Approach

Treatment is complex and requires a collaborative effort between paediatric surgeons, expert pathologists, paediatric oncologists, radiologists, and radiation oncologists.

Patients should be promptly referred to a paediatric cancer centre. Treatment generally includes surgical resection and chemotherapy, with or without radiotherapy, depending on the stage, histology, and biology of the tumor.

Tumour 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] See Criteria.

COG recommends upfront nephrectomy followed by adjuvant chemotherapy and/or radiotherapy, whereas SIOP recommends preoperative and post-operative chemotherapy and/or radiotherapy.[4] The goal of therapy for both approaches is to reduce therapy burden and avoid toxicity in patients with low-risk tumours, and augment therapy for patients with higher-risk tumours. 

Subsequent treatment regimens are based on the patient's risk of recurrence, defined by the following prognostic factors:[53][73][94][95][99]

  • Histological (presence or absence of anaplasia)

  • Clinical (staging, patient age, tumour weight, response of lung metastases to chemotherapy)

  • Molecular/biological (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' tumour who do not have a known tumour predisposition syndrome.[52][104]​​ The surgeon should avoid tumour spillage or incomplete removal. Selective sampling of lymph nodes should be performed.[104] Palpation of renal vein and inferior vena cava will identify any tumour thrombi (usually free-floating) and may allow for careful removal of the thrombus.[52]

Partial nephrectomy may be carefully considered for some patients.[4] Nephron-sparing surgery (NSS) is the goal for patients with a genetic predisposition syndrome for Wilms' tumour, bilateral Wilms' tumour, or congenital kidney abnormalities, such as solitary kidney or horseshoe kidney.[94] Evidence is limited to support the use of NSS for unilateral Wilms' tumour.[94][105]​ However, SIOP specifies certain conditions in which NSS is acceptable for non-syndromic unilateral Wilms' tumours: small tumour volume (<300 mL) and the expectation of a substantial remnant kidney function in patients with tumours <300 mL who never had lymph node involvement.[99]

Upfront nephrectomy is contraindicated if any of the following apply:[48][52]​

  • The patient has a solitary kidney, bilateral Wilms' tumour, or genetic risk factors for the development of bilateral Wilms' tumour

  • There are extensive adhesions to adjacent vital structures such that removing the kidney and tumour requires removal of the other structures (e.g., spleen, pancreas, colon)

  • The patient has respiratory compromise

  • There is intraluminal extension of a tumour thrombus above the level of the hepatic veins

If a tumour is unresectable, COG recommends an open biopsy or core needle biopsy with a minimum of 10-12 non-necrotic cores to ensure sufficient tissue for molecular testing. Performing a tumour biopsy results in upstaging to local stage III disease.[4][52] SIOP does not routinely recommend pretreatment biopsy.[53]

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][106]​​

Chemotherapy

Wilms' tumour 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]

SIOP recommends upfront chemotherapy for patients newly diagnosed with Wilms' tumour aged ≥6 months prior to any attempt at resection regardless of initial stage. SIOP prioritises this approach to avoid intraoperative spillage due to tumour rupture, and to decrease the size of the tumour, making it more amenable to resection (thereby decreasing post-operative complications).[73]

COG prioritises upfront resection to reduce inaccurate staging of the tumour and potential under- or over-treatment.[107] COG recommends upfront biopsy and preoperative chemotherapy if the tumour extends into inferior vena cava above the hepatic vein or the primary tumour is unresectable at presentation. Preoperative chemotherapy (without biopsy) is recommended by COG if both kidneys are involved.[52]

Radiotherapy

Wilms' tumour is highly radiosensitive; however, not all children with Wilms tumor require radiotherapy.[108]

In the COG approach, radiotherapy (either flank irradiation or whole abdomen irradiation) is used for the regional management of local stage III favourable histology Wilms' tumour (staging at primary tumor regardless of metastases), and relapsed and anaplastic Wilms' tumour.[4] 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][99][108] 

Patients with favourable histology Wilms' tumours with lung metastasis who do not show complete response to chemotherapy at week 6 receive whole lung irradiation.[71] 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]

In the SIOP approach, radiotherapy to the flank is administered to patients with stage II Wilms' tumour with diffuse anaplasia or stage III Wilms' tumour (intermediate-risk and high-risk).[4] In the SIOP UMBRELLA protocol, CT-only nodules with a transverse diameter of at least 3 mm are treated as metastases.[99] Pulmonary radiotherapy is only administered for lung metastases lacking complete response by post-operative week 10 and in all cases with high-risk tumours, despite response to treatment.[4][99][108]​​

Extrapulmonary metastatic lesions may also receive radiotherapy; however, treatment of extrapulmonary metastatic lesions is highly individualised.[106]

COG treatment approach

Recommends upfront nephrectomy for patients with unilateral renal masses who do not have known Wilms' tumour predisposition.[4][52]​​

This may be followed by chemotherapy with or without irradiation depending on staging and histology of tumour.[95]​

COG treatment approach: favourable histology

Favourable histology Wilms' tumours are subdivided by COG into the following recurrence risk categories (based on staging, histology, molecular markers, and biological factors):[95][96]​​[98]​​​​

  • Very-low risk: <2 years of age, <550 g tumour 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 tumour weight, stage I or II, without LOH at combined 1p and 16q

  • Standard risk: stage I or II tumours 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

Tumour stage and risk category are used to determine post-operative treatment.

Stage I

  • COG very-low risk: nephrectomy followed by observation alone (no chemotherapy, no radiaotherapy).[98][109]​​​​ 

  • COG low-risk: nephrectomy followed by post-operative chemotherapy with vincristine and dactinomycin (EE-4A regimen).[109] Radiation is not recommended.

  • COG standard-risk: nephrectomy followed by post-operative chemotherapy with vincristine, dactinomycin, and doxorubicin (DD-4A regimen).[109][110]​ Radiation is not recommended.

Stage II

  • COG low risk: nephrectomy followed by post-operative chemotherapy with EE-4A regimen.[109] Radiation is not recommended.

  • COG standard risk: nephrectomy followed by post-operative chemotherapy with DD-4A regimen. Radiation is not recommended.[109][110]

Stage III

  • COG standard risk: nephrectomy followed by post-operative chemotherapy with DD-4A regimen and abdominal/flank irradiation.[111] 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]

  • COG higher risk: nephrectomy followed by post-operative 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][110]

  • 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 post-operatively. 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 post-operative chemotherapy with DD-4A regimen.[109] 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] 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]

    • Patients with an incomplete/slow response of pulmonary metastatic lesions at week 6 are switched to regimen M and receive whole lung irradiation.[71]

  • COG higher risk: nephrectomy followed by post-operative chemotherapy with DD-4A regimen for 6 weeks, then switched to regimen M, and receive whole lung irradiation or radiation to non-lung sites of metastasis.[109][110] Abdomen/flank radiation is given to patients with local/abdominal stage III disease.

  • Patients who cannot undergo upfront nephrectomy have tumour 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] Higher-risk patients receive whole lung radiation or radiotherapy to non-lung sites of metastasis.[109][110]

Stage V

  • Bilateral Wilms' tumour or bilaterally predisposed unilateral Wilms' tumour: preoperative chemotherapy followed by nephron-sparing surgery and modified post-operative chemotherapy based on histological response.[109][113][97] The goal of preoperative chemotherapy is to shrink the tumour to allow maximum preservation of renal parenchyma.[97]

  • For patients with bilateral Wilms' tumour, or with bilaterally predisposed unilateral Wilms' tumour with metastatic disease, vincristine, dactinomycin, and doxorubicin (VAD regimen) are given preoperatively.[113]

  • ​For patients with bilaterally predisposed unilateral Wilms' tumour that is localised (no metastatic disease), vincristine and dactinomycin (VA regimen) are used preoperatively.[113]

  • Radical nephrectomies can potentially be avoided and nephron-sparing surgery used to preserve renal parenchyma and function.[113]

  • 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]

COG treatment approach: unfavourable histology

For patients with unfavourable histology, treatment differs depending on whether anaplasia is focal or diffuse.[109]

Stage I

  • Focal or diffuse: nephrectomy followed by post-operative chemotherapy with DD-4A regimen and flank irradiation.[115]​​[116]

Stage II

  • Focal: nephrectomy followed by post-operative chemotherapy with DD-4A regimen and flank irradiation.[109][116][117]

  • Diffuse: nephrectomy followed by post-operative chemotherapy with vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, and irinotecan (revised UH-2 regimen), and flank irradiation.[109][118]​ 

Stage III

  • Focal: nephrectomy followed by post-operative chemotherapy with DD-4A regimen and abdomen/flank irradiation, with a boost to residual tumour.[116][117]​​​​

  • Diffuse: nephrectomy followed by post-operative chemotherapy with revised UH-2 regimen and abdomen/flank irradiation, with a boost to residual tumour.[109][116][117][118]

Stage IV

  • Focal: nephrectomy followed by post-operative 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][117]​​

  • Diffuse: nephrectomy followed by post-operative chemotherapy with revised UH-2 regimen and abdomen/flank irradiation with a boost to residual tumour.[109][118]​ Radiotherapy is given to metastatic sites.

Stage V

  • Bilateral Wilms' tumour or bilaterally predisposed unilateral Wilms' tumour: preoperative chemotherapy followed by nephron-sparing surgery and modified post-operative chemotherapy based on histological response.[97][109][113]​​

  • For patients with bilateral Wilms' tumour, or with bilaterally predisposed unilateral Wilms' tumour with metastatic disease: VAD regimen is used preoperatively.[113]

  • ​For patients with bilaterally predisposed unilateral Wilms' tumour that is localised (no metastatic disease): VA regimen is used preoperatively.[113]

  • Radical nephrectomies can potentially be avoided and nephron-sparing surgery used to preserve renal parenchyma and function.[113]

  • 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]

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' tumour (prior to any attempt at resection, regardless of initial stage).[73][99]​​ Nepherectomy is followed by post-operative chemotherapy with or without irradiation, depending on SIOP post-operative staging and histology of tumour.[4][99]

Imaging studies stage patients at diagnosis as having localised (stages I-III), metastatic (stage IV), or bilateral (stage V) disease.[73]

SIOP histological classification divides patients with all stages (I to IV) into 3 groups: low-risk (completely necrotic Wilms' tumour), high-risk (blastemal type and diffuse anaplasia), and intermediate-risk tumours (all other types).[53][73]​​​​​

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' tumour.[99][119]

Stage I

  • SIOP low-risk: preoperative chemotherapy with dactinomycin and vincristine (AV regimen) for 4 weeks, followed by nephrectomy and no post-operative chemotherapy or irradiation.

  • SIOP intermediate-risk: preoperative chemotherapy (AV regimen for 4 weeks) followed by nephrectomy and post-operative chemotherapy (AV regimen for 4 weeks). No irradiation.

  • SIOP high-risk: preoperative chemotherapy (AV regimen for 4 weeks) followed by nephrectomy and post-operative 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 post-operative chemotherapy (AV regimen for 27 weeks). No irradiation.

  • SIOP intermediate-risk: preoperative chemotherapy (AV regimen for 4 weeks) followed by nephrectomy and post-operative chemotherapy. Patients with stromal or epithelial-type disease are treated with AV regimen for 27 weeks; patients with non-stromal- or non-epithelial-type disease (i.e., mixed and focal anaplasia-type tumours) 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 post-operative 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 post-operative 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 post-operative chemotherapy. Patients with tumour volume after preoperative chemotherapy <500 mL of any subtype or tumour volume ≥500 mL of stromal or epithelial-type disease are treated with AV regimen for 27 weeks; patients with tumour volume ≥500 mL of non-stromal- or non-epithelial-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 post-operative 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. Post-operative chemotherapy decisions depend on re-stratification of patients based on response to treatment, histology of the primary tumour and the metastatic tumour (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 post-operative 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). Post-operative chemotherapy with AVD regimen for 27 weeks if low-risk disease or intermediate-risk disease if representative nodule resection had completely necrotic metastasis. Post-operative 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][118]

Stage V

  • Preoperative chemotherapy with AV regimen for a maximum of 12 weeks with evaluation of response at 6 weeks followed by surgery. Each tumour is subclassified and staged separately to determine post-operative 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] The UMBRELLA protocol recommends discussion with the SIOP-RTSG surgical panel to assess the feasibility of nephron-sparing surgery and minimise the risk of upstaging by incomplete resection of the tumour.[99]

Tumour recurrence

Treatment of recurrent Wilms' tumours must be individualised to the patient, based on prior chemotherapy treatment, as well as the location of relapse.

Recurrent tumours are typically managed with chemotherapy agents that were not used for primary therapy.[99][121][122][123][124][125]​​​

The use of high-dose chemotherapy with autologous stem cell rescue or clinical trials utilising novel chemotherapy regimens or agents may be considered.[99][126][127][128]​​

Local control using surgery and/or radiation is highly individualised to the patient. Surgical resection of relapsed disease is considered when complete resection seems possible or when it is useful to evaluate histological tumour response.[99] The use of radiotherapy to initially non-irradiated sites is accepted, but the approach to previously irradiated sites must be individualised.[99]

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