Wilms’ Tumor –
Indications for
Radiotherapy
Tasha McDonald M.D.
Parag Sanghvi M.D.
Department of Radiation Medicine
Treatment


Based on cooperative group philosophies
3 major groups
National Wilm’s Tumor Study (NWTS)
 Societe Internationale d’Oncologie Pediatrique
(SIOP)
 United Kingdom Children’s Cancer Study Group
(UKCCSG)

NWTS Strategy


Assess local extent, degree of anaplasia,
presence of unusual histology, presence of LN
involvement
Assess without preoperative treatment
Gather prognostic clues
 Avoid misdiagnosis
 Customize therapy

NWTS 1 – 4 Schema
NWTS 1 (1969 – 1974)
D’Angio GJ, et al. Cancer 64:349-360, 1989
•
•
•
•
Is postoperative radiotherapy necessary in group I
disease?
Is single agent chemo with vincristine or actinomycin
D equivalent to combining these drugs for group II
and III disease?
Is preoperative vincristine of value in group IV
disease?
Radiation doses adjusted for age
Birth – 18 mo 18 to 24 Gy
 18 – 30 mo 24 to 30 Gy
 31- 40 mo 30 to 35 Gy
 41 mo or older 35 – 40 Gy

NWTS 1 Results





Post-op XRT not needed for group I <2 yo
Actino/Vincr better than either agent alone for
group II and III
Preop vincristine not useful in group IV
RFS for group I patients >2 yo w/Actino +RT
84%
RFS for group II/III w/Actino/Vincr/XRT
84%
NWTS 1 Results

2-year relapse free survival



Poor prognostic factors






Favorable histology 89%
Unfavorable histology 29%
Large tumor size
Lymph node involvement
Age >2 years
No radiation dose response between 10-40 Gy
Delays of up to 10 days for post-op tx found
acceptable
Whole abdominal XRT not necessary for tumor spills
confined to the flank
NWTS 2 1974- 1979



Can Vincr & Actino substitute for RT in older
children with Group I disease?
Are protracted periods of adjuvant Vincr &
Actino helpful for Groups II – IV?
Is addition of Adriamycin to Actino and Vincr
of value in Groups II – IV?
NWTS 2 Results




Vincr & Actino can substitute for RT in Group
I disease
6 months = 15 months Actino/Vincr for Group
I
Addition of Adria to Actino/Vincr/XRT for
Groups II-IV provided benefit
Worse 2-year survival for lymph node + (54% vs
82%) and patients with unfavorable histology
(54% vs 90%)
NWTS 3 1979 – 1985
Green DM, et al. Pediatr Clin North Am 38:475-488, 1991



Patients stratified by Stage instead of Group
FH & UH incorporated in the treatment algorithm
Five questions





Can duration of chemotherapy shortened for Stage I FH?
Can RT be eliminated for Stage II FH?
What is the minimum effective RT dose for Stage III FH?
Is Adriamycin clearly beneficial and necessary for Stages II &
III FH?
Will Cyclophosphamide improve survival in Stages I – IV
UH and Stage IV FH?
NWTS 3
•
•
•
•
Stage I FH: Vinc/Actino (no RT) 24 vs 10 weeks
Stage II FH: 3 vs. 2 drugs (? Adriamycin necessity),
+/- XRT 20 Gy
Stage III FH: 10 vs. 20 Gy, 3 vs. 2 drugs
Stage IV FH and all UH: XRT/3 drugs +/cyclophosphamide
NWTS 3 Results

Stage I: 10 wks vs. 6 months equivalent (VA)


Stage II: no difference between 2 or 3 drugs with
or without XRT


4-year RFS 89% OS 96%
4-year RFS 87% OS 91%
Stage III: No stat sig difference in abdominal
relapse between 10 and 20 Gy, trend favored use
of Adriamycin or 20 Gy

4-year RFS 82% OS 91%
NWTS 3 Results

Stage IV: 4 drugs equal to 3 drugs (both include
abdominal and lung XRT)


4-year RFS 79% OS 80%
Anaplasia
4 drugs better than 3 drugs for stage II-IV
 Clear cell sarcoma patients had trend toward
improvement with Cyclophosphamide
 25% OS for rhabdoid in both arms

NWTS 4 1986 - 1994


Addressed issues of minimization of therapy
and customization by Stage & Histology
Evaluate the role of pulse dosed chemotherapy
NWTS 4 Schema
NWTS 4 Results


Pulse–intensive chemotherapy feasible, produce
less hematologic toxicity and allow for increased
drug dose-intensity
Cost analysis showed savings of $790,000 a year
in the US if all Wilms’ patients were treated on
pulse-intensive regimens
NWTS 5 Schema
NWTS 5 Results
LOH 1p / 16q


LOH 1p associated with significantly worse RFS in
Stage II but not Stage III/IV
Suggests that adverse effects of LOH 1p can be
overcome by more aggressive chemotherapy
NWTS 5 Selected Results - FH




Stage I FH 4 y RFS 92% OS 98%
Stage II FH 4 y RFS 83% OS 92%
Stage III FH (included RT) 4 y RFS 85.3% OS
93.9%
Stage IV FH 4 y EFS 74.6% (most of these
patients had lung mets and received pulmonary
RT)
NWTS 5 Selected Results UH

Diffuse Anaplasia 2 y
EFS






Stage I 64.3 %
Stage II 79.5%
Stage III 62.7%
Stage IV 33.6%
CCSK
Stage I –IV 4y RFS
77.6%

6/9 Stage IV patients
relapsed

Rhabdoid Tumors





Stage I 50%
Stage II 33.3%
Stage III 33.3%
Stage IV 21.4 %
Stage V 0%
Selected Results from NWTS 5




High rate relapse for Stage I patients with diffuse
anaplasia (10/29 patients, 5 deaths); 4 y/o RFS 64.3 %
High rate of relapse for Stage I focal anaplasia (3/9
patients, 2 deaths)
Improved control of Stage I CCSK patients 4 y/o RFS
100% (0/14 patients)
There was a subset of “very low risk” patients - < 2
years, Stage I FH, <550 g who were initially assigned to
NO adjuvant therapy; interim analysis showed 2 y EFS
86.5% which was lower than expected; this arm was
subsequently closed
Current Protocols

AREN 0532

FH Stage I through FH Stage III Standard Risk
AREN 0533 / AREN 0321

AREN 0533
FH Stage III High Risk
 FH Stage IV


AREN 0321
UH Wilms’
 Clear Cell Sarcoma of the Kidney
 Rhabdoid Tumor
 RCC

AREN 0533
Eliminate pulmonary
RT in Stage IV FH
Rapid Responders
Who gets XRT today

Favorable Histology




Stage I & II NO RT
Stage III RT to Tumor Bed
(10.8 Gy) or Whole Abdomen
RT (10.5 Gy**)
Stage IV RT to tumor bed or
Whole abdomen if the primary
tumor would have otherwise
qualified as Stage III; RT to
metastases
Stage V – Stage each side
independently; if Stage III
then treat as above

Anaplastic Histology

Stage I Localized RT to
tumor bed (10.8 Gy)

Stage II – Localized RT to
tumor bed (10.8 Gy)

Stage III – Localized RT to
tumor bed (19.8 Gy) or
Whole Abdomen (19.5 - 21
Gy)

Stage IV – If primary tumor
would qualify as Stage I then
no RT; if Stage II or III as
above; RT to metastases
Who gets XRT today

Clear Cell Sarcoma of the Kidney

Stage I – NO RT except for if LN sampling or
pathology review not performed (0 -10.8 Gy)
Stage II – Localized RT to tumor bed (10.8 Gy)
 Stage III – Localized or Whole Abdomen** akin to
FH Stage III (10.8 Gy/10.5 Gy**)
 Stage IV – Treat primary tumor again based on
Stage; treat metastases

Who gets XRT today?

Rhabdoid Tumor
Stage I – Localized RT to tumor bed
 Stage II – Localized RT to tumor bed
 Stage III – Localized or Whole Abdomen** akin to
FH Stage III
 Stage IV – Treat primary tumor again based on
Stage; treat metastases


All stages get RT!!! Dose is age-dependent
<12 months 10.8 Gy
 ≥ 12 months 19.8 Gy /19.5 - 21 Gy**

M.K.




20 mo girl with Rhabdoid Tumor of the kidney
with presumed metastases to bone and lungs;
intraop tumor spillage
Dx: 4/3/07
Treated per protocol AREN0321
Recommendations would be for RT
Whole lung to 12 Gy
 Femur met to 25.2 Gy
 Whole abdomen to 19.5-21 Gy

Current Radiotherapy Guidelines
Tumor Bed/Flank RT



XRT should start by day 10 post-op (surgery day is day
1) but no later than day 14
Fraction size is 1.8 Gy unless large field
Radiation dose for flank/tumor bed is 10.8 Gy except



Stage III Diffuse Anaplasia & Rhabdoid Tumor 19.8 Gy
Boost gross residual disease with additional 9 -10.8 Gy
Limit dose to more than ½ of uninvolved liver to 19.8
Gy
Current Radiotherapy Guidelines
Tumor Bed/Flank RT





Dose to more than 1/3 of the contralateral
kidney or residual kidney for bilateral Wilms’
should not exceed 14.4 Gy
Tumor Bed is determined by pre-operative CT
Includes kidney + tumor + 1 cm margin
Treat all of the vertebral body to avoid scoliosis
Recommend AP/PA for fields; IMRT allowed
for boost
Treatment Fields - Flank
Treatment Fields – Whole Abdomen


Used for patients with diffuse peritoneal seeding, gross tumor
spillage within the abdominal cavity during surgery or pre-op
intraperitoneal rupture
Portals






Superior – 1 cm above diaphragm
Inferior – Bottom of obturator foramen
Lateral – 1 cm beyond lateral abdominal wall
Shield femoral heads
Total Dose 10.5 Gy (1.5 Gy / fx) except for patients with
Diffuse Anaplasia or Rhabdoid Tumors (19.5 – 21 Gy)
If need to boost for diffuse unresectable peritoneal implants
then can treat whole abdomen to 21 Gy; shield remaining kidney
to not get more than 14.4 Gy
Treatment Fields – Whole Abdomen
A.M.






3 yo 10 month girl
Presented with one day of severe abd pain
Outside ED: UA + blood, Tx to OHSU ED
U/S 12 x 12 cm abd mass
CT c/a/p: 12 x 12 x 13.6 cm RUQ mass arising
from upper pole of kidney with evidence of
tumor rupture; no evidence of mets
Admitted to DCH
A.M.
A.M.




4/6/07: Taken to OR for attempted resection
but biopsy only secondary to size of tumor;
then developed compartment syndrome
Path: favorable histology Wilm’s
4/9/07: Resection with spillage of tumor into
abdomen; + bx’s of diaphragm, liver, adrenal
and rectocaval fibrous tissue
STAGE III Favorable Histology Wilm’s
A.M. Treatment

Resection: 4/9/07


Chemotherapy


Tumor spillage
DD4A
RT: 4/18/07
Whole Abdomen
 AP:PA
 Dose: 1050 cGy (150 cGy x 7)

A.M. DRR
A.M. DVH
Current Radiotherapy Guidelines –
Lung Irradiation





AREN 0533 allows for omission of Lung RT in FH patients
who achieve CR with 3 drug chemotherapy (based on CT
scan at Week 6)
Whole Lung XRT for patients with CXR & CT defined
pulmonary metastases is 12 Gy / 8 fx (1.5 Gy /fx); 10.5 Gy if <
12 months old
Localized foci of lung disease persisting 2 weeks after 12 Gy can
be excised or given additional 7.5 Gy
Treat both lungs regardless of the number or location of visible
metastases
Patients with CT only pulmonary mets – at the discretion of the
treating institution
Current Radiotherapy Guidelines –
Lung Irradiation

Treatment Fields




Superior border – Above the Clavicles
Inferior border - Approximately to L1
Caution with lung boosts; upto 10% rate of
pneumonopathy in patients who received 14 Gy whole
lung RT or large volume RT
In infants < 18 months, trial of chemotherapy alone is
suggested; if resolution of lung mets does not occur
within 4 weeks of therapy; then give 9 Gy to both lungs
with a single 1.5 Gy boost to specific nodules
Treatment Fields - Lungs
Pulmonary RT


Rationale behind omitting upfront pulmonary RT
comes from several studies
SIOP 9





Stage IV patients with pre-op chemotherapy
57/59 patients had lung metastases; 56 had FH
40/59 patients had CR in the lung to chemotherapy or
additional metastatectomy
In these 40 patients, 4 y RFS was 67.5% and OS was 87.5%
70% of these patients were spared whole – lung irradiation
When sub group analysis done by histology; in FH OS was
82.9%
CT only Pulmonary Metastases –
NWTS 4 & 5





In NWTS 4& 5 pulmonary mets were defined as
presence of nodules on CXR
There were 171 patients with CT only detected
mets but not CXR
29 were Stage I or II and received Vincr +
Actino D  5 y EFS 54%
58 were Stage III and received Vincr + Actino
D + Adriamycin  5 y EFS 81%
84 were Stage IV and majority received
pulmonary XRT  5 y EFS 78%
CT only Pulmonary Metastases


Patients who received Lung XRT had 1
pulmonary relapse, 1 pulmonary progression
and 5 toxic deaths (2 attributed to pulmonary
RT)
Patients who did not receive Lung XRT had 6
pulmonary relapses; no toxic deaths
C.H.






3 yo girl
Presented with one week of fussiness,
abdominal pain
Mom palpated mass in abdomen
Saw PCP-direct admit to DCH
U/S abd and CT abd showed Rt renal mass with
IVC involvement
CXR/CT chest: multiple pulmonary nodules
C.H.
C.H.




Surgery on 4/20/07: Complete resection/ Rt
nephrectomy with minimal tumor spillage confined to
the renal hilum
Dx: Stage IV favorable histology Wilm’s
Chemo: per NWTS-5, regimen DD4A
RT:




Whole lung/Rt flank began on 4/30/07
AP:PA
1200 cGy (150 cGy x 8 fx)
Will get CT chest 2 weeks out (5/24) and if persistent bulky
disease may boost with 750 cGy
Hicks DRR
Hicks DVH
Current Radiotherapy Guidelines Metastases

Liver
Use RT only if lesions unresectable because of
location or extent
 Tumor + 2 cm margin; 1.8 Gy / fraction
 Treat to 25.2 Gy to 39.6 Gy
 Limit dose to 75 % of liver to less than 30.6 Gy
 If whole liver involved, treat to 19.8 Gy
 Limit dose to remaining kidney to 14.4 Gy with a
posterior block

Current Radiotherapy Guidelines Metastases

Brain


Bone




25.2 Gy
Entire bone does not need to be treated
3 cm margin
Lymph Node (Not Surgically removed)


Whole Brain XRT to 21.6 Gy then boost of 10.8 Gy (1.8
Gy/fx)
19.8 Gy
Adolescent and young adults (≥ 16 years) receive 30.6
Gy to sites of metastases
Treatment of Relapse

Children with relapsed FH Wilm’s can have a
favorable outcome based on
Initial Stage
 Time from initial diagnosis
 Site of relapse
 Previous therapy

Treatment of Relapse

Adverse factors for relapsed Wilms’
Prior Adriamycin based chemotherapy
 Relapse < 12 months from initial diagnosis
 Intra-abdominal relapse after previous abdominal
RT

Treatment of Relapse
Restaging





Stage 1R – Localized Disease, completely
excised
Stage 2R – Gross total resection with evidence
of regional spread
Stage 3R – Residual non-hematogenous tumor
present and confined to abdomen
Stage 4R – Hematogenous mets present
Stage 5R – bilateral Renal involvement
Treatment of Relapse –
Radiotherapy Guidelines


Radiotherapy is administered to patients at site
of relapse
Dose to infradiaphragmatic sites

Complete Remission after Surgery (1R/2R) who
have either received no previous RT or have received
10.8 Gy
Birth – 12 months – 12.6 - 18 Gy
 13 months or older – 21.6 Gy


Gross Residual Disease after Surgery
Should get a boost
 Total dose including boost should not exceed 30 Gy

Treatment of Relapse –
Radiotherapy Guidelines

Dose to infradiaphragmatic sites

Total Nominal Dose (including previous RT)
<36 months – should not exceed 30.6 Gy
 >36 months – should not exceed 39.6 Gy

Total Spine dose should not exceed 41.4 Gy
 Total Liver dose should not exceed 30.6 Gy
 Total Remaining Kidney dose should not exceed
19.8 Gy

Treatment of Relapse –
Radiotherapy Guidelines

Lung Irradiation

Complete remission & No previous RT
≤ 18 months: 9 Gy; 1.5 Gy/fx
 > 18 months: 12 Gy, 1.5 Gy/fx


Gross Residual Disease after surgical resection & No
previous RT


Can boost gross disease with additional 7.5 Gy
Liver, Brain, Bone mets

Follow guidelines from NWTS 5
L.L.



4/06 Dx with Stage I favorable histology Wilm’s
at age 3
S/p complete resection Rt renal
mass/nephrectomy
Chemo:
CCG 5941 protocol/regimen EE4A
 18 weeks Vincr/Actino
 Finished chemo 7/06


Close f/u
L.L.





Regular F/U appt 3/14/07
Asymptomatic
Abd U/S: 5.6 cm mass in Rt renal fossa
CT abdomen: 5.9 x 4.3 cm homogeneous mass
in Rt renal fossa
CT chest: no metastatic disease
Lawson
L.L.





Surgery on 3/19/07: complete resection
Pathology: Recurrent favorable histology Wilm’s
Stage 1R
Chemotherapy: Vincristine, Actinomycin D per
NWTS-5 relapse protocol, regimen 1
RT began 4/13/07
2160 cGy to Rt flank
 180 cGy x 12 fx
 AP:PA

L.L. DRR
L.L. DVH
T.B.





12 yo girl with hx of Stage IV Wilm’s Tumor dx in
December 2003
Tx’ed with chemo (Vincr/Actino/Doxo) and RT (12
Gy to whole lung/whole abd)
8/2004: relapse with pulmonary nodules tx with
carbo/etop/ifos/melphalan w/ stem cell rescue
2/06: abdominal relapse s/p resection and
carbo/topotecan
2/07: 4 x 10 cm mass in left ileopsoas muscle with
extension into spinal canal at T12-L1
T.B.





Tx: Palliative RT
RT to left flank
2520 cGy
180 cGy x 14 fx
Total abd dose = 3720 cGy (including RT in
2003)
Beach DRR
Acknowledgements




Dr. Carol Marquez (for teaching us everything I
know about Wilms’)
Dr. Charles Thomas
Dr. Kamal Patel
Dr. Christopher Lee