This document summarizes findings from a review of 66 studies comparing outcomes of nephron sparing surgery (NSS) versus radical nephrectomy (RN) for Wilms' tumor in children. The studies included data from 4022 patients, 1040 of whom underwent NSS. NSS was associated with smaller tumor sizes but a higher rate of neoadjuvant chemotherapy use compared to RN. Reported rates of tumor rupture, recurrence, end stage renal disease, and overall survival were similar between the two surgical approaches. Outcomes have improved over time for both RN and NSS. While NSS appears to provide comparable oncologic outcomes to RN, limitations in the available data prevent direct comparison between the surgical techniques.

1. NEPHRON SPARING SURGERY
(NSS) IN WILMS’ TUMOR
DR ARKA BANERJEE
M.CH. RESIDENT
PAEDIATRIC SURGERY
MAMC
MODERATOR: DR S. S. PANDA

2. SIOP
Multicentre experience (Prospective)
To review the current SIOP NSS-experience with special emphasis on the risk of upstaging the tumor due to the
surgical technique used
Level of evidence – 2

3. INTRODUCTION
Most frequently occurring malignant pediatric tumor of the kidney
Bilateral – 5%
Goal of NSS: To preserve as much parenchymal reserve capacity as possible, whilst still achieving
complete surgical excision with adequate margins (to protect the patient from excessive renal
parenchymal loss in case of future contra lateral trauma or metachronous WT)
Standard procedure for uWT: Total Nephrectomy
Current therapeutic strategy (for bilateral tumors): NACT f/b Partial nephrectomy

4. INTRODUCTION
Most frequently occurring malignant pediatric tumor of the kidney
Bilateral – 5%
Goal of NSS: To preserve as much parenchymal reserve capacity as possible, whilst still achieving
complete surgical excision with adequate margins (to protect the patient from excessive renal
parenchymal loss in case of future contra lateral trauma or metachronous WT)
Standard procedure for uWT: Total Nephrectomy
Current therapeutic strategy (for bilateral tumors): NACT f/b Partial nephrectomy
Successful

5. METHODS
Nov, 2001 to July, 2012
3320 uWT
Case report forms
◦ Nephrectomy procedure
◦ Surgical approach
◦ Tumor appearance
◦ Involvement of adjacent structures
◦ Extent of resection (complete or incomplete)
◦ Summary of operative procedure (biopsy only, total nephrectomy or nephron sparing surgery)
◦ Surgical complications
◦ Pathology information – local pathologist and central review
◦ Histological subtype
◦ Tumor stage

6. METHODS
Tumors were staged according to the SIOP trials criteria
All patients had neo-adjuvant chemotherapy and delayed surgery followed by risk-adapted post-op
chemotherapy (and radiotherapy in stage III)
Pre-operative treatment
◦ Localized tumors – VA × 4 wks
◦ Weekly Vincristine (1.5 mg/m2)
◦ 2-weekly Actinomycin D (45 μg/m2)
◦ Metastatic tumors – VAD × 6 wks
◦ Weekly Vincristine (1.5 mg/m2)
◦ 2-weekly Actinomycin D (45 μg/m2)
◦ Doxorubicin (2 doses of 50 mg/m2)
The results between the two surgical treatment groups compared
◦ Complications
◦ Local recurrence
◦ FYS (5 year-survival) rates
Special emphasis was put to analyze the potential adverse influence of NSS on staging

7. STATISTICS
Patient characteristics, such as operative complications, were compared using Fisher exact tests
The association between stage distribution and the type of resection was tested with Cochran Armitage test
Wilcoxon-Mann Whitney test was used to test for differences in median volume at diagnosis and volume at surgery.
Survival curves were presented according to the Kaplan-Meier method
Event free survival (EFS): Time from the date of diagnosis to first documented disease progression/recurrence/death (of
any cause)
Overall survival (OS): Time from the date of diagnosis to death of any cause
Patients without an event (death) were censored at the date that they were last known to be alive
Time to event endpoints was compared using log-rank tests.

8. RESULTS
3320 pts with uWT recorded
◦ 2800 (84%) had an unequivocal surgical resection
◦ Type of surgery
◦ TN – 2709 (97%)
◦ NSS – 91 (3%)
◦ Partial Nephrectomy – 62 (68%)
◦ Wedge resection – 20 (22%)
◦ Enucleation – 4 (4%)
◦ Technical information missing concerning the type of NSS – 5 (5%)
◦ Disease
◦ Localized – 2377
◦ Metastatic – 423
◦ 2 (<1%) underwent NSS

9. RESULTS
Median F/U – 43 mts
◦ TN – 49.1 mts
◦ NSS – 36.9 mts
Tumor capsule rupture (No significant difference)
◦ TN – 3%
◦ NSS – 2%
Lymph node rupture – 3% (in both)
Surgical complications (No significant difference) p = 0.052
◦ TN – 137/2709 (5%)
◦ NSS – 9/91 (10%)
Type of complications – similar in both groups

10. RESULTS: STRATIFICATION
Post op staging
Histologic risk grouping – equally distributed in both groups
◦ All 11 patients in NSS group with high risk histology were blastemal type
STAGE TN NSS
I 1294 (48%) 59 (65%)
II 638 (24%) 13 (14%)
III 712 (26%) 12 (13%)
Missing 65 (2%) 7 (8%)

11. RESULTS: TUMOR VOLUME
Tumor volumes were significantly lower in NSS
◦ At diagnosis p < 0.001
◦ At surgery p < 0.001

12. RESULTS: NSS for Stage III tumor
12 pts in NSS group had Stage III tumor
◦ Positive margins (M+) – 8/12 (67%)
◦ 5 were M+ LN–
◦ 2 were M+ LN– but also had a tumor rupture
◦ 1 was LN positive (M+ LN+) – underwent enucleation Positive margin could be avoided with TN
◦ LN positive (M –LN+) – 3/12
◦ Rupture alone (M– LN–) – 1/12
Treatment of M+ in NSS group
◦ Conversion to TN – 3 (1 received RT also)
◦ Radiotherapy only – 3
◦ Local therapy, if given, not recorded – 2

13. RESULTS: TN for Stage III tumor
712 pts in TN group had Stage III tumor
◦ Positive margins (M+) – 355/712 (50%) [Tumor reaching the inked surface of resected specimen]
◦ 187 were M+ LN–
◦ 66 were M+ LN– but also had a tumor rupture
◦ 102 were M+ LN+
◦ 22/102 had a tumor rupture also
◦ LN positive (M– LN+) – 193
◦ 22 were M– LN+ and had tumor rupture also
◦ Rupture alone (M– LN–) – 50
◦ Reason unknown – 92

14. RESULTS: RELAPSE
Tumor relapse
◦ TN – 344 (13%)
◦ NSS – 4 (4%)
Relapse at primary site
◦ TN – 49 (2%)
◦ NSS – 1 (1%)
Relapse at primary site as well as at other sites
◦ TN – 47 (2%)
◦ NSS – 1 (1%) M+LN– with major intra-op rupture; treated with post-op RT and alive till date

15. RESULTS: SURVIVAL
Survival after NSS
◦ OS – 100
◦ EFS – 94.9
Survival after TN
◦ OS – 91.9 p=0.02
◦ EFS – 84.1 p=0.02
Survival after NSS in localized disease
◦ OS – 100
◦ EFS – 94.8
Survival after TN in localized disease
◦ OS – 94.4 p=0.06
◦ EFS – 86.5 p=0.06

16. DISCUSSION
First protocolized prospective experience with the use of NSS in the treatment of uWT
3% of all patients were subjected to NSS (Expected no of eligible pts: 5–10%)
◦ Reflects the surgeons’
◦ adherence to protocol which states that partial nephrectomy is not recommended in a classical unilateral WT (not associated with
a WT-predisposition syndrome)
◦ prudence to apply a relatively new surgical technique to uWT
Highly selective subgroup of patients treated with NSS
◦ Higher proportion of stage I tumors and smaller proportion of stage III tumors when
compared to those that underwent a TN
◦ Significantly smaller tumor volumes both at diagnosis and at surgery
Protocol guidelines stating that NSS should be restricted to small, polar or peripherally non-
infiltrating tumors were adhered to quite strictly

17. DISCUSSION
Rupture rate (2-3%) – not influenced by the surgical technique
More complications occurred in the NSS group (10% vs. 5% occurring in the TN group) – not
significant
◦ Expectation: different types of complications for the two surgical techniques
◦ Reflects the limitations of the standard surgical record form rather than the similarity of the
complications
No difference in EFS and OS between NSS and TN once tumor stage had been taken into
consideration
◦ Larger percentage of patients with metastatic disease in the TN group may explain the apparent
difference in favor of NSS

18. RECOMMENDATIONS
NSS – feasible and safe, provided recommendations on suitable tumor
configuration are adhered to
Although the low (4%) relapse rate did not contribute to mortality, one must remain
aware of the potential pitfalls that could threaten the patient
◦ The surgeon cannot predict the nodal status or histological subtype and positive nodes can
come as a surprise (although especially in small tumors that are eligible for NSS, lymph nodes
usually are tumor negative)
◦ In patients with positive nodes, the kidney remnant will be subjected to radiotherapy that
may hamper the future function of the remaining nephrons so carefully strived to secure
But what about patients with negative lymph nodes who became stage III due to a
positive surgical margin?
◦ Should usually receive radiotherapy which may not have been required if complete surgical
clearance had been achieved through total nephrectomy

19. RECOMMENDATIONS
Positive surgical margins may also occur after TN
◦ Reflects tumor growth outside the capsule or the surgical procedure
Goal of NSS is to preserve renal function without compromising complete tumor
resection – What is the effect of additional radiotherapy on the long term function
of the kidney remnant?
◦ Some papers point to an adverse effect of RT to the contra-lateral kidney whilst others report
the preservation thereof after radiotherapy of the kidney remnant
◦ The SIOP 2001 protocol dictates radiotherapy to the tumor bed in case of positive margins,
positive lymph nodes and/or tumor spill
◦ Insufficient evidence to know whether additional surgical therapy on top of the radiotherapy
is superior to radiotherapy alone

20. CONCLUSION
Nephron Sparing Surgery, a new approach for uWT has now been shown to be safe in a small
and highly selected proportion of uWT patients – concordant with the intention of the SIOP
2001 protocol
The event-free and overall survival after NSS appears to be as good as after Total Nephrectomy
in the patient group not skewed by metastatic disease with an equal local relapse rate as after
TN
The gain of nephrons after NSS still needs to be carefully weighed against the potential risk of
inducing stage III with the consequence of abdominal radiotherapy

21. COG
Qualitative non-pooled systematic review
Level of evidence: 1

22. INTRODUCTION
Most common solid renal malignancy in children
Estimated annual incidence rate – 7 to 10 cases per million (<15 years age group)
Bilateral WT – 5-7% of children with renal tumors
Mx – Multimodality therapy, including radical nephrectomy via a transperitoneal approach
Historically, nephron-sparing surgery (NSS) was reserved for bilateral WT or children with a
solitary kidney in whom preservation of renal function was mandatory
◦ Major challenge in these children was to preserve renal function while adequately treating the tumors
Mx of bilateral WT – NACT f/b Radical nephrectomy (RN) of the more involved kidney and NSS
on the less involved contralateral kidney
◦ Bilateral WT patients have been noted to have a significant risk of ESRD due to perioperative renal
insults in addition to tumor recurrence and subsequent nephrectomy

23. INTRODUCTION
Modern management of bilateral WT – NACT f/b NSS (first-line treatment)
Bilateral and/or syndromic WT protocol for COG
◦ 6 to 12 weeks of vincristine, dactinomycin, and doxorubicin prior to resection
◦ Following surgery, adjuvant chemotherapy and radiation therapy regimen depending on tumor histology and
staging
AREN0534 trial of COG encourages NSS in children with
◦ Bilateral WT
◦ Unilateral WT in children with syndromes which predispose to renal failure
◦ Metachronous development of WT in the contralateral kidney
Objective
◦ To examine the accumulated literature on the use of NSS among children with WT, both unilateral and bilateral
Aim
◦ Assess the reported outcomes of NSS
◦ Compare these to the current gold standard surgical treatment of WT, RN

24. METHODS
Electronic databases searched for studies published between 1980-2014 based upon PRISMA
guidelines
Restricted to articles retrieved under a second search for the terms “pediatric” or “child” or
“children”
Reference lists of included studies were manually screened for any additional studies
Manual search for unpublished abstracts presented at relevant scientific meetings
Included English-language studies of children (aged  18 yrs) diagnosed with Wilms tumor that
compared the outcomes or effects of NSS vs. RN
Two reviewers independently reviewed all study abstracts in duplicate with disagreements resolved
by the senior author
Full text articles appearing to meet selection criteria were reviewed and study data was abstracted

25. RESULTS
694 publications identified with an
additional 3 reports
◦ 118 studies were selected for full text review
◦ Exclusions
◦ 15 studies due to a focus on disease other than Wilms’
tumor
◦ 5 due to inability to extract out pediatric specific data
◦ 18 due to duplicate reporting or review of previous reports
◦ 15 due to insufficient reporting of data on RN and NSS
patients
◦ Total 66 studies met all criteria and were
included in the final review
◦ 60 (91%) – retrospective cohorts/case series (including an
administrative database analysis)
◦ 6 (9%) – prospective data

26. RESULTS: PATIENT COHORT
4022 patients
◦ M – 1632 (41%)
◦ Ages - < 1 mt to 18 yrs
◦ B/L – 1153 (29%)
◦ Including 4 metachronous contralateral tumours
◦ Mean size
◦ RN – 5-14 cm
◦ NSS – 1.5-9 cm
◦ NSS done in
◦ 1040 (26%) patients
◦ 1311 (32%) kidneys
◦ RN done in
◦ 2962 (74%) patients
◦ 2844 (68%) kidneys
◦ NACT given in
◦ 195 (7%) of RN pts
◦ 248 (24%) of NSS pts

27. RESULTS: STRATIFICATION
Variably reported
B/L WT
◦ Local stage infrequently reported
◦ Discordant local staging per kidney
Histology (similar between RN and NSS groups)
SURGERY STUDIES FAVORABLE UNFAVORABLE
Aggregate (RN/NSS) 24 86 % 14%
RN 2 92 % 8 %
NSS 8 94 % 6 %

28. RESULTS: STRATIFICATION
Tumor stage
◦ Patients chosen for NSS were more likely to have a lower-staged tumor than those undergoing RN
More uniform reporting standards would help elucidate the extent to which histology and stage
impact outcome and how they should be implemented in patient selection
SURGERY STUDIES STAGE I STAGE II STAGE III STAGE IV STAGE V
Aggregate
(RN/NSS)
21 33 % 37 % 19 % 5 % 7 %
RN 7 34 % 31 % 20 % 15 % -
NSS 14 49 % 32 % 18 % 0.6 % 1 %

29. OUTCOMES
Presented variably
◦ Direct comparison of outcomes data could not be performed
SURGERY
TUMOR RUPTURE RECURRECNCE ESRD OS
Studies
Mean
(Range)
Studies
Mean
(Range)
Studies
Mean
(Range)
Studies
Mean
(Range)
RN 3
13 %
(0 – 40 %)
14
12 %
(0 – 38 %)
12
8 %
(0 – 50 %)
24 85 %
(50 – 100 %)
NSS 7
7 %
(0 – 25 %)
33
11 %
(0 – 60 %)
28
3 %
(0 – 18 %)
35 88 %
(35 – 100 %)

30. OUTCOMES
Improved outcomes over time
SURGERY 1980s 2010s
RN 61 % 99 %
NSS 87 % 93 %

31. DISCUSSION
Most studies detailing outcomes of surgical techniques for resection of WT were retrospective cohorts and case series
Most current studies of RN and NSS patients appear to show similar tumor rupture, recurrence, ESRD and OS outcomes
between the 2 techniques
◦ Selection bias: Patients chosen for NSS are likely to be different than the average RN patient
◦ Reporting bias: Poor results with a new or controversial technique (such as NSS) are less likely to be reported than poor results with a
well-established technique (such as RN)
An RCT of RN vs. NSS would thus be likely to have a significant impact on modern management of WT
◦ Logistical issues
Adult RCC – Recent publications suggest that NSS provides a risk reduction in
◦ All cause mortality
◦ Cancer specific mortality
◦ Severe chronic kidney disease
*Supported by a systematic review which drew the same conclusion regarding malignant renal tumors less than 4.0 cm

32. DISCUSSION
Why NSS in uWT?
◦ Prospectful data from adult studies
◦ Increasing familiarity of surgeons/urologists with NSS
◦ ESRD was the 2nd most common cause of death among WT survivors (after cardiovascular causes)
◦ Only relevant in the context of successful cancer treatments
◦ Implies that the theoretical benefits of NSS must be considered against any potential risks in terms of
◦ Cancer recurrence
◦ EFS (event-free survival) from tumor spill or positive margins
4thNational Wilms’ Tumor Study
◦ Intraoperative tumor spill nearly doubled their risk of death (HR 1.94) as compared to patients without tumor spill
SEER, SIOP and COG
◦ Relatively few patients currently undergo NSS
◦ Benefits of NSS clearly need to be weighed against the potential downside risks of compromised oncologic outcomes
in the name of improved nephron counts

33. DISCUSSION: CHALLENGES
Technical considerations of removing a large tumor from a small kidney
◦ Is tumor enucleation alone sufficient?
◦ Is a margin of normal parenchyma required
◦ If yes, how much margin is required?
Longo et al – compared simple enucleation and partial nephrectomy for T1 renal masses; enucleation
was associated with
◦ Similar warm ischemia time
◦ Lower intraoperative blood loss
◦ Shorter operative time
◦ Decreased risk of positive surgical margins
Kieran et al – positive margins did not impact survival in patients with bilateral WT undergoing NSS
◦ Small study – 21 patients total, only 5 of whom had positive margins
◦ Patients with positive margins also underwent additional confounding therapy in the form of flank irradiation

34. DISCUSSION: CHALLENGES
Training issues in the use of NSS
◦ Most WT are treated by pediatric surgeons who may or may not have been trained in the use of NSS
during their residency or fellowship
◦ Ritchey et al –reported significant quality differences between pediatric surgeons and general surgeons in terms of WT surgical
management
◦ Differences between pediatric urologists and pediatric surgeons have recently been studied for RN with few clinically significant
differences noted
Role of NACT
◦ Reduces tumor volume
◦ Improves technical feasibility of NSS
◦ Improves surgical positive margin rates
◦ Current COG protocol (AREN0534)
◦ 6-12 weeks of preoperative chemotherapy (without biopsy, prior to surgical removal of tumor) for children with
◦ Bilateral tumors
◦ Syndromic associations

35. DISCUSSION: CHALLENGES
Patient selection
◦ Cost and Ferrar
◦ Only 25% of children with unilateral WT are candidates for NSS
◦ Only 1% of these children actually undergo NSS
◦  One of the goals of future research efforts should be to determine which children can
safely undergo NSS
◦ Ehrlich et al – reported on 39 patients with unilateral WT who underwent NSS
◦ 9/39 (23%) were found to have positive margins or intraoperative tumor spill – received additional chemotherapy
and radiation due to surgical factors
◦ Despite this, the FYS in those patients was 96%
◦ NSS feasibility, however, can be aided by preoperative imaging
◦ Sensitivity – 87%
◦ Specificity – 97%
◦ Accuracy – 93%

36. LIMITATIONS
A trial of RN and NSS would be technically challenging to plan and accomplish
Most included studies were retrospective case series with highly variable reporting quality
This level of evidence is generally recognized as suboptimal for inclusion in meta-analyses
Any comparisons of these studies will be significantly limited by their
◦ Small numbers
◦ Inconsistent reporting
◦ Inherent methodological biases of the study designs

37. SUMMARY
Most contemporary studies reporting the use of NSS in children with WT report similar long-
term outcomes to RN in regards to
◦ ESRD
◦ Tumor recurrence
◦ Tumor rupture
◦ OS
These studies are significantly limited by their inherent methodological flaws
No randomized controlled trial of NSS and RN use in children with WT
 Significant opportunities for future research on the use of NSS in children with WT
The short- and long-term risks and benefits of NSS and RN as “gold standard” treatment for all
children are ripe areas for future comparative effectiveness research

38. CONCLUSION
Most existing studies are relatively small, non-randomized, retrospective studies
Significant opportunities for future research on the use of NSS in children with WT
◦ Which children are most (and least) likely to benefit from NSS ?
◦ What is the optimal surgical technique ?
◦ Whether preoperative chemotherapy plays a role in NSS ?
◦ What is acceptable variation in the use of NSS among centers and among providers ?

39. Level of evidence: 5

40. Role of partial nephrectomy in the management of unilateral Wilms tumours is controversial
The benefits of preserving as much functioning renal tissue as possible must be balanced against
the increased risk of local recurrence
NWTSG report for bilateral Wilms tumours showed that partial nephrectomy specimens with
incomplete resection margins had a high rate of local recurrence (16%)
◦ This compares with a local recurrence rate of 3.2% after radical nephrectomy
UKW-3 trial (1991) – To ascertain the feasibility of partial nephrectomy in unilateral low grade
Wilms tumours
◦ If, after total nephrectomy, the surgeon thought that a partial nephrectomy might have been possible,
s/he was asked to mark the proposed resection line on the kidney specimen but to do a radical
nephrectomy as normal
◦ The pathologist was asked to report on whether the tumour would have been excised completely and
how much renal tissue would have remained
◦ The surgical and pathology reports of all patients entered into the UKW-3 trial (between 1st October
1991 and 30th March 2001) recorded as suitable for partial nephrectomy were studied in detail
◦ To be considered feasible for partial nephrectomy, there had to be
◦ Clear resection margins
◦ No vascular invasion
◦ No pelvic invasion
◦ At least 50% of unaffected kidney left behind

41. UKW-3 trial (1991)
◦ 842 patients with Wilms tumour
◦ 43 (6.5%) were considered, by the operating surgeon, as candidates for partial nephrectomy
◦ Unfortunately, there was no recorded instance when the kidney was marked
◦ The pathologist only addressed the question in 20/43
◦ 14 (70%) patients would not have had complete tumour clearance
◦ Psitive lateral resection margins (3)
◦ Tumour in vein (2)
◦ Tumour invading the renal pelvis (7)
◦ Less than 50% of normal kidney remaining (10)
◦ 12 patients had partial nephrectomy
◦ 11 patients – no information on whether the remaining kidney tissue functioned
◦ 1 patient with duplex kidney – the remaining upper pole did not function
◦ In conclusion, the question concerning partial nephrectomy was poorly addressed due to failure to
follow study protocol
◦ In the majority of cases (70%) where feasibility has been assessed, the surgeon did not accurately
predict which tumours could be resected by partial nephrectomy
◦ Difficult to see how further prospective data on this subject will be forthcoming
◦ If further studies are planned then a major effort needs to be made to get surgeons and pathologists to
rigorously co-ordinate their studies of individual kidney specimens

42. THANK YOU !