C K MX Wilms Tumor abdominal distention

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					                 St. Jude Clinical Lecture:                                 St. Jude Clinical Lecture:
                       03 May 2006                                                03 May 2006




                    Wilms Tumor                                                 Wilms Tumor




                                                          Judith Wilimas, MD
            Jeffrey Dome, MD     Judith Wilimas, MD
                                                          Member, Hematology/Oncology
                                                          Medical Dir., Central America - International Outreach
                                                          Medical Dir., Morocco - International Outreach




    History of Treatment in the                                  Clinical Presentation
     United States and Europe                         • Distention or abdominal mass -
• 1950 Surgery and radiotherapy: 40-50%                 80%
  survival                                            • Abdominal pain - 20-30%
• 1960 Availability of vincristine and                • Hematuria - 20-30%
  dactinomycin: 60%                                   • Fever - 20-30%
• 1970 Availability of doxorubicin: 70%               • Hypertension - 25%
• 1980 - 2005 Advances in surgery, pathology,         • Stigmata of some
  radiology and therapy: 90%                            syndrome - 2%




                                                                                                                   1
                                                       Patterns of Dissemination
                 Pathology                          Local:
                                                    • Penetration of the renal capsule into
                                                      peri-renal tissues
• Favorable Histology – 80-90%
                                                    • Blood vessels - tumor thrombus
• Anaplasia – 5-10%
                                                    • Nodes
• Other renal tumors – 5-10%
                                                    Hematogenous metastases:
  – Clear cell sarcoma of the kidney
                                                    • lungs liver
  – Rhabdoid tumor
  – Renal cell carcinoma
                                                    • brain/bones (not Wilms tumor but clear
                                                      cell sarcoma or rhabdoid tumor)




                                                                       St. Jude Clinical Lecture:
                                                                             03 May 2006
        Presurgical Evaluation
  •   Abdominal ultrasound
                                                                           Wilms Tumor
  •   Abdominal CAT scan
  •   Chest x-ray
  •   CAT scan of the lungs (debatable)
  • Clear cell sarcoma, renal cell carcinoma, and
    rhabdoid tumor of the kidney: MRI of the
    brain, bone scan, skeletal survey
                                                     Jeffrey Dome, MD
                                                     Hematology/Oncology
                                                     St. Jude Children’s Research Hospital




                                                                                                    2
                                                           Wilms Tumor
      Therapeutic Modalities                            NWTS-
                                                        NWTS-5 (1995-     2002)


• Surgery                                      Favorable histology (no anaplasia):
                                               • Stage I & II: VCR/AMD x 18 weeks
• Chemotherapy (vincristine,                   • Stage III: RT to abdomen + VCR/AMD/DOX
  dactinomycin, doxorubicin)                     x 24 weeks
• Radiotherapy (if necessary)                  • Stage IV: RT to abdomen/lungs +
                                                 VCR/AMD/DOX x 24 weeks




             Wilms Tumor                          Treatment Results:NWTS-4
           NWTS-
           NWTS-5 (1995
                      -      2002)                   Favorable Histology
                                                           -
                                                       (NWTS 5not yet published)
Diffuse Anaplasia:
                                                                RFS                  OS
• Stage I: VCR/AMD x 18 weeks
         -
• Stage II IV: RT + VCR/DOX/Etoposide/     •   Stage I        95% (2-yr)          99% (2-yr)
  Cyclophosphamide x 24 weeks              •   Stage II       86% (8-yr)          97% (8-yr)
Focal Anaplasia:
                                           •   Stage III      91% (8-yr)          98% (8-yr)
• Stage I: VCR/AMD x 18 weeks
         -
• Stage II IV: RT+VCR/AMD/DOX x 24 weeks   •   Stage IV       81% (2-yr)          90% (2-yr)
                                                                      Green, JCO, 1998
                                                                      Breslow, Cancer, 2004




                                                                                               3
        Treatment Results: NWTS-5                              Percent of Patients by Stage
    Anaplastic Histology (Diffuse & Focal)             Stage     El Salvador   Peru   NWTS      SIOP*
                                  4-year                  I       10%          17%     39%        61%
                          RFS              OS            II       25%          29%     26%        22%
•   Stage I               70%              82%          III        31%         31%     23%         17%
•   Stage II              82%              81%           IV        24%         20%     12%         --
•   Stage III             68%              72%           V         10%          4%      5%
•   Stage IV              38%              38%
                               Dome, Proc ASCO, 2005
                                                       *Preoperative chemotherapy
                               Manuscript submitted




     Reasons for Better Survival in the                    Centers of Pediatric Oncology
        United States and Europe                                      (SIOP)
                                                         • Full time pediatric oncologist
    •   Better health care for children                  • Specialists: surgeon, pathologist,
    •   Protocol based therapy                             infectologist, nurses
    •   Multidisciplinary teams
                                                         • Parent group
    •   New therapies
                                                         • Training
                                                         • National program




                       Patient 1
    •  A 4 year old boy
    • Symptoms: Abdominal pain and distention
    • Chest x-ray: Normal
    • CAT scan: Thorax - several nodules, Abdomen
      - mass
    • Surgery: Right nephrectomy and lung biopsy




                                                                                                         4
                                                        Patient 1

                                          • Diagnosis: Stage IV Wilms tumor
                                          • Therapy: VDA, radiotherapy
                                          • Result: Living without complications




      Favorable Histology                               Patient 2
            Wilms
• Median age at diagnosis 3-4 years          • A 15 month old girl
                                             • Symptoms:
• Presentation with an abdominal mass
                                                –Abdominal mass found by the mother
• Survival 90%                                  –Blood pressure 172/106
• What is the importance of nodules          • Ultrasound, CAT scan: Large bilateral
 seen only on the CAT scan?                   tumors
                                             • Needle biopsy
                       Owens, JCO, 2002




                                                                                       5
                                                        Patient 2

                                             • Diagnosis: Fetal
                                               rhabdomyomatous Wilms tumor
                                             • Therapy: VDA, Radiotherapy,
                                               Surgery
                                             • Slow and incomplete response
                                             • Result: Living with half a kidney




Fetal Rhabdomyomatous
      Wilms Tumor                                       Patient 3

•   20% bilateral                             • A 7-month old boy
•   Large masses, partial response            • Symptoms: Hemangioma,
                                                abdominal mass, stiff neck
•   Metastases are rare
                                              • CAT scan: Abdominal mass
•   Young children
                                              • Pathology: Hemangioma and
•   NOT rhabdoid tumor
                                                metastatic rhabdoid tumor
                Maes P, Eur J Cancer, 1999




                                                                                   6
                                                     Malignant Rhabdoid
                Patient 3                            Tumor of the Kidney
                                              • Median age at diagnosis 11 months
• Diagnosis: Metastatic rhabdoid tumor
  of the kidney                               • 15% PNET posterior/medial cranial
• Therapy: ICE, Radiotherapy                   fossa
                                              • Hypercalcemia
• Result: Died after a few months
                                              • Resistant to treatment, metastasize
                                               widely; death in the year after diagnosis

                                                                 Wagner, J Ped Hem Onc, 2002




                Patient 4
• A 7 year old boy
• Symptoms: Abdominal pain, mass found by
  the father
• Chest x-ray: mediastinal adenopathy
• CAT scan: Para-spinal mass with vertebral
  destruction
• Biopsy




                                                                                               7
                                                                         Patient 4

                                                         • Diagnosis: Clear cell sarcoma of the
                                                           kidney
                                                         • Therapy: ICE, VDA, Radiotherapy
                                                         • Result: Died after 6 years and several
                                                           relapses




 Clear Cell Sarcoma of the                               New Information About Wilms
          Kidney                                           Tumor (NWTSG/COG)
                                                         • Combined LOH at 1p AND 16q is an
• Bone metastases (20%)                                    adverse prognostic indicator for FH Wilms
• Late relapses                                            tumor.
• Mortality 30 – 40%                                     • Upcoming COG studies will augment
                                                           therapy for patients with LOH:
• Improved outcome with doxirubicin                                                  - rugs, no XRT
                                                           – Stage I/II FH with LOH: 3 d
                                                                                       - rugs
                                                           – Stage III/IV FH with LOH: 3 d plus
                                  Seibel, JCO, 2004          cyclo/etoposide plus XRT
                                                                                         Grundy, JCO, 2005




New Information About Wilms                              New Information About Wilms
  Tumor (NWTSG/COG)                                             Tumor (SIOP)
 – Localized spill during surgery is associated          • Predominance of viable blastemal cells after
   with increased risk of local recurrence. The new        pre-nephrectomy chemotherapy is
   NWTSG/COG staging system will treat this as             associated with adverse outcome
   stage III                                                             - 0
                                                           – Current SIOP 201 study augments therapy for
 – Patients without lymph node biopsies had more             such patients
   local recurrences than those with positive nodes      • Complete necrosis after pre-nephrectomy
                                                           chemotherapy is associated with excellent
                         Shamberger, Annals Surg, 1999     outcome
                                                                              Boccon-Gibod, Med Ped Onc, 2000
                                                                              Weirich, Annals Oncology, 2001




                                                                                                                8
Promising Biological Prognostic                                                      Recurrent Wilms Tumor
           Markers
        (still require further study)
                                                                             • Most recurrences occur within 2 years
• High telomerase RNA expression                                             • Favorable prognostic features:
  associated with recurrence in FH Wilms                                          -relapse>12 months after diagnosis
  tumor (Dome, JCO, 2005)                                                         -favorable histology
• Gain of chromosome 1q associated with                                           -solitary pulmonary nodule
  adverse outcome (Lu, Lancet, 2002)                                              -primary treatment with only VCR/AMD
                                                                                  -relapse outside primary RT field




                                                                                 Improved Survival after Relapse
Treatment of Recurrent Wilms Tumor                                      1
                                                                                                       (1969-
                                                                                              St. Jude (1969-2000)
                                                                       0.9

• Active combinations:                                                 0.8


  – ICE (ifos/carbo/etoposide)                                         0.7                      1984-2000 (n=20)             p=0.002
                                                         Probability




                                                                       0.6
  – Cyclo/etoposide and carbo/etoposide
                                                                       0.5
                                       -
  – Topotecan active in xenograft models
                                                                       0.4
     • Phase II study of topotecan ongoing at St. Jude
                                                                       0.3
       (WILTOP study)                                                                                                    1969-1983 (n=34)
                                                                       0.2

• Benefit of high-dose therapy/stem cell rescue                        0.1

  is unclear                                                            0
                                                                             0   3    6   9      12      15        18   21       24    27   30


                                                                                                Years after Relapse
                                                                                                                             Dome, JPHO, 2002




                Wilms Tumor
               Future Directions

    • Molecular and biologic studies to                                                          Questions
      determine more specific prognostic
      factors.                                                                                      &
    • Therapy developed to reduce the risk                                                       Answers
      of late effects of treatment
    • Improved results for anaplastic
      tumors and recurrent FH Wilms
      tumor




                                                                                                                                                 9
                            End

                 Judith Wilimas, MD
                  Jeffrey Dome, MD




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Description: C K MX Wilms Tumor abdominal distention