Wilms Tumor Indications for Radiotherapy

1
Wilms Tumor Indications for Radiotherapy

• Tasha McDonald M.D.
• Parag Sanghvi M.D.
• Department of Radiation Medicine

2
Treatment

• Based on cooperative group philosophies
• 3 major groups
• National Wilms Tumor Study (NWTS)
• Societe Internationale dOncologie Pediatrique
  (SIOP)
• United Kingdom Childrens Cancer Study Group
  (UKCCSG)

3
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

4
NWTS 1 4 Schema
5
NWTS 1 (1969 1974) DAngio GJ, et al. Cancer
64349-360, 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

6
NWTS 1 Results

• Post-op XRT not needed for group I lt2 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 gt2 yo w/Actino RT 84
• RFS for group II/III w/Actino/Vincr/XRT 84

7
NWTS 1 Results

• 2-year relapse free survival
• Favorable histology 89
• Unfavorable histology 29
• Poor prognostic factors
• Large tumor size
• Lymph node involvement
• Age gt2 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

8
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?

9
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)

10
NWTS 3 1979 1985 Green DM, et al. Pediatr Clin
North Am 38475-488, 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?

11
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

12
NWTS 3 Results

• Stage I 10 wks vs. 6 months equivalent (VA)
• 4-year RFS 89 OS 96
• Stage II no difference between 2 or 3 drugs with
  or without XRT
• 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

13
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

14
NWTS 4 1986 - 1994

• Addressed issues of minimization of therapy and
  customization by Stage Histology
• Evaluate the role of pulse dosed chemotherapy

15
NWTS 4 Schema
16
NWTS 4 Results

• Pulseintensive 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

17
NWTS 5 Schema
18
NWTS 5 ResultsLOH 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

19
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)

20
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

21
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 -
  lt 2 years, Stage I FH, lt550 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

22
Current Protocols

• AREN 0532
• FH Stage I through FH Stage III Standard Risk

23
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

24
AREN 0533
Eliminate pulmonary RT in Stage IV FH Rapid
Responders
25
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

26
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

27
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
• lt12 months 10.8 Gy
• 12 months 19.8 Gy /19.5 - 21 Gy

28
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

29
Current Radiotherapy GuidelinesTumor 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

30
Current Radiotherapy GuidelinesTumor 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

31
Treatment Fields - Flank
32
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

33
Treatment Fields Whole Abdomen
34
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

35
A.M.
36
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 Wilms
• 4/9/07 Resection with spillage of tumor into
  abdomen bxs of diaphragm, liver, adrenal and
  rectocaval fibrous tissue
• STAGE III Favorable Histology Wilms

37
A.M. Treatment

• Resection 4/9/07
• Tumor spillage
• Chemotherapy
• DD4A
• RT 4/18/07
• Whole Abdomen
• APPA
• Dose 1050 cGy (150 cGy x 7)

38
A.M. DRR
39
A.M. DVH
40
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 lt 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

41
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 lt 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

42
Treatment Fields - Lungs
43
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

44
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

45
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

46
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

47
C.H.
48
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 Wilms
• Chemo per NWTS-5, regimen DD4A
• RT
• Whole lung/Rt flank began on 4/30/07
• APPA
• 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

49
Hicks DRR
50
Hicks DVH
51
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

52
Current Radiotherapy Guidelines - Metastases

• Brain
• Whole Brain XRT to 21.6 Gy then boost of 10.8 Gy
  (1.8 Gy/fx)
• Bone
• 25.2 Gy
• Entire bone does not need to be treated
• 3 cm margin
• Lymph Node (Not Surgically removed)
• 19.8 Gy
• Adolescent and young adults ( 16 years) receive
  30.6 Gy to sites of metastases

53
Treatment of Relapse

• Children with relapsed FH Wilms can have a
  favorable outcome based on
• Initial Stage
• Time from initial diagnosis
• Site of relapse
• Previous therapy

54
Treatment of Relapse

• Adverse factors for relapsed Wilms
• Prior Adriamycin based chemotherapy
• Relapse lt 12 months from initial diagnosis
• Intra-abdominal relapse after previous abdominal
  RT

55
Treatment of RelapseRestaging

• 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

56
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

57
Treatment of Relapse Radiotherapy Guidelines

• Dose to infradiaphragmatic sites
• Total Nominal Dose (including previous RT)
• lt36 months should not exceed 30.6 Gy
• gt36 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

58
Treatment of Relapse Radiotherapy Guidelines

• Lung Irradiation
• Complete remission No previous RT
• 18 months 9 Gy 1.5 Gy/fx
• gt 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

59
L.L.

• 4/06 Dx with Stage I favorable histology Wilms
  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

60
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

61
Lawson
62
L.L.

• Surgery on 3/19/07 complete resection
• Pathology Recurrent favorable histology Wilms
• 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
• APPA

63
L.L. DRR
64
L.L. DVH
65
T.B.

• 12 yo girl with hx of Stage IV Wilms Tumor dx in
  December 2003
• Txed 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

66
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)

67
Beach DRR
68
Acknowledgements

• Dr. Carol Marquez (for teaching us everything I
  know about Wilms)
• Dr. Charles Thomas
• Dr. Kamal Patel
• Dr. Christopher Lee