Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version

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Stage Information for Wilms Tumor

Both the results of the imaging studies and the surgical and pathologic findings at nephrectomy are used to determine the stage of disease. The stage is the same for tumors with FH or anaplastic histology. Thus, the stage information is characterized by a statement of both criteria (for example, stage II, FH or stage II, anaplastic histology).[161,173]

The staging system was originally developed by the NWTS Group and is still used by the COG. The staging system used in North America and incidence by stage are outlined below.[161]

Stage I

In stage I Wilms tumor (43% of patients), all of the following criteria must be met:

• Tumor is limited to the kidney and is completely resected.
• The renal capsule is intact.
• The tumor is not ruptured or biopsied before being removed.
• No involvement of renal sinus vessels.
• No evidence of the tumor at or beyond the margins of resection.
• All lymph nodes sampled are negative.

For a tumor to qualify for certain therapeutic protocols such as very low-risk stage I, regional lymph nodes must be examined microscopically. Lymph node sampling is strongly recommended for all patients, even in the absence of clinical abnormal nodes, to achieve the most accurate stage.

Stage II

In stage II Wilms tumor (20% of patients), the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:

• There is regional extension of the tumor (i.e., penetration of the renal capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below).
• Blood vessels in the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor cells. Margins are clear.
• Vascular extension of tumor is considered stage II only if it is completely removed en bloc in the nephrectomy specimen.

All lymph nodes sampled are negative.

Rupture or spillage confined to the flank, including biopsy of the tumor, is now included in stage III by the COG Renal Tumor Committee (COG RTC); however, data to support this approach are controversial.[140,174]

Stage III

In stage III Wilms tumor (21% of patients), there is postsurgical residual nonhematogenous tumor that is confined to the abdomen. Any one of the following may occur:

• Lymph nodes in the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax or other extra-abdominal sites is a criterion for stage IV.)
• The tumor has penetrated through the peritoneal surface.
• Tumor implants are found on the peritoneal surface.
• Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination).
• The tumor is not completely resectable because of local infiltration into vital structures.
• Tumor rupture before surgery or any spill during surgery is considered stage III.
• Any biopsy is performed, regardless of type—Tru-cut biopsy, open biopsy, or fine-needle aspiration—before the tumor is removed.
• The tumor is removed in more than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus in the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor in the vena cava into the thoracic vena cava and heart is considered stage III, rather than stage IV, even though outside the abdomen—and it can even be stage II if completely resected en bloc with the nephrectomy specimen.

Lymph node involvement and microscopic residual disease are reported as highly predictive of outcome in patients with stage III FH Wilms tumor.[175]

Stage IV

In stage IV Wilms tumor (11% of patients), one of the following is present:

• Hematogenous metastases (lung, liver, bone, brain).
• Lymph node metastases outside the abdominopelvic region.

The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present. According to the criteria described above, the primary tumor is assigned a local stage, which determines local therapy. For example, a patient may have stage IV, local stage III disease.

Stage V

In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. The current paradigm treats all patients with bilateral Wilms tumor the same for the first 6 or 12 weeks. After definitive surgery, the treatment is based on the highest stage of the remaining kidneys and the posttreatment pathology.[141]

Treatment of Wilms Tumor

Treatment option overview for Wilms tumor

Because of the relative rarity of Wilms tumor, all patients with this tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon and/or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) who have experience treating children with Wilms tumor is necessary to determine and implement optimal treatment.

Most randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups (COG RTC and SIOP). Differences between the two groups affect staging and classification. There are two standard approaches to Wilms tumor treatment: the COG RTC uses immediate surgery for all unilateral tumors and the SIOP uses preoperative chemotherapy as the first step in treatment. Both groups use postoperative chemotherapy, except for selected cases who do not receive chemotherapy, and in advanced stages, radiation therapy is used in a risk-adapted approach.

• COG RTC (includes the previous NWTS Group): The NWTS Group established standard treatment for Wilms tumor in North America, consisting of initial nephrectomy (when feasible) followed by chemotherapy and, in some patients, radiation therapy.[176-178] This approach allows for early and accurate histologic diagnosis, collection of biologic materials unaltered by therapy, and staging information, such as the presence of tumor spill or tumor involvement in lymph nodes, before chemotherapy is administered.
• SIOP: SIOP is a European consortium whose trials provide preoperative chemotherapy before definitive resection for patients with renal tumors. This results in fewer tumor spills during surgery and lower postoperative stage.[179] When the histological features of Wilms tumors from patients who underwent immediate surgery were compared with the histological features of those who received preoperative chemotherapy, preoperative chemotherapy was shown to significantly alter the histology, with fewer blastemal and mixed histology types in the tumors. Additionally, there were fewer stage III tumors in the preoperative chemotherapy group.[180]
• Both SIOP and COG treat infants younger than 6 months with a primary nephrectomy.[181]

This summary focuses on the NWTS (now COG RTC) results and studies.

The major treatment and study conclusions of NWTS-1, NWTS-2, NWTS-3, NWTS-4, and NWTS-5 are as follows:

1. Routine, postoperative radiation therapy of the flank is not necessary for children with stage I tumors or stage II tumors with FH when postnephrectomy combination chemotherapy consisting of vincristine and dactinomycin is administered.[178]
2. The prognosis for patients with stage III FH is best when treatment includes either (a) dactinomycin, vincristine, doxorubicin, and 10.8 Gy of radiation therapy to the flank; or (b) dactinomycin, vincristine, and 20 Gy of radiation therapy to the flank. Whole abdominal radiation is indicated for extensive intraperitoneal disease or widespread intraperitoneal tumor spill with possible boost to gross residual disease.[178]
3. The addition of cyclophosphamide at the protocol dose (10 mg/kg/d for 3 days every 6 weeks) to the combination of vincristine, dactinomycin, and doxorubicin does not improve prognosis for patients with stage IV FH tumors.[178]
4. A single dose of dactinomycin per course (stages I–II FH, stage I anaplastic histology, stage III FH, stages III–IV, or stages I–IV clear cell sarcoma of the kidney) is equivalent to the divided-dose courses, results in the same EFS, achieves greater dose intensity, and is associated with less toxicity and expense.[182]
5. Eighteen weeks of therapy is adequate for patients with stage I and stage II FH, and stage III and IV patients can be treated with 6 months of therapy instead of 15 months.[148,176,182-184]
6. Gain of 1q is associated with inferior survival in unilateral FH Wilms tumor. It is the single most powerful predictor of outcome, and in the presence of 1q gain, neither 1p nor 16q loss is significant. In the absence of 1q gain in unilateral FH Wilms tumor, 1p and/or 16q loss retain some prognostic significance and are associated with a higher risk of recurrence.[97,99]

Surgery

The following operative principles have also evolved from NWTS trials:

1. The most important role for the surgeon is to ensure complete tumor removal without rupture and assess the extent of disease. Radical nephrectomy and lymph node sampling via a transabdominal or thoracoabdominal incision is the procedure of choice.[185] A flank incision is not performed because it provides limited exposure to the kidney.
   For patients with resectable tumors, preoperative biopsy or intraoperative biopsy is not performed because either would upstage the tumor in the current COG staging system.[185]
2. Routine exploration of the contralateral kidney is not necessary if technically adequate imaging studies do not suggest a bilateral process. If the initial imaging studies suggest bilateral kidney involvement, treatment approaches should facilitate renal-sparing surgery.[136]
3. About 2% of Wilms tumor cases have ureteral involvement. The presence of gross hematuria, nonfunctioning kidney, or hydronephrosis suggests the tumor may extend into the ureter, and cystoscopy is recommended. En bloc resection to avoid tumor spill is recommended.[186]
4. The surgeon needs to be aware of the risk of intraoperative spill, especially in patients who have right-sided and large tumors, as noted in a review of cases of intraoperative spill among 1,131 patients registered on COG study AREN03B2 (NCT00898365).[187]
5. Even if stage IV disease (e.g., pulmonary metastases) is evident on imaging, resection of the renal tumor should be considered. Treatment of local stage I or II Wilms tumor in the setting of distant metastasis does not require local radiation therapy.

Renal-sparing surgery remains controversial and is not recommended, except for children with the following:[188,189]; [190][Level of evidence: 3iiB]

• A solitary kidney.
• Predisposition to bilateral tumors. Some children who are predisposed to bilateral tumors and who have very small tumors detected by screening ultrasonography may be considered for renal-sparing surgery to preserve renal tissue.[188]
• Horseshoe kidney. Wilms tumor arising in a horseshoe kidney is rare, and accurate preoperative diagnosis is important for planning the operative approach. Primary resection is possible in most cases. Inoperable cases can usually be resected after chemotherapy.[191]
• Wilms tumor in infants with Denys-Drash or Frasier syndrome (to delay the need for dialysis).

Renal-sparing surgery does not appear to be feasible for most patients at the time of diagnosis because of the location of the tumor within the kidney, even in patients with very low-risk tumors.[192] In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor after administration of chemotherapy to shrink the tumor mass is considered investigational.[193,194]

Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[185,195] Furthermore, any suspicious node basin is sampled. Margins of resection, residual tumor, and any suspicious node basins are marked with titanium clips.

Wilms tumor rarely invades adjacent organs; therefore, resection of contiguous organs is seldom indicated. There is an increased incidence of complications occurring in more extensive resections that involve removal of additional organs beyond the diaphragm and adrenal gland. This finding has led to the recommendation in current COG protocols that patients in whom nephrectomy will require removal of additional organs should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection.[196] Primary resection of liver metastasis is not recommended.[197]

Chemotherapy

Preoperative chemotherapy before nephrectomy is indicated in the following situations, which have been listed previously under situations requiring a biopsy (refer to the Diagnostic and Staging Evaluation for Wilms Tumor section of this summary for more information):[185,196,198-201]

• Wilms tumor in a solitary kidney.
• Synchronous bilateral Wilms tumor.
• Extension of tumor thrombus in the inferior vena cava above the level of the hepatic veins. About 4% of Wilms tumor patients present with inferior vena cava or atrial involvement, and 11% of patients present with renal vein involvement. Embolization of a caval thrombus to the pulmonary artery is rare but can be lethal, and the presence of a thrombus must be identified preoperatively to prevent this occurrence and guide treatment.[137,145]
• Tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structures (e.g., spleen, pancreas, or colon but excluding the adrenal gland).
• Inoperable Wilms tumor.
• Pulmonary compromise resulting from extensive pulmonary metastases.

Preoperative chemotherapy follows a biopsy. The biopsy may be performed through a flank approach.[145,202-206] Adequate tissue is essential for accurate histological assessment and molecular studies. Preoperative chemotherapy includes doxorubicin in addition to vincristine and dactinomycin unless anaplastic histology is present; in such cases, chemotherapy then includes treatment with regimen I (refer to Table 2). The chemotherapy generally makes tumor removal easier by decreasing the size and vascular supply of the tumor; it may also reduce the frequency of surgical complications.[140,145,196,198,207,208]

In North America, the use of preoperative chemotherapy in patients with evidence of a contained preoperative rupture has been suggested to avoid intraoperative spill, but this is controversial.[209,210] The preoperative diagnosis of a contained retroperitoneal rupture on CT is difficult, even for experienced pediatric radiologists.[134]

Newborns and all infants younger than 12 months who will be treated with chemotherapy require a 50% reduction in chemotherapy dose compared with the dose given to older children.[211] Dosing for infants (younger than 12 months) will be calculated per kilogram of weight, not body surface area. This reduction diminishes the toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.[212]

Liver function tests in children with Wilms tumor are monitored closely during the early course of therapy because hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) have been reported in these patients.[213,214] Dactinomycin or doxorubicin should not be administered during radiation therapy. Patients who develop renal failure while undergoing therapy can continue receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be given at full doses; however, dactinomycin is associated with severe neutropenia. Reductions in dosing these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed while the patient is receiving therapy.[215,216]

Augmentation of therapy improves EFS for patients with FH Wilms tumor and loss of heterozygosity of 1p/16q. In the AREN0532 (NCT00352534) and AREN0533 (NCT00379340) trials, patients with stage I and stage II FH Wilms tumor who were treated with the DD-4A regimen (dactinomycin, vincristine, and doxorubicin) demonstrated a 4-year EFS rate of 87.3%, compared with the 4-year EFS rate of 68.8% (P = .042) for stage I and stage II patients treated on the NWTS-5 trial. Patients with stage III and stage IV disease had a 4-year EFS rate of 90.2% when treated with regimen M, compared with a 61.3% 4-year EFS rate (P = .001) for stage III and stage IV patients treated on the NWTS-5 trial. Trends toward improved 4-year survival rates were seen in stage I and II patients and in stage III and IV patients.[217][Level of evidence: 3iiiDi]

Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III. In a study of 1,488 patients with Wilms tumors who underwent surgery and radiation therapy, delay in starting radiation therapy after surgery of greater than 14 days was associated with an increased risk of mortality for patients with nonmetastatic Wilms tumor.[218][Level of evidence: 3iiiA]

Table 2 describes the accepted chemotherapy regimens used to treat Wilms tumor.

Table 2. Accepted Chemotherapy Regimens for Wilms Tumor

Regimen Name	Regimen Description
Regimen EE-4A [99]	Vincristine, dactinomycin × 18 weeks postnephrectomy
Regimen DD-4A [99]	Vincristine, dactinomycin, doxorubicin × 24 weeks; baseline nephrectomy or biopsy with subsequent nephrectomy
Regimen I [151]	Vincristine, doxorubicin, cyclophosphamide, etoposide × 24 weeks postnephrectomy
Regimen M [219]	Vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide with subsequent radiation therapy

Radiation therapy

Radiation therapy is used to improve local control and treat sites of metastatic disease. Radiation therapy has historically been dependent on stage and histology, but more recently is also guided by the tumor molecular signature.[220]

1. COG approach:
   Upfront surgery provides histologic confirmation and tumor extent, providing the rationale for adjuvant therapy, including radiation therapy. Besides histology, postoperative risk factors for worse local control include: (1) incomplete resection, (2) positive margins, and (3) nodal involvement. Radiation therapy is not used in patients with stage I or stage II FH Wilms tumor. For patients with FH Wilms tumor, flank or abdominal radiation therapy is used for treatment in stage III tumors. (Refer to Table 3 for more information.) In cases of unfavorable histology (focal or diffuse anaplasia), flank or abdominal radiation therapy is indicated for all patients.
   • Flank radiation therapy covers the tumor bed, involved nodal region, and entire adjacent vertebral bodies at 10.8 Gy in six fractions. The dose of radiation therapy was based on the results of the NWTS-3 study where there was no increase in abdominal relapse for stage III FH patients receiving 10 Gy versus 20 Gy with DD-4A chemotherapy.[221]
   • Whole-abdominal radiation therapy of 10.5 Gy in seven fractions is used to treat diffuse spill or peritoneal metastasis.
   • In the closed COG AREN0321 (NCT00335556) study, the radiation therapy dose to the tumor bed was 10.8 Gy in six fractions, with the exception of patients with stage III diffuse anaplasia, where the dose of 19.8 Gy in 11 fractions was used.
   • Results of the early NWTS studies (1 and 2) suggest that a radiation therapy delay of more than 10 days from surgery results in worse local control, particularly in unfavorable histology Wilms tumor.[222,223] However, no difference in local control was found if radiation therapy was delayed more than 10 days from surgery for patients with stages II to IV FH tumors treated on NWTS-3 or NWTS-4.[93] More recent data from the National Cancer Database confirms improved survival in patients with nonmetastatic Wilms tumor who received adjuvant radiation therapy less than or equal to 14 days postoperatively.[218]
   • Results from the NWTS-3 and NWTS-4 trials indicate that there is no survival benefit of whole-lung irradiation in the setting of lung metastases seen on CT scan only.[224] Current COG guidelines allow for whole-lung irradiation omission in cases of FH disease without extrapulmonary metastases, loss of heterozygosity at 1p and 16q, and complete response at 6 weeks after vincristine, dactinomycin, and doxorubicin.[220] When whole-lung irradiation is given, a dose of 12 Gy in eight fractions is indicated for children older than 18 months and 9 Gy in six fractions for patients younger than 18 months with pulmonary metastasis.
   • Other sites of metastatic disease in Wilms tumor are uncommon and may include liver, extra-abdominal nodes, brain, and bone. In the COG AREN0533 (NCT00379340) study, the radiation therapy dose recommendations for patients younger than 16 years are 19.8 Gy in 11 fractions to liver and gross residual nodes, 21.6 Gy in 17 fractions to the whole brain with a boost of 10.8 Gy in six fractions to gross metastatic disease in the brain, and 25.2 Gy in 14 fractions for bone metastasis. For patients older than 16 years, the radiation therapy dose to the whole brain and bone is increased to 30.6 Gy in 17 fractions.

Table 3. Radiation Therapy Guidelines in Children’s Oncology Group AREN0532, AREN0533, and AREN0321 Protocols

Local/Locoregional Disease
XRT = radiation therapy.
aRequires whole-abdominal XRT at 1.5 Gy daily fraction size. Patients with diffuse unresectable peritoneal implants receive 21 Gy.
bWhole-lung irradiation is given at 1.5 Gy daily fraction size.
cNot all patients receive radiation therapy.
dA boost is given for macroscopic disease.
	Stage I	Stage II	Stage III	Stage III (diffuse spill, peritoneal metastasis, preoperative rupture)a
Favorable histology	No XRT	No XRT	10.8 Gy	10.5 Gy
Focal anaplasia	10.8 Gy	10.8 Gy	10.8 Gy	10.5 Gy
Diffuse anaplasia	10.8 Gy	10.8 Gy	19.8 Gy	10.5 Gy + 9 Gy boost
	Metastatic Disease
	Stage IV Lung	Stage IV Liver	Stage IV Brain	Stage IV Bone
Favorable histology	10.5 Gy for age <12 monthsb,c; 12 Gy for age >12 monthsb,c	19.8 Gy +/- 5.4 to 10.8 Gy boostd	21.6 Gy + 10.8 Gy boost for age <16 years; 30.6 Gy for age >16 years	25.2 Gy for age <16 years; 30.6 Gy for age >16 years
Focal or diffuse anaplasia	10.5 Gy for age <12 monthsb; 12 Gy for age >12 monthsb	19.8 Gy +/- 5.4 to 10.8 Gy boostd	21.6 Gy + 10.8 Gy boost for age <16 years; 30.6 Gy for age >16 years	25.2 Gy for age <16 years; 30.6 Gy for age >16 years

Treatment of stage I Wilms tumor

Table 4 provides an overview of the standard treatment options and survival data for patients with stage I Wilms tumor, based on published results.

Table 4. Overview of Standard Treatment Options for Stage I Wilms Tumora

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to Table 2 for chemotherapy regimen descriptions)
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[99] Shamberger et al.,[152] Fernandez et al.,[220] Dix et al.,[217] and Daw et al.[225]
bOne patient with a pulmonary relapse 4.12 years after diagnosis.
FH <24 mo/tumor weight <550g	90%	100%	Surgery, including lymph node biopsy only
FH >24 mo/tumor weight >550g	94% RFS	98%	Nephrectomy + lymph node sampling followed by regimen EE-4A
FH with LOH 1p/16q (n = 8)	100% EFS	100%	Nephrectomy + lymph node sampling followed by regimen DD-4A
FA	100%	100% (n = 8)	Nephrectomy + lymph node sampling followed by regimen DD-4A and XRT
DA	100%b	100% (n = 10)	Nephrectomy + lymph node sampling followed by regimen DD-4A and XRT

The COG validated the hypothesis that nephrectomy only is appropriate therapy for patients younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g in the AREN0532 (NCT00352534) trial. The NWTS-5 trial investigated this approach for children younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g.

Evidence (surgery only for children younger than 2 years at diagnosis with stage I FH tumor that weighed <550 g):

1. The AREN0532 (NCT00352534) trial was designed to confirm the findings from NWTS-5 that adjuvant chemotherapy could be omitted for children younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g. A total of 116 patients met the criteria for very low-risk Wilms tumor and were enrolled on the study.[152,220,226]
   • Twelve patients relapsed.
   • The estimated 4-year EFS rate was 89.7%, and the OS rate was 100%.
   • 11p15 methylation status was associated with relapse (20% relapse with loss of heterozygosity, 25% relapse with loss of imprinting, and 3.3% relapse with retention of the normal imprinting [P = .011]).
   • Risk of developing metachronous Wilms tumor is very low in patients with very low-risk Wilms tumor who lack evidence of an underlying syndrome.
2. The AREN0321 (NCT00335556) study demonstrated that outcomes for patients with stage I anaplastic Wilms tumor were improved with the addition of doxorubicin and flank radiation therapy to vincristine/dactinomycin therapy.[225]
   • Four-year EFS and OS rate estimates were 100% in AREN0321, compared with 70% and 81.5%, respectively, in an updated analysis of 27 patients from NWTS-5 (median follow up, 13.3 years). One patient with diffuse anaplasia relapsed 4.12 years after diagnosis on the AREN0321 trial.
   • The addition of doxorubicin and radiation therapy to AREN0321 was on the basis of the pattern of relapse observed in stage I anaplastic Wilms tumor in the abdomen and distant sites in the NWTS-5 trial.
   • Retrospective analysis of all patients with stage I anaplastic Wilms tumor treated on NWTS-1 through NWTS-5 and AREN0321 showed a significant improvement in EFS for patients treated with doxorubicin (4-year EFS rate, 97.2% vs. 77.5%; P = .01), but no difference in EFS according to flank radiation therapy was shown (4-year EFS rate, 91.7% vs. 80.2%; P = .15).
   • The rate of local recurrence was low (3.6%) and appeared to be similar for patients who received flank radiation therapy (4%) and patients who did not receive flank radiation therapy (6.2%). Local relapse occurred only in patients with diffuse anaplasia.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of stage II Wilms tumor

Table 5 provides an overview of the standard treatment options and survival data for patients with stage II Wilms tumor, based on published results.

Table 5. Overview of Standard Treatment Options for Stage II Wilms Tumora

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to Table 2 for chemotherapy regimen descriptions)
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[99] Dome et al.,[151] and Dix et al.[217]
FH	86% RFS	98%	Nephrectomy + lymph node sampling followed by regimen EE-4A
FH LOH 1p/16q (n = 24)	83% EFS	100%	Nephrectomy + lymph node sampling followed by regimen DD-4A
FA	80% EFS	80% (n = 5)	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
DA	83% EFS	82%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen I

On NWTS-3, NWTS-4, and NWTS-5, patients with intraoperative spill were divided into two groups: (1) those with diffuse spillage involving the whole abdominal cavity; and (2) those with local spillage confined to the flank. Patients with diffuse spillage were treated with radiation therapy to the entire abdomen and three-drug chemotherapy (vincristine, dactinomycin, and doxorubicin), whereas patients with local spillage were treated with vincristine and dactinomycin only. On the basis of an analysis of patients treated on NWTS-3 and NWTS-4 indicating that patients with stage II disease and local spillage had inferior OS compared with patients with stage II disease without local spillage, COG studies treat patients with local spillage with doxorubicin and flank radiation.[227] This approach is controversial and has not been tested; therefore, it should not be considered standard.

In a review of 499 patients from NWTS-4 with stage II FH Wilms tumor, 95 of the patients experienced tumor spill. The 8-year RFS and OS rates for patients who experienced intraoperative tumor spill and were treated with vincristine and dactinomycin without flank radiation therapy were lower, at 75.7% and 90.3%, than the 85% and 95.6% rates for those who did not experience tumor spill. None of these differences achieved statistical significance.[174]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of stage III Wilms tumor

Table 6 provides an overview of the standard treatment options and survival data for patients with stage III Wilms tumor, based on published results.

Table 6. Overview of Standard Treatment Options for Stage III Wilms Tumora

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to Table 2 for chemotherapy regimen descriptions)
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[99] Dome et al.,[151] Fernandez et al.,[228] and Dix et al.[217]
FH (all patients)	88% EFS	97%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FH (without LOH of 1p and/or 16q) and positive lymph nodes	85% EFS	97%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FH (without LOH of 1p and/or 16q) and negative lymph nodes	97% EFS	99%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FH (with LOH of 1p and 16q) (n = 31)	87% EFS	94%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen M
FA	88% RFS	100% (n = 8)	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FA (preoperative treatment)	71% RFS	71% (n = 7)	Preoperative treatment with regimen DD-4A followed by nephrectomy + lymph node sampling and abdominal XRT
DA	46% EFS	53% (n = 16)	Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling and abdominal XRT
DA	65% EFS	67%	Immediate nephrectomy + lymph node sampling followed by abdominal XRT and regimen I

Loss of heterozygosity of 1p or 16q was shown to influence EFS but not OS in 588 patients with stage III FH Wilms tumor treated on the COG AREN0532 protocol. When combined, lymph node status and loss of heterozygosity status provided a strong predictor of excellent EFS and OS when both were absent, with a 4-year EFS rate of 97%, and an OS rate of 99%.[228][Level of evidence: 2Di] The outcome was poorer for patients having both positive lymph nodes and loss of heterozygosity of 1p or 16q, with a 4-year EFS rate of 74%. However, the 4-year OS rate was not influenced, at 92%.[228] On the basis of these results, therapy was augmented for patients with loss of heterozygosity of 1p/16q for patients enrolled on the AREN0533 trial. Patients with stage III and stage IV Wilms tumor with loss of heterozygosity were treated with regimen M. The 4-year EFS rate was 90.2%, and the OS rate was 96.1%, compared with a 4-year EFS rate of 61.3% (P = .001) and a 4-year OS rate of 86.0% (P = .087) for patients in the NWTS-5 trial. There was a suggestion of improvement in survival; however, the study was not powered to detect differences in survival.[217][Level of evidence: 3iiiDi]

Early initiation of radiation therapy is a critical component of multimodal therapy for patients with nonmetastatic Wilms tumor. In a review of 1,488 patients with Wilms tumor who underwent surgery and radiation therapy, a surgery-to-radiation therapy interval of greater than 14 days was associated with an increased risk of mortality (hazard ratio, 2.13; P = .013). This underscores the importance of initiating radiation therapy within 14 days of surgery, which is specified in Wilms tumor treatment protocols.[218][Level of evidence: 3iiiA]

For patients classified as stage III purely on the basis of local spill, refer to the Treatment of stage II Wilms tumor section of this summary.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of stage IV Wilms tumor

Table 7 provides an overview of the standard treatment options and survival data for patients with stage IV Wilms tumor, based on published results.

Table 7. Overview of Standard Treatment Options for Stage IV Wilms Tumora

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to Table 2 for chemotherapy regimen descriptions)
CR = complete response; DA = diffuse anaplasia; EFS = event-free survival; FA = focal anaplasia; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[99] Dome et al.,[151] Dix et al.,[219] and Dix et al.[217]
bAbdominal XRT is planned according to local stage of renal tumor.
cPulmonary XRT is reserved for patients with chest x-ray/chest computed tomography evidence of pulmonary metastases.
dRefer to the AREN0533 (NCT00379340) study for more information.
FH	76% RFS	86%	Nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, bilateral pulmonary XRT,c and regimen DD-4A
FH (with isolated lung nodules)	85% EFS	96%	Nephrectomy + lymph node sampling, followed by abdominal XRT,b +/- bilateral pulmonary XRT,c and regimen DD-4A or regimen Md
FH (with isolated lung nodules with CR to DD-4A)	83% EFS	94%	Nephrectomy + lymph node sampling, followed by abdominal XRTb and regimen DD-4A
FH (with isolated lung nodules with incomplete response to DD-4A)	92% EFS	96%	Nephrectomy + lymph node sampling, followed by abdominal XRTb and bilateral pulmonary XRTc and regimen M
FH (with LOH of 1p and/or 16q) (n = 20)	95% EFS	100%	Nephrectomy + lymph node sampling, abdominal XRTb radiation to sites of metastasesb, and regimen M
FA	61% EFS	72% (n = 11)	Nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, bilateral pulmonary XRT,c and regimen DD-4A
DA	33% EFS	33% (n = 15)	Immediate nephrectomy + lymph node sampling followed by abdominal XRT,b radiation to sites of metastases, whole-lung XRT,c and regimen I
DA (preoperative treatment)	31% EFS	44% (n = 13)	Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, and whole-lung XRTc

Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. Historically, chest x-rays were used to detect pulmonary metastases. The introduction of CT created controversy because many patients had lung nodules detected by chest CT scans that were not seen on chest x-rays. Management of newly diagnosed patients with FH Wilms tumor who have lung nodules detected only by CT scans (with negative chest x-ray) has elicited controversy as to whether they need to be treated with additional intensive treatment that is accompanied by acute and late toxicities.

Evidence (treatment of pulmonary nodules detected by chest CT scan only):

1. A retrospective review of 186 patients from NWTS-4 and NWTS-5 with CT-only–detected lung nodules reported on the use of doxorubicin, vincristine, and dactinomycin versus the use of two drugs.[229]
   • Patients who received doxorubicin, vincristine, and dactinomycin with or without lung irradiation had a 5-year EFS rate of 80% versus an EFS rate of 56% for patients receiving only two drugs (P = .004).
   • There was no difference in EFS according to whether the lung was irradiated.
   • There was no difference in the 5-year OS rate (87% vs. 86%).

Retrospective studies from Europe have examined the impact of omitting pulmonary radiation in patients with pulmonary metastases diagnosed by chest x-ray. European investigators omitted radiation from the treatment of most patients with Wilms tumor and pulmonary metastases as identified on chest x-ray who were treated on the SIOP-93-01 (NCT00003804) trial. The European approach to renal tumors differs from the approach used in North America. All patients who were shown to have a renal tumor by imaging underwent 9 weeks of prenephrectomy chemotherapy consisting of vincristine, dactinomycin, and doxorubicin.

Evidence (omission of pulmonary irradiation):

1. In a retrospective SIOP study, 234 newly diagnosed patients with Wilms tumor presenting with pulmonary metastases were treated according to the response of the pulmonary metastases to the prenephrectomy chemotherapy.[230]
   1. Patients who were in complete remission (67%) after 6 weeks of therapy continued with the same chemotherapy and did not require radiation to their lungs.
      • The 5-year EFS rate was 77%, and the OS rate was 88%.
   2. Patients who had residual pulmonary metastases were evaluated for metastasectomy.
      • Thirty-seven patients (17%) obtained complete remission with surgery, and their outcome was similar to that of the group of patients who were treated with chemotherapy. Tumor viability in the resected pulmonary metastases was not a factor for omitting radiation therapy.
      • The 5-year EFS rate was 84%, and the OS rate was 92%.
   3. Patients with residual pulmonary metastases that were incompletely resected or inoperable received more aggressive chemotherapy consisting of ifosfamide/anthracycline alternating with carboplatin/etoposide for 9 weeks.
      • Patients showing a complete remission at that time were spared pulmonary radiation and continued with chemotherapy, whereas patients with residual pulmonary metastases continued with additional chemotherapy (to complete 34 weeks) and pulmonary irradiation. The 5-year OS rate was 48%, compared with the OS rates for patients who responded to chemotherapy alone (88%) and those who underwent metastasectomy (92%) (P < .001).
      • Patients with high-risk histologies, such as anaplastic Wilms tumor, were treated with more aggressive chemotherapy but had a poorer outcome, compared with that of patients with nonanaplastic histologies (5-year OS rate, 87% vs. 33%; P < .001).
2. The COG AREN0533 (NCT00379340) study applied a new strategy for patients with FH Wilms tumor and isolated lung metastases to improve EFS while reducing exposure to lung irradiation on the basis of the European experience. Therapy was adjusted on the basis of lung nodule response and tumor-specific loss of heterozygosity at 1p and 16q.[219][Level of evidence: 3iiiDi]
   • Of the 292 patients enrolled in the study, 133 patients (42%) showed a complete lung nodule response after 6 weeks of DD-4A (vincristine, dactinomycin, doxorubicin) and continued receiving the same chemotherapy without lung radiation therapy. The 4-year EFS rate was 80%, and OS rate was 96%.
   • Patients who had an incomplete lung nodule response (n = 145) or loss of heterozygosity at 1p/16q (n = 18) received lung radiation therapy and four cycles of cyclophosphamide/etoposide in addition to the DD-4A drugs (regimen M). The 4-year EFS rate was 89%, and the OS rate was 95% for the incomplete lung nodule response group without loss of heterozygosity. Of the patients with pulmonary metastases only and loss of heterozygosity, the 4-year EFS and OS rates were 100%.
   • In a post hoc analysis of 1q gain in 212 patients enrolled in AREN0533 who had DNA available, patients with lung nodule complete remission with 1q gain had a significantly worse 4-year EFS rate (86% vs. 57%, P = .001) and trend toward inferior OS rates (97% vs. 89%). Relapses were predominantly pulmonary. There was no difference in outcome for patients with incomplete lung nodule response on the basis of 1q gain.
   • Regimen M has a higher potential for late effects (increased risk of secondary leukemias and risk of infertility related to a cumulative dose of cyclophosphamide of 8.8 g/m2).
   • COG showed that initial lung radiation therapy could be avoided in approximately 40% of patients. OS was excellent; however, there was a trend toward more events than expected (expected, 15% and observed, 20%; P = .052).

Although fewer patients were spared pulmonary radiation when treated in the COG trial than in the European trials, it is important to note several differences between the studies and why the studies cannot be directly compared.[219,230] Patients in Europe receive a more dose-dense regimen of dactinomycin and doxorubicin before their pulmonary metastases are reevaluated than do patients in North America (135 ug/kg dactinomycin and 100 mg/m2 doxorubicin in Europe, compared with 45 ug/kg dactinomycin and 45 mg/m2 of doxorubicin in North America). European studies allow lung radiation therapy to be omitted for patients with a complete remission achieved by chemotherapy or pulmonary metastasectomy, whereas radiation therapy was only omitted in the United States for patients with a complete remission with chemotherapy alone. Imaging studies were not centrally reviewed in the European studies, whereas they were in the United States, and the definition of complete remission may have been more stringent in the AREN0533 (NCT00379340) trial.

The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.[197]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Treatment of stage V Wilms tumor and those predisposed to developing bilateral Wilms tumor

Currently, there is not a standard approach for the treatment of stage V Wilms tumor (bilateral Wilms tumor at diagnosis) and those predisposed to developing Wilms tumor; however, for the first time, a prospective study of the treatment of patients with bilateral Wilms tumor has been completed and provides guidance for the approach.[141]

Management of a child with bilateral Wilms tumor is very challenging. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.[231]

Historically, based on the NWTS-4 and NWTS-5 trials and trials performed in Europe, patients with bilateral Wilms tumor have had a lower EFS and OS than have patients with localized Wilms tumor. The NWTS-4 study reported that the 8-year EFS rate for patients with bilateral FH Wilms tumor was 74%, and the OS rate was 89%; for patients with anaplastic histology, the EFS rate was 40%, and the OS rate was 45%.[164] The NWTS-5 study reported that the 4-year EFS rate for all bilateral Wilms tumor patients was 56%, and the OS rate was 81%; the 4-year EFS rates for patients with FH (65%), focal anaplastic histology (76%), and diffuse anaplastic histology (25%) were also reported.[99,151] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[163,232] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%).[232] The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.

Treatment options for stage V Wilms tumor include the following:

1. Preoperative chemotherapy and resection for bilateral Wilms tumor.
2. Renal transplant.

Preoperative chemotherapy and resection for bilateral Wilms tumor

For patients with bilateral Wilms tumor, the goal of therapy is to preserve as much renal tissue as possible without compromising overall outcome. This approach is used to avoid the late effect of end-stage renal disease, which can be caused by underlying germline genetic aberrations and treatment-related loss of functional renal tissue. End-stage renal disease occurs more frequently in patients with bilateral Wilms tumor (12% nonsyndromic) than in patients with unilateral Wilms tumor (<1%). Functional renal outcome is considerably better after bilateral nephron-sparing surgery than after other types of surgery.[141]

Traditionally, patients have undergone bilateral renal biopsies, with staging of each kidney followed by preoperative chemotherapy. In the first prospective multi-institutional treatment trial (COG AREN0534 [NCT00945009]), pretreatment biopsies were not required if results of imaging tests were consistent with Wilms tumor.[141] This approach was taken because the bilateral occurrence of non-Wilms renal tumors is very low. Also, core-needle and wedge biopsies are not highly successful in identifying anaplasia in Wilms tumor.[142] In the setting of an unusual clinical situation, such as age older than 10 years or atypical imaging features, when a diagnosis other than Wilms should be considered, a tissue diagnosis is obtained.[141]

For patients who are treated with preoperative chemotherapy, the tumor pathology needs to be evaluated after 4 to 8 weeks. For patients not treated in a clinical trial, the ideal time to perform a biopsy or resection is unknown because minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. A planned attempt at resection or biopsy of apparently unresectable tumor is undertaken no later than 12 weeks from diagnosis. Continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may miss anaplastic histology or chemotherapy-induced differentiation (including rhabdomyomatous differentiation) and thus increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor, and these tumors respond poorly to chemotherapy.[164]

Once the diagnosis is confirmed, a complete resection is performed. Histologic confirmation of the diagnosis is not straightforward. In a series of 27 patients from NWTS-4, discordant pathology (unilateral anaplastic tumor) was seen in 20 cases (74%), which highlights the need to obtain tissue from both kidneys. Seven children who were later diagnosed with diffuse anaplastic tumors had core biopsies performed to establish the diagnosis; however, anaplasia was not found. Anaplasia was identified in only three of the nine patients when an open-wedge biopsy was performed and in seven of nine patients who had a partial or complete nephrectomy.[164]

The decision to administer chemotherapy and/or radiation therapy after biopsy or a second-look operation is dependent on the tumor's response to initial therapy. More aggressive therapy is required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[173,233,234]

End-stage renal disease is the most clinically significant morbidity in patients with bilateral Wilms tumor and can be caused by underlying germline genetic aberrations, as well as treatment-related loss of functional renal tissue. Long-term monitoring of renal function is required after treatment for bilateral disease.

Evidence (preoperative chemotherapy and resection for bilateral Wilms tumor):

1. The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (utilizing three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy on the basis of histologic response.[141]
   • For the arm that treated children with bilateral Wilms tumor, results showed that central review of imaging, surgical resection within 12 weeks of diagnosis, and response-based and histology-based postoperative therapy improved EFS and OS, when compared with the historical outcomes of children with bilateral Wilms tumor.
   • For the 189 patients with bilateral Wilms tumor, 4-year EFS rate was 82.1% (95% confidence interval [CI], 73.5%–90.8%), and the OS rate was 94.9% (95% CI, 90.1%–99.7%). Because biopsy was not performed before treatment in this series, some of the patients enrolled may have had only nephrogenic rests and not a true Wilms tumor. This finding may have improved these survival figures over historical controls.
   • One of the aims of the study was that 75% of patients undergo definitive surgery by 12 weeks. After induction chemotherapy, 163 of 189 patients (84%) underwent definitive surgical treatment in at least one kidney by 12 weeks, and 39% of patients retained parts of both kidneys.
   • Chemotherapy after surgery was tailored according to histologic response. The 4-year EFS rate was 84.1% for FH tumors, 58.2% for anaplastic histology tumors, and 82% for blastemal-type tumors.
   • Because of the higher risk of renal failure in patients with bilateral Wilms tumor than in patients with unilateral Wilms tumor, one of the goals of the study was that 50% of the patients undergo bilateral nephron-sparing surgery. This threshold was not met, with only 39% of patients successfully treated with bilateral nephron-sparing surgery.
   • Based on the above study, the recommendation was to continue with three-drug preoperative chemotherapy for 6 to 12 weeks followed by nephron-sparing surgery whenever possible. After resection, postoperative therapy is based on the histology of the resected specimen. The disappointing use of nephron-sparing surgery in this study may have been because of the level of experience of the surgeons in this multi-institutional study.
2. In a retrospective review of 93 children with bilateral Wilms tumor registered at Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) centers over a 21-year period, 43 patients were treated with vincristine and dactinomycin preoperatively and 37 patients were treated with vincristine, dactinomycin, and doxorubicin. The duration of preoperative chemotherapy ranged from 1 week to 40 weeks (median, 12 weeks).[163]
   • The 4-year DFS rate was 67%, and the OS rate was 80%.
   • There was a trend toward better EFS in nonmetastatic patients receiving vincristine, dactinomycin, and doxorubicin preoperatively (4-year EFS rate, 84%) than for patients receiving vincristine and dactinomycin (4-year EFS rate, 65%), but this was not significant.
   • The bilateral renal parenchyma was preserved in 48% of patients.
3. In a retrospective review of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 (NCT00003804) guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.[235]
   • The 5-year EFS rate was 83.4%, and the OS rate was 89.5%.
   • All but one of the patients had renal-sparing surgery in at least one kidney.
   • Despite the good survival, 14% of the patients developed end-stage renal disease.
4. In a retrospective review from St. Jude Children's Research Hospital, investigators described their experience with preoperative chemotherapy followed by renal-sparing procedures in children with bilateral FH Wilms tumor.[236]
   • In a series, 39 of 42 patients with bilateral FH Wilms tumor underwent successful bilateral renal-sparing procedures after receiving preoperative chemotherapy. Three patients underwent unilateral nephrectomy with contralateral nephron-sparing surgery. Three patients required early (within 4 months) repeat nephron-sparing surgery for residual tumor. In the long term, seven patients had local tumor recurrence, and three patients had intestinal obstruction.
   • The OS rate was 86% (mean follow-up, 4.1 years). Of the six patients who died, five had diffuse anaplastic histology.
   • All of the patients had an estimated glomerular filtration rate of more than 60 mL/min/1.73m2 at the last follow-up; none of the patients developed end-stage renal disease.
   • The authors concluded that bilateral renal-sparing surgery is almost always feasible and can be done safely with good oncologic outcomes in patients with synchronous, bilateral Wilms tumor. It should be considered even if preoperative imaging studies suggest that the lesions are unresectable. Sparing of renal parenchyma is likely to help preserve renal function in children who are at significant risk of chronic renal insufficiency. Careful long-term follow-up is required to fully assess the potential progression of renal dysfunction.
   • A follow-up review of these patients revealed the following: 8 of 36 patients underwent repeat nephron-sparing surgery, and an additional two patients required a third nephron-sparing surgery. Six of these patients were alive without disease at the 4.5-year follow-up. The two patients who died had blastemal-predominant histology.[237]

Renal transplant

Renal transplant for children with stage V Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy because most relapses occur within 2 years of diagnosis.[238] Similarly, renal transplant for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.[238]

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

(Refer to the Treatment of Recurrent Childhood Kidney Tumors section of this summary for information about recurrent disease.)

Follow-up after treatment

For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasonography examination every 3 months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for Beckwith-Wiedemann syndrome).

Late effects after Wilms tumor therapy

Children treated for Wilms tumor are at increased risk of developing the following:

• Premature mortality after Wilms tumor diagnosis. In 1,441 5-year survivors of Wilms tumor, a substantial increase in cumulative mortality from 5.4% to 22.7% was noted from 30 to 50 years after Wilms tumor diagnosis. Excess deaths after 30 years were attributed to subsequent malignant neoplasms (50%) and cardiac-related causes (25%).[239] Radiation therapy was a risk factor for both outcomes.
• Subsequent malignant neoplasms.[239-241] Digestive cancers and breast cancer are the most frequent subsequent neoplasms, and radiation therapy is a risk factor. Women treated with lower doses of radiation to large volumes of breast tissue for a childhood cancer have a risk of breast cancer that is higher than previously recognized. The cumulative incidence of invasive breast cancer in Wilms tumor survivors who had received pulmonary radiation for metastatic Wilms tumor is nearly 15% by age 40 years.[242]
• Congestive heart failure. The risk of congestive heart failure is influenced by dose of doxorubicin received, radiation to the heart, and female sex.[241,243]
• Complications of pregnancy.[244]
• End-stage renal disease. The cumulative incidence of end-stage renal disease caused by chronic renal failure at 20 years from diagnosis of Wilms tumor is low, at 3.1% for patients with bilateral Wilms tumor and less than 1% for those with unilateral Wilms tumor.[81] Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible.

(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

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