in SIOP 2001 for metastatic patients with completely necrotic, local stage III WT.

2.2. Statistical Analysis

Event-free survival and overall survival were calculated from the date of diagnosis. Event-free survival was considered as time to loco-regional or distant recurrence, or death from any cause. Overall survival was time to death from any cause. Event-free patients at the end of follow-up were censored at that moment. For the current study, 5 year event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan–Meier method.

The median follow-up was calculated using the reverse Kaplan–Meier method. Statistical analysis was performed using the statistical software SAS version 9.2 and R version 4.01 [13].

3. Results

3.1. Patient Characteristics

Between June 2001 and December 2017, 703 patients with metastatic WT were included in the SIOP 2001 study. Of these, 47 (7%) patients had histologically confirmed completely necrotic, local stage III WT. Twenty-one were males and 26 were females. Median age at diagnosis was 50 months (interquartile range 14–144). Median follow-up was 6.6 years (range 1–151 months). Forty-five had lung metastases (11 of them combined with other localisations), one patient had liver/peritoneal metastasis only, and one patient had a tumour thrombus in the renal vein and the inferior vena cava with bilateral pulmonary arterial embolism only. Since this last patient cannot strictly be considered as metastatic, in the absence of intraparenchymal lung metastasis, she was excluded from the statistical analysis, but she still is in continuous complete remission 12 years after initial diagnosis. In all 47 cases, information on radiotherapy was available. Abdominal radiotherapy was administered in 29 patients (62%; 29 flank/abdominal irradiation and 9 combined with lung irradiation). Eighteen patients received neither radiotherapy to the abdomen nor to the metastatic site. All 18 non-irradiated patients had lung metastases, either alone or combined with other localisations, and their lung metastatic status at the time of nephrectomy was as follows: 10 patients had shown complete response (CR) after chemotherapy alone, 2 patients had CR after surgery to the metastases, 5 patients had partial response after chemotherapy and incomplete resection or had multiple irresectable metastases, and in 1 patient, this information was missing. Patient, tumour, and treatment characteristics are depicted in Table 1.

Table 1.

Patient, tumour, and treatment characteristics of totally necrotic, local stage III, stage IV Wilms tumours.

RT No RT
N = 29 N = 18
Flank/Abdomen Flank/Abdomen/Lung Total
N = 20 N = 9 N = 29
Gender Male 9 2 11 10
Female 11 7 18 8
Tumour site Right 10 7 17 9
Left 10 2 12 9
Reason for local stage III SM positive 7 2 9 7
LN positive 6 4 10 9
SM and LN positive 4 3 7 0
Tumour rupture 1 0 1 1
Peritoneal implants 1 0 1 0
SM positive and peritoneal implants 1 0 1 0
NA 0 0 0 1
Metastatic site Lung only 15 5 20 14
Lung combined 3 4 7 4
Liver/abdomen 1 0 1 0
Other 1 0 1 0
Postoperative chemotherapy regimen AVD 12 3 15 16
AV-2 1 0 1 0
High-risk 6 6 12 2
NA 1 0 1 0
Metastatic status after preoperative chemotherapy and surgery Metastases absent with chemotherapy alone 9 1 10 10
Completely excised 3 2 5 2
Incompletely excised or multiple irresectable 7 6 13 5
NA 1 0 1 1
Recurrence status Yes 1 1 2 0
No 19 8 27 18
Collaborative group GCBTTW 0 0 0 1
GPOH 3 0 3 9
SFCE 4 0 4 3
SIOP-NL 9 2 11 4
CCLG 4 7 11 1
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Abbreviations: SM: surgical margin, LN: lymph node, UK: unknown, RT: radiotherapy, A: actinomycin D, V: vincristine, D: doxorubicin, NA: not available, GCBTTW: Brasil, GPOH: Germany and Austria, SFCE: France, SIOP-NL: all other European countries that registered through the SIOP-Office, The Netherlands, CCLG: United Kingdom.

3.2. Disease Control and Survival

Two of the 47 patients (4%) relapsed. Both developed lung recurrence, one of them (who had lung and liver metastasis at diagnosis) combined with concurrent abdominal relapse. Both patients eventually died from disease within the first 2 years post-diagnosis. Both patients had received abdominal radiotherapy during first-line treatment, combined with lung irradiation in one of them. No relapse occurred in patients treated without radiotherapy (Figure S3). Of the 47 patients, 18 achieved complete remission with chemotherapy alone at week six; only one of them received radiotherapy to the metastatic site. Among the 29 patients who did not attain complete remission at week six, 13 switched to the high-risk CDCV postoperative chemotherapy regimen. One of these patients relapsed. Details on relapse patterns are depicted in Table 2. The 5year EFS and OS were 95% (95% CI 88–100) and 95% (95% CI 88–100), respectively (Figure 1).

Table 2.

Patient and treatment summary.

Patient No Age (Months) Gender Reason for Stage III Metastasis CR at Week 6 Metastasis CR at Week 10 (After CHT and Surgery) Metastasis Surgically Removed Postoperative CHT Schema Abdominal RT Directed RT Dose (Gy) Elective/Boost RT Metastasis Directed Outcome
1 61 F SM and LN + Yes Yes No AVD Yes 14.4/10.8 No CR/Alive
2 37 F SM + No No No AVD Yes 14.4 No CR/Alive
3 26 F SM + Yes Yes No AV-2 Yes 14.4 No CR/Alive
4 87 M SM and LN + No Yes Yes AVD Yes 16 No CR/Alive
5 37 M SM and LN + Yes Yes No AVD Yes 14.4/10.8 No CR/Alive
6 50 F LN + No No No High-risk Yes 14.4/10.8 No CR/Alive
7 43 M SM + No No No High-risk Yes 14.4 No CR/Alive
8 70 F LN + Yes Yes No AVD Yes 15 No CR/Alive
9 77 M LN + Yes Yes No High-risk Yes 14.4/10.8 Yes CR/Alive
10 28 M LN + No No No AVD Yes 14.4 No CR/Alive
11 39 M Rupture Yes Yes No AVD Yes 14.4 No CR/Alive
12 68 M Peritoneal implants No Yes Yes AVD Yes 21 No CR/Alive
13 53 M SM + Yes Yes No AVD Yes 14.4 No CR/Alive
14 28 F SM + No No No High-risk Yes 14.4 No CR/Alive
15 36 M Peritoneal implants and SM + No No Yes High-risk Yes 19.5 No CR/Alive
16 85 M SM + No Yes Yes High-risk Yes 20 No CR/Alive
17 48 F LN + No No No High-risk Yes 14.4 No CR/Alive
18 69 F LN + No No No AVD Yes 14.4 Yes CR/Alive
19 44 M SM and LN + No Yes Yes High-risk Yes 15 Yes CR/Alive
20 95 F SM and LN + No No No AVD Yes 14.4 Yes CR/Alive
21 14 F LN + No No No High-risk Yes 15 Yes CR/Alive
22 49 F SM and LN + Yes Yes No AVD Yes 14.4 No CR/Alive
23 48 F LN + No No No High-risk Yes 14.4/7.5 Yes Relapse/Dead
24 97 F SM + No No No AVD Yes 14.4/10.8 Yes CR/Alive
25 41 F LN + Yes Yes No AVD Yes 14.4/10.8 No CR/Alive
26 44 F SM + No NA NA NA Yes 21 No Relapse/Dead
27 105 F SM + No Yes Yes High-risk Yes 15/6 Yes CR/Alive
28 99 F LN + Yes Yes No AVD Yes 21 No CR/Alive
29 97 F SM and LN + No No No High-risk Yes 14.4/10.8 Yes CR/Alive
30 38 F LN + Yes Yes No AVD No - No CR/Alive
31 48 F SM + Yes Yes No AVD No - No CR/Alive
32 43 F SM + No NA NA AVD No - No CR/Alive
33 75 M LN + Yes Yes No AVD No - No CR/Alive
34 23 M SM + Yes Yes No AVD No - No CR/Alive
35 49 M LN + No No No High-risk No - No CR/Alive
36 87 M LN + No No No AVD No - No CR/Alive
37 35 M LN + No No No High-risk No - No CR/Alive
38 68 F SM + No No No AVD No - No CR/Alive
39 67 M LN + Yes Yes No AVD No - No CR/Alive
40 40 M LN + Yes Yes No AVD No - No CR/Alive
41 144 M LN + No Yes Yes AVD No - No CR/Alive
42 52 F LN + No No No AVD No - No CR/Alive
43 75 M LN + Yes Yes No AVD No - No CR/Alive
44 53 F SM + No Yes No AVD No - No CR/Alive
45 72 M SM + Yes Yes No AVD No - No CR/Alive
46 50 F Rupture No No No AVD No - No CR/Alive
47 59 F SM + No Yes No AVD No - No CR/Alive
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Abbreviations: CR: complete remission, CHT: chemotherapy, RT: radiotherapy, F: female, M: male, NA: not available, SM +: surgical margins positive, LN +: lymph node(s) positive, A: actinomycin D, V: vincristine, D: doxorubicin.

Figure 1.

Figure 1

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Overall survival (OS) and event-free survival (EFS) for patients with completely necrotic, local stage III, stage IV Wilms tumour.

4. Discussion

In SIOP 2001, no specific recommendations on postoperative radiotherapy were made for patients with metastatic, completely necrotic, local stage III WT, achieved after 6 weeks of preoperative chemotherapy. Omission of radiotherapy was carried out in a significant number of patients. The results of the current analysis suggest that withdrawing radiotherapy from the treatment strategy in this category of patients does not impact either loco-regional control or survival.

Around 7–10% of WT patients demonstrate completely necrotic histology after preoperative chemotherapy [10,11]. As defined in the revised SIOP working classification of renal tumours of childhood, a completely necrotic condition is assessed if no viable tumour tissue is identified on gross and microscopic examination [14,15]. This histology has been correlated with good prognosis, reaching survival rates of 100% in patients with metastatic disease [4,11]. Over the past few decades, substantial treatment advances for WT have permitted a stepwise refinement of risk-adapted strategies in an attempt to reduce the treatment-related morbidity of WT survivors. In localised patients, the omission of doxorubicin in non-high-risk histology after preoperative chemotherapy has become current practice according to the SIOP–RTSG [16]. Similarly, the avoidance of flank/abdominal radiotherapy in local stage I–II non-anaplastic histology and of lung radiotherapy in the case of complete remission of lung metastasis (subsequent to either preoperative chemotherapy or to pulmonary metastasectomy) has been standardised [4,6,17,18]. Whether radiotherapy to the primary or metastatic site is required in metastatic patients with completely necrotic (LR), local stage III WT, is still a subject of discussion. In SIOP 93-01, patients with metastatic LR, local stage III WT, achieved after 6 weeks of preoperative chemotherapy consisting of actinomycin D (15 µgr/kg), vincristine (1.5 mg/m2) and epirubicin (50 mg/m2), received abdominal radiotherapy (15 Gy to the initial tumour volume with or without a boost of 10–15 Gy to areas of potential risk), and radiotherapy to the metastases if no complete response was attained at the time of re-evaluation after preoperative chemotherapy (15 Gy followed by optional boost of 10 Gy to areas of residual disease).

Based on the good outcomes of patients with completely necrotic WT, all stages combined, treated according to SIOP 9 (i.e., 5 year OS 98%), no abdominal radiotherapy was recommended for patients with a completely necrotic localised disease (stages I–III) in the SIOP 2001 protocol (Table S3) [11]. Since no clear recommendations were made on the indication of radiotherapy for patients with metastatic completely necrotic, local stage III WT, differences in interpretation of the protocol recommendations led to the appearance of two groups, where 40% of these patients did not receive radiotherapy and none of them developed recurrence. This finding suggests that further radiotherapy dose de-escalation in this patient category is safe, as was proven in the sequential SIOP studies for other risk categories depending on stage, histology, and response to preoperative chemotherapy [18,19,20,21]. In the current analysis, 44% of the patients who did not reach complete remission of the metastatic site after preoperative chemotherapy were treated postoperatively according to the high-risk chemotherapy regimen, showing no differences in outcomes in comparison to the group that received the three-drug combination regimen. This observation requires us to question the necessity of switching to high-risk chemotherapy, since the outcome seems similar to that of patients treated with VAD. The decision to switch to high-risk chemotherapy should be on a per patient basis, taking into consideration the decrease in metastatic burden (very good partial response) and preferably the histology of the metastases. Moreover, it should be emphasised that the only two relapses occurred in patients having received radiotherapy (one of them including pulmonary radiotherapy), while none of the 18 patients who did not receive any radiotherapy relapsed. However, the retrospective character of the study and the small sample size should be noted as limitations. In the absence of a feasible randomised clinical trial that can address this question, the excellent outcomes presented are encouraging. The strengths of this study are the consecutive prospective registration and data collection of all patients included in the SIOP 2001 study protocol.

Long-term survivors of Wilms tumours are at an increased risk of developing multifactorial treatment-related morbidity and mortality. The most frequent complications after abdominal radiotherapy are cardiovascular, followed by musculoskeletal development impairment and treatment-induced secondary malignancies, as well as metabolic, renal, and gonadal problems [22,23,24,25,26,27]. The avoidance of pulmonary radiotherapy may preclude medium- and long-term cardiac and respiratory morbidity in WT survivors. In addition, various respiratory disorders, such as reduced lung total capacity, interstitial pneumonia, and, consequently, exercise-induced dyspnoea, are common sequelae after pulmonary radiotherapy [28,29,30,31,32,33]. Radiotherapy alone may cause congestive heart failure, and the risk increases exponentially when combined with anthracyclines [25,34]. Musculoskeletal and soft tissue growth abnormalities, such as breast hypoplasia, hypothyroidism, and an increased risk of secondary malignancies, may also be induced by the use of pulmonary radiotherapy [29,30]. It is to be expected that the omission of abdominal and, if applicable, pulmonary radiotherapy in metastatic completely necrotic, local stage III WT patients will contribute to a risk reduction of treatment-related sequelae [8]. Therefore, the ongoing SIOP–RTSG UMBRELLA protocol does not recommend radiotherapy in these patients [1].

5. Conclusions

The results of this descriptive study demonstrate that the outcome of patients with stage IV, local stage III, completely necrotic Wilms tumours is excellent, and that the omission of radiotherapy, after preoperative chemotherapy, in first-line treatmentdoes not seem to have an impact on survival. Avoidance of radiotherapy in this patient category has the potential to reduce the treatment toxicity burden in Wilms tumour survivors.

Acknowledgments

The SIOP WT 2001 study was funded by Cancer Research UK (grant C1188/A8687), the UK National Cancer Research Network and Children’s Cancer and Leukaemia Group (CCLG) (who supported the UK section), Société Française des Cancers de l’Enfant and Association Leon Berard Enfant Cancéreux and Enfant et Santé (who supported the French section), Gesellschaft für Pädiatrische Onkologie und Hämatologie and Deutsche Krebschilfe (grant 50-2709-Gr2, who supported the German section), Grupo Cooperativo Brasileiro para o Tratamento do Tumor de Wilms and Sociedade Brasileira de Oncologia Pediátrica (who supported the Brazilian section), and the Spanish Society of Pediatric Haematology and Oncology and the Spanish Association Against Cancer (who supported the Spanish section), and SIOP-NL. K P-J is partly supported by the National Institute for Health Research Biomedical Research Centre Funding Scheme. We acknowledge the enormous efforts made by more than 1000 clinicians, radiologists, and pathologists working at the 251 childhood cancer treatment centres in this study from 28 countries who enrolled and followed up with patients in this study, and the patients and their families for their participation.

Supplementary Materials

The following are available online at https://www.mdpi.com/2072-6694/13/5/976/s1, Table S1: Revised SIOP working classification of renal tumours of childhood (2001), Table S2: SIOP staging criteria for renal tumours of childhood, Table S3: Summary of postoperative treatment for patients with localised disease Wilms tumour treated according to the SIOP 2001 protocol. Figure S1: Summary of postoperative treatment for stage IV, non-high-risk histology Wilms tumour (SIOP 2001 protocol), Figure S2: Summary of indications for postoperative radiotherapy and definition of clinical target volume as per SIOP 2001 protocol; Figure S3: Patient population flowchart.

Click here for additional data file. (370.8KB, pdf)

Author Contributions

Conceptualisation, R.D.F., R.F., M.v.G., M.M.v.d.H.-E., G.O.J. and A.C.V.; methodology, R.D.F., R.F., M.v.G., M.M.v.d.H.-E., G.O.J. and A.C.V.; software, R.D.F. and H.v.T.; validation, R.D.F., R.F., M.v.G., M.M.v.d.H.-E., G.O.J. and A.C.V.; formal analysis, R.D.F., M.M.v.d.H.-E., G.O.J., M.v.G., A.C.V. and H.v.T.; investigation, R.D.F., R.F., M.v.G., K.P.-J., R.A.-S., B.d.C., G.L.R.V., M.M.v.d.H.-E., G.O.J. and A.C.V.; resources, R.D.F., R.F., M.v.G., M.M.v.d.H.-E., G.O.J. and A.C.V.; data curation, R.D.F., R.F., M.v.G., K.P.-J., R.A.-S., B.d.C., G.L.R.V., M.M.v.d.H.-E., G.O.J. and A.C.V.; writing—original draft preparation, R.D.F., R.F., M.v.G., M.M.v.d.H.-E., G.O.J. and A.C.V.; writing—review and editing, R.D.F., R.F., M.v.G., H.v.T., C.P., K.P.-J., R.A.-S., B.d.C., G.L.R.V., N.G., X.M., P.M., D.S., C.R., M.M.v.d.H.-E., G.O.J. and A.C.V.; visualisation, R.D.F.; supervision, R.D.F., M.v.G., G.O.J., M.M.v.d.H.-E., A.C.V.; funding acquisition, not applicable; project administration, R.D.F., M.v.G., M.M.v.d.H.-E., G.O.J. and A.C.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki. The current analysis is based on the data of the SIOP 2001 study, which was approved by the Ethics Committee of Erasmus Medical Center (protocol code MEC 202.134/2001/122) on 13 March 2002.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Data are contained within the article or Supplementary Materials.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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