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Wilms Tumor Indications for Radiotherapy

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					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
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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
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NWTS 1 Results
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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
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2-year relapse free survival
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Favorable histology 89% Unfavorable histology 29% Large tumor size Lymph node involvement Age >2 years

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Poor prognostic factors
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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
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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
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Patients stratified by Stage instead of Group FH & UH incorporated in the treatment algorithm Five questions
   

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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
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Stage I: 10 wks vs. 6 months equivalent (VA)
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4-year RFS 89% OS 96%

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Stage II: no difference between 2 or 3 drugs with or without XRT
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4-year RFS 87% OS 91%

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Stage III: No stat sig difference in abdominal relapse between 10 and 20 Gy, trend favored use of Adriamycin or 20 Gy
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4-year RFS 82% OS 91%

NWTS 3 Results
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Stage IV: 4 drugs equal to 3 drugs (both include abdominal and lung XRT)
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4-year RFS 79% OS 80%

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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
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NWTS 4 1986 - 1994
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Addressed issues of minimization of therapy and customization by Stage & Histology Evaluate the role of pulse dosed chemotherapy

NWTS 4 Schema

NWTS 4 Results
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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

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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
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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
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Diffuse Anaplasia 2 y EFS
   

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Rhabdoid Tumors
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Stage I 64.3 % Stage II 79.5% Stage III 62.7% Stage IV 33.6%

   

Stage I 50% Stage II 33.3% Stage III 33.3% Stage IV 21.4 % Stage V 0%

 

CCSK Stage I –IV 4y RFS 77.6%
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6/9 Stage IV patients relapsed

Selected Results from NWTS 5
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
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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
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AREN 0532
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FH Stage I through FH Stage III Standard Risk

AREN 0533 / AREN 0321
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AREN 0533
FH Stage III High Risk  FH Stage IV
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

AREN 0321
UH Wilms’  Clear Cell Sarcoma of the Kidney  Rhabdoid Tumor  RCC
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AREN 0533
Eliminate pulmonary RT in Stage IV FH Rapid Responders

Who gets XRT today


Favorable Histology
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Anaplastic Histology
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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

Stage I Localized RT to tumor bed (10.8 Gy)
Stage II – Localized RT to tumor bed (10.8 Gy)



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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
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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.
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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
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Stage III Diffuse Anaplasia & Rhabdoid Tumor 19.8 Gy

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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
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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
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Used for patients with diffuse peritoneal seeding, gross tumor spillage within the abdominal cavity during surgery or pre-op intraperitoneal rupture Portals
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Superior – 1 cm above diaphragm Inferior – Bottom of obturator foramen Lateral – 1 cm beyond lateral abdominal wall Shield femoral heads

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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.
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 
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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.
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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
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Resection: 4/9/07
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Tumor spillage DD4A

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Chemotherapy
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RT: 4/18/07
Whole Abdomen  AP:PA  Dose: 1050 cGy (150 cGy x 7)
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A.M. DRR

A.M. DVH

Current Radiotherapy Guidelines – Lung Irradiation
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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
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Treatment Fields
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Superior border – Above the Clavicles Inferior border - Approximately to L1

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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
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Rationale behind omitting upfront pulmonary RT comes from several studies SIOP 9
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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
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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
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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.
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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.
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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
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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
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Brain
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Whole Brain XRT to 21.6 Gy then boost of 10.8 Gy (1.8 Gy/fx) 25.2 Gy Entire bone does not need to be treated 3 cm margin 19.8 Gy

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Bone
  

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Lymph Node (Not Surgically removed)
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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
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Treatment of Relapse
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Adverse factors for relapsed Wilms’
Prior Adriamycin based chemotherapy  Relapse < 12 months from initial diagnosis  Intra-abdominal relapse after previous abdominal RT
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Treatment of Relapse Restaging
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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
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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


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Gross Residual Disease after Surgery
Should get a boost  Total dose including boost should not exceed 30 Gy
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Treatment of Relapse – Radiotherapy Guidelines
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Dose to infradiaphragmatic sites
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Total Nominal Dose (including previous RT)
<36 months – should not exceed 30.6 Gy  >36 months – should not exceed 39.6 Gy
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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
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Lung Irradiation
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Complete remission & No previous RT
≤ 18 months: 9 Gy; 1.5 Gy/fx  > 18 months: 12 Gy, 1.5 Gy/fx
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Gross Residual Disease after surgical resection & No previous RT
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Can boost gross disease with additional 7.5 Gy

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Liver, Brain, Bone mets
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Follow guidelines from NWTS 5

L.L.
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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


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Close f/u

L.L.
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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.
 
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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.
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   

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.
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 
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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


				
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