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Title: Dr: NASHWA NAZMY ABDELAZIZ,M.D


1

WILMS TUMOR    
  • Dr NASHWA NAZMY ABDELAZIZ,M.D
  • Radiation Oncology and nuclear Medicine Dept.
  • Faculty of Medicine, Ain Shams University.

2
PEDIATRIC TUMORSEwing's Sarcoma,Neuroblastoma
and Wilms tumor
  • John A. Kalapurakal MD
  • Associate Professor, Radiation Oncology
  • Northwestern University Medical School
  • Chicago, Illinois

3
REFERENCS
  • ASTRO 2006-2007
  • NCI PEDIATRIC TUMORS GUIDELINES 2008
  • GUNDERSON
  • Radiotherapy in practice EBRT by Peter Hoskin
  • Evidence based Radiation Oncology
  • Practical RT Planning by Jane Dobbs,Ann Barret,
    and Ash Dan

4
Incidence of common tumors
  • Approximately
  • 12,400 childhood -cancer cases annually in the
    U.S.
  • Leukemia, 3100
  • Brain Tumors, 2100
  • Hodgkin'sDisease, 1100
  • ST Sarcomas, 920
  • Bone Tumors, 690
  • Neuroblastoma, 670
  • Wilm's Tumor, 520

5
5y os
  • Hepatic Tumor135
  • Retinoblastoma 3
  • Renal Tumor (WT) 6
  • Sympathetic Nervous 7 System (NB)
  • Bone Sarcoma (ES) 5
  • SoftTissue 6
  • Sarcoma (RMS)
  • Germ Cell Tumor 3
  • Carcinoma
  • Lymphoma (HD) 14
  • Brain Tumor 18
  • Leukemias 31
  • Others 7
  • 59
  • 93
  • 92
  • 64
  • 58
  • 64
  • 87
  • 90
  • 91
  • 65
  • 77

6
LEARNING OBJECTIVES
  • Present an overview of epidemiology,
  • pathology and clinical presentation
  • Explain current evaluation and staging
  • Review current treatment guidelines with
    emphasis on radiation therapy
  • Discuss treatment results and toxicities

7
Annual Incidence Rates (per million children lt5
years) and Percent distribution in U.Schildren
8
WILMS TUMOR
  • Most common malignant renal tumor of
  • childhood
  • Approximately 500 cases annually in the US
  • Peak incidence between 3 and 4 years
  • In few children occurs as part of a congenital
    malformation syndrome (WAGR, Denys- Drash,
    Beckwith-Wiedemann)

9
WILMS TUMOR
  • Sotos' syndrome (characterized by cerebral
    gigantism), and
  • Simpson-Golabi-Behemel syndrome (characterized
    by macroglossia, macrosomia, renal and skeletal
    abnormalities, and increased risk of embryonal
    cancers).
  • Klippel-Trénaunay syndrome, a unilateral limb
    overgrowth syndrome, is not associated with
    Wilms' tumor.
  • Examples of non overgrowth syndromes associated
    with Wilms' tumor (42 Wilms' tumor incidence)
    are isolated aniridia trisomy 18 Wilms' tumor,
    aniridia, ambiguous genitalia, and mental
    retardation (WAGR) syndrome Bloom's syndrome,
    and

10
WILMS TUMOR
  • Denys-Drash syndrome (characterized by
    intersexual disorders, nephropathy, and Wilms'
    tumor).
  • The constellation of WAGR syndrome occurs in
    association with an interstitial deletion on
    chromosome 11 (del 11p 13).
  • Children with pseudo-hermaphroditism and/or
    renal disease (glomerulonephritis or nephrotic
    syndrome) who develop Wilms' tumor may have the
    Denys-Drash or Frasier syndrome (characterized by
    male hermaphroditism, primary amenorrhea, chronic
    renal failure, and other abnormalities), both of
    which are associated with mutations in the WT1
    gene at chromosome 11p13. Children with a
    predisposition to develop Wilms tumor (e.g.,
    Beckwith-Wiedemann syndrome, hemihypertrophy, or
    aniridia) should be screened with ultrasound
    every 3 months until they reach 8 years.

11
WILMS TUMOR Pathology
  • Most are solitary lesions 12 may be multifocal
    7 may involve both kidneys
  • Gross appearance WT has uniform pale gray
    color with hemorrhage and necrosis
  • Soft and friable and can be easily ruptured
    (spontaneous or iatrogenic)

12
WILMS TUMOR
13
WILMS TUMOR
  • Classic WT is triphasic with 3 cell types
  • blastemal, stromal and epithelial
  • HP appearance correlates with prognosis
  • 90 are of FH subtype
  • 3 entities under UH subtypes (NWTS)
  • Anaplasia, CCSK, rhabdoid tumor of kidney (RTK)

14
WILMS TUMOR
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16
WILMS TUMOR
  • Anaplasia presence of large nuclei,
  • hyperchromasia and mitotic figures
  • Anaplasia may be focal or diffuse
  • Observed in 5 of WT
  • CCSK and RTK are not considered WT

17
WILMS TUMOR
  • Although most patients with a histologic
    diagnosis of Wilms tumor fare well with current
    treatment, approximately 10 of patients have
    histopathologic features that are associated with
    a poorer prognosis, and, in some types, with a
    high incidence of relapse and death. Wilms tumor
    can be separated into 2 prognostic groups on the
    basis of histopathology
  •                  Favorable histology
    Histologically mimics development of a normal
    kidney consisting of 3 cell types blastemal,
    epithelial (tubules), and stromal. Not all tumors
    are triphasic, and monophasic patterns may
    present diagnostic difficulties. There is no
    anaplasia in the tumor.
  •                  Anaplastic histology May be
    focal or diffuse (extreme cellular pleomorphism
    and atypia). Focal anaplasia does not confer a
    poor prognosis, while diffuse anaplasia does
    (except for stage I). Focal anaplasia is defined
    as the presence of one or a few sharply localized
    regions of anaplasia within a primary tumor

18
  • Anaplastic histology
  • Anaplastic histology is the single most important
    histologic predictor of response and survival in
    patients with Wilms tumor. There are two
    histologic criteria for anaplasia, both of which
    must be present for the diagnosis. They are the
    presence of multipolar polyploid mitotic figures
    with marked nuclear enlargement and
    hyperchromasia. Anaplasia correlates best with
    responsiveness to therapy rather than to
    aggressiveness. It is most consistently
    associated with poor prognosis when it is
    diffusely distributed and when identified at
    advanced stages. This is the reason why focal
    anaplasia and diffuse anaplasia are
    differentiated, both pathologically and
    therapeutically.
  • Anaplasia is associated with resistance to
    chemotherapy and may still be detected after
    preoperative chemotherapy.

19
WILMS TUMOR
  • Clear Cell Sarcoma
  • Clear cell sarcoma of the kidney (CCSK) is not a
    Wilms tumor variant, but it is an important
    primary renal tumor associated with a
    significantly higher rate of relapse and death
    than favorable histology Wilms tumor. In
    addition to pulmonary metastases, clear cell
    sarcoma also spreads to bone, brain, and soft
    tissue.
  • The classic pattern of CCSK is defined by nests
    or cords of cells separated by regularly spaced
    arborizing fibrovascular septa.

20
WILMS TUMOR
  • Rhabdoid Tumor of the Kidney
  • Initially thought to be a rhabdomyosarcomatoid
    variant of Wilms tumor, it is a distinctive and
    highly malignant tumor type. The most distinctive
    features of rhabdoid tumors of the kidney are
    rather large cells with large vesicular nuclei, a
    prominent single nucleolus, and in some cells,
    the presence of globular eosinophilic cytoplasmic
    inclusions. The cell of origin is unknown. A
    distinct clinical presentation with fever,
    hematuria, young age (mean 11 months), and high
    tumor stage at presentation suggests a diagnosis
    of rhabdoid tumor of the kidney (RTK). RTK tends
    to metastasize not only to the lungs, but also to
    the brain. As many as 10 to 15 of patients with
    RTK also have central nervous system lesions.

21
WILMS TUMOR
  • Neuroepithelial Tumors of the Kidney
  • Neuroepithelial tumors of the kidney (NETK) are
    extremely rare and demonstrate a unique
    proclivity for young adults. It is a highly
    aggressive neoplasm, more often presenting with
    penetration of the renal capsule, extension into
    the renal vein, and metastases.
  • Primary NETK consist of primitive
    neuroectodermal tumors characterized by CD99
    (MIC-2) immunostaining and the EWS/FLI-1 or
    closely related gene fusion products and small
    cell carcinomas characterized by chromogranin
    positivity. The 2 subtypes may be difficult to
    distinguish. Within both types of NETK, focal,
    atypical histologic features have been seen
    including clear cell sarcoma, rhabdoid tumor,
    malignant peripheral nerve sheath tumors, and
    paraganglioma

22
WILMS TUMOR
  • Cystic Partially Differentiated Nephroblastoma
  • Cystic partially differentiated nephroblastoma is
    a rare cystic variant of Wilms' tumor (1) with
    unique pathologic and clinical characteristics.
    Several pathologic features distinguish this
    neoplasm from standard Wilms' tumor. Patients
    with stage I disease have a 100 survival rate
    with surgery alone. Patients with stage II
    disease have an excellent outcome with tumor
    resection followed by postoperative vincristine
    and dactinomycin

23
WILMS TUMOR
  • Natural History
  • WT often localized at diagnosis, as surgery and
    RT curative in 50
  • Local spread into the renal sinus or the
  • intrarenal blood and lymphatic vessels
  • Spread to peritoneal cavity may occur, gt after
    ,pre or intraoperative rupture
  • Common sites of metastases - lungs (80),
  • lymph nodes, and liver, rarely brain

24
WILMS TUMOR
  • Clinical Presentation
  • Most present with abdominal swelling
  • Pain, hematuria and fever may be present
  • Hypertension (?renin) in 25
  • Signs of Wilms tumor associated syndromes
  • aniridia, hemihypertrophy, GU
    abnormalitieshypospadias, cryptorchidism and
  • pseudohermaphroditism

25
WILMS TUMOR
  • Work Up
  • HP
  • Blood and Urine
  • Imaging Ultrasound, CT scan, MRI, Bone
  • scan (CCSK), MRI brain (CCSK,RTK)
  • Reveals an intrarenal SOL, presence of
  • thrombus in IVC, LN, bilateral tumors,
  • distant metastases
  • RTK second primary ATRT posterior fossa
  • (10-15)

26
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27
WILMS TUMOR
28
WILMS TUMOR
29
WILMS TUMOR
  • Stage I (43 of patients)
  • In stage I Wilms tumor, all of the following
    criteria must be met
  • Tumor is limited to the kidney and is completely
    resected.
  • The renal capsule is intact.
  • The tumor is not ruptured or biopsied prior to
    removal.
  • No involvement of renal sinus vessels.
  • No evidence of the tumor at or beyond the margins
    of resection.
  •  Note For a tumor to qualify for certain
    therapeutic protocols as stage I, regional lymph
    nodes must be examined microscopically.

30
WILMS TUMOR
  • Stage II (20 of patients)
  • In stage II Wilms tumor, the tumor is completely
    resected, and there is no evidence of tumor at or
    beyond the margins of resection. The tumor
    extends beyond the kidney as evidenced by any one
    of the following criteria
  • There is regional extension of the tumor (i.e.,
    penetration of the renal sinus capsule, or
    extensive invasion of the soft tissue of the
    renal sinus, as discussed below).
  • Blood vessels within the nephrectomy specimen
    outside the renal parenchyma, including those of
    the renal sinus, contain tumor.
  •  Note Rupture or spillage confined to the
    flank, including biopsy of the tumor, is no
    longer included in stage II and is now included
    in stage III.

31
WILMS TUMOR
  • Stage III (21 of patients)
  • In stage III Wilms tumor, there is residual
    nonhematogenous tumor present following surgery
    that is confined to the abdomen. Any one of the
    following may occur
  • Lymph nodes within the abdomen or pelvis are
    involved by tumor. (Lymph node involvement in the
    thorax or other extra-abdominal sites is a
    criterion for stage IV.)
  • The tumor has penetrated through the peritoneal
    surface.
  • Tumor implants are found on the peritoneal
    surface.
  • Gross or microscopic tumor remains
    postoperatively (e.g., tumor cells are found at
    the margin of surgical resection on microscopic
    examination).
  • The tumor is not completely resectable because of
    local infiltration into vital structures.
  • Tumor spillage occurs either before or during
    surgery.
  • The tumor is treated with preoperative
    chemotherapy and was biopsied (using tru-cut
    biopsy, open biopsy, or fine-needle aspiration)
    before removal.
  • The tumor is removed in more than one piece
    (e.g., tumor cells are found in a separately
    excised adrenal gland a tumor thrombus within
    the renal vein is removed separately from the
    nephrectomy specimen). Extension of the primary
    tumor within vena cava into thoracic vena cava
    and heart is considered stage III, rather than
    stage IV even though outside the abdomen.

32
WILMS TUMOR
  • Stage IV (11 of patients)
  • In stage IV Wilms tumor, hematogenous metastases
    (lung, liver, bone, brain), or lymph node
    metastases outside the abdominopelvic region are
    present. (The presence of tumor within the
    adrenal gland is not interpreted as metastasis
    and staging depends on all other staging
    parameters present.)
  • Stage V (5 of patients)
  • In stage V Wilms tumor, bilateral involvement by
    tumor is present at diagnosis. An attempt should
    be made to stage each side according to the above
    criteria on the basis of the extent of disease.
    The 4-year survival is 94 for those patients
    whose most advanced lesion is stage I or stage
    II, and 76 for those whose most advanced lesion
    is stage III.

33
WIL MS TUMOR COG Staging Surgical
  • Staging
  • I Tumor limited to kidney and completely
    excised. No penetration of capsule or involvement
    of renal sinus vessels
  • II Tumor extends beyond kidney but is
    completely excised. There is
  • penetration of capsule or involvement of renal
    sinus vessels
  • III Residual tumor remains after surgery lymph
    nodes involved, local spillage or needle biopsy,
    diffuse peritoneal contamination, peritoneal
    implants found, surgical margins positive-either
    microscopically or grossly, transected tumor
    thrombus, piecemeal resection, unresectable tumor
  • IV Hematogenous metastases to lung, liver,
    bone, brain or lymph node metastasis outside the
    abdomen
  • V Bilateral Wilms tumor

34
WILMS TUMOR Prognostic Factors Tumor
Stage Tumor Histology Age Children lt 24
months Molecular markers LOH at 1p and 16q
Telomerase expression
35
WILMS TUMOR LOH at 1 p and 16q
  • NWTS-5 prospectively analyzed prognostic
  • value
  • RR for relapse for LOH at both regions -
  • significantly higher in stage I/II and stage
  • III/IV FH (vs no or either LOH)
  • RR for death for LOH at both regions
    significantly higher in stage I/II and stage
    III/IV FH (vs no or either LOH)

36
WILMS TUMOR Joint effect of LOH 1p and 16q
for Stage I/II FH
37
Treatment Option Overview
  • Wilms tumor
  • Because of the relative rarity of this tumor, all
    patients with Wilms tumor should be considered
    for entry into a clinical trial. Treatment
    planning by a multidisciplinary team of cancer
    specialists (pediatric surgeon or pediatric
    urologist, pediatric radiation oncologist, and
    pediatric oncologist) with experience treating
    Wilms tumor is required to determine and
    implement optimum treatment.
  • The National Wilms Tumor Study Group, which is
    now part of the Childrens Oncology Group, has
    established standard treatment for Wilms tumor
    in North America which consists of surgery
    followed by chemotherapy and, in some patients,
    radiation therapy. The major treatment
    conclusions of the National Wilms Tumor Studies
    (NWTS 1-4) are

38
conclusions of the National Wilms Tumor Studies
(NWTS 1-4) are
  • 1.       Routine, postoperative radiation therapy
    of the flank is not necessary for children with
    stage I tumors or stage II tumors with favorable
    histology (FH) when postnephrectomy combination
    chemotherapy consisting of vincristine and
    dactinomycin is administered.
  • 2.       The prognosis for patients with stage
    III/FH is best when treatment includes (a)
    dactinomycin, vincristine, doxorubicin, and 1,080
    cGy of radiation therapy to the flank or (b)
    dactinomycin, vincristine, and 2,000 cGy of
    radiation therapy to the flank.

39
conclusions of the National Wilms Tumor Studies
(NWTS 1-4) are
  • 3.       The addition of cyclophosphamide to the
    combination of vincristine, dactinomycin, and
    doxorubicin does not improve prognosis for
    patients with stage IV/FH tumors.
  • 4.       Single-dose (pulse-intensive) treatment
    with dactinomycin (stages I-II/FH, stage I
    anaplastic), and doxorubicin (stage III/FH,
    stages III-IV, or stages I-IV clear cell sarcoma
    of the kidney) is equivalent to the divided-dose
    courses, and results in the same event-free
    survival, greater dose intensity, and is
    associated with less toxicity and expense.

40
conclusions of the National Wilms Tumor Studies
(NWTS 1-4) are
  • 5.       Eighteen weeks of therapy is adequate
    for patients with stage I/FH whereas other
    patients can be treated with 6 months of therapy
    instead of 15 months.
  • 6.       Tumor-specific loss of heterozygosity
    for combined 1p and 16q predicts recurrence of FH
    Wilms' tumor and may be used to select patients
    for more aggressive treatment.

41
  • Operative principles have evolved from NWTS
    trials. The most important role for the surgeon
    is to ensure complete tumor removal without
    rupture and perform an assessment of the extent
    of disease. Radical nephrectomy-lymph node
    sampling via a transabdominal incision is the
    procedure of choice. Partial nephrectomy remains
    controversial and is not recommended in the
    NWTS-5 guidelines. Rarely, very small tumors may
    be discovered by ultrasound screening, and these
    cases may be considered for partial nephrectomy

42
  • Hilar, periaortic, iliac, and celiac lymph node
    sampling is mandatory. Furthermore, any
    suspicious node basin should be sampled. Margins
    of resection, residual tumor, and any suspicious
    node basins should be marked with titanium clips.
    Liver wedge resection or partial duodenal or
    colonic resections are acceptable for complete en
    bloc excision. Wilms tumor arising in a
    horseshoe kidney is rare and accurate
    preoperative diagnosis is important in planning
    the operative approach. Primary resection is
    possible in most cases. Inoperable cases can
    usually be resected after chemotherapy.

43
  • Patients with massive, nonresectable unilateral
    tumors, bilateral tumors, or venacaval tumor
    thrombus above the hepatic veins are candidates
    for preoperative chemotherapy because of the risk
    of initial surgical resection. Preoperative
    chemotherapy should follow a biopsy, which may be
    performed percutaneously.
  • Preoperative chemotherapy makes tumor removal
    easier and may reduce the frequency of surgical
    complications.
  • Current therapy in North America for patients
    diagnosed by needle biopsy alone is for a stage
    III tumor (in the absence of metastases) of
    favorable or anaplastic histology.

44
  • Newborns and all infants younger than 12 months
    require a reduction in chemotherapy doses to 50
    of those given to older children.
  • This reduction diminishes toxic effects reported
    in children in this age group enrolled in NWTS
    studies while maintaining an excellent overall
    outcome.
  • Liver function tests in children with Wilms
    tumor should be monitored closely during the
    early course of therapy based on hepatic toxic
    effects (veno-occlusive disease) reported in
    those patients

45
  • Dactinomycin should not be administered during
    radiation therapy. Children treated for Wilms
    tumor are at increased risk for developing second
    malignant neoplasms. This risk depends on the
    intensity of their therapy, including the use of
    radiation and doxorubicin, and on possible
    genetic factors
  • Congestive heart failure has been shown to be a
    risk in children treated with doxorubicin with
    the degree of risk influenced by cumulative
    doxorubicin dose, radiation to the heart, and
    gender (females at increased risk).

46
WILMS TUMOR
  • WT-Surgery
  • Initial treatment for most children in the US
  • Transperitoneal approach, abdominal
    exploration, opposite kidney, and LN sampling,
    Radical nephrectomy
  • WT are large and compress adjacent organs
  • without invasion
  • Radical en bloc resections of adjacent organs
    not recommended
  • Precautions to avoid tumor spillage

47
WILMS TUMOR
  • NWTS-1 (1969-1974)
  • Role of RT in group I WT patients ?
  • Postoperative RT not necessary for children lt
    2 years of age with group I tumors receiving AMD
  • RFS with AMD VCR for irradiated group II, III
    children was better than that with either agent
    alone

48
WILMS TUMOR
  • NWTS-2 (1974-1979)
  • Addition of VCR to AMD eliminate the need for
    RT
  • in group I patients ?
  • Age (lt 2 vs gt 2 yrs) did not influence outcome
  • RFS in children gt 2 yrs was 89 compared to 77
  • (RT) and 58 (-RT) in NWTS-1
  • RT not recommended in group I tumors
  • Chemotherapy duration (6 months or 15 months)
  • did not influence survival

49
WILMS TUMOR
  • NWTS-2 (1974-1979)
  • Group II-IV tumors had superior RFS with ADR to
    AMDVCR
  • Histology As in NWTS-1 UH tumors had poorer
    outcomes

50
WILMS TUMOR
  • NWTS-1 and 2
  • Age-adjusted dose schedule was employed for
    flank RT
  • lt18 months of age - 18-24 Gy
  • 19-30 months - 24-30 Gy
  • 31-40 months - 30-35 Gy
  • gt 40 months - 35-40 Gy

51
WILMS TUMOR
  • NWTS-3 (1979-1985)
  • Role of RT in stage II FH patients ?
  • Dose of RT in stage II-III FH patients ?
  • Stage II FH tumors do not need RT or ADR to VCR
    AMD
  • Stage III FH tumors 10 Gy ADR, AMD,VCR had
    similar local control rates as 20 Gy
  • RT and ADR were eliminated in gt 60 and RT dose
    reduced from 40 Gy to 10 Gy

52
WILMS TUMOR
  • NWTS 1-5
  • RT delay of gt10 was associated withpoor outcome
    especially in UH tumors
  • The borders of the field were defined initially
    by IVP, but later by CT volume
  • NWTS 3-5 superior border need not extend up to
    the dome of the diaphragm

53
WILMS TUMOR
  • Anaplastic Wilms Tumor
  • NWTS-5 281 of 2596 patients (11)
  • 4-year RFS and OS for stage I (VCR, AMD alone)
    70 and 83
  • 4-year RFS for stages II, III and IV tumors
    were 83, 65 and 33
  • COG study augment therapy for stage I, III and
    IV tumors

54
WILMS TUMOR Long-term results of NWTS-3 and -4
55
  • The SIOP studies have used primarily
    preoperative therapy. The first SIOP trial
    found that preoperative irradiation reduced the
    incidence of tumor spillage but did not
    increase survival.
  • SIOP-5, reported in 1983, showed that
    preoperative vincristine was as effective
    as preoperative irradiation plus dactinomycin in
    preventing tumor rupture.

56
  • In SIOP-6, all patients received preoperative
    chemotherapy and were randomly assigned by
    operative stage. Patients with stage I disease
    were randomly assigned to either 17 or 38 weeks
    of vincristine and dactinomycin and showed no
    difference in survival.
  • Stage II patients with negative lymph nodes
    (SIOP staging is not identical to NWTS
    staging) were randomly assigned to receive or
    not receive radiation therapy. Seven of 50
    nonirradiated patients relapsed below the
    diaphragm, compared with 1 of 58 irradiated
    patients.

57
  • In SIOP-9, there was a randomization as
    to the length of prenephrectomy therapy with
    vincristine and dactinomycin (4 versus 8
    weeks). No advantage was noted for 8 weeks of
    therapy.
  • The current protocol, SIOP-93-01, gives no
    further therapy for patientswith stage I tumors
    after preoperative chemotherapy and nephrectomy,
    provided the tumors are considered low grade
    by SIOP pathologists.
  • Patients with high-grade tumors and higher
    stages are given more intensive therapy.

58
WILMS TUMOR
  • Current Clinical Treatment Guidelines
  • COG protocol will use LOH at both 1p and
  • 16q in addition to tumor stage and pathology
    for tumor-risk groups stratification
  • Goal reduce treatment-related toxicity
    inlow-risk tumors and increase treatment
    intensity of high-risk tumors

59
WILMS TUMOR Stage I
  • Regardless of histology, all stage I Wilms tumor
    patients have an excellent prognosis with the
    same treatment.
  • Favorable-histology (FH) tumors (the 4-year
    relapse-free survival RFS rate is 92, and the
    4-year survival rate is 98)
  •                  Nephrectomy with lymph node
    sampling and 18 weeks of chemotherapy with
    vincristine and pulse-intensive dactinomycin
    (NWTS Regimen EE-4A).
  • Focal or diffuse anaplasia (the 2-year RFS rate
    is 86, and the 2-year survival rate is 85.5)
  •                  Nephrectomy with lymph node
    sampling and 18 weeks of chemotherapy with
    vincristine and pulse-intensive dactinomycin.

60
WILMS TUMOR Stage II
  • Favorable-histology tumors (the 4-year
    relapse-free survival rate is 85, and the 4-year
    survival rate is 96)
  •                  Nephrectomy with lymph node
    sampling and 18 weeks of chemotherapy with
    vincristine and pulse-intensive dactinomycin.
  • Focal anaplasia
  •                  Nephrectomy with lymph node
    sampling, abdominal radiation, and 24 weeks of
    chemotherapy with vincristine, doxorubicin, and
    pulse-intensive dactinomycin.
  • Diffuse anaplasia (the 4-year survival rate is
    70)
  • Nephrectomy with lymph node sampling, abdominal
    radiation, and 24 weeks of chemotherapy with
    vincristine, doxorubicin, etoposide,
    cyclophosphamide, and mesna.

61
WILMS TUMOR Stage III
  • Favorable-histology tumors (the 4-year
    relapse-free survival rate is 90, and the 4-year
    survival rate is 95) with or without focal
    anaplasia
  •                  Nephrectomy with lymph node
    sampling, abdominal radiation, and 24 weeks of
    chemotherapy with vincristine, doxorubicin, and
    pulse-intensive dactinomycin (NWTS Regimen
    DD-4A).
  • Diffuse anaplasia (the 4-year survival rate is
    56)
  • Nephrectomy with lymph node sampling, abdominal
    radiation, and 24 weeks of chemotherapy with
    vincristine, doxorubicin, etoposide,
    cyclophosphamide, and mesna (NWTS Regimen I).

62
WILMS TUMOR Stage IV
  • Favorable-histology tumors (the 4-year
    relapse-free survival rate is 80, and the 4-year
    survival rate is 90)
  •                  Nephrectomy with lymph node
    sampling, abdominal radiation according to local
    stage of renal tumor, bilateral pulmonary
    radiation for patients with chest x-ray evidence
    of pulmonary metastases, and 24 weeks of
    chemotherapy with vincristine, doxorubicin, and
    pulse-intensive dactinomycin.
  • Focal anaplasia
  •                  Nephrectomy with lymph node
    sampling, abdominal radiation according to local
    stage of renal tumor, bilateral pulmonary
    radiation for patients with chest x-ray evidence
    of pulmonary metastases, and 24 weeks of
    chemotherapy with vincristine, doxorubicin, and
    pulse-intensive dactinomycin.
  • Diffuse anaplasia (the 4-year survival rate is
    17)
  • Nephrectomy with lymph node sampling, abdominal
    radiation, whole-lung radiation for patients with
    chest x-ray evidence of pulmonary metastases, and
    24 weeks of chemotherapy with vincristine,
    doxorubicin, etoposide, cyclophosphamide, and
    mesna

63
WILMS TUMOR
  • Stage V Wilms Tumor
  • The treatment of children with bilateral Wilms'
    tumor must be individualized. The goals of
    therapy are to eradicate all tumor and to
    preserve as much normal renal tissue as possible
    with the hope of decreasing the risk of chronic
    renal failure among these children.
  • Studies demonstrate no difference in survival
    for children who undergo initial bilateral biopsy
    followed by chemotherapy and then surgical
    resection compared with patients who have initial
    resection followed by chemotherapy.

64
WILMS TUMOR Stage V Wilms Tumor
  • Initially, patients should undergo bilateral
    renal biopsies with staging of each kidney.
    Primary tumor excision should not be attempted,
    but patients should be given preoperative
    chemotherapy. Initial treatment is with
    vincristine and dactinomycin (NWTS Regimen EE-4A)
    if the renal tumors are of favorable histology
    and not more extensive than stage II. Those with
    higher stage and favorable histology disease
    should receive doxorubicin, vincristine, and
    dactinomycin (NWTS Regimen DD-4A), and those with
    anaplastic histology should receive
    cyclophosphamide in addition to vincristine,
    doxorubicin, and etoposide (NWTS Regimen I).
  • Following 6 weeks of chemotherapy, the patient
    should be reassessed. If serial imaging studies
    show no further reduction in tumor, a second-look
    surgical procedure should be performed (partial
    nephrectomy or wedge excision) if negative
    margins can be obtained otherwise, another
    biopsy should be done to confirm viable tumor.

65
WILMS TUMOR Stage V Wilms Tumor
  • Chemotherapy and/or radiation therapy following
    the second-look operation is dependent on the
    response to initial therapy, with more aggressive
    therapy required for patients with inadequate
    response to initial therapy observed at the
    second procedure.
  • Approximately 10 of patients with bilateral
    tumors have anaplastic histology and may benefit
    from more aggressive chemotherapy and radiation
    therapy and an aggressive surgical approach at
    the second-look operation.

66
  • Stage V Wilms tumor
  • Renal transplantation for children with Wilms
    tumor is usually delayed until 1 to 2 years have
    passed without evidence of malignancy.
  • Similarly, renal transplantation for children
    with Denys-Drash syndrome and Wilms tumor, all of
    whom require bilateral nephrectomy, is generally
    delayed 1 to 2 years after completion of
    treatment for the tumor.

67
WILMS TUMOR Inoperable Tumors
  • Treatment Options
  • Patients who have tumors with caval extension
    above the hepatic veins or that are so massive
    that their surgeons consider the risk of initial
    surgical removal too great should be biopsied and
    treated with preoperative chemotherapy.
  • If surgery is performed on a patient with caval
    or atrial extension, care should be taken to
    ensure that appropriate resources are available
    for pediatric cardiopulmonary bypass.
  • On the National Wilms Tumor Study-5 (NWTS-5),
    these patients are treated after biopsy by
    initial chemotherapy with vincristine and
    dactinomycin with or without doxorubicin. If no
    reduction in tumor size has occurred after using
    3 drugs, then radiation therapy should be used.

68
WILMS TUMOR Inoperable Tumors
  • Surgery is performed as soon as sufficient tumor
    shrinkage has occurred, generally at week 6 of
    therapy. If resection of the tumor cannot occur
    at this time, the patient should undergo a
    second-look procedure to confirm a persistent
    tumor. Failure of the tumor to shrink could be a
    result of a predominance of skeletal or benign
    elements. Patients are subsequently treated as
    for stage III tumors, which includes
    postoperative radiation therapy.
  • Because of the 5 to 10 error rate in
    preoperative diagnosis of renal masses after
    radiographic assessment, confirmation of the
    diagnosis by biopsy (which may be performed
    percutaneously) should be obtained prior to
    chemotherapy.

69
Clear cell sarcoma of the kidney
  • The approach for treating clear cell sarcoma of
    the kidney (CCSK) is different from Wilms tumor
    since the overall survival of children with CCSK
    remains considerably lower than patients with
    favorable histology Wilms tumor. In the NWTS-3
    study, the addition of doxorubicin to the
    combination of vincristine, dactinomycin, and
    radiation therapy resulted in an improvement in
    disease-free survival for patients with CCSK.
  • NWTS-4 showed that patients treated with
    vincristine, doxorubicin, and dactinomycin for 15
    months had an improved relapse-free survival
    compared with patients treated for 6 months
    (87.5 vs. 60.6 at 8 years). The overall
    survival has improved for patients with CCSK from
    NWTS-3 to NWTS-4 (83 vs. 66.9 at 8 years).
  • Under the NWTS-5 study, children with stage I-IV
    CCSK were treated with a new chemotherapeutic
    regimen combining vincristine, doxorubicin,
    cyclophosphamide, and etoposide in an attempt to
    further improve the survival of these high-risk
    groups. All patients received radiation therapy
    to the tumor bed.

70
Rhabdoid tumor of the kidney
  • Patients with rhabdoid tumor of the kidney
    continue to have a poor prognosis (lt25 survival)
    despite aggressive therapy.

71
Clear Cell Sarcoma of the Kidney
  • Clear cell sarcoma of the kidney (CCSK) (the
    8-year relapse-free survival rate for localized
    CCSK stages I-III is 88, but late relapses have
    been known to occur)
  • Treatment options under clinical evaluation
  • The following is an example of a national and/or
    institutional clinical trial that is currently
    being conducted. .
  •                  Nephrectomy, abdominal
    radiation using 1,080 cGy for all patients,
    whole-lung radiation for patients with pulmonary
    metastasis, and 24 weeks of chemotherapy with
    vincristine, doxorubicin, etoposide, and
    cyclophosphamide.

72
Rhabdoid Tumor of the Kidney
  • (the 4-year disease-free survival rate for
    stages I-IV is 23, and the 4-year overall
    survival rate is 25)
  • No satisfactory treatment has been developed for
    these children. National Wilms Tumor Study-5
    (NWTS-5) closed the treatment arm for rhabdoid
    tumor with cyclophosphamide, etoposide, and
    carboplatin because of poor outcome. Combinations
    of etoposide and cisplatin etoposide and
    ifosfamide and ifosfamide, carboplatin, and
    etoposide (ICE chemotherapy) have been used.

73
WILMS TUMOR
  • Chemotherapy Regimens
  • Regimen EE4A - VCR/AMD x 18 weeks
    post-nephrectomy
  • Regimen DD 4A - VCR/AMD/ADR x 24 weeks post
    nephrectomy
  • Regimen M - VCR/AMD/ADR CY/ETOP
  • Regimen I - VCR/DOX/CY CY/ETOP x 24 weeks
  • Regimen UH1 - CY/CARBO/ETOP VCR/DOX/CY

74
WILMS TUMORCOG Risk Group Classification FH WT
75
WILMS TUMOR
76
WILMS TUMOR
77
WILMS TUMOR COG protocol- RT guidelines
78
RT TECHNIQUE
  • Patients with disease confined to the operative
    site need irradiation to the flank only, even
    if there has been local spillage of tumor.
  • Parallel opposed fields using 4-MV or 6-MV
    photons are preferred. The treatment
    portals should encompass the tumor bed and the
    site of the excised kidney with a 2- to 3-cm
    margin.
  • The medial border must cross the midline to
    include the entire width of the vertebrae so
    to minimize growth disturbances.
  • A tangential abdominal wall shield can be used.
  • When whole-abdomen irradiation is
    administered, shaped portals must be used,
    and the femoral heads and acetabulum must
    be shielded
  • Whole-lung irradiation is used if there are
    lung metastases .
  • Shaped fields spare normal soft tissues.
  • Dosages for FH bilateral Wilms' tumor
    should be limited to 10 Gy to the second kidney.

79
WILMS TUMOR
  • COG-RT
  • Timing of RT
  • FH cases preferably by day 9 but no later than
    day 14
  • UH patients RT should start no later than day 9
  • RT Dose (Flank/WA) - 10 Gy with 3 drugs in stage
    III FH and all UH patients except
  • RTK and stage III DA patients-20 Gy
  • WLI 12 Gy at 1.5 Gy/fraction

80
Recommended radiation therapy doses in NWTS-5
  • FH, Favorable histology CCSK, clear cell sarcoma
    of the kidney.
  • Flank irradiation , except whole-abdomen
    irradiation for gross diffuse residual disease,
    diffuse peritoneal implants, preoperative
    anterior rupture, or diffuse abdominal
    operative spillage.

81
  • Simulation film of anteroposterior portal of
    the flank showing inclusion of the entire width
    of the vertebral body in the irradiated volume

82
  • CT scan of a patient with large left-sided
    Wilms' tumor showing displacement and caliceal
    Involvement.
  • The intestines are mainly displaced to the right.

83
WILMS TUMOR
84
WILMS TUMOR
85
  • Stage IV Wilms tumor
  • For patients with stage IV (FH) Wilms tumor, the
    role of pulmonary irradiation has been examined
    retrospectively (based on chest x-ray results)
    and is being examined prospectively (based on
    computerized tomography (CT) scan results) to
    identify clinical and radiological features in
    patients that suggest that radiation can be
    omitted in certain subsets. Investigators in the
    United Kingdom reviewed outcomes in children with
    stage IV Wilms tumor with pulmonary metastases at
    diagnosis and the factors that contributed to the
    decision to withhold pulmonary radiation.
    Patients who underwent pulmonary irradiation had
    a 9 year EFS of 79 versus 53 in patients who
    did not, although there was no difference in OS.
    Pulmonary radiation decreased the chance of lung
    relapse (8 vs 23). No consistent features could
    be identified to aid in the selection of patients
    who could safely avoid pulmonary irradiation

86
  • Anteroposterior portal for the whole-abdomen
    and flank portals used in irradiation of
    patients with stage III Wilms' tumors.
  • The upper margin of the abdominal field must
    include the diaphragm.
  • The acetabulum and femoral head should be
    excluded from the irradiated volume to decrease
    the probability of slipped femoral epiphysis.
  • Whole-abdomen irradiation is no longer
    frequently used in patients with Wilms' tumor.

87
WILMS TUMOR
88
  • Patient receiving partial-abdomen plus
    whole-lung irradiation en bloc. Notice that the
    portals come below the apparent costophrenic
    angles and that there is a single, large,
    right upper lobe metastasis, an unusual finding
    in Wilms' tumor.

89
WILMS TUMOR Bilateral Wilms Tumor (BWT) -NWTS
  • When poor response to CT? prompt biopsy instead
    of prolonging duration of CT
  • 38 pts (NWTS-4) poor response median 7m CT
  • 25 BWT had DA 0/7 pts (needle by.), 3/9 (wedge
    by.) and 7/9 (partial or total nephrectomy)
  • CT duration after needle by. -20 wks, wedge
    by.- 39m
  • Earlier by. and resection of tumors not
    responding to CT?, avoid prolonged ineffective
    therapy for DA
  • Induction CT? second look surgery 6 weeks?
    definitive surgery 12 weeks ? CT H/P response

90
WILMS TUMOR Renal parenchymal sparingsurgery
(AREN 0534)
  • Renal failure in unilateral WT 0.25
  • 38 risk of renal failure WAGR and DDS
  • Other gps high risk for metachronous WT
    (aniridia, BWS, idiopathic hemihypertrophy)
  • Goals is to facilitate PN in 25 of high risk
  • children with 2-drug chemotherapy
  • Patients screened (CR/MRI q2m 1 yr then US q 3
    m for 8 yrs) should be amenable to PN

91
WILMS TUMOR
  • BWT-COG Study
  • To improve 4 year EFS to 73 for BWT
  • To prevent complete removal of at least one
    kidney in 50 pts by pre-nephrectomy 3-drug CT
  • To facilitate partial nephrectomy in lieu of
    nephrectomy in syndromic WT with renephrectomy
    2-drug CT

92
WILMS TUMOR
  • BWT - RT
  • RT-10.8 Gy stage III FH/any stage UH tumors
    after partial or radical nephrectomy
  • Renal sparing RT 3D-CRT, IMRT or Implant
  • FH (hilar/polar, lt 3 cm, PR to chemotherapy)
  • Contralateral nephrectomy
  • FH (hilar/polar, lt 3 cm, PR to CT)
  • Positive margins after salvage surgery x 2
  • 21.6 Gy (1-2 cm margin)

93
WILMS TUMOR
  • UKW3 Randomized Trial
  • Prospectively compared NWTS and SIOP approaches
    in 205 patients
  • Significant down staging with SIOP therapy
    (Stage III 90 vs70)
  • No ruptures (SIOP) vs 15 (NWTS)
  • 20 reduction in ADR/RT (SIOP)
  • Similar 5 yr EFS (80) and OS (89)

94
WILMS TUMOR
  • Relapsed Wilms tumor
  • NWTS-5
  • 72 children who relapsed after therapy with
    VCR, AMD only (stages I, II) treated stratum on B
  • Surgery, RT (20Gy), chemotherapy (regimen
    I-VCR, DOX,CTX, Etop)
  • 4 yr EFS/OS were 71 and 82 respectively
  • Lung mets only 4 yr EFS/OS - 68/81

95
Relapsed Wilms tumor
  • Children with relapsed favorable-histology Wilms
    tumor have a variable prognosis, depending on the
    site of relapse, the time from initial diagnosis
    to relapse, and their previous therapy. Favorable
    prognostic factors include no prior treatment
    with doxorubicin, relapse more than 12 months
    after diagnosis, and intra-abdominal relapse in a
    patient not previously treated with abdominal
    radiation

96
Relapsed Wilms tumor
  • Wilms tumor patients whose initial therapy
    consisted of immediate nephrectomy followed by
    chemotherapy with vincristine and dactinomycin
    who relapse can be successfully retreated.
    Fiftyeight patients were treated on the National
    Wilms Tumor Study-5 (NWTS-5) relapse protocol
    with surgical excision when feasible, radiation
    therapy and alternating courses of vincristine,
    doxorubicin and cyclophosphamide and etoposide
    and cyclophosphamide. Fouryear event-free
    survival (EFS) after relapse was 71 and overall
    survival (OS) was 82. For those patients who
    relapsed only to their lungs the 4year EFS after
    relapse was 68 and OS was 81

97
Relapsed Wilms tumor
  • Approximately 50 of unilateral Wilms tumor
    patients who relapse or progress after initial
    treatment with vincristine, dactinomycin and
    doxorubicin and radiation can be successfully
    retreated. Sixty patients were treated on the
    NWTS-5 relapse protocol with alternating courses
    of cyclophosphamide/etoposide and
    carboplatin/etoposide, surgery and radiation
    therapy. EFS (4year) and OS were 42 and 48,
    respectively, and 49 and 53 for patients who
    relapsed in the lungs only

98
Relapsed Wilms tumor
  • Patients with stages IIIV anaplastic-histology
    tumors at diagnosis have a very poor prognosis
    upon recurrence. The combination of ifosfamide,
    etoposide, and carboplatin has demonstrated
    activity in this group of patients, but
    significant hematologic toxic effects have been
    observed. While high-dose chemotherapy followed
    by autologous hematopoietic stem cell transplant
    has been utilized, an intergroup study of the
    former Pediatric Oncology Group and the former
    Childrens Cancer Group used a salvage induction
    regimen of cyclophosphamide and etoposide (CE)
    alternating with carboplatin and etoposide (PE)
    followed by delayed surgery.

99
Relapsed Wilms tumor
  • Disease-free patients were assigned to
    maintenance chemotherapy with five cycles of
    alternating CE and PE, and the remainder of
    patients to ablative therapy and autologous
    marrow transplant. All patients received local
    radiation therapy. The 3-year survival was 52
    for all eligible patients, while the 3-year
    survival was 64 and 42 for the chemotherapy
    consolidation and autologous marrow transplant
    subgroups, respectively. The outcome of
    hematopoietic stem cell rescue in selected
    patients may be superior, however, patients with
    gross residual disease going into transplant do
    not do as well. Patients in whom such salvage
    attempts fail should be offered treatment on
    available phase I or phase II studies.

100
Late Toxicity NWTS
  • CHF in NWTS 1-4 4.4 _at_ 20 years (females, DOX
    dose, WLI, Left flank RT)
  • Renal Failure in unilateral WT low (0.25)
  • Renal failure in BWT low 3.8 (NWTS-4)
  • Offspring of irradiated (flank) women gt risk
    for low birth weight, prematurity and congenital
    malformations
  • Pregnancy outcomes Fetal malposition and
    premature labor significantly gt with RT
  • Flank RT dose response noted, higher complication
    rates gt 25 Gy

101
Late Toxicity NWTS
  • Incidence of Scoliosis after 10-12 Gy, 12.1 to
    23.9 Gy, and 24 to 40 Gy were 8, 46, and 63
  • Present RT volumes, total doses, use of MV
    x-rays rates of scoliosis low
  • Incidence of SMN in NWTS 1.6 _at_ 15 years (RT
    dose 35 Gy, DOX dose, treatment for relapse)

102
  • John A. Kalapurakal MD
  • Northwestern University
  • Chicago, IL
  • (312) 926-3761
  • j-kalapurakal_at_northwestern.edu

103
THANK YOU
104
THANK YOU
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