Approach

Treatment is complex and requires a collaborative effort between pediatric surgeons, expert pathologists, pediatric oncologists, and radiation oncologists. Patients should be promptly referred to a major cancer center. Treatment consists of nephrectomy in all patients, as well as chemotherapy and/or radiation therapy depending on the staging and histology 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.[3] The approaches differ in that COG recommends upfront nephrectomy followed by adjuvant chemotherapy and/or radiation, whereas SIOP recommends preoperative and postoperative chemotherapy and/or radiation.[3] Despite this difference, the goal of therapy for both is to reduce therapy burden and avoid toxicity in patients with low-risk tumors, and augment therapy for patients with high-risk tumors.

Subsequent treatment regimens are based on the patient's risk of recurrence, defined by histologic (i.e., presence or absence of anaplasia), clinical (i.e., staging, patient age, tumor weight), molecular markers, and biologic (i.e., loss of heterozygosity [LOH], at 1p and 16q) prognostic factors.[41][55][72][73][75] Recommendations are for the use of trained pediatric oncologists, radiation oncologists, and surgeons only.

Surgery

Surgery is a very important part of the treatment of all stages of disease as it provides local control and prevents metastatic spread. Radical nephrectomy is recommended as standard in all patients using a transperitoneal approach.[40] The surgeon should avoid tumor spillage or incomplete removal. Selective sampling of lymph nodes should also be performed.[72] 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.[40]

Alternative surgical techniques (e.g., laparoscopic nephrectomy, partial nephrectomy) may be carefully considered in some patients.[3] Nephron-sparing surgery is used for patients with a genetic predisposition syndrome for Wilms tumor, bilateral disease, and congenital abnormalities, such as solitary kidney or horseshoe kidney.[72] Evidence is limited to support nephron-sparing surgery for unilateral Wilms tumor.[72][81] However, the SIOP UMBRELLA protocol has specified certain conditions in which nephron-sparing surgery 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.[75]

A tumor is usually deemed unresectable if: it is a solitary kidney, bilateral Wilms tumor, or there are 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); there is respiratory compromise; or there is intraluminal extension of a tumor thrombus above the level of the hepatic veins.[40] These scenarios could lead to increased morbidity and/or mortality. Biopsy remains controversial, but an open biopsy with a minimum of 10-12 cores is required in the COG protocol if a tumor is unresectable.[3][40]

Any suspicious metastatic lesion (hepatic or intra-abdominal) should be either biopsied or resected at the time of initial surgery.[40]

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%.[3]

SIOP recommends upfront chemotherapy for patients newly diagnosed with Wilms tumor ages ≥6 months prior to any attempt at resection regardless of initial stage, as SIOP believes this avoids intraoperative spillage due to tumor rupture and results in a decrease in the size of the tumor, making it more amenable to resection, thereby decreasing postoperative complications.[55]

COG argues that this approach leads to inaccurate staging of the tumor and potential under- or overtreatment.[82] COG recommends preoperative chemotherapy only if tumor extends into inferior vena cava above the hepatic vein, primary tumor is unresectable at presentation, or both kidneys are involved.[40]

Radiation therapy

Wilms tumor is highly radiosensitive. 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.[40][75]

Radiation therapy (either flank irradiation or whole abdomen irradiation) is used for the regional management of COG stage III or IV favorable histology Wilms tumor, and relapsed and anaplastic Wilms tumor.[3] Patients with primary favorable histology Wilms tumors with lung metastasis who do not show complete response to chemotherapy at week 6 receive whole lung irradiation.[83] 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 loss of heterozygosity (LOH) 1p/16q or 1q gain.[84]

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).[3] In the SIOP UMBRELLA protocol, CT-only nodules with a transverse diameter of at least 3 mm are treated as metastases.[75] 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.[3][75]

Extrapulmonary metastatic lesions may also receive radiation therapy.

COG treatment approach

Recommends upfront nephrectomy for patients with unilateral renal masses who do not have known Wilms tumor predisposition.[3] This is followed by chemotherapy and/or irradiation depending on staging and histology of tumor.

Favorable histology Wilms tumors are subdivided by COG into the following recurrence risk categories based on staging, histology, molecular markers, and biologic factors:[74]

  • Very-low risk: <2 years of age, <550 g tumor weight, stage I, any LOH status

  • Low risk: any age or tumor weight, stage I or II, but no LOH at 1p and 16q

  • Standard risk: stage I tumors ≥550 g with LOH at 1p and 16q, or any weight stage II with LOH, or stage III/IV with no LOH

  • High risk: stage III or IV with LOH at 1p and 16q.

Stage I:

  • COG very-low risk: nephrectomy followed by observation alone and a protocol directed approach to relapse (COG study #AREN0532).[84][85]​​ Patients not enrolled in a study are treated with vincristine and dactinomycin (EE-4A regimen).[84]​ Radiation is not recommended.

  • COG low-risk: nephrectomy followed by postoperative chemotherapy with EE-4A regimen (COG study #AREN0532).[84] Radiation is not recommended.

  • COG standard-risk: nephrectomy followed by postoperative chemotherapy. COG recommends vincristine, dactinomycin, and doxorubicin (DD-4A regimen; known as AVD in SIOP UMBRELLA 2016 protocols).[84][86] Radiation is not recommended.

Stage II:

  • COG low-risk: nephrectomy followed by postoperative chemotherapy with EE-4A regimen.[84] Radiation is not recommended.

  • COG standard-risk: nephrectomy followed by postoperative chemotherapy. COG recommends DD-4A regimen if LOH is present. Radiation is not recommended.[84][86]

Stage III:

  • COG standard-risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and abdominal/flank irradiation (COG study #AREN0532).[87]

  • COG high-risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen for 6 weeks, and then switched to regimen M (vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide), as well as abdominal/flank irradiation (COG study #AREN0533).[84][86]

Stage IV:

  • COG standard-risk: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and abdominal/flank irradiation (COG study #AREN0533).[84] Patients with pulmonary metastases with a complete response at week 6 continue receiving DD-4A regimen chemotherapy without bilateral pulmonary irradiation.[83] If there is an incomplete/slow response of pulmonary metastatic lesions at week 6, the patient should receive whole lung irradiation and be switched to chemotherapy regimen M.[83]

  • COG high-risk: nephrectomy followed by postoperative chemotherapy with M regimen.[84][86]

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.[84][88][89] The goal of preoperative chemotherapy is to shrink the tumor to allow maximum preservation of renal parenchyma.[89]

  • Radical nephrectomies can potentially be avoided and nephron-sparing surgery (e.g., unilateral total nephrectomy with contralateral partial nephrectomy, bilateral partial nephrectomy, unilateral total nephrectomy, and unilateral partial nephrectomy) used to preserve renal parenchyma and function.[88]

  • Each side should be individually staged and treated according to the guidelines above.

  • Partial nephrectomy may not be sufficient for high-risk patients due to a high incidence of recurrence.[90][91][92]

  • Rarely, disease is extensive bilaterally resulting in renal failure and need for a renal transplant.[93]

For patients with unfavorable histology, treatment differs depending on whether anaplasia is focal or diffuse.[84]

Stage I:

  • Focal or diffuse: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and flank irradiation (COG study #AREN0321).[94]

Stage II:

  • Focal: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and flank irradiation.[95]

  • Diffuse: nephrectomy followed by postoperative chemotherapy and flank irradiation (COG study #AREN0321). Early chemotherapy regimens used DD-4A with the addition of cyclophosphamide.[95] This was later intensified by changing to a regimen of vincristine, doxorubicin, and cyclophosphamide alternating with cyclophosphamide and etoposide (regimen 1), which resulted in additional improvements in patient outcomes.[95] The addition of carboplatin to the regimen 1 agents (regimen UH-1; known as HR-1 in SIOP UMBRELLA 2016 protocols) was studied for use in stages II to IV of diffuse anaplastic Wilms tumor; however, the increased toxicity necessitated modification to reduce the doxorubicin, cyclophosphamide, and etoposide exposure (revised UH-1).[84][96]

Stage III:

  • Focal: nephrectomy followed by postoperative chemotherapy with DD-4A regimen and abdomen/flank irradiation, with a boost to residual tumor.[95]

  • Diffuse: nephrectomy followed by postoperative chemotherapy with revised UH-1 regimen and abdomen/flank irradiation, with a boost to residual tumor.[84][96]

Stage IV:

  • Focal or diffuse: nephrectomy followed by postoperative chemotherapy with revised UH-1 regimen, or UH-2 regimen (revised UH-1 with additional vincristine and irinotecan) in patients with poor/partial response to chemotherapy and abdomen/flank irradiation with a boost to residual tumor.[84][96] Patients with lung metastasis receive whole lung irradiation.

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.[84][88][89]

  • Radical nephrectomies can potentially be avoided and nephron-sparing surgery (e.g., unilateral total nephrectomy with contralateral partial nephrectomy, bilateral partial nephrectomy, unilateral total nephrectomy, and unilateral partial nephrectomy) used to preserve renal parenchyma and function.[88]

  • Each side should be staged individually and treated according to the guidelines above.

  • Partial nephrectomy may not be sufficient for high-risk patients due to a high incidence of recurrence.[90][91][92]

  • Rarely, disease is extensive bilaterally, resulting in renal failure and need for a renal transplant.[93]

SIOP treatment approach

Recommends preoperative chemotherapy before nephrectomy, followed by postoperative chemotherapy and/or irradiation depending on SIOP postoperative staging and histology of tumor.[3][75]

Patients are staged at diagnosis by imaging studies into localized (stages I-III), metastatic (stage IV), or bilateral (stage V) disease.[55] 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).[41][55]​​

Treatment guidance is taken from the UMBRELLA SIOP-Renal Tumor Study Group (RTSG) 2016 protocol (referred to as the UMBRELLA protocol), which succeeds the SIOP-2001 protocol.[75]

The UMBRELLA protocol recommends direct surgery instead of preoperative chemotherapy for children <6 months old and the consideration of fine-needle biopsy for patients who have unusual clinical presentations or unusual findings on imaging to decrease the risk of misdiagnosis of Wilms tumor.[75]

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 etoposide, carboplatin, cyclophosphamide, and doxorubicin 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.[84][96]

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.[91] 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.[75]

Tumor recurrence

Recurrent tumors are managed by use of chemotherapy agents that were not used for primary therapy.[75][97][98]

The use of high-dose therapy with autologous stem cell transplantation or clinical trials utilizing novel chemotherapy regimens may be considered.[75][99][100][101]

Surgical resection of relapsed disease is considered when surgery seems possible or when it is useful to evaluate histologic tumor response.[75] The use of radiation therapy to initially non-irradiated sites is accepted, but recommendations for the approach to previously irradiated sites is difficult, because of the many different situations encountered.[75]

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