Title: Dr: NASHWA NAZMY ABDELAZIZ,M.D
1WILMS TUMOR
- Dr NASHWA NAZMY ABDELAZIZ,M.D
- Radiation Oncology and nuclear Medicine Dept.
- Faculty of Medicine, Ain Shams University.
2PEDIATRIC TUMORSEwing's Sarcoma,Neuroblastoma
and Wilms tumor
- John A. Kalapurakal MD
- Associate Professor, Radiation Oncology
- Northwestern University Medical School
- Chicago, Illinois
3REFERENCS
- 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
4Incidence 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
6LEARNING 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
7Annual Incidence Rates (per million children lt5
years) and Percent distribution in U.Schildren
8WILMS 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)
9WILMS 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
10WILMS 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.
11WILMS 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)
12WILMS TUMOR
13WILMS 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)
14WILMS TUMOR
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16WILMS 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
17WILMS 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.
19WILMS 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.
20WILMS 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.
21WILMS 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
22WILMS 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
23WILMS 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
24WILMS 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
25WILMS 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)
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27WILMS TUMOR
28WILMS TUMOR
29WILMS 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.
30WILMS 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.
31WILMS 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.
32WILMS 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.
33WIL 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
34WILMS TUMOR Prognostic Factors Tumor
Stage Tumor Histology Age Children lt 24
months Molecular markers LOH at 1p and 16q
Telomerase expression
35WILMS 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)
36WILMS TUMOR Joint effect of LOH 1p and 16q
for Stage I/II FH
37Treatment 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
38conclusions 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.
39conclusions 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.
40conclusions 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).
46WILMS 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
47WILMS 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
48WILMS 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
49WILMS 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
50WILMS 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
51WILMS 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
52WILMS 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
53WILMS 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
54WILMS 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.
58WILMS 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
59WILMS 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.
60WILMS 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.
61WILMS 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).
62WILMS 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
63WILMS 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.
64WILMS 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.
65WILMS 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.
67WILMS 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.
68WILMS 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.
69Clear 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.
70Rhabdoid tumor of the kidney
- Patients with rhabdoid tumor of the kidney
continue to have a poor prognosis (lt25 survival)
despite aggressive therapy.
71Clear 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.
72Rhabdoid 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. -
73WILMS 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
74WILMS TUMORCOG Risk Group Classification FH WT
75WILMS TUMOR
76WILMS TUMOR
77WILMS TUMOR COG protocol- RT guidelines
78RT 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.
79WILMS 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
80Recommended 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.
83WILMS TUMOR
84WILMS 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.
87WILMS 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.
89WILMS 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
90WILMS 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
91WILMS 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
92WILMS 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)
93WILMS 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)
94WILMS 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
95Relapsed 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
96Relapsed 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
97Relapsed 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
98Relapsed 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.
99Relapsed 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.
100Late 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
101Late 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
103THANK YOU
104THANK YOU