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. Vujani&cacute;, 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 (