Treatment of Wilms Tumor

Surgical Considerations
The initial therapy for most children with Wilms tumor is radical nephrectomy.
Nephrectomy should be performed via a transperitoneal approach. The surgeon is responsible for
determining the extent of tumor. Accurate staging is essential for the subsequent determination
of the need for radiation therapy and the appropriate chemotherapy regimen. Thorough
exploration of the abdominal cavity is necessary to exclude local tumor extension, liver and
nodal metastases, and peritoneal seeding. Exploration of the contralateral kidney is no longer
mandated before nephrectomy if preoperative CT or MRI demonstrates a normal kidney (Ritchey
et al, 2005). The renal vein and IVC are palpated to exclude intravascular tumor extension before
vessel ligation. Wilms tumor extends into the IVC in approximately 6% of cases and may be
clinically asymptomatic in more than 50% (Ritchey et al, 1988; Shamberger et al, 2001). The
adrenal gland can be spared without increasing the risk for tumor spill or recurrence if it is not in
close proximity to the tumor (Kieran et al, 2013a). Selective sampling of suspicious nodes is an
essential component of local tumor staging. Formal retroperitoneal lymph node dissection is not
recommended (Othersen et al, 1990; Shamberger et al, 1999). Extensive lymph node dissection,
particularly above the renal hilum, can result in chylous ascites (Weiser et al, 2003). In a review
of NWTS-4 and NWTS-5 patients, 12.5% of patients did not have lymph node sampling
performed (Kieran et al, 2012). The likelihood of having a positive lymph node was greater if
more than seven lymph nodes were sampled, but EFS was not improved with removal of more
lymph nodes.
The other major responsibility when performing a nephrectomy for Wilms tumor is
complete removal of the tumor without contamination of the operative field. Gentle handling of
the tumor throughout the procedure is mandatory to avoid tumor spillage. A recent COG study
reported intraoperative tumor spillage in 9.7% of patients undergoing primary nephrectomy
(Gow et al, 2013). Multivariate analysis demonstrated that spillage was more common with
right-sided tumors and larger tumors. Avoiding tumor spillage has a real impact on patient
outcomes because these patients have an increase in local abdominal relapse (Shamberger et al,
1999). Shamberger and colleagues identified risk factors for local tumor recurrence as tumor
spillage, unfavorable histology, incomplete tumor removal, and absence of any lymph node
sampling (Shamberger et al, 1999). This study included both stage II and III disease. The risk of
recurrence was highest in patients with stage II disease. More recent COG studies have treated
all spill patients as having stage III disease. Review of these patients shows that the greatest risk
of recurrence in stage III disease is associated with positive lymph nodes or residual disease
(Ehrlich et al, 2013). Tumor spillage was not predictive of recurrence, likely because of the
increased therapy currently given to these patients.
There have been several reports of laparoscopic nephrectomy for Wilms tumor. This is
usually done in conjunction with preoperative chemotherapy and is likely more feasible after the
tumor is reduced in size (Duarte et al, 2009). Experience with open nephrectomy after
chemotherapy has shown that these tumors are less prone to tumor spillage (Powis et al, 2013).
Although prechemotherapy laparoscopic nephrectomy has been reported, many more procedures
will need to be performed to determine if there is an increased risk of tumor spillage, residual
disease, or surgical complications (Barber et al, 2009).
Removing a large renal tumor in a small child is associated with some morbidity. NWTS-
4 patients undergoing primary nephrectomy had an 11% incidence of surgical complications
(Ritchey et al, 1999). The most common complications encountered were hemorrhage and small
bowel obstruction (Ritchey et al, 1992, 1993a, 1999). Factors that have been associated with an
increased risk for surgical complications are higher tumor stage, tumor size greater than 10 cm,
incorrect preoperative diagnosis, thoracoabdominal incision, intracaval tumor extension, and
resection of other visceral organs.
Preoperative chemotherapy may influence surgical complication rates by producing
tumor shrinkage. A recent report from the UKCCSG compared the complication rate for patients
undergoing immediate nephrectomy versus delayed nephrectomy performed after 6 weeks of
chemotherapy (Powis et al, 2013). They found significantly fewer complications in those
undergoing delayed nephrectomy (1% vs. 5.8%). They also noted a much higher rate of tumor
rupture or spill in those undergoing immediate nephrectomy (14.6% vs. 0%). This is similar to
the rate of intraoperative tumor spill after immediate nephrectomy recently reported by the COG
(Gow et al, 2013).

Cooperative Group Trials

Multiple randomized clinical trials have been conducted by the NWTSG, COG, SIOP,
and UKCCSG to determine the appropriate role for each of the therapeutic modalities available.
Patients are stratified into different treatment groups based on stage and pathology. The goals of
these trials are to decrease the intensity of therapy for most patients in an effort to prevent late
sequelae of treatment while maintaining excellent OS. National Wilms Tumor Study Group and
Children’s Oncology Group. The NWTSG was formed in 1969 to study Wilms tumor. The early
NWTSG studies, NWTS-1 (1969 to 1973) and NWTS-2 (1974 to 1978), showed that the
combination of VCR and AMD was more effective than the use of either drug alone. The
addition of DOX was found to improve survival for stage III and IV patients, and postoperative
flank irradiation was unnecessary for stage I patients (D’Angio et al, 1976, 1981). A major
achievement of the early trials was identification of prognostic factors that allowed stratification
of patients into high-risk and low-risk treatment groups. Patients with positive lymph nodes and
diffuse tumor spill were found to be at increased risk of abdominal relapse and therefore
considered stage III and given postoperative irradiation. One of the most important findings was
the identification of the unfavorable histologic features that have a very adverse impact on
survival.
NWTS-3 (1979 to 1986) demonstrated that stage I and II patients could be treated with
18 weeks of AMD and VCR without irradiation (D’Angio et al, 1989). For stage III favorable-
histology disease, 10.8 Gy of abdominal irradiation was shown to be as effective as 20 Gy in
preventing abdominal relapse if DOX was added to VCR and AMD. NWTS-4 (1987 to 1994)
proved that treatment durations of 6 months produced comparable outcomes to 15 months of
therapy for patients with stage II to IV favorable-histology tumors (Green et al, 1998). The
NWTSG has assessed the impact of postoperative irradiation on flank recurrence and survival
(Breslow et al, 2006a; Kalapurakal et al, 2010; Green et al, 2014). The investigators found that
abdominal recurrence rates after tumor spillage were significantly higher among patients treated
with two- or three-drug chemotherapy without radiation therapy. Irradiation with 10 Gy appeared
to be successful in reducing tumor recurrence rates after tumor spillage, and 20 Gy even more so.
Although radiation did decrease the incidence of flank recurrence, there was only an increase in
OS for stage II patients with tumor spillage. This was attributed to a lower postrecurrence
mortality rate in unirradiated patients. The overall risk for relapse is low in stage II favorable-
histology disease with spillage, and one must weigh the risks of late effects of intensified
treatment versus benefit of decreased relapse (Green et al, 2014).
NWTS-5 (1995 to 2003) was a single-arm therapeutic trial. One of the major aims of the
trial was to confirm the usefulness of LOH for chromosomes 16q and 1p to predict increased risk
of tumor relapse and death (Grundy et al, 2005). Another objective was to evaluate the efficacy
of treatment regimens for AHWT. Stage I patients with anaplastic tumors were treated with
AMD and VCR, but this resulted in a low 4-year EFS of 69.5% (Dome et al, 2006). A new
intensified chemotherapy regimen used for patients with stage II to IV diffuse anaplasia did not
result in an improved survival.
In NWTS-5, children younger than 2 years with stage I favorablehistology tumors
weighing less than 550 g were defined as having very-low-risk Wilms tumor (VLRWT) and did
not receive chemotherapy after nephrectomy. This portion of the study was closed early when
the number of tumor relapses exceeded the limit allowed by the design of the study (Green et al,
2001a). A recent long-term review of this cohort was completed, comparing the outcomes with
those of similar patients treated with postoperative AMD and VCR (Shamberger et al, 2010).
The 5-year EFS for surgery alone was 84% compared with 97% for the treated group, but the 5-
year OS was equivalent between the two groups at 98% and 99%, respectively (P = .70). There is
a trade-off between more intensive therapy and the potential long-term sequelae for the 16% of
children who relapse versus the avoidance of any postoperative chemotherapy in the majority. As
noted earlier, COG investigators hope to use biologic prognostic factors to select patients who do
not require adjuvant therapy. All VLRWT patients registered in NWTS-5 who did not receive
adjuvant chemotherapy were analyzed for LOH at 11p15 and for WT1 mutation. LOH, as
determined by 11p15 methylation analysis, was significantly associated with relapse in VLRWT,
as were WT1 abnormalities (Perlman et al, 2011). If these results are validated in an independent
cohort of patients, it would be worthwhile to conduct a clinical trial that uses molecular genetic
factors rather than the arbitrarily defined clinical factors of patient age and tumor weight to
identify patients with stage I favorable-histology Wilms tumor who do not require adjuvant
therapy. It is anticipated that such a trial would expand the number of patients who would be
candidates to be treated with surgery only.
 Relapse. A uniform approach for the treatment of tumor relapse was used in NWTS-5.
Patients with relapsed Wilms tumor may be divided into risk groups according to OS rates after
salvage therapy (Spreafico et al, 2009). Children with nonanaplastic Wilms tumor who relapse
after therapy with only VCR and/or AMD are considered at standard risk and have survival rates
in the 70% to 80% range (Green et al, 2007). Patients with nonanaplastic Wilms tumor who
relapse after therapy with three or more agents are defined as having high risk and have survival
rates in the 40% to 50% range (Malagolowkin et al, 2008). The very-high-risk group includes
recurrent anaplastic or blastemal-type Wilms tumor; these patients have survival rates in the 10%
range (Reinhard et al, 2008).
The first generation of COG studies (2006 to 2013) grouped patients by risk for
recurrence (very low, low, standard, and high). The COG again examined the role of surgery-
only treatment for patients with stage I favorable-histology Wilms tumor in which the tumor and
kidney weighed less than 550 g and patient age was below 2 years. Children with stage I or II
favorable-histology Wilms tumor and LOH of 1p and 16q were treated with VCR, AMD, and
DOX without radiotherapy. Patients with stage III favorablehistology Wilms tumor disease
without LOH of 1p and 16q were treated with VCR, AMD, and DOX and irradiation of the flank
or abdomen. The COG evaluated a response-based approach for management of children with
pulmonary metastases. Those with resolution of the pulmonary lesions on chest CT after 6 weeks
of chemotherapy were continued on treatment with VCR, AMD, and DOX. Patients who did not
have resolution of the pulmonary lesions by week 6 received more intensive chemotherapy and
pulmonary irradiation. Children with stage I to III focal AHWT and stage I diffuse AHWT were
treated with AMD, VCR, DOX, and abdominal irradiation. Patients with stage II, III, or IV (no
measurable disease) diffuse AHWT, stage IV focal AHWT, stage IV clear cell sarcoma, or stage
I to III malignant rhabdoid tumor were treated with a new chemotherapy regimen to try to
improve OS. All of the COG studies are closed to patient accrual with the exception of the renal-
sparing study (see later).
Wilms tumor occasionally occurs in adults. Earlier reports suggested that the outcome for
adults with Wilms tumor was poor and that they require more intensive therapy (Arrigo et al,
1990). More recent reviews of adult patients with favorable-histology Wilms tumor have found
improved survival compared with prior reports (Kalapurakal et al, 2004a; Reinhard et al, 2004a;
Ali et al, 2012). The recommendation is that adult patients receive stage-appropriate combined-
modality therapy.
International Society of Paediatric Oncology. In the randomized clinical trials conducted
by SIOP, preoperative therapy is given before surgery. This approach usually results in tumor
shrinkage (Fig. 155-10), reducing the risk of intraoperative rupture or spill (Lemerle et al, 1976).
A greater number of patients have post-chemotherapy stage I tumors as a result of disappearance
of micrometastases after neoadjuvant therapy. This was thought to be a significant advantage in
terms of decreasing morbidity of treatment, particularly the late effects of radiotherapy.
Early SIOP studies evaluated prenephrectomy radiation therapy (Lemerle et al, 1976).
SIOP-5 (1976 to 1980) showed that use of 4 weeks of AMD and VCR was as effective as
prenephrectomy radiation therapy in avoiding surgical tumor rupture and increasing the
proportion of patients with low-stage disease (Lemerle et al, 1983). SIOP-6 (1980 to 1987)
demonstrated that patients with postchemotherapy stage I disease can safely be treated with 18
weeks of AMD and VCR (Tournade et al, 1993). However, patients with postchemotherapy
stage II tumors and negative lymph nodes were found to have a higher rate of abdominal relapse
if postoperative irradiation was omitted (Tournade et al, 1993). An anthracycline was
subsequently added for treatment of these children. SIOP-6 confirmed the need for a three-drug
chemotherapy regimen after nephrectomy for patients with postchemotherapy stage II lymph
node positive and stage III tumors. SIOP-9 (1987 to 1993) demonstrated that the relapse rate for
stage II patients with negative lymph nodes without radiation therapy was reduced with
epirubicin (Tournade et al, 2001). This study also demonstrated that treatment with VCR and
AMD for 4 weeks versus 8 weeks had comparable rates of stage distribution and tumor
shrinkage in patients with stage I to III disease. The majority of tumor shrinkage was noted in the
first 4 weeks of therapy. Radiotherapy was limited to patients with stage II node-positive and
stage III disease, resulting in 18% of patients being irradiated (Graf et al, 2000). There were 59
children with stage I to -IV tumors who had complete tumor necrosis induced by chemotherapy,
and 98% of these children had no evidence of disease at 5 years (Boccon-Gibod et al, 2000).
The SIOP 93-01 study (1993 to 2001) evaluated a reduction in postoperative therapy for
patients with stage I intermediate risk and anaplastic Wilms tumor (de Kraker et al, 2004;
Reinhard et al, 2004b; Graf et al, 2012). Patients were randomized to receive either 4 or 18
weeks of postoperative chemotherapy with AMD and VCR. Two-year EFS was 91.4% after 4
weeks and 88.8% after 18 weeks of therapy, demonstrating that survival can be maintained while
shortening the duration of postnephrectomy therapy. Patients with stage II or III disease with
low- or intermediate-risk histology received 4 weeks of AMD and VCR before surgery.
Postoperative chemotherapy consisted of AMD, VCR, and epirubicin/DOX for 27 weeks. Flank
or whole-abdomen irradiation was given for stage III disease. With a median follow-up of 8
years, 5-year EFS was 90% and OS was 95%. Patients with blastemal-type histology had a worse
prognosis, with 62% EFS at 5 years. They comprised only 10% of patients but contributed to one
third of the relapses and deaths. The other important prognostic factors were a large tumor
volume at surgery and stage III disease.
The SIOP 2001 study asked whether patients with stage II or III intermediate-risk
histology Wilms tumors could be safely treated without an anthracycline. Data from SIOP 93-01
had suggested that survival was not adversely affected when nonviable tumor was identified in
the renal sinus and/or perirenal fat after preoperative chemotherapy (Vujanic et al, 2009). A total
of 583 patients were randomized from 2001 to 2009 (Pritchard-Jones et al, 2011). For stage II or
stage III intermediate-risk histology Wilms tumor, there was no significant disadvantage in
removing DOX from postoperative chemotherapy. The SIOP group now recommends 6 months
only of VCR and AMD rather than a three-drug regimen including DOX. This will significantly
reduce the number of children receiving this cardiotoxic drug.
United Kingdom Children’s Cancer Study Group. The UKCCSG has conducted several
trials using prenephrectomy chemotherapy, but, unlike SIOP, this group performed biopsy before
treatment (Pritchard et al, 1995; Mitchell et al, 2000; Pritchard-Jones et al, 2003). This is done to
avoid giving chemotherapy to infants and children with benign tumors, which account for 1% of
lesions thought to be Wilms tumor on imaging studies (Tournade et al, 2001). The other reason
to perform biopsy is to avoid giving inappropriate chemotherapy to non-Wilms tumors, which
often require more intensive therapy. The UKW3 trial noted a 12% incidence of non-Wilms
tumors in patients with the typical features of Wilms tumor on imaging studies (Vujanic et al,
2003). The UKW1 and UKW2 studies evaluated the single agent VCR for treatment of stage I
favorable-histology tumors (Pritchard et al, 1995; Mitchell et al, 2000). The OS of 96%
compares well with two-drug chemotherapy, but age greater than 4 years was considered an
adverse prognostic factor (Pritchard-Jones et al, 2003).
The UKW3 trial randomly assigned patients to either immediate surgery or to 6 weeks of
preoperative chemotherapy and then delayed surgery (Mitchell et al, 2006). EFS and OS at 5
years were similar in the two groups. Around 20% of survivors avoided treatment with DOX or
radiotherapy as a result of favorable stage distribution after preoperative therapy. The researchers
concluded, like the SIOP group, that all children with nonmetastatic Wilms tumorshould receive
chemotherapy before tumor resection.

Preoperative Chemotherapy (Children’s Oncology Group Recommendations)

On the COG renal tumor protocols, treatment is dependent on surgical and pathologic
staging after immediate nephrectomy. There are, however, some situations wherein preoperative
chemotherapy is recommended. These include children for whom renal-sparing surgery is
planned (Blute et al, 1987), tumors inoperable at surgical exploration (Ritchey et al, 1994), and
tumor extension into the IVC above the hepatic veins (Ritchey et al, 1993b; Shamberger et al,
2001; Szavay et al, 2004). The last two conditions are associated with an increased risk for
surgical complications if primary nephrectomy is performed (Ritchey et al 1992).
Inoperable Tumors. The surgeon, not the oncologist or radiotherapist, must make the
determination that a tumor is inoperable. This decision should not be based on preoperative
imaging studies, which can overestimate local tumor extension. As noted earlier, not all renal
masses in children represent Wilms tumor (Vujanic et al, 2003; Reinhard et al, 2004b). If the
tumor is found to be unresectable, pretreatment with chemotherapy almost always reduces the
bulk of the tumor and renders it resectable (Ritchey et al, 1994; Grundy et al, 2004). Patients
who are staged with imaging studies alone and receive preoperative chemotherapy before
nephrectomy are also at risk for understaging (Tournade et al, 1993). A patient determined to
have an inoperable tumor should be considered to have stage III disease and should be treated
accordingly (Ritchey et al, 1994).
Repeat imaging is performed after 6 weeks of chemotherapy. Experience in SIOP has
shown that the majority of reduction (48%) in tumor volume occurs in the first 4 weeks of
therapy (Tournade et al, 2001) but that reduction extends out through 8 weeks (62%). After there
has been adequate shrinkage of the tumor, definitive resection can usually be completed. A
clinically good response (by imaging) is usually associated with a pathologically good response
in terms of regressive histologic changes (Zuppan et al, 1991; Weirich et al, 2001). The converse
is not always true. The distribution of histologic subtypes is different after preoperative
chemotherapy compared with primary surgery, with differentiation of the tumor occurring after
chemotherapy. Stromal- and epithelialpredominant tumors are found more often after treatment
with preoperative chemotherapy. These histologic subtypes may demonstrate a poor clinical
response to therapy but have an excellent prognosis if the tumor is completely excised. Patients
with progressive disease have a poor prognosis, and these patients will require treatment with a
more intensive chemotherapeutic regimen (Ritchey et al, 1994; Ora et al, 2007).
Bilateral Wilms Tumors. Synchronous bilateral Wilms tumors occur in 5% to 7% of
children with Wilms tumor (Blute et al, 1987; Coppes et al, 1989; Montgomery et al, 1991).
Children with bilateral tumors should not undergo initial radical nephrectomy. These children
should receive preoperative chemotherapy with the goal of tumor shrinkage and renal-sparing
surgery (Blute et al, 1987; Coppes et al, 1989; Kumar et al, 1998; Hamilton et al, 2011).
Preservation of renal tissue is important to decrease the incidence of renal failure, which
approaches 15%, at 15 years after treatment in patients with bilateral Wilms tumor (Ritchey et al,
1996; Breslow et al, 2005). The most common cause for renal failure was the need for bilateral
nephrectomy for persistent or recurrent tumor in the remaining kidney after initial nephrectomy.
Complete nephrectomy can be avoided in the majority of patients if a careful protocol is
followed and the surgery is performed by surgeons experienced in renal-sparing techniques
(Davidoff et al, 2008; Fuchs et al, 2011).
The current COG protocol for patients with bilateral Wilms tumor recommends 6 weeks
of chemotherapy before surgery. Biopsy is not needed if the radiographic picture is consistent
with Wilms tumor. Tumor response is assessed after 6 weeks with CT or MRI to determine the
reduction in tumor volume and feasibility of partial resection. Patients with tumors amenable to
renal-sparing procedures can proceed with surgery. Imaging cannot, however, predict the
histology of the tumor based on changes in volume of the tumor after chemotherapy (Weirich et
al, 2001; Olsen et al, 2004). Tumors not responding to therapy require bilateral open biopsy to
determine histology. Open biopsies are recommended because they are more accurate than
percutaneous needle biopsies when assessing for anaplasia, and bilateral biopsies are recommend
because anaplasia is found to be discordant between the two kidneys in 83% of children
(Hamilton et al, 2006). Failure to achieve a reduction in volume is likely a result of tumor
differentiation (Fig. 155-11) (Weirich et al, 2001; Anderson et al, 2002; Shamberger et al, 2006).
Differentiated tumors may show a poor clinical response to therapy, but they have an excellent
prognosis if the tumor is completely excised. If renal-sparing surgery is not feasible, additional
chemotherapy is then given based on the biopsy findings, but all patients should proceed to
surgical resection within 12 weeks of starting therapy. Continuing treatment beyond 12 weeks
will not likely provide any additional reduction in tumor burden.
At the time of second-look surgery, partial nephrectomy or wedge excision of the tumor
is preferred with an attempt to achieve negative margins. The kidney with the lower tumor
burden is addressed first. Tumor enucleation may be considered in lieu of a formal partial
nephrectomy. This is often needed for large centrally located tumors when removal of a margin
of renal tissue would compromise the vascular supply to the kidney (Cozzi et al, 1996; Horwitz
et al, 1996). The concern is that enucleation will be more likely to result in positive surgical
margins. For favorable-histology tumors, adjuvant therapy may still achieve a good outcome
(Cozzi et al, 1996; Horwitz et al, 1996; Davidoff et al, 2008). However, if there is anaplasia in
the resected specimen, a positive margin will adversely affect survival and requires additional
resection. Even when large bilateral masses remain after initial chemotherapy, a high percentage
of children can be successfully managed with renalsparing surgery (Davidoff et al, 2008). It is
easy to underestimate the amount of renal parenchyma that can be salvaged as a result of
compression by the tumor; therefore nephron-sparing surgery should be considered in all patients
(Fig. 155-12). One concern regarding enucleation of large centrally located tumors is the
potential for positive surgical margins. Kieran and colleagues reported a 23% incidence of
positive surgical margins in a cohort of 21 patients with bilateral Wilms tumor undergoing renal-
sparing surgery (Kieran et al, 2013b). They did not demonstrate an increased risk of local
recurrence, but this was a small number of patients, with all receiving 10.5-Gy flank radiation.
Radical nephrectomy may be needed in a kidney with extensive tumor involvement.
Bilateral nephrectomies and dialysis are rarely required when the tumors fail to respond to
chemotherapy and radiation therapy. This is the most common cause of renal failure in patients
with bilateral Wilms tumor (Ritchey et al, 1996). Fortunately, anephric patients can still be
administered chemotherapy with some modifications (Feusner et al, 2008). The recommended
interval between successful completion of treatment of the Wilms tumor and renal
transplantation varies (Penn, 1979; Kist-van Holthe et al, 2005). Some advocate a waiting period
of 2 years to ensure that the patient does not develop metastatic disease; others have found that a
1-year interval is sufficient (Gregoriev et al, 2012). Patients who develop renal failure after
renal-sparing surgery should have removal of the remaining renal tissue before transplant to
prevent tumor recurrence after starting immunosuppression (Kubiak et al, 2004).
All patients treated for bilateral Wilms tumor require close longterm follow-up. SIOP
investigators noted that late relapses have occurred in patients with bilateral Wilms tumor more
than 4 years after treatment and recommended long-term follow-up (Coppes et al, 1989). These
patients should also have frequent assessment of renal function, urine protein, and blood
pressure.
Partial Nephrectomy for Unilateral Tumors. Several centers have explored the role of
parenchymal-sparing procedures in children with unilateral Wilms tumors (McLorie et al, 1991;
Cozzi et al, 1996; Moorman-Voestermans et al, 1998; Haecker et al, 2003; Linni et al, 2003;
Zani et al, 2005). The primary motivation for this approach is concern about late occurrence of
renal dysfunction after unilateral nephrectomy. However, the incidence of renal failure after
nephrectomy for most children with unilateral Wilms tumor is low, 0.6% at 20 years after
treatment (Breslow et al, 2005; Lange et al, 2011). The risk of renal failure is higher for patients
with genitourinary anomalies, DDS, and WAGR. As noted earlier, this is a result of mutation of
WT1, which is necessary for normal renal development. Syndromic patients are more likely to
have smaller tumors identified on screening studies that are more amenable to renal-sparing
surgery (Romao et al, 2012).
 Most Wilms tumors are too large at diagnosis to allow partial nephrectomy. After
preoperative chemotherapy, partial nephrectomy can be performed in 10% to 15% of patients.
Only the occasional child with Wilms tumor will have a lesion small enough to allow partial
nephrectomy at diagnosis—for example, tumors detected on screening studies for Beckwith-
Wiedemann syndrome and aniridia (see Fig. 155-6). As noted earlier, there are concerns
regarding staging after chemotherapy, requiring some patients to receive added therapy to
prevent local recurrence. Another concern is the increased risk for local recurrence after partial
nephrectomy (Horwitz et al, 1996; Haecker et al, 2003). Patients who develop intra-abdominal
relapse have a markedly decreased survival (Shamberger et al, 1999).
The COG is conducting a renal-sparing protocol for select patients with unilateral Wilms
tumors known to be at risk for bilateral disease or at increased risk for renal failure. These
patients are managed with a strict surgical protocol to minimize risk for residual disease (Cozzi
et al, 2004). The lesion should be completely excised with a margin of normal renal parenchyma.
These patients should not undergo partial nephrectomy if the tumor cannot be removed at stage I.
Patients with high-risk histologic patterns such as anaplasia or persistent blastemal-predominant
tumor after chemotherapy should be treated with complete nephrectomy because these tumors
have resistance to chemotherapy (Reinhard et al, 2008).

Late Effects of Treatment

Numerous organ systems are subject to the late sequelae of anticancer therapy. Clinicians
must be aware of the spectrum of problems that face children as they grow into adulthood. Our
understanding of late effects in Wilms tumor survivors has been advanced through two large
studies. The Childhood Cancer Survivor Study (CCSS) is a retrospectively ascertained cohort of
20,346 childhood cancer survivors diagnosed from 1970 to 1986. The CCSS reported a
cumulative incidence of 65% for all chronic health conditions in Wilms tumor survivors at 25
years after completion of therapy (Termuhlen et al, 2011). The cumulative incidence of severe
(grades 3 or 4) chronic health conditions was 24% (Termuhlen et al, 2011). The NWTSG Late
Effects Study followed patients treated in NWTS-1 to NWTS-5. Despite the greatly improved
therapy for Wilms tumor over time, the NWTSG Late Effects Study showed that survivors
remain at elevated risk for death compared with the general population for many years after their
original diagnosis (Cotton et al, 2009).

Fertility and Pregnancy

Gonadal radiation can produce hypogonadism and temporary azoospermia in boys
(Kinsella et al, 1989). The severity of damage is radiation dose dependent. The Leydig cells are
more radioresistant than the germ cells, but higher doses can produce damage resulting in
inadequate production of testosterone. This can result in delayed sexual maturation.
Chemotherapeutic agents can also adversely affect testicular function (Mustieles et al, 1995).
Pelvic irradiation and exposure to alkylating agents are risk factors for ovarian failure and
premature menopause in female Wilms tumor survivors (Green et al, 2009). Very few
pregnancies have been reported in patients who received whole abdominal radiation therapy
(Green et al, 2010). Pregnancy complications were evaluated extensively through the NWTSG.
The offspring of irradiated female patients are at risk for low birth weights and premature birth.
Radiation portals that include the pelvis and doses exceeding 20 Gy increase the risk of
miscarriage (Kalapurakal et al, 2004b).

Second Malignancies
An increased incidence of second malignant neoplasms has been noted in children treated
for Wilms tumor. There is a 1% cumulative incidence at 10 years post-diagnosis, and a rising
incidence thereafter (Breslow et al, 1988b; Taylor et al, 2008; Breslow et al, 2010). One of the
greatest risk factors is prior irradiation, and most tumors occur in the radiation field (Breslow et
al, 1988b; Bassal et al, 2006; Taylor et al, 2008). The incidence of leukemia is highest during the
first 5 years after Wilms tumor treatment. The incidence of solid tumors increases fivefold from
age 15 years to age 40 years.

Cardiac Effects
The risk of cardiotoxicity in Wilms tumor survivors has been carefully studied. In a
review of patients entered in NWTS-1, NWTS-2, NWTS-3, and NWTS-4, the frequency of
congestive heart failure was 4.4% among DOX-treated patients who received this drug as part of
their initial chemotherapy regimen (Green et al, 2001b). The risk was increased if the patient
received whole-lung or left-flank irradiation. Of note, only one patient with congestive heart
failure received a DOX cumulative dose below 150 mg/m2, which is used in contemporary
North American treatment regimens. However, subclinical cardiotoxicity was not assessed, and it
is possible that clinical effects with modern regimens will become apparent with longer follow-
up.