Management of Wilms' Tumor
Moderator:Dr Sushmita Ghoshal
History
The first description from Thomas F. Rance (1814)
Max Wilms thoroughly reviewed the literature and added 7 new patients in his 1899 monograph Die Mischgeschwuelste
Wilms also described the histologically mixed tumors of other urogenital organs
Wilms M. Die Mischgeschwulste der Nieren. Leipzig, Arthur Georgi, 1899
Epidemiology
Annual incidence of Wilms' tumor in the United States was 7.6 cases per million children younger than 15 years.
6% of pediatric tumors commonest abdominal pediatric tumor
5th most common childhood cancer.
Frequency higher in blacks, lower in Asians
Male to female ratio is:
0.92:1.00 for unilateral disease
0.60:1.00 for bilateral disease
5th most common childhood cancer.500 new cases are diagnosed annually in the USA.
Epidemiology
Mean age of diagnosis:
46.9 months for females (29.5 mo for B/L tumors)
41.5 months for males (32.6 mo for B/L tumors)
Separate Indian population based data non existent
However HBCR have reported varying rates.
Largest study by Thiruanathapuram reports that Wilms' Tumors account for 5.4% of all pediatric malignancies
Several reports find it to be the 2nd most common solid pediatric tumor in India (after HD)
Sharma S, Mishra K, Agarwal S, Khanna G. Solid tumors of childhood. Indian J Pediatr 2004;71:501-504
Pathogenesis
Renal Development
Metanephric blastema
The theory of double induction states that both the mesoblastic blastema and the ureteric bud induce differentiation in each other. Cells from the blastema subsequently differentiate to the mature tubules and glomeruli.
Nephrogenic Rests
Perinephric rests are persistent mesoblastic tissues beyond the 36th week of gestation
Two types:
Intralobular (assoc. with WAGR, DDS etc)
Perilobular (assoc. with BWS)
Wilms Tumorigenesis
Genetics of Wilms Tumor
Three candidate gene loci identified:
Chromosome 11p13 (WT-1 gene):
WAGR syndrome (gene deletions)
Denys Drash Syndrome (point mutations)
Paternal gene is silenced
Chromosome 11q15(WT- 2 gene):
Beckwith -Wiedemann Syndrome (gene deletions)
Paternal gene is not silenced - double dose
Chromosome 16 gene not identified
Pathology
Histology
Usually a large tumor compressing the normal renal parenchyma
Tumor usually has a intact fibrous capsule with prominent veins
Lymphatic / vascular invasion common.
Yellowish color with heterogeneous appearance hemorrhagic/cystic areas.
Tumor Components
The Tumor is characterized by a triphasic mixture of primitive blastemal elements with numerous abortive glomeruli and tubules surrounded with a rich stroma.
Special Points
Triphasic nature of tumor allows diversity in histology
Pathological features associated with poor prognosis:
Diffuse anaplasia
Anaplasia in extra-renal tumor
Predominant blastemal pattern
Histology: Anaplastic
Anaplasia:
Giant Tumor cell nucleus (> 3 times diameter of surrounding cell) with chromatin condensation
Mulitpolar mitotic figures
Marked Hyperchromatism
All these 3 criteria have to be fulfilled in order for the tumor to be classified as anaplastic Wilms tumor.These criteria were given by Beckwith and Palmer in 1948
Diffuse Anaplasia
Present in any extrarenal site, including vessels of the renal sinus.
Present in a random biopsy specimen.
Unequivocally expressed in one region of the tumor, but with extreme nuclear pleomorphism elsewhere in the lesion.
Present in more than one tumor slide, unless
It is known that every slide showing anaplasia came from the same region of the tumor or
Anaplastic foci on the various slides are minute and surrounded on all sides by nonanaplastic tumor.
Initial definition of diffuse anaplasia as given by Beckwith was a quantitative one in the sense that it required the at least 10% of the HPF had to show the anaplastic changes.As per this system there was no difference in the outcomes for patients with focal or diffuse anaplasia.However in the revised system given by Bonadio et al in 1985 a topgraphical approach was adop-eted.
Anaplastic Wilms Tumor
Seen in 5-10% patients overall 80 - 90% have DA.
Female preponderance: F:M ratio 2:1 for DA
More common in older children (rare below 2yrs)
Anaplastic features are commonly seen in the blastemal component
These areas are preserved after chemotherapy (SIOP results)
Most present in later /advanced stages with extra-renal extensions
Metastasis is commoner 86% develop metastatsis (MC Lung)
Time to development of of mets early within 1 yr of diagnosis
Survival (both DFS and OS) poorer than classical variant Poorer for DA than FA (41% vs 75% respectively)
Classification
NWTS
Low Risk
Mesoblatic
Intermediate risk
FH Wilms tumor
High risk
Anaplastic
Focal
Diffuse
CSSk
Rhabdoid tumor
SIOP
Low risk
Cystic partially diff. WT
Mesoblastic Nephroma
WT with fibroadenomatous structures
Highly diff. epithelial WT
Intermediate risk
Non anaplastic WT
High risk
Anaplastic WT
CSSK
Rhabdoid tumor
Clinical Features
Symptoms
Classically appears as a silent abdominal mass during childhood (60-70%)
Other symptoms:
Pain Abdomen (30-40%)
Flank pain and rapid enlargement of the mass (2 to bleeding in the tumor)
Hematuria (25%)
Fever (20%)
Physical Examination
Primary tumor
Smooth, rounded lobulated mass in the loin
Attached kidney may be felt
Doesn't move with respiration
Other features:
Hypertension (25%)
Varicocele (tumor thrombus in IVC)
Associated genitourinary abnormalities
Associated stigma of congenital anomalies
Congenital Anomalies
Around 9 - 10% of individuals with Wilms tumour have a congenital anomaly
Long term F/U of individuals reveals a syndrome in 17% patients
Congenital Anomalies
High risk (>20%)
WT1 deletions (including WAGR syndrome)
Truncating and pathogenic missense WT1 mutations (including Denys-Drash syndrome)
Familial Wilms tumour
Perlman syndrome
Mosaic variegated aneuploidy
Fanconi anaemia D1/Biallelic BRCA2 mutations
Moderate risk (520%)
WT1 intron 9 splice mutations (Frasier syndrome)
Beckwith-Wiedemann syndrome
Simpson-Golabi-Behmel syndrome caused by GPC3 mutations/deletions
Low risk ( 2yrs were significant prognostic variables
In children < 2yrs age there was non significant improvement in the 4 yr OS.
No radiation dose response observed despite age modulated radiation doses.
SIOP 1 (1971-74)
Questions:
Is addition of preoperative radiation to postoperative radiation better?
Is Single postoperative course of Actinomycin D equivalent to multiple courses(6)?
M&M:
Randomized.
N = 194 (397 eligible)
10% erroneous diagnosis
Answers:
Preoperative RT reduced the risk of intraoperative tumor rupture from 33% to 4% ( p = 0.001)
Significant reduction in 5yr recurrence free survival 51% vs 27% (but no difference in 8 yr survival)
No survival disadvantage of 6 courses of Act D over 1 course (15 g/d x 5 days)
SIOP 1 results
Preoperative RT reduced the risk of intraoperative tumor rupture from 33% to 4% ( p = 0.001)
Significant reduction in 5yr recurrence free survival 51% vs 27% (but no difference in 8 yr survival)
No survival disadvantage of 6 courses of Act D over 1 course (15 g/d x 5 days)
NWTS 2 (1974-79)
Questions:
Can Vincristine and ActD substitute for RT in Older Children with Group I disease?
Is long course adjuvant ActD + Vcr better in group I disease?
Is addition of Adjuvant doxorubicin helpful in stage II - IV disease?
M&M:
Randomized.
N = 495
Answers:
Survival in patients not receiving radiation was not impaired if post op Vcr + ActD was given
15 months of ActD + Vcr was not better than a 6 months course.
Significant improvement in the 3 yrs RFS (88% vs 70%) with the use of patients with stage II/III (FH)
Significant improvement on addition of Adriamycin to Stage IV patients too.(3 yr RFS 60% vs 43%)
Signifant impact of lymphnode involvement with 2yr RFS reduced to 54% from 82% for node positive patients
NWTS 2
NWTS 2 results
Survival in patients not receiving radiation was not impaired if post op Vcr + ActD was given
15 months of ActD + Vcr was not better than a 6 months course.
Significant improvement in the 3 yrs RFS (88% vs 70%) with the use of patients with stage II/III (FH)
Significant improvement on addition of Adriamycin to Stage IV patients too.(3 yr RFS 60% vs 43%)
Signifant impact of lymphnode involvement with 2yr RFS reduced to 54% from 82% for node positive patients
SIOP 2 (1974-76)
Questions:
Is addition of preoperative radiation (20 Gy) and Actinomycin D to postoperative radiation better?
M&M:
Non randomized.
N = 86 (397 eligible)
Answers:
Preoperative RT reduced the risk of intraoperative tumor rupture from 20% to 5% ( p = 0.0025)
Survival 61% in patients receiving preop RT
However most patients who did not receive preop RT had smaller tumors.
It is not necessary to give 2 drugs for 15 weeks in patients with WT
Reduced need for WAR secondary to reduction in risk of tumor rupture
SIOP 5 (1977-80)
Questions:
Is Preoperative ActD (15 g/kg/d x 3 days x 2 courses) + Vincristine (1.5mg/m2 x weekly x 4 courses) equal to 1 course of Act D + Preop RT (20 Gy)
M&M:
Randomized.
N = 172
Answers:
Use of preoperative CCT did not impact the survival parameters or reduced the risk of tumor rupture as compared to pre-op RT + CCT.
Downstaging was equal in both groups (43% vs 52% stage I)
Overall 3 yr survival same (89% vs 83%)
Major change in the pathological pattern e.g. massive necrosis more common with preop CCT + RT arm (53% vs 17%, p < 0.001)
SIOP 5 results
Use of preoperative CCT did not impact the survival parameters or reduced the risk of tumor rupture as compared to pre-op RT + CCT.
Downstaging was equal in both groups (43% vs 52% stage I)
Overall 3 yr survival same (89% vs 83%)
Major change in the pathological pattern e.g. massive necrosis more common with preop CCT + RT arm (53% vs 17%, p < 0.001)
NWTS 3 (1979-85)
Questions:
Can Duration of Chemotherapy be shorted for stage I FH?
Can radiotherapy be eliminated for stage II FH patients?
Maximum effective RT dose for stage III FH patients?
Is Adriamycin necessary in stage II / III FH patients?
Will cyclophosphamide improve the survival in stage I III UFH and Stage IV patients?
M&M:
Randomized.
N = 1160
Answers:
Short Course therapy equivalent to long course CCT in stage I FH (10 wk Vcr + ActD)
4 yrs RFS equivalent in patients with stage II FH with / without RT
10 Gy equivalent to 20 Gy in stage III FH, however patients with receiving Adriamycin + 10 Gy was 4% vs 10% in patients receiving 10 Gy with Vcr + ActD
Cyclophosphamide was helpful in patients with focal anaplasia where it improved the 4 yr RFS.
NWTS 3
NWTS 3 Results
Short Course therapy equivalent to long course CCT in stage I FH (10 wk Vcr + ActD)
4 yrs RFS equivalent in patients with stage II FH with / without RT
10 Gy equivalent to 20 Gy in stage III FH, however patients with receiving Adriamycin + 10 Gy was 4% vs 10% in patients receiving 10 Gy with Vcr + ActD
Cyclophosphamide was helpful in patients with focal anaplasia where it improved the 4 yr RFS.
SIOP 6 (1980-87)
Questions:
Is radiation (20 Gy) required in stage II patients in the post-op period?
Benefit of addition of doxorubicin in stage III patients vs intensified AV regimen?
Impact of long course of postoperative Act D (38 weeks vs 17 weeks)?
M&M:
Randomized.
N = 396
Answers:
In Stage II patients there were 8 relapses in non irradiated patients and 7 were infield compared to 1 relapse in 58 patients with local recurrence.
However all patients who died did so as a result of disseminated Wilms Tumor
There was no difference in 4 yr OS (85% vs 90%) in the two arms
In stage I patients there was no significant benefit of the short course chemotherapy
In stage III patients there was a significant advantage in the addition of post op Doxorubicin
SIOP 6 results
In Stage II patients there were 8 relapses in non irradiated patients and 7 were infield compared to 1 relapse in 58 patients with local recurrence.
However all patients who died did so as a result of disseminated Wilms Tumor
There was no difference in 4 yr OS (85% vs 90%) in the two arms
In stage I patients there was no significant benefit of the short course chemotherapy
In stage III patients there was a significant advantage in the addition of post op Doxorubicin
SIOP 9 (1987-93)
Questions:
Appropiate duration of preop CCT 4 weeks vs 8 weeks?
Stage adapted adjuvant therapy intoduced.
M&M:
Randomized.
N = 382 (852 registered)
Answers:
4 weekly schedule of preoperative chemotherapy did not adversly impact upon the downstaging or the survival
5 yr OS was 92% vs 87% favouring the short course arm (p = NS)
Overall incidence of stage I tumors 63%
However in the stage II patients who did not receive flank RT there was a local relapse rate of 6.6%
The use of a more intensive AVE protocol in non irradiated patients with stage IIN0 disease was mandated by the findings of the SIOP 6 results.
SIOP 9 results
4 weekly schedule of preoperative chemotherapy did not adversly impact upon the downstaging or the survival
5 yr OS was 92% vs 87% favouring the short course arm (p = NS)
Overall incidence of stage I tumors 63%
However in the stage II patients who did not receive flank RT there was a local relapse rate of 6.6%
The use of a more intensive AVE protocol in non irradiated patients with stage IIN0 disease was mandated by the findings of the SIOP 6 results.
NWTS 4
Questions:
Asked if a CCT regimen with reduced economic burden was effective: i.e. pulsed intensive ActD + Vcr in stage I-II FH patients and pulsed intensive ActD+Vcr+Dox in stage III-IV FH and stage I-IV UFH?
Impact of reduction of treatment duration from 15 months to 6 months in FH stage II IV tumors.
Age modulated radiation doses were used as in NWTS-1 for UFH stage I-IV.
M&M:
Randomized.
N = 495
Answers:
No significant difference was demonstrated between the 2-year relapse-free percentages for patients treated with the pulse-intensive regimens (89.4% vs 90.5%)
Pulse-intensive regimens produced less hematologic toxicity than the standard regimens,
The administered drug dose-intensity was greater on the pulse-intensive regimens.
At least $790,000 per year would have been saved if all United States children with stages I to IV favorable-histology Wilms' tumor were treated using the pulse-intensive regimens.
Use of shorter course of chemotherapy produced no reduction in the control or survival rates (4 yr RFS 88.7% vs 89.8%)
NWTS 4
NWTS 4
NWTS 5 results
No significant difference was demonstrated between the 2-year relapse-free percentages for patients treated with the pulse-intensive regimens (89.4% vs 90.5%)
Pulse-intensive regimens produced less hematologic toxicity than the standard regimens,
The administered drug dose-intensity was greater on the pulse-intensive regimens.
At least $790,000 per year would have been saved if all United States children with stages I to IV favorable-histology Wilms' tumor were treated using the pulse-intensive regimens.
Use of shorter course of chemotherapy produced no reduction in the control or survival rates (4 yr RFS 88.7% vs 89.8%)
SIOP 93-01/GPOH
Questions:
Treatment of stage I anaplastic / intermediate grade tumors with 4 weeks post operative program vs 8 weeks.
M&M:
Randomized.
N = 440
Answers:
No difference in the preliminary results as far as OS and DFS are concerned.
NWTS 5
It was a non randomized study to evaluate the prognostic factors involved in WT
Also evaluated the impact of Surgery alone in children < 2yrs with FH stage I tumors weighing < 550 gms
Trial closed early due to RFS at 2 yrs < 90% (expected cufoff) actual value 86% ; OS still remained at 100%
LOH at Chr 1p and 16q were significant in determining an adverse prognosis.
UKW-3 trial
Randomized comparison of preoperative CCT vs Immediate Surgery
Conducted by the UK Children's Cancer Study Group
Time period: 1991 2001
Pre-CCT trucut biopsy mandatory
V
V
V
V
V
V
A
A
Preoperative Chemotherapy*
Immediate Surgery
Delayed Surgery after 6 weeks
Protocol specific Adjuvant Therapy
Vincristine: 1.5 mg/m2 weeklyActinomycinD: 1.5mg/m2
* Preoperative Adriamycin in doses of 30mg/m2 x 3 weekly was given in event of pre-op unfavorable histology
1. Christopher Mitchell, et al., Immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic Wilms' tumour: Results of a randomised trial (UKW3) by the UK Children's Cancer Study Group, European Journal of Cancer 42, no. 15 (October 2006): 2554-2562, http://www.sciencedirect.com/science/article/B6T68-4KM46R9-3/2/7aff096dc2dc54b7f3107e5849ab9202.
Adjuvant Therapy
1. Christopher Mitchell, et al., Immediate nephrectomy versus preoperative chemotherapy in the management of non-metastatic Wilms' tumour: Results of a randomised trial (UKW3) by the UK Children's Cancer Study Group, European Journal of Cancer 42, no. 15 (October 2006): 2554-2562, http://www.sciencedirect.com/science/article/B6T68-4KM46R9-3/2/7aff096dc2dc54b7f3107e5849ab9202.
Results: Pretreatment Biopsy
No needle track seeding
No increase in risk of recurrence
Resulted in another diagnosis in 12% patients
In 4% biopsy was not diagnostic
Complications:
Fall in hemoglobin 20%
Flank pain 19%
Massive tumor bleed with emergency nephrectomy in 1 patient
1. Anna Kelsey Gordan M. Vujanić, The role of biopsy in the diagnosis of renal tumors of childhood: Results of the UKCCSG Wilms tumor study 3, Medical and Pediatric Oncology 40, no. 1 (2003): 18-22, http://dx.doi.org/10.1002/mpo.10216.
Results: Down-staging
11% increase in stage I population (65.2% vs 54.3%, p = 0.13)
Significant improvement in down staging of stage III tumors (28% vs 9%, p = 0.008)
15 tumor ruptures in the immediate surgery vs 0 in the preoperative CCT group
Local relapses increased (11% vs 5% , p = NS)
No difference in OS / EFS
Results: Surgical Aspects
Duration of surgery reduced significantly (96 min vs 104 min, p =0.0004)
Reduced blood loss
Reduced adhesions and ease of resection
Reduced risk of ruptures
1. C. A. Safdar, et al., WILMSTUMOUR: A COMPARISON OF SURGICAL ASPECTS IN PATIENTS WITH OR WITHOUT PRE-OPERATIVE CHEMOTHERAPY, J Coll Physicians Surg Pak 16, no. 8 (2006): 521-4.
Impact of the trial
6 week course of preoperative CCT results in a more favourable stage distribution
Reduced risk of tumor spillage and surgical complications
Reduced overall treatment burden in the delayed treatment group due to stage adopted therapy:
19.8% reduction in need for Doxorubicin and RT
11.4% reduction in need for Actinomycin D
Question for future? - Is doxorubicin needed in the management of stage II patients after preoperative therapy (SIOP 2001 trial looking into the issue!!)
Wilms Tumor in special situations
Relapsed / Refractory WT
The most frequent site of relapse overall is the lungs
54% of all relapses were isolated pulmonary events
Factors that indicate an increased likelihood of salvaging relapsed tumors :
Tumors with favourable histology
Recurred only in the lungs
Relapse in the abdomen where radiotherapy had not been included in the primary treatment;
Relapse that occurred more than 12 months from diagnosis.
The overall survival following relapse was only 24 -30 % .
Relapsed / Refractory WT
Best results till date have been reported with the use of ICE regimen (Ifosfamide / Carboplatin / Etoposide) given initially by the SFOP.
Doses for Ifosfamide were 1.8 g/m2/d x 5 days, Carboplatin 400 mg/m2/d x 2 days, and etoposide 100 mg/m2/d x 5days (Abu-Ghosh et al)
RR 73- 80%
Survival 50 -60 % at 3yrs
Recent St Jude study evaluated modified doses of carboplatin (Calvert's Formula) to reduce the toxicity.
Investigational chemotherapeutic agents: Irinotecan and oxaliplatin
In children with relapse without remission High dose chemotherapy with stem cell transplantation is an alternative.
RT for Recurrent Tumors
For recurrent tumors recommendations are:
< 12 mo of age: 12.618 Gy
In older children 21.6 Gy if previous radiation dose is 10.8 Gy.
A boost dose of up to 9 Gy to gross residual after surgery.
Total dose including previous irradiation not to exceed:
30.6 Gy (
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