Pediatric Wilms

== Compare Wilms' to Neuroblastoma ==

Epidemiology

General

  • 500 cases Dx in the United States per year
  • Greater than 90% 4-year survival
  • Up from 80% between 1975-1984
  • Girls > Boys
  • African American > Caucasian > Asian: 3x more common in black children (U.S., Africa)
  • Most common in children 1-5 years old
  • Mean age in boys:
    • Unilateral 41.5 mo; Bilateral 29.5 mo
  • Mean age in girls
    • Unilateral 46.9 mo; Bilateral 32.6
    • Bilateral Disease in approximately 7% of cases

Presentation and Evaluation

Etiology

  • Also known as nephroblastoma
  • Malignant neoplasm of the kidney that is thought to arise from nephrogenic rests
  • Nephrogenic Rests – Foci of cells that represent abnormally persistent nephrogenic blastema

Syndroms/ Genetics

  • Normally develops in otherwise healthy children, but 10% occur with recognized malformations
Gene Locus Association
WT1 11p13 Non-overgrowth; (WAGR, Denys-Drash )
WT2 11p15.5 Overgrowth; (Beckwith-Wiedemann)

Pathology

  • Classic histology is triphasic
  • Blastemal, stromal, and epithelial elements
  • Characterized as favorable histology or unfavorable histology based on anaplasia
  • Criteria for Anaplasia
  • Nuclear diameter 3x that of adjacent cells
  • Marked nuclear hyperchromatism
  • Multipolar abnormal mitotic figures
  • Anaplastic changes confined to single region of tumor
  • Excludes extrarenal anaplasia

Clinical Presentation

  • Classic presentation is an asymptomatic abdominal mass
  • Associated symptoms (25% of cases)
  • Malaise
  • Pain
  • Microscopic or gross hematuria
  • Hypertension (due to increased Renin activity)

Routes of Spread

Diagnostic Studies

  • Abdominal Imaging
  • Goals
  • Localize abdominal mass to the kidney
  • Confirm normal contralateral kidney
  • Ultrasound – Initial study of choice
  • CT Scan – Helps evaluate resectability, lymph node status, and hepatic involvement
  • Other imaging
  • Chest x-ray (most common metastasis = lung)
  • Clear Cell Sarcoma (r/o mets to bone/brain)
  • Bone scan, skeletal survey, and brain CT/MRI
  • Rhabdoid Tumor (r/o mets to brain)
  • Brain CT/MRI

Labs
CBC, Bun/Cr, LFT’s, Ca++, UA
Urine catecholamines if neuroblastoma has not been ruled out

NWTS Staging

Stage Description
I Complete resection and limited to kidney,
capsule intact
II Complete resection but extends beyond kidney
tumors biopsied prior to resection
local flank spillage
III Residual or Nonhematogenous Mets
LN+
unresectable tumors
and diffuse peritoneal spillage
IV Hematogenous metastasis
Lung, Liver, Bone, or other distant sites
V Bilateral renal involvement

NWTS = National Wilms’ Tumor Study
NWTS Staging Principles
Staged following surgery and before chemotherapy
Worse prognosis in NWTS trials with LN+
Hemorrhage or hematoma before or during surgery is thought to worsen prognosis
If given preoperative chemotherapy due to unresectability, tumor is at least Stage III
If a pulmonary density is detected on CT only (but not chest x-ray), use abdominal tumor stage or else confirm metastasis with a biopsy (controversial).

  • The most critical factor between the NWTS and SIOP renal tumor staging is that the NWTS is a “Pretherapy stage” and the SIOP is a “Post therapy stage” in which tumors are often “Downstaged” by prior chemotherapy or radiotherapy.

SIOP Staging

Stage Description
I Tumor limited to the kidney, complete excision
II Tumor extending outside the kidney, complete excision
Invasion of regional lymph nodes (IIN1)
Invasion of ureter or extrarenal vessels
III Invasion beyond the capsule with incomplete excision
Preop or periop Bx or rupture
Peritoneal mets
Invasion of para-aortic LN below renal artery
IV Distant metastases
V Bilateral renal tumors

Poor Prognostic Factor

Patient Related

  • Age > 2

Tumor Related

  • Lymph node positive - Most important prognostic factor
  • UnFavorable Histology
  • Stage (III and IV)
  • Tumor mass > 550 g
  • Loss of Heterozygosity (LOH) at 1p or 16q
  • DNA Index > 1.50 (positive) – under investigation

Treatment Related

  • Incomplete resection
  • Treatment started after post-op day 9

Treatment

Stage Treatment
I, FH, age>2 and tumor < 550 g Surgery Only (Follow with CXR and Abd US q 3 mo x 1 yr)
I, FH (others); I, Anaplastic; II, FH 24 wks Pulse Intensive VA, no XRT
III, FH; IV, FH with abdominal stage III 24 wks Pulse Intensive VAA and 1080 cGy XRT
II-IV, Focal anaplasia 24 wks P/I VAA and 1080 cGy XRT
I-IV, Clear Cell Sarcoma; II-IV, Diffuse anaplasia Vincristine, adriamycin, VP-16, Cytoxan and 1080 cGy XRT
I-IV Rhabdoid Tumor Carboplatin, VP-16, Cytoxan and 1080 cGy XRT

Treatment Timing

  • Surgical resection (nephrectomy)
  • RT as needed < 14 days post resection
    • Lung field given separately from abdominal field
  • VA given concurrently with RT
    • Vincristine and D-actinomycin
  • VAA x 4 cycles after RT
    • vincristine, actinomycin, and adriamycin.

RT, Indications

  • Favorable histology, Stage III
  • Favorable histology, Stage IV with abdominal stage III
  • Focal and diffuse anaplastic, Stage II-IV
  • Clear Cell Sarcoma and Rhabdoid Tumor, Stage I-IV

RT, Technique

FLANK

FLANK

Flank Radiation Portals

  • Outline of kidney + tumor with 1 cm margin
  • Extend across midline to include vertebral body and bilateral para-aortic LN’s

RT Dose and Timing

  • Commonly 180 cGy x 6 fractions (1080 cGy) – All histological subtypes are treated to 1000 cGy
  • Radiation Therapy should commence by Post-op Day 9 (patient must be stable)

Indications for flank radiation

  • LN+
  • Residual Tumor
  • Local operative spill
  • Stage II-IV anaplastic histology
  • Stage I-IV clear cell and rhabdoid tumor

WHOLE ABDOMINAL

WAR

Whole Abdomen Portal

  • Diaphragms to inferior obturator foramina
  • Shield femoral heads
  • If there is residual bulk disease after surgery (>3 cm), can do a coned down boost field with a 1 cm margin.

RT Dose and Timing

  • Commonly 180 cGy x 6 fractions (1080 cGy) – All histological subtypes are treated to 1000 cGy
  • Radiation Therapy should commence by Post-op Day 9 (patient must be stable)

Indications for Whole Abdominal

  • Peritoneal seeding
  • Preoperative intraperitoneal rupture
  • Diffuse operative spill

LUNG

LUNG

Lung Portals

  • encompass both apices as well as posterior inferior extent of the lungs
  • average field extends above the clavicles to L1
  • shoulders are excluded and avoid uninvolved kidney

Dose and Timing

  • Bilateral whole lungs to 1200 cGy (8 fractions)
  • Treat separately from the abdominal field (so need to feather)

RT Indications for Lung Radiation

  • Lung metastasis found on CXR (not CT!)
  • If residual mets 2 weeks after tx, can give additional 750 cGy or else surgery

Liver mets

  • Completely resected – no xrt
  • Incomplete/unresected – 2 cm margin
  • Diffuse disease – 1980 cGy to entire liver with smaller boost volumes of 540 to 1080 cGy.

Others mets

  • (distant LN, bone, brain) – 3060 cGy

Infants

  • < 18 months old get a trial of chemo first

Outcome

Complications

  • Acute Effects of Radiation
  • Nausea/vomiting/diarrhea
  • Myelosuppression
  • Late Effects of Radiation
  • Second malignancy (6% at 20 yrs in NWTS)
  • Scoliosis, soft tissue hypoplasia, ovarian failure, azospermia
  • Chemotherapy-specific Effects
  • Especially CHF (due to adriamycin)

Summary

  • Wilms’ Tumor is the most common childhood GU malignancy.
  • Surgery is the initial treatment option and the basis for the NWTS Staging System.
  • The NWTS trials have resulted in an excellent survival (90%) for most children with this disease.
  • Risk stratification has allowed us to achieve this improved survival while reducing therapy for low risk patients and minimizing the side effects associated with the treatment.

Studies

NWTS-1

  • 333 randomized patients, 1969-1973
  • Major conclusions
  • Stage I FH: Post-op flank XRT is not necessary in children < 2 years old.
  • Stage II-III: Vincristine + actinomycin D (VA) is more effective than either drug alone.
  • Stage IV: Preoperative vincristine does not improve relapse free or overall survival.

NWTS-2

  • 513 randomized patients, 1974-1978
  • Major conclusions
  • Stage I FH: VA chemotherapy for 6 months has equivalent 2-yr RFS vs. 15 months.
  • Stage II-IV: Addition of adriamycin to VA chemotherapy (VAA) improved 2-yr RFS.
  • LN+ worsens prognosis (2-yr RFS 54% vs. 82%)
  • Staging was adjusted to reflect this prognostic significance.

NWTS-3

  • 1979-1986
  • Major conclusions
  • Stage II FH: There was no benefit with the addition of Adriamycin or XRT to 15 mos. of VA chemotherapy.
  • Stage III FH: Addition of adriamycin to VA was superior to VA alone, and VAA + 1000 cGy of Abdominal XRT was equivalent to VA + 2000 cGy.
  • Major Conclusions (continued)
  • Stage IV FH: Addition of cyclophosphamide to VAA did not improve results
  • Stage IV UH: Addition of cyclophosphamide to VAA was superior to VAA alone, for all UH except focal anaplasia

NWTS-4

  • 1986-1994
  • Focused on socioeconomic issues and decreasing treatment length
  • Major conclusions
  • Pulse-intensive regimens are as effective as standard regimens.
  • Stage II-IV FH and Stage I-IV Clear Cell Sarcoma: 6 months of chemotherapy was as effective as 15 months of chemotherapy.

NWTS-5

NWTS-5 will not randomize patients

  • Focus is on tumor genetics and risk stratification
  • Loss of heterozygosity at 16q or 1p is thought to be a negative prognostic factor
  • DNA Index > 1.5 is thought to be a negative prognostic factor

SIOP 6

Eligibility (subgroup)

  • stage II N0 (Post chemotherapy but would have been stage III due to margins+ or LN+).

Treatment

  • preoperative chemotherapy (Vcr & ActD) for children
  • surgery
  • post-surgical radiotherapy 20 Gy (randomized)

Results

Treatment Local Relpases
20 Gy 0 of 58
No XRT 6 of 50

Conclusion

  • Study closed early based on results
  • Down staging due to chemotherapy does not eliminate the necessity for radiation.
    • Prenephrectomy (chemotherapy) altered pathologic findings
    • ie. patients who would have been margins+ or lymph nodes+ became stage II N0
    • the down staging lead to reduced therapy (ie. XRT) and increased local failure
Bibliography
1. Cox J, Ang K. Radiation Oncology: rationale Technique Results. 8th ed. New York: Mosby, 2003.
2. Gunderson L, Tepper J: Clinical Radiation Oncology. 2nd ed. China: Elsevier 2007.
3. Devita V, Hellman S, Rsenberg S: Cancer: Principles and practice of Oncology. 7th ed. Philadelphia: Lippincott, 2005.
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