Preoperative Weekly Paclitaxel_

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					    WILMS TUMOR

*Radiation Oncology and nuclear Medicine Dept.
Faculty of Medicine, Ain Shams University.
Ewing's Sarcoma,
                     • John A.
Neuroblastoma and Wilms tumorKalapurakal
                      • Associate Professor,
                        Radiation Oncology
                      • Northwestern
                        University Medical
                      • Chicago, Illinois
 • ASTRO 2006-2007
 • Radiotherapy in practice: EBRT by Peter
 • Evidence based Radiation Oncology
 • Practical RT Planning by Jane
   Dobbs,Ann Barret, and Ash Dan
Incidence of common tumors
 • Approximately              • Leukemia, 3100
 • 12,400 childhood -         • Brain Tumors, 2100
   cancer cases annually in   • Hodgkin'sDisease,
   the U.S.                     1100
                              • ST Sarcomas, 920
                              • Bone Tumors, 690

                              • Neuroblastoma, 670
                              • Wilm's Tumor, 520
                   %              5y os
•   Hepatic Tumor135
•   Retinoblastoma      3%    •   59%
•   Renal Tumor (WT)    6%
•   Sympathetic Nervous 7%
                              •   93%
    System (NB)
•   Bone Sarcoma (ES) 5%      •   92%
•   SoftTissue          6%
•   Sarcoma (RMS)
                              •   64%
•   Germ Cell Tumor     3%    •   58%
•   Carcinoma
•   Lymphoma (HD)      14%    •   64%
•   Brain Tumor        18%
•   Leukemias          31%    •   87%
•   Others               7%
                              •   90%
                              •   91%
                              •   65%
                              •   77%

 •  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
Annual Incidence Rates (per million children <
   5 years) and Percent distribution in U.S
• Most common malignant renal tumor of
• 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-
• Sotos' syndrome (characterized by cerebral gigantism),
• 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'
• 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
• 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.
 • Most are solitary lesions; 12% may be
   multifocal; 7% may involve both
 • Gross appearance : WT has uniform
   pale gray color with hemorrhage and
 • Soft and friable and can be easily
   ruptured (spontaneous or iatrogenic)
• Classic WT is triphasic with 3 cell types:
 blastemal, stromal and epithelial
• HP appearance correlates with
• ~90% are of FH subtype
• 3 entities under UH subtypes (NWTS):
 Anaplasia, CCSK, rhabdoid tumor of
  kidney (RTK)
• 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
• 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
• 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.
• 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.[
• 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.[
• 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
• Cystic Partially Differentiated
• 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
• 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, >
  after ,pre or intraoperative rupture
• Common sites of metastases - lungs (80%),
   lymph nodes, and liver, rarely brain
•   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
• Work Up
• H&P
• 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
• Stage I (43% of patients)
• In stage I Wilms tumor, all of the following criteria must be
• 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
• 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.]
• 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
•   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.
• 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.
WIL MS TUMOR COG Staging – Surgical

• Staging
• • I Tumor limited to kidney and completely excised. No
  penetration of capsule or involvement of renal sinus
• • II Tumor extends beyond kidney but is completely
  excised. There is
• penetration of capsule or involvement of renal sinus
• • 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
WILMS TUMOR Prognostic Factors

•   Tumor Stage
•   Tumor Histology
•   Age: Children < 24 months
•   Molecular markers: LOH at 1p and 16q
•   Telomerase expression
WILMS TUMOR LOH at 1 p and 16q

 • • NWTS-5 prospectively analyzed prognostic
 • • 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)
         WILMS TUMOR
Joint effect of LOH 1p and 16q for Stage
                 I/II FH
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
• The National Wilms’ Tumor Study Group, which is now
  part of the Children’s 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:
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
 • 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.
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.
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.
• 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
• 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.
• 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.
• 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
• 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).

• 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
• NWTS-1 (1969-1974)
• • Role of RT in group I WT patients ?
• • Postoperative RT not necessary for
  children < 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
• NWTS-2 (1974-1979)
• • Addition of VCR to AMD eliminate the need for RT
  in group I patients ?
• • Age (< 2 vs > 2 yrs) did not influence outcome
• • RFS in children > 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
• NWTS-2 (1974-1979)
• • Group II-IV tumors had superior RFS
  with ADR to AMD+VCR
• • Histology: As in NWTS-1 UH tumors
  had poorer outcomes
• NWTS-1 and 2
• • Age-adjusted dose schedule was
  employed for flank RT
• <18 months of age - 18-24 Gy
• 19-30 months - 24-30 Gy
• 31-40 months - 30-35 Gy
• > 40 months - 35-40 Gy
• 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
• • RT and ADR were eliminated in > 60% and
  RT dose reduced from 40 Gy to 10 Gy
• NWTS: 1-5
• • RT delay of >10 was associated
  withpoor outcome especially in UH
• • 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
• 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
Long-term results of NWTS-3 and -4
• 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.
• 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.
• 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.
• Current Clinical Treatment
• • COG protocol will use LOH at both 1p and
  16q in addition to tumor stage and
  pathology for tumor-risk groups
• • Goal: reduce treatment-related toxicity
  inlow-risk tumors and increase treatment
  intensity of high-risk tumors
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.
 WILMS TUMOR                       Stage II
• Favorable-histology tumors (the 4-year relapse-free
  survival rate is 85%, and the 4-year survival rate is
            Nephrectomy with lymph node sampling and 18
  weeks of chemotherapy with vincristine and pulse-intensive
• 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.
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
• Nephrectomy with lymph node sampling, abdominal
  radiation, and 24 weeks of chemotherapy with
  vincristine, doxorubicin, etoposide,
  cyclophosphamide, and mesna (NWTS Regimen I).
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
• 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
• 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
• 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
WILMS TUMOR                            Stage V Wilms’
• 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.
WILMS TUMOR               Stage V Wilms’
 • 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
• 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
WILMS TUMOR                          Inoperable
• 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
• 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
WILMS TUMOR                         Inoperable
• 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
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.
Rhabdoid tumor of the kidney

 • Patients with rhabdoid tumor of the
   kidney continue to have a poor
   prognosis (<25% survival) despite
   aggressive therapy.
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.
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.
• Chemotherapy Regimens
• • Regimen EE4A - VCR/AMD x 18 weeks post-
• • 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
• Regimen UH1 - CY/CARBO/ETOP;
COG Risk Group Classification: FH WT
COG protocol- RT guidelines
• 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.
• • Timing of RT
• FH cases preferably by day 9 but no later
  than day 14
• UH patients RT should start no later than day
• 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
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.
• Simulation film of
  portal of the flank
  showing inclusion of
  the entire width of
  the vertebral body
  in the irradiated
• CT scan of a patient
  with large left-sided
  Wilms' tumor
  displacement and
• The intestines are
  mainly displaced to
  the right.
• 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
• 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
• Whole-abdomen irradiation
  is no longer frequently
  used in patients with Wilms'
• 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.
WILMS TUMOR Bilateral Wilms Tumor
 • • 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.-
 • • 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
WILMS TUMOR Renal parenchymal sparing
surgery   (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
• BWT-COG Study
• • To improve 4 year EFS to 73% for
• • 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
• 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, < 3 cm, PR to chemotherapy)
  –   Contralateral nephrectomy
  –   FH (hilar/polar, < 3 cm, PR to CT)
  –   Positive margins after salvage surgery x 2
  –   21.6 Gy (1-2 cm margin)
• UKW3 Randomized Trial
• • Prospectively compared NWTS and
  SIOP approaches in 205 patients
• • Significant down staging with SIOP
  therapy (Stage I&II: 90% vs70%)
• • No ruptures (SIOP) vs 15% (NWTS)
• • 20% reduction in ADR/RT (SIOP)
• • Similar 5 yr EFS (80%) and OS (89%)
• 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%
• • Lung mets only: 4 yr EFS/OS - 68%/81%
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
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. Fifty–eight
   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. Four–year event-free survival
   (EFS) after relapse was 71% and overall survival
   (OS) was 82%. For those patients who relapsed only
   to their lungs the 4–year EFS after relapse was 68%
   and OS was 81
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 (4–year) and OS were 42% and
   48%, respectively, and 49% and 53% for
   patients who relapsed in the lungs only
Relapsed Wilms tumor
 • Patients with stages II–IV 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 Children’s Cancer Group used a salvage
   induction regimen of cyclophosphamide and
   etoposide (CE) alternating with carboplatin and
   etoposide (PE) followed by delayed surgery.
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.
Late Toxicity: NWTS

 • • CHF in NWTS 1-4: 4.4% @ 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: > risk for
   low birth weight, prematurity and congenital
 • Pregnancy outcomes: Fetal malposition and
   premature labor significantly > with RT
 • Flank RT dose response noted, higher complication
   rates > 25 Gy
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% @
   15 years (RT dose 35 Gy, DOX dose,
   treatment for relapse)
• John A.
  Kalapurakal MD
• Northwestern
• Chicago, IL
• (312) 926-3761
• j-