Treatment is complex and requires a collaborative effort between pediatric surgeons, expert pathologists, pediatric oncologists, radiologists, and radiation oncologists.
Patients should be promptly referred to a pediatric cancer center. Treatment generally includes surgical resection and chemotherapy, with or without radiation therapy, depending on the stage, histology, and biology of the tumor.
Tumor staging
Patients are staged at nephrectomy using either the Children's Oncology Group (COG) or the International Society of Paediatric Oncology (SIOP) staging systems.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
See Criteria.
COG recommends upfront nephrectomy followed by adjuvant chemotherapy and/or radiation, whereas SIOP recommends preoperative and postoperative chemotherapy and/or radiation.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
The goal of therapy for both approaches is to reduce therapy burden and avoid toxicity in patients with low-risk tumors, and augment therapy for patients with higher-risk tumors.
Subsequent treatment regimens are based on the patient's risk of recurrence, defined by the following prognostic factors:[53]Vujanić GM, Gessler M, Ooms AHAG, et al. The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol. Nat Rev Urol. 2018 Nov;15(11):693-701.
https://www.nature.com/articles/s41585-018-0100-3
http://www.ncbi.nlm.nih.gov/pubmed/30310143?tool=bestpractice.com
[73]Vujanić GM, Parsons LN, D'Hooghe E, et al. Pathology of Wilms' tumour in International Society of Paediatric Oncology (SIOP) and Children's Oncology Group (COG) renal tumour studies: similarities and differences. Histopathology. 2022 Jun;80(7):1026-37.
http://www.ncbi.nlm.nih.gov/pubmed/35275409?tool=bestpractice.com
[94]de Campos Vieira Abib S, Chui CH, Cox S, et al. International Society of Paediatric Surgical Oncology (IPSO) surgical practice guidelines. Ecancermedicalscience. 2022 Feb 17;16:1356.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023308
http://www.ncbi.nlm.nih.gov/pubmed/35510137?tool=bestpractice.com
[95]Nelson MV, van den Heuvel-Eibrink MM, Graf N, et al. New approaches to risk stratification for Wilms tumor. Curr Opin Pediatr. 2021 Feb 1;33(1):40-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919941
http://www.ncbi.nlm.nih.gov/pubmed/33394739?tool=bestpractice.com
[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
Histologic (presence or absence of anaplasia)
Clinical (staging, patient age, tumor weight, response of lung metastases to chemotherapy)
Molecular/biologic (e.g., loss of heterozygosity [LOH] at combined 1p and 16q)
Surgery
Important for treating all stages of disease, surgery provides local control and prevents metastatic spread. Radical nephrectomy using a transperitoneal approach is recommended as standard in all patients with a unilateral Wilms tumor who do not have a known tumor predisposition syndrome.[48]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Wilms tumor (nephroblastoma) [internet publication].
https://www.nccn.org/guidelines/category_1
[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
The surgeon should avoid tumor spillage or incomplete removal. Selective sampling of lymph nodes should be performed.[48]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Wilms tumor (nephroblastoma) [internet publication].
https://www.nccn.org/guidelines/category_1
Palpation of renal vein and inferior vena cava will identify any tumor thrombi (usually free-floating) and may allow for careful removal of the thrombus.[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
Partial nephrectomy may be carefully considered for some patients.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
Nephron-sparing surgery (NSS) is the goal for patients with a genetic predisposition syndrome for Wilms tumor, bilateral Wilms tumor, or congenital kidney abnormalities, such as solitary kidney or horseshoe kidney.[94]de Campos Vieira Abib S, Chui CH, Cox S, et al. International Society of Paediatric Surgical Oncology (IPSO) surgical practice guidelines. Ecancermedicalscience. 2022 Feb 17;16:1356.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023308
http://www.ncbi.nlm.nih.gov/pubmed/35510137?tool=bestpractice.com
Evidence is limited to support the use of NSS for unilateral Wilms tumor.[94]de Campos Vieira Abib S, Chui CH, Cox S, et al. International Society of Paediatric Surgical Oncology (IPSO) surgical practice guidelines. Ecancermedicalscience. 2022 Feb 17;16:1356.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023308
http://www.ncbi.nlm.nih.gov/pubmed/35510137?tool=bestpractice.com
[105]Vanden Berg RN, Bierman EN, Noord MV, et al. Nephron-sparing surgery for Wilms tumor: a systematic review. Urol Oncol. 2016 Jan;34(1):24-32.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681627
http://www.ncbi.nlm.nih.gov/pubmed/26254695?tool=bestpractice.com
However, SIOP specifies certain conditions in which NSS is acceptable for nonsyndromic unilateral Wilms tumors: small tumor volume (<300 mL) and the expectation of a substantial remnant kidney function in patients with tumors <300 mL who never had lymph node involvement.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
Upfront nephrectomy is contraindicated if any of the following apply:[48]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Wilms tumor (nephroblastoma) [internet publication].
https://www.nccn.org/guidelines/category_1
[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
The patient has a solitary kidney, bilateral Wilms tumor, or genetic risk factors for the development of bilateral Wilms tumor
There are extensive adhesions to adjacent vital structures such that removing the kidney and tumor requires removal of the other structures (e.g., spleen, pancreas, colon)
The patient has respiratory compromise
There is intraluminal extension of a tumor thrombus above the level of the hepatic veins
If a tumor is unresectable, COG recommends an open biopsy or core needle biopsy with a minimum of 10-12 nonnecrotic cores to ensure sufficient tissue for molecular testing. Performing a tumor biopsy results in upstaging to local stage III disease.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
SIOP does not routinely recommend pretreatment biopsy.[53]Vujanić GM, Gessler M, Ooms AHAG, et al. The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol. Nat Rev Urol. 2018 Nov;15(11):693-701.
https://www.nature.com/articles/s41585-018-0100-3
http://www.ncbi.nlm.nih.gov/pubmed/30310143?tool=bestpractice.com
Suspicious metastatic lesions (hepatic or intra-abdominal) may be biopsied or resected at the time of initial surgery for diagnostic or therapeutic purposes. Decisions about extrapulmonary metastatic lesions are highly individualized.[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
[106]Benedetti DJ, Varela CR, Renfro LA, et al. Treatment of children with favorable histology Wilms tumor with extrapulmonary metastases: a report from the COG studies AREN0533 and AREN03B2 and NWTSG study NWTS-5. Cancer. 2024 Mar 15;130(6):947-61.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.35099
http://www.ncbi.nlm.nih.gov/pubmed/37933882?tool=bestpractice.com
Chemotherapy
Wilms tumor is sensitive to chemotherapy. The treatment approach recommended by SIOP differs from COG; however, both approaches yield excellent outcomes with overall survival rates of >90%.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
SIOP recommends upfront chemotherapy for patients newly diagnosed with Wilms tumor ages ≥6 months prior to any attempt at resection regardless of initial stage. SIOP prioritizes this approach to avoid intraoperative spillage due to tumor rupture, and to decrease the size of the tumor, making it more amenable to resection (thereby decreasing postoperative complications).[73]Vujanić GM, Parsons LN, D'Hooghe E, et al. Pathology of Wilms' tumour in International Society of Paediatric Oncology (SIOP) and Children's Oncology Group (COG) renal tumour studies: similarities and differences. Histopathology. 2022 Jun;80(7):1026-37.
http://www.ncbi.nlm.nih.gov/pubmed/35275409?tool=bestpractice.com
COG prioritizes upfront resection to reduce inaccurate staging of the tumor and potential under- or overtreatment.[107]D'Angio GJ. The National Wilms Tumor Study: a 40 year perspective. Lifetime Data Anal. 2007 Dec;13(4):463-70.
http://www.ncbi.nlm.nih.gov/pubmed/18027087?tool=bestpractice.com
COG recommends upfront biopsy and preoperative chemotherapy if the tumor extends into inferior vena cava above the hepatic vein or the primary tumor is unresectable at presentation. Preoperative chemotherapy (without biopsy) is recommended by COG if both kidneys are involved.[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
Radiation therapy
Wilms tumor is highly radiosensitive; however, not all children with Wilms tumor require radiation therapy.[108]Pater L, Melchior P, Rübe C, et al. Wilms tumor. Pediatr blood cancer. 2021 May;68(suppl 2):e28257.
https://onlinelibrary.wiley.com/doi/10.1002/pbc.28257
http://www.ncbi.nlm.nih.gov/pubmed/32893998?tool=bestpractice.com
In the COG approach, radiation therapy (either flank irradiation or whole abdomen irradiation) is used for the regional management of local stage III favorable histology Wilms tumor (staging at primary tumor regardless of metastases), and relapsed and anaplastic Wilms tumor.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
In most cases, flank radiation is used; whole abdominal radiation is only used in cases with peritoneal seeding, preoperative tumor rupture, or an intraoperative spill that is widespread in the opinion of the operating surgeon.[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
[108]Pater L, Melchior P, Rübe C, et al. Wilms tumor. Pediatr blood cancer. 2021 May;68(suppl 2):e28257.
https://onlinelibrary.wiley.com/doi/10.1002/pbc.28257
http://www.ncbi.nlm.nih.gov/pubmed/32893998?tool=bestpractice.com
Patients with favorable histology Wilms tumors with lung metastasis who do not show complete response to chemotherapy at week 6 receive whole lung irradiation.[71]Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children's Oncology Group AREN0533 study. J Clin Oncol. 2018 Jun 1;36(16):1564-70.
https://ascopubs.org/doi/10.1200/JCO.2017.77.1931
http://www.ncbi.nlm.nih.gov/pubmed/29659330?tool=bestpractice.com
Omission of whole lung irradiation is an acceptable strategy for patients with isolated pulmonary metastasis with lung nodule complete response after 6 weeks of chemotherapy, except for those with combined LOH of 1p and 16q, or 1q gain.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
In the SIOP approach, radiation therapy to the flank is administered to patients with stage II Wilms tumor with diffuse anaplasia or stage III Wilms tumor (intermediate-risk and high-risk).[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
In the SIOP UMBRELLA protocol, CT-only nodules with a transverse diameter of at least 3 mm are treated as metastases.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
Pulmonary radiation therapy is only administered for lung metastases lacking complete response by postoperative week 10 and in all cases with high-risk tumors, despite response to treatment.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
[108]Pater L, Melchior P, Rübe C, et al. Wilms tumor. Pediatr blood cancer. 2021 May;68(suppl 2):e28257.
https://onlinelibrary.wiley.com/doi/10.1002/pbc.28257
http://www.ncbi.nlm.nih.gov/pubmed/32893998?tool=bestpractice.com
Extrapulmonary metastatic lesions may also receive radiation therapy; however, treatment of extrapulmonary metastatic lesions is highly individualized.[106]Benedetti DJ, Varela CR, Renfro LA, et al. Treatment of children with favorable histology Wilms tumor with extrapulmonary metastases: a report from the COG studies AREN0533 and AREN03B2 and NWTSG study NWTS-5. Cancer. 2024 Mar 15;130(6):947-61.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.35099
http://www.ncbi.nlm.nih.gov/pubmed/37933882?tool=bestpractice.com
COG treatment approach
Recommends upfront nephrectomy for patients with unilateral renal masses who do not have known Wilms tumor predisposition.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
[52]Lopyan NM, Ehrlich PF. Surgical management of Wilms tumor (nephroblastoma) and renal cell carcinoma in children and young adults. Surg Oncol Clin N Am. 2021 Apr;30(2):305-23.
http://www.ncbi.nlm.nih.gov/pubmed/33706902?tool=bestpractice.com
This may be followed by chemotherapy with or without irradiation depending on staging and histology of tumor.[95]Nelson MV, van den Heuvel-Eibrink MM, Graf N, et al. New approaches to risk stratification for Wilms tumor. Curr Opin Pediatr. 2021 Feb 1;33(1):40-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919941
http://www.ncbi.nlm.nih.gov/pubmed/33394739?tool=bestpractice.com
COG treatment approach: favorable histology
Favorable histology Wilms tumors are subdivided by COG into the following recurrence risk categories (based on staging, histology, molecular markers, and biologic factors):[95]Nelson MV, van den Heuvel-Eibrink MM, Graf N, et al. New approaches to risk stratification for Wilms tumor. Curr Opin Pediatr. 2021 Feb 1;33(1):40-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919941
http://www.ncbi.nlm.nih.gov/pubmed/33394739?tool=bestpractice.com
[96]Dome JS, Fernandez CV, Mullen EA, et al. Children's Oncology Group's 2013 blueprint for research: renal tumors. Pediatr Blood Cancer. 2013 Jun;60(6):994-1000.
http://www.ncbi.nlm.nih.gov/pubmed/23255438?tool=bestpractice.com
[98]Fernandez CV, Perlman EJ, Mullen EA, et al. Clinical outcome and biological predictors of relapse after nephrectomy only for very low-risk Wilms tumor: a report from Children's Oncology Group AREN0532. Ann Surg. 2017 Apr;265(4):835-40.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145762
http://www.ncbi.nlm.nih.gov/pubmed/27811504?tool=bestpractice.com
Very-low risk: <2 years of age, <550 g tumor weight, stage I, without loss of heterozygosity (LOH) at 11p15, without LOH at combined 1p and 16q, provided lymph nodes were sampled and proved negative
Low risk: any age or tumor weight, stage I or II, without LOH at combined 1p and 16q
Standard risk: stage I or II tumors with LOH at combined 1p and 16q, or stage III/IV with no LOH at combined 1p and 16q
Higher-risk: stage III or IV with LOH at combined 1p and 16q, or stage IV with metastases to site other than lungs
Tumor stage and risk category are used to determine postoperative treatment.
Stage I
COG very-low risk: nephrectomy followed by observation alone (no chemotherapy, no radiation therapy).[98]Fernandez CV, Perlman EJ, Mullen EA, et al. Clinical outcome and biological predictors of relapse after nephrectomy only for very low-risk Wilms tumor: a report from Children's Oncology Group AREN0532. Ann Surg. 2017 Apr;265(4):835-40.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5145762
http://www.ncbi.nlm.nih.gov/pubmed/27811504?tool=bestpractice.com
[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
COG low risk: nephrectomy followed by postoperative chemotherapy with vincristine and dactinomycin (EE-4A regimen).[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
Radiation is not recommended.
COG standard-risk: nephrectomy followed by postoperative chemotherapy with vincristine, dactinomycin, and doxorubicin (DD-4A regimen).[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[110]Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for combined loss of heterozygosity 1p and 16q in favorable histology Wilms tumor: a Children's Oncology Group AREN0532 and AREN0533 study report. J Clin Oncol. 2019 Oct 20;37(30):2769-77.
https://ascopubs.org/doi/10.1200/JCO.18.01972
http://www.ncbi.nlm.nih.gov/pubmed/31449468?tool=bestpractice.com
Radiation is not recommended.
Stage II
COG low risk: nephrectomy followed by postoperative chemotherapy with EE-4A regimen.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
Radiation is not recommended.
COG standard risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen. Radiation is not recommended.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[110]Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for combined loss of heterozygosity 1p and 16q in favorable histology Wilms tumor: a Children's Oncology Group AREN0532 and AREN0533 study report. J Clin Oncol. 2019 Oct 20;37(30):2769-77.
https://ascopubs.org/doi/10.1200/JCO.18.01972
http://www.ncbi.nlm.nih.gov/pubmed/31449468?tool=bestpractice.com
Stage III
COG standard risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and abdominal/flank irradiation.[111]Fernandez CV, Mullen EA, Chi YY, et al. Outcome and prognostic factors in stage III favorable-histology Wilms tumor: a report from the Children's Oncology Group study AREN0532. J Clin Oncol. 2018 Jan 20;36(3):254-61.
https://ascopubs.org/doi/10.1200/JCO.2017.73.7999
http://www.ncbi.nlm.nih.gov/pubmed/29211618?tool=bestpractice.com
Inferior outcomes have been reported in patients with positive lymph nodes and LOH of 1p or 16q when treated with DD-4A regimen; intensification of therapy is being explored for these patients.[112]Evageliou N, Renfro LA, Geller J, et al. Prognostic impact of lymph node involvement and loss of heterozygosity of 1p or 16q in stage III favorable histology Wilms tumor: a report from Children's Oncology Group Studies AREN03B2 and AREN0532. Cancer. 2024 Mar 1;130(5):792-802.
https://pmc.ncbi.nlm.nih.gov/articles/PMC10993001
http://www.ncbi.nlm.nih.gov/pubmed/37902955?tool=bestpractice.com
COG higher risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen for 6 weeks, and then switched to vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide (regimen M), as well as abdominal/flank irradiation.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[110]Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for combined loss of heterozygosity 1p and 16q in favorable histology Wilms tumor: a Children's Oncology Group AREN0532 and AREN0533 study report. J Clin Oncol. 2019 Oct 20;37(30):2769-77.
https://ascopubs.org/doi/10.1200/JCO.18.01972
http://www.ncbi.nlm.nih.gov/pubmed/31449468?tool=bestpractice.com
Patients who cannot undergo upfront nephrectomy have a tumor biopsy performed, followed by neoadjuvant chemotherapy. For COG standard-risk patients, DD-4A regimen is given until delayed nephrectomy. Chemotherapy with DD-4A regimen is then completed postoperatively. Higher-risk patients are given DD-4A regimen for 6 weeks and then switched to regimen M until delayed nephrectomy. Chemotherapy with regimen M is then completed.
Stage IV
COG standard-risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
Abdomen/flank radiation is given to patients with local/abdominal stage III disease.
Patients with pulmonary metastases with a complete response at week 6 continue receiving DD-4A regimen chemotherapy without whole lung irradiation.[71]Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children's Oncology Group AREN0533 study. J Clin Oncol. 2018 Jun 1;36(16):1564-70.
https://ascopubs.org/doi/10.1200/JCO.2017.77.1931
http://www.ncbi.nlm.nih.gov/pubmed/29659330?tool=bestpractice.com
However, intensification of chemotherapy and whole lung irradiation can be considered in patients with a 1q gain. Rate of event-free survival is lower for patients with 1q gain receiving standard treatment.[71]Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children's Oncology Group AREN0533 study. J Clin Oncol. 2018 Jun 1;36(16):1564-70.
https://ascopubs.org/doi/10.1200/JCO.2017.77.1931
http://www.ncbi.nlm.nih.gov/pubmed/29659330?tool=bestpractice.com
Patients with an incomplete/slow response of pulmonary metastatic lesions at week 6 are switched to regimen M and receive whole lung irradiation.[71]Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children's Oncology Group AREN0533 study. J Clin Oncol. 2018 Jun 1;36(16):1564-70.
https://ascopubs.org/doi/10.1200/JCO.2017.77.1931
http://www.ncbi.nlm.nih.gov/pubmed/29659330?tool=bestpractice.com
COG higher risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen for 6 weeks, then switched to regimen M, and receive whole lung irradiation or radiation to nonlung sites of metastasis.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[110]Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for combined loss of heterozygosity 1p and 16q in favorable histology Wilms tumor: a Children's Oncology Group AREN0532 and AREN0533 study report. J Clin Oncol. 2019 Oct 20;37(30):2769-77.
https://ascopubs.org/doi/10.1200/JCO.18.01972
http://www.ncbi.nlm.nih.gov/pubmed/31449468?tool=bestpractice.com
Abdomen/flank radiation is given to patients with local/abdominal stage III disease.
Patients who cannot undergo upfront nephrectomy have tumor biopsy performed, followed by neoadjuvant and adjuvant chemotherapy. Abdominal/flank radiation is given. Standard-risk patients with pulmonary metastases who do not show complete response to adjuvant chemotherapy at week 6 receive whole lung irradiation.[71]Dix DB, Seibel NL, Chi YY, et al. Treatment of stage IV favorable histology Wilms tumor with lung metastases: a report from the Children's Oncology Group AREN0533 study. J Clin Oncol. 2018 Jun 1;36(16):1564-70.
https://ascopubs.org/doi/10.1200/JCO.2017.77.1931
http://www.ncbi.nlm.nih.gov/pubmed/29659330?tool=bestpractice.com
Higher-risk patients receive whole lung radiation or radiation therapy to nonlung sites of metastasis.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[110]Dix DB, Fernandez CV, Chi YY, et al. Augmentation of therapy for combined loss of heterozygosity 1p and 16q in favorable histology Wilms tumor: a Children's Oncology Group AREN0532 and AREN0533 study report. J Clin Oncol. 2019 Oct 20;37(30):2769-77.
https://ascopubs.org/doi/10.1200/JCO.18.01972
http://www.ncbi.nlm.nih.gov/pubmed/31449468?tool=bestpractice.com
Stage V
Bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor: preoperative chemotherapy followed by nephron-sparing surgery and modified postoperative chemotherapy based on histologic response.[97]Ehrlich PF, Chi YY, Chintagumpala MM, et al. Results of treatment for patients with multicentric or bilaterally predisposed unilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Cancer. 2020 Aug 1;126(15):3516-25.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.32958
http://www.ncbi.nlm.nih.gov/pubmed/32459384?tool=bestpractice.com
[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
The goal of preoperative chemotherapy is to shrink the tumor to allow maximum preservation of renal parenchyma.[97]Ehrlich PF, Chi YY, Chintagumpala MM, et al. Results of treatment for patients with multicentric or bilaterally predisposed unilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Cancer. 2020 Aug 1;126(15):3516-25.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.32958
http://www.ncbi.nlm.nih.gov/pubmed/32459384?tool=bestpractice.com
For patients with bilateral Wilms tumor, or with bilaterally predisposed unilateral Wilms tumor with metastatic disease, vincristine, dactinomycin, and doxorubicin (VAD regimen) are given preoperatively.[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
For patients with bilaterally predisposed unilateral Wilms tumor that is localized (no metastatic disease), vincristine and dactinomycin (VA regimen) are used preoperatively.[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
Radical nephrectomies can potentially be avoided and nephron-sparing surgery used to preserve renal parenchyma and function.[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
Each kidney should be individually staged and treated according to the guidelines above.
Rarely, disease is extensive bilaterally requiring bilateral complete nephrectomies and resulting in renal failure and need for a renal transplant.[114]Aronson DC, Slaar A, Heinen RC, et al. Long-term outcome of bilateral Wilms tumors (BWT). Pediatr Blood Cancer. 2011 Jul 1;56(7):1110-3.
http://www.ncbi.nlm.nih.gov/pubmed/21370428?tool=bestpractice.com
COG treatment approach: unfavorable histology
For patients with unfavourable histology, treatment differs depending on whether anaplasia is focal or diffuse.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
Stage I
Focal or diffuse: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and flank irradiation.[115]Daw NC, Chi YY, Kim Y, et al. Treatment of stage I anaplastic Wilms' tumour: a report from the Children's Oncology Group AREN0321 study. Eur J Cancer. 2019 Sep;118:58-66.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690766
http://www.ncbi.nlm.nih.gov/pubmed/31325873?tool=bestpractice.com
[116]Armstrong AE, Daw NC, Renfro LA, et al. Treatment of focal anaplastic Wilms tumor: a report from the Children's Oncology Group AREN0321 and AREN03B2 studies. Cancer. 2025 Jan 15;131(2):e35713.
http://www.ncbi.nlm.nih.gov/pubmed/39803937?tool=bestpractice.com
Stage II
Focal: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and flank irradiation.[116]Armstrong AE, Daw NC, Renfro LA, et al. Treatment of focal anaplastic Wilms tumor: a report from the Children's Oncology Group AREN0321 and AREN03B2 studies. Cancer. 2025 Jan 15;131(2):e35713.
http://www.ncbi.nlm.nih.gov/pubmed/39803937?tool=bestpractice.com
[117]Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol. 2006 May 20;24(15):2352-8.
http://www.ncbi.nlm.nih.gov/pubmed/16710034?tool=bestpractice.com
Diffuse: nephrectomy followed by postoperative chemotherapy with vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, and irinotecan (revised UH-2 regimen), and flank irradiation.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[118]Daw NC, Chi YY, Kalapurakal JA, et al. Activity of vincristine and irinotecan in diffuse anaplastic Wilms tumor and therapy outcomes of stage II to IV disease: results of the Children's Oncology Group AREN0321 study. J Clin Oncol. 2020 May 10;38(14):1558-68.
https://ascopubs.org/doi/10.1200/JCO.19.01265
http://www.ncbi.nlm.nih.gov/pubmed/32134700?tool=bestpractice.com
Stage III
Focal: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and abdomen/flank irradiation, with a boost to residual tumour.[116]Armstrong AE, Daw NC, Renfro LA, et al. Treatment of focal anaplastic Wilms tumor: a report from the Children's Oncology Group AREN0321 and AREN03B2 studies. Cancer. 2025 Jan 15;131(2):e35713.
http://www.ncbi.nlm.nih.gov/pubmed/39803937?tool=bestpractice.com
[117]Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol. 2006 May 20;24(15):2352-8.
http://www.ncbi.nlm.nih.gov/pubmed/16710034?tool=bestpractice.com
Diffuse: nephrectomy followed by postoperative chemotherapy with revised UH-2 regimen and abdomen/flank irradiation, with a boost to residual tumour.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[116]Armstrong AE, Daw NC, Renfro LA, et al. Treatment of focal anaplastic Wilms tumor: a report from the Children's Oncology Group AREN0321 and AREN03B2 studies. Cancer. 2025 Jan 15;131(2):e35713.
http://www.ncbi.nlm.nih.gov/pubmed/39803937?tool=bestpractice.com
[117]Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol. 2006 May 20;24(15):2352-8.
http://www.ncbi.nlm.nih.gov/pubmed/16710034?tool=bestpractice.com
[118]Daw NC, Chi YY, Kalapurakal JA, et al. Activity of vincristine and irinotecan in diffuse anaplastic Wilms tumor and therapy outcomes of stage II to IV disease: results of the Children's Oncology Group AREN0321 study. J Clin Oncol. 2020 May 10;38(14):1558-68.
https://ascopubs.org/doi/10.1200/JCO.19.01265
http://www.ncbi.nlm.nih.gov/pubmed/32134700?tool=bestpractice.com
Stage IV
Focal: nephrectomy followed by postoperative chemotherapy with vincristine, doxorubicin, cyclophosphamide, carboplatin, and etoposide (revised UH-1 regimen) and abdomen/flank irradiation, with boost to residual tumor. Radiation to metastatic sites is included.[116]Armstrong AE, Daw NC, Renfro LA, et al. Treatment of focal anaplastic Wilms tumor: a report from the Children's Oncology Group AREN0321 and AREN03B2 studies. Cancer. 2025 Jan 15;131(2):e35713.
http://www.ncbi.nlm.nih.gov/pubmed/39803937?tool=bestpractice.com
[117]Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol. 2006 May 20;24(15):2352-8.
http://www.ncbi.nlm.nih.gov/pubmed/16710034?tool=bestpractice.com
Diffuse: nephrectomy followed by postoperative chemotherapy with revised UH-2 regimen and abdomen/flank irradiation with a boost to residual tumour.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[118]Daw NC, Chi YY, Kalapurakal JA, et al. Activity of vincristine and irinotecan in diffuse anaplastic Wilms tumor and therapy outcomes of stage II to IV disease: results of the Children's Oncology Group AREN0321 study. J Clin Oncol. 2020 May 10;38(14):1558-68.
https://ascopubs.org/doi/10.1200/JCO.19.01265
http://www.ncbi.nlm.nih.gov/pubmed/32134700?tool=bestpractice.com
Radiation therapy is given to metastatic sites.
Stage V
Bilateral Wilms tumor or bilaterally predisposed unilateral Wilms tumor: preoperative chemotherapy followed by nephron-sparing surgery and modified postoperative chemotherapy based on histologic response.[97]Ehrlich PF, Chi YY, Chintagumpala MM, et al. Results of treatment for patients with multicentric or bilaterally predisposed unilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Cancer. 2020 Aug 1;126(15):3516-25.
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.32958
http://www.ncbi.nlm.nih.gov/pubmed/32459384?tool=bestpractice.com
[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
For patients with bilateral Wilms tumor, or with bilaterally predisposed unilateral Wilms tumor with metastatic disease: VAD regimen is used preoperatively.[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
For patients with bilaterally predisposed unilateral Wilms tumor that is localized (no metastatic disease): VA regimen is used preoperatively.[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
Radical nephrectomies can potentially be avoided and nephron-sparing surgery used to preserve renal parenchyma and function.[113]Ehrlich P, Chi YY, Chintagumpala MM, et al. Results of the first prospective multi-institutional treatment study in children with bilateral Wilms tumor (AREN0534): a report from the Children's Oncology Group. Ann Surg. 2017 Sep;266(3):470-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629006
http://www.ncbi.nlm.nih.gov/pubmed/28795993?tool=bestpractice.com
Each kidney should be individually staged and treated according to the guidelines above.
Rarely, disease is extensive bilaterally, requiring bilateral complete nephrectomies and resulting in renal failure and need for a renal transplant.[114]Aronson DC, Slaar A, Heinen RC, et al. Long-term outcome of bilateral Wilms tumors (BWT). Pediatr Blood Cancer. 2011 Jul 1;56(7):1110-3.
http://www.ncbi.nlm.nih.gov/pubmed/21370428?tool=bestpractice.com
SIOP treatment approach
The UMBRELLA International Society of Paediatric Oncology (SIOP)-Renal Tumor Study Group (RTSG) 2016 protocol (known as the UMBRELLA protocol) recommends upfront chemotherapy for patients ages ≥6 months newly diagnosed with Wilms tumor (prior to any attempt at resection, regardless of initial stage).[73]Vujanić GM, Parsons LN, D'Hooghe E, et al. Pathology of Wilms' tumour in International Society of Paediatric Oncology (SIOP) and Children's Oncology Group (COG) renal tumour studies: similarities and differences. Histopathology. 2022 Jun;80(7):1026-37.
http://www.ncbi.nlm.nih.gov/pubmed/35275409?tool=bestpractice.com
[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
Nepherectomy is followed by postoperative chemotherapy with or without irradiation, depending on SIOP postoperative staging and histology of tumor.[4]Spreafico F, Fernandez CV, Brok J, et al. Wilms tumour. Nat Rev Dis Primers. 2021 Oct 14;7(1):75.
https://www.nature.com/articles/s41572-021-00308-8
http://www.ncbi.nlm.nih.gov/pubmed/34650095?tool=bestpractice.com
[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
Imaging studies stage patients at diagnosis as having localized (stages I-III), metastatic (stage IV), or bilateral (stage V) disease.[73]Vujanić GM, Parsons LN, D'Hooghe E, et al. Pathology of Wilms' tumour in International Society of Paediatric Oncology (SIOP) and Children's Oncology Group (COG) renal tumour studies: similarities and differences. Histopathology. 2022 Jun;80(7):1026-37.
http://www.ncbi.nlm.nih.gov/pubmed/35275409?tool=bestpractice.com
SIOP histologic classification divides patients with all stages (I through IV) into 3 groups: low-risk (completely necrotic Wilms tumor), high-risk (blastemal type and diffuse anaplasia), and intermediate-risk tumors (all other types).[53]Vujanić GM, Gessler M, Ooms AHAG, et al. The UMBRELLA SIOP-RTSG 2016 Wilms tumour pathology and molecular biology protocol. Nat Rev Urol. 2018 Nov;15(11):693-701.
https://www.nature.com/articles/s41585-018-0100-3
http://www.ncbi.nlm.nih.gov/pubmed/30310143?tool=bestpractice.com
[73]Vujanić GM, Parsons LN, D'Hooghe E, et al. Pathology of Wilms' tumour in International Society of Paediatric Oncology (SIOP) and Children's Oncology Group (COG) renal tumour studies: similarities and differences. Histopathology. 2022 Jun;80(7):1026-37.
http://www.ncbi.nlm.nih.gov/pubmed/35275409?tool=bestpractice.com
For children <6 months, the UMBRELLA protocol recommends upfront surgery and consideration of fine-needle biopsy for patients with unusual clinical presentations, or unusual findings on imaging, to decrease the risk of misdiagnosis of Wilms tumor.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
[119]Jackson TJ, Brisse HJ, Pritchard-Jones K, et al. How we approach paediatric renal tumour core needle biopsy in the setting of preoperative chemotherapy: a review from the SIOP Renal Tumour Study Group. Pediatr Blood Cancer. 2022 Sep;69(9):e29702.
https://onlinelibrary.wiley.com/doi/10.1002/pbc.29702
http://www.ncbi.nlm.nih.gov/pubmed/35587187?tool=bestpractice.com
Stage I
SIOP low-risk: preoperative chemotherapy with dactinomycin and vincristine (AV regimen) for 4 weeks, followed by nephrectomy and no postoperative chemotherapy or irradiation.
SIOP intermediate-risk: preoperative chemotherapy (AV regimen for 4 weeks) followed by nephrectomy and postoperative chemotherapy (AV regimen for 4 weeks). No irradiation.
SIOP high-risk: preoperative chemotherapy (AV regimen for 4 weeks) followed by nephrectomy and postoperative chemotherapy with dactinomycin, vincristine, and doxorubicin (AVD regimen; known as DD-4A in COG protocols) for 27 weeks. No irradiation.
Stage II
SIOP low-risk: preoperative chemotherapy (AV regimen) for 4 weeks, followed by nephrectomy and postoperative chemotherapy (AV regimen for 27 weeks). No irradiation.
SIOP intermediate-risk: preoperative chemotherapy (AV regimen for 4 weeks) followed by nephrectomy and postoperative chemotherapy. Patients with stromal or epithelial-type disease are treated with AV regimen for 27 weeks; patients with nonstromal- or nonepithelial-type disease (i.e., mixed and focal anaplasia-type tumors) are treated with AVD regimen for 27 weeks. No irradiation.
SIOP high-risk: preoperative chemotherapy with AV regimen for 4 weeks, followed by nephrectomy and postoperative chemotherapy with etoposide, carboplatin, cyclophosphamide, and doxorubicin (HR-1 regimen; known as UH-1 in COG protocols) for 34 weeks. Flank irradiation is indicated in patients with diffuse anaplasia.
Stage III
SIOP low-risk: preoperative chemotherapy with AV regimen for 4 weeks, followed by nephrectomy and postoperative chemotherapy with the AV regimen for 27 weeks. No irradiation.
SIOP intermediate-risk: preoperative chemotherapy with AV regimen for 4 weeks, followed by nephrectomy and postoperative chemotherapy. Patients with tumor volume after preoperative chemotherapy <500 mL of any subtype or tumor volume ≥500 mL of stromal or epithelial-type disease are treated with AV regimen for 27 weeks; patients with tumor volume ≥500 mL of nonstromal- or nonepithelial-type disease are treated with AVD regimen for 27 weeks. Flank irradiation is indicated.
SIOP high-risk: preoperative chemotherapy with AV regimen for 4 weeks, followed by nephrectomy and postoperative chemotherapy with HR-1 regimen for 34 weeks. Flank irradiation is indicated.
Stage IV
Preoperative treatment for metastatic (stage IV) disease in the UMBRELLA protocol includes AVD regimen for 6 weeks followed by reassessment imaging and surgery. Postoperative chemotherapy decisions depend on restratification of patients based on response to treatment, histology of the primary tumor and the metastatic tumor (if resected), and the size of metastatic lesions.
SIOP low- or intermediate-risk with complete or very good partial remission of metastatic lesions to preoperative AVD: nephrectomy with postoperative chemotherapy (AVD regimen) for 27 weeks (decision on the cumulative dose of doxorubicin depends on size of lung metastases). Patients achieving a complete response after induction chemotherapy do not need pulmonary irradiation. Viable pulmonary metastases are resected then irradiated.
SIOP low- or intermediate-risk with partial remission of metastatic lesions to preoperative AVD: nephrectomy and resection of metastatic nodules (if feasible). Postoperative chemotherapy with AVD regimen for 27 weeks if low-risk disease or intermediate-risk disease if representative nodule resection had completely necrotic metastasis. Postoperative chemotherapy with HR-1 regimen for 34 weeks if intermediate-risk disease if representative nodule resection confirmed viable metastasis or if nodule resection is not feasible. Irradiation to metastases in intermediate-risk disease. Consider irradiation to metastases in low-risk disease if resection of nodule resection is not feasible.
SIOP high-risk: recommends discussion of the best current treatment approach with the principal investigator for stage IV disease. The SIOP-RTSG board follows suggestions from COG studies on stage IV disease, which include combinations of vincristine, irinotecan, cyclophosphamide, carboplatin, etoposide, and doxorubicin.[109]Dome JS, Mullen EA, Dix DB, et al. Impact of the first generation of Children's Oncology Group clinical trials on clinical practice for Wilms tumor. J Natl Compr Canc Netw. 2021 Aug 1;19(8):978-85.
https://jnccn.org/view/journals/jnccn/19/8/article-p978.xml
http://www.ncbi.nlm.nih.gov/pubmed/34416705?tool=bestpractice.com
[118]Daw NC, Chi YY, Kalapurakal JA, et al. Activity of vincristine and irinotecan in diffuse anaplastic Wilms tumor and therapy outcomes of stage II to IV disease: results of the Children's Oncology Group AREN0321 study. J Clin Oncol. 2020 May 10;38(14):1558-68.
https://ascopubs.org/doi/10.1200/JCO.19.01265
http://www.ncbi.nlm.nih.gov/pubmed/32134700?tool=bestpractice.com
Stage V
Preoperative chemotherapy with AV regimen for a maximum of 12 weeks with evaluation of response at 6 weeks followed by surgery. Each tumor is subclassified and staged separately to determine postoperative chemotherapy.
Nephron-sparing surgery is advocated for bilateral disease and may include tumorectomy, wedge resection, polar resection, heminephrectomy, nephrectomy on one side, and partial resection, thus avoiding bilateral radical nephrectomies.[120]Kieran K, Davidoff AM. Nephron-sparing surgery for bilateral Wilms tumor. Pediatr Surg Int. 2015 Mar;31(3):229-36.
http://www.ncbi.nlm.nih.gov/pubmed/25633157?tool=bestpractice.com
The UMBRELLA protocol recommends discussion with the SIOP-RTSG surgical panel to assess the feasibility of nephron-sparing surgery and minimize the risk of upstaging by incomplete resection of the tumor.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
Tumor recurrence
Treatment of recurrent Wilms tumors must be individualized to the patient, based on prior chemotherapy treatment, as well as the location of relapse.
Recurrent tumors are typically managed with chemotherapy agents that were not used for primary therapy.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
[121]Speafico F, Pritchard Jones K, Malogolowkin MH, et al. Treatment of relapsed Wilms tumors: lessons learned. Expert Rev Anticancer Ther. 2009 Dec;9(12):1807-15.
http://www.ncbi.nlm.nih.gov/pubmed/19954292?tool=bestpractice.com
[122]Oostveen RM, Pritchard-Jones K. Pharmacotherapeutic management of Wilms tumor: an update. Paediatr Drugs. 2019 Feb;21(1):1-13.
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[123]Malogolowkin M, Cotton CA, Green DM, et al. Treatment of Wilms tumor relapsing after initial treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor Study Group. Pediatr Blood Cancer. 2008 Feb;50(2):236-41.
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[124]Green DM, Cotton CA, Malogolowkin M, et al. Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group. Pediatr Blood Cancer. 2007 May;48(5):493-9.
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[125]Schneller N, Daw N, Throckmorton W, et al. Outcomes of relapsed favorable-histology Wilms tumor in non-clinical trial setting. Pediatr Blood Cancer. 2025 Jan;72(1):e31347.
http://www.ncbi.nlm.nih.gov/pubmed/39394977?tool=bestpractice.com
The use of high-dose chemotherapy with autologous stem cell rescue or clinical trials utilizing novel chemotherapy regimens or agents may be considered.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
[126]Dome JS, Graf N, Geller JI, et al. Advances in Wilms tumor treatment and biology: progress through international collaboration. J Clin Oncol. 2015 Sep 20;33(27):2999-3007.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567702
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[127]Malogolowkin MH, Hemmer MT, Le-Rademacher J, et al. Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis. Bone Marrow Transplant. 2017 Nov;52(11):1549-55.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665725
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[128]Brok J, Mavinkurve-Groothuis AMC, Drost J, et al. Unmet needs for relapsed or refractory Wilms tumour: mapping the molecular features, exploring organoids and designing early phase trials - a collaborative SIOP-RTSG, COG and ITCC session at the first SIOPE meeting. Eur J Cancer. 2021 Feb;144:113-22.
http://www.ncbi.nlm.nih.gov/pubmed/33341445?tool=bestpractice.com
Local control using surgery and/or radiation is highly individualized to the patient. Surgical resection of relapsed disease is considered when complete resection seems possible or when it is useful to evaluate histologic tumor response.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com
The use of radiation therapy to initially nonirradiated sites is accepted, but the approach to previously irradiated sites must be individualized.[99]van den Heuvel-Eibrink MM, Hol JA, Pritchard-Jones K, et al. Position paper: rationale for the treatment of Wilms tumour in the UMBRELLA SIOP-RTSG 2016 protocol. Nat Rev Urol. 2017 Dec;14(12):743-52.
https://www.nature.com/articles/nrurol.2017.163
http://www.ncbi.nlm.nih.gov/pubmed/29089605?tool=bestpractice.com