PET Imaging of a Wilms Tumor

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					              St. Jude Solid Tumor Board                           St. Jude Solid Tumor Board
                   27 February 2009                                     27 February 2009


                                                                        PET Imaging
                  PET Imaging                                        of a Wilms Tumor
               of a Wilms Tumor



                          Shulkin,
                    Barry Shulkin, MD
                  Jesse Jenkins, III, MD
                   Andrew Davidoff, MD
                        Pai-Panandiker,
               Atmaram Pai-Panandiker, MD

                                                         Shulkin,
                                                Barry L. Shulkin, MD, MBA




• 4-year-old girl
                                            • Physical exam – large right sided
• May 2006 – 1 week constipation and          abdominal mass crossing midline
  abdominal enlargement
                                            • PH – unremarkable
• Physical exam – abdominal mass
                                            • FH – nothing particularly informative
• Referred to LBCMC – CT confirmed
                                            • SH – lives with parents and 21 y/o brother
  abdominal mass
• Sent to SJCRH




                                                                                                1
              Jeffrey S. Dome MD                                                JD Main Considerations
                                                                          • Clear cell variant of Wilms
                                                                          • Anaplastic Wilms

                                                                          • Less likely
                                                                            – ACC
                                                                            – Primary hepatic tumor (HCC)
                                                                            – Epithelioid sarcoma


http://www.childrensnational.org/research/faculty/bios/ccir/Dome_j.aspx




                                                                                                    St. Jude Solid Tumor Board
                                                                                                         27 February 2009
                    Needle biopsy
 • 5/26/06                                                                               Needle Biopsy of Right Kidney
                                                                                                and Omentum
 • Interventional radiology
                                                                                                           5/26/06




                                                                               Jesse J. Jenkins, III, MD




                                                                                                                                 2
                                                        WT1
                                                 Immunohistochemistry




                   St. Jude Solid Tumor Board
                        27 February 2009
                                                             FDG PET CT Scan
                        PET Imaging
                     of a Wilms Tumor           • 5/30/06




         Shulkin,
Barry L. Shulkin, MD, MBA




                                                                               3
        Therapy
• ICE
  – Ifosfamide
  – Carboplatin
  – Etoposide

  Alternating with

• VDC
  – Vincristine
  – Doxorubicin
  – Cyclophosphamide




                       4
                          St. Jude Solid Tumor Board
                               27 February 2009
                                                              National Wilms Tumor Study
               Pre- or Postoperative Therapy
               Pre-                                                Group (NWTSG)
                     for Wilms tumor?

                                                            • immediate nephrectomy
                                                            • post-operative chemotherapy and
                                                              radiation therapy administered
                                                              based on the surgical pathologic
     Andrew Davidoff, MD                                      stage




International Society of Pediatric                                    Primary Nephrectomy
        Oncology (SIOP)                                   • Benefits
                                                              – accurate histology
  • pre-nephrectomy chemotherapy                                  • no influence of treatment effect
                                                                  • benign v. malignant

  • delayed surgery                                                   – congenital lesions, mesoblastic nephroma, angiolipoma
                                                                      – anaplastic Wilms, rhabdoid, clear cell sarcoma, renal cell
                                                              – accurate stage
  • post-nephrectomy adjuvant therapy                             • particularly lymph node involvement
    as dictated by histology, stage,                      • Disadvantages
    response                                                  – higher incidence of tumor rupture
                                                                  • similar incidence in single-institution review
                                                                      – Hall et al, J Pediatr Surg, 2006 (Hospital for Sick Children, Toronto)




 Pre-nephrectomy Chemotherapy                             COG indications for
• Advantages                                              pre-nephrectomy chemotherapy
   – Fewer complications (SIOP-93-01 vs NWTS-5)
       • Overall: 6.4% vs 9.8% (p=0.12)                 • Intravenous tumor thrombus extending above the level of the
       • lower incidence of tumor rupture                 hepatic veins
           – 2.2% vs 15.3% (p<0.001)                       – risk of tumor embolus
   – Assess tumor response → change therapy                – need for cardiopulmonary bypass
   – “downstaging” of patients
                                                        • Unable to tolerate surgery
       • Stage III: 14.2% vs 30.4% (p<0.001)
       • lower the use of XRT
                                                           – general condition (e.g. nutrition)
                                                           – extensive pulmonary metastases→respiratory insufficiency
• Disadvantages
   – 5% diagnostic error rate
                                                        • Bilateral Wilms tumor
       • benign tumors or non-Wilms malignant tumors       – tumor in solitary, horseshoe kidney
   – “Downstaging”                                      • “Evidence” of pre-operative rupture
       • SIOP-6, stage II +/- XRT                       • “Unresectable”
           – more local recurrence when not given XRT
           – now give adriamycin for stage II              – Size alone is NOT an indication




                                                                                                                                                 5
                                                         St. Jude Solid Tumor Board
                                                              27 February 2009
 Pre- or Postoperative
                                            Right Nephrectomy with Sampling of
      therapy for                           Lymph Nodes, Peritoneal Nodules &
                                                    Paraduodenal Mass
    Wilms tumor?                                                      7/14/06




Remains an unresolved controversy
                                    Jesse J. Jenkins, III, MD




                                                                Right Kidney



     Right Kidney




                                                                           ?


                                                Questions and Answers
   Peritoneal Nodules
                                              Some questions were asked without
  Paraduodenal Mass
                                                    a microphone nearby
                                                 and may be difficult to hear.




                                                                                      6
                               St. Jude Solid Tumor Board
                                    27 February 2009
                                                                                                            Historical data
                                   Radiation Therapy                                   • Now 7 y/o (dx at 4) with hemi-hypertrophy and FH Stage
                                                                                         IV (lung) Wilms’ tumor of the right kidney
                                         8/30/06
                                                                                       • Pre-operative chemotherapy initiated 5/2006

                                                                                         Sup/ant di ti l        t diagnosis
                                                                                       • S / t mediastinal LAD at di     i

                                                                                       • Pre-operative (7/14/06) diffuse tumor spillage noted
                                                                                         (prior biopsy on 5/26/06)

                                                                                       • Peri-nephric and aorto-caval LN negative
                    Pai-Panandiker,
            Atmaram Pai-Panandiker, MD                                                     – LN chains negative by PET, primary heterogeneous uptake




          Association with 3 congenital
                                                                                                  NWTSG RT dose data
                   syndromes
   • Denys-Drash                               point mutation WT-1                     NWTS-1
       – Intersexual disorder (ambiguous genitalia,                                    • Group I
         pseudohermaphrodism, streak gonads)                                               – Arm 1 = AMD + RT (18-40Gy by stage/age)
       – Nephropathy                                                                       – Arm 2 = AMD alone
       – >90% incidence of Wilms’ Tumor                                                        • < 2 y/o RT made no diff when added to AMD
   • WAGR                                                                                      • ≥ 2 y/o RT + AMD adds benefit
       – Wilms, Aniridia, GU malformation, Mental Retardation                          • Groups II/III
       – 33% develop Wilms’ Tumor                                                          – VCN vs AMD vs VA
                                                                                               • For VCN or AMD alone, no difference @ 4yrs ~70% OS
   • Beckwith-Wiedemann                        linked to WT-2                                  • VA –  OS significantly ~ 80-90% @ 4yrs
       – Overgrowth complex –hemihypertrophy, organomegaly,                            • Group IV
         macroglossia, omphalocoele, predilection for embryonal tumors                     – Pre-operative VCN, then VA post-op vs
       – <5% incidence of Wilms’ Tumor, but synch/metach bilateral                         – Post-op RT + VA
         disease rates are higher                                                              • Pre-op VCN not helpful

                                                                                      ALL NWTS studies showed decrement to OS if post-op RT delayed > post-op day 9




                                                                                            NWTS – 3 (added staging and
                              NWTS - 2
                                                                                              histology to stratification)
   • Gp I: post-op VA (no RT)
                                                                                       • Stage I: post-op, no RT
       – 6 months VA vs 15 months VA                                                       – No diff between 10 wks vs 6 months VA
       – No diff, 6 months standard (OS~90%)                                           • Stage II: post-op, 4 arms (no RT vs 20 Gy)
   • Gp II-IV: post-op RT (same age dependent scale                                        – Chemo = VAA x 15 months vs Intensive VAA x 15 months
                                                                                               • No benefit to adding Doxo or RT
     from NWTS 1) & chemo
                                                                                       • Stage III: post-op, RT (RND 10 vs 20 Gy)
       – 15 months VA vs 15 months VAA                                                     – Intensive VA x 15 months vs VAA x 15 months
       – FH II/III = 3 yr OS ~80-90%                                                           • RT to 10 Gy for St III FH suffices, Doxo adds OS benefit
            • Doxo adds significant survival benefit~10%                               • Stage IV(all UH/any St): post-op, RT to 20 Gy
                – Improved 82% OS to 92 % OS with doxo                                     – RND VAA vs VAA + CYT x 15 months
                                                                                               • CYT no benefit to St IV FH, helps focally anaplastic and CCSK, not
   • Gp IV VAA = 3 yr OS ~ 60% vs 44% w/o doxo                                                   RTK
                                                                                               • VAA + WLI/WAI had 4 yr OS ~ 81%

Lung mets initially got 14 Gy, but 10% developed pneumonitis: dropped dose to 12 Gy




                                                                                                                                                                      7
                                                                              Stage    FH                                       Anaplastic            CCK/Rhabdoid
                       NWTS - 4                                               I-II     •No RT                                   •Stage I: no RT       •All receive flank or
                                                                                                                                •Stage II: flank RT   abdomen RT
• Minimization of therapy and toxicity                                        III      •Flank RT: If involving renal hilar      •The same as FH       •The same as FH
   – Economic assessment                                                               nodes, gross or microscopic disease      stage III             stage III
                                                                                       confined to the flank, or PA nodes
• For St III/IV FH, St I-IV CCSK                                                       •WART: peritoneal seeding, gross
   – VAA vs pulsed/intense VAA                                                         residual abdominal disease, intra-
                                                                                       p           p         p           y
                                                                                       peritoneal spill or rupture. 10.8Gy in
        Chemotx was RND 26 vs 65 weeks
      • Ch     t                    k                                                  6 fx, boost tumor >3cm to an
      • FH got 10.8 Gy abdominal RT                                                    additional 10.8Gy.
      • 12 Gy WLI for St IV
   – No diff, between risk groups, P/I vs non-P/I or length                   IV       •Treat abdomen as per the intra-         •The same as FH       • The same as FH
     of chemotherapy                                                                   abdominal stage (ie for local stage      Stage IV              stage IV except stage I
      • Risk of relapse increased for:                                                 I/II, no RT)                                                   and II abdominal
          – Higher stage, aggressive histologies, + margins, + nodes, older            •Whole lung: resect or 12Gy, boost                             disease is also
            children, incomplete resection, spillage or tumor rupture                  persistent mets to 19.5Gy                                      irradiated.
                                                                                       •Irradiate liver in certain
                                                                                       circumstances




Wilms’ Tumor – Low and Standard                                                       Wilm’s Tumor – High Risk Therapy
   Risk Therapy (AREN 0532)                                                                    (AREN 0533)
• No RT for FH Stage
  I/II
   – Relapsed disease
     treated at primary or
     met site as indicated
• Focal anaplasia now
  treated (incl. Stage I)
                                                                                    • Radiotherapy starts by post-op day 9
• Stage III FH: flank vs
  WAI                                                                               • By nature, planning commonly 2-dimensional
   – Local vs diffuse                                                               • Patient age and under-development    toxicities
     disease                                                                          – Bone growth, renal, bowel, lung and secondary cancers




Wilm’s Tumor – High Risk Therapy                                                      Wilms Tumor – High Risk Therapy
         (AREN 0533)                                                                           (AREN 0533)




                                                                                                                                                                                8
                 Toxicities
•   Orthopedic
•   Hepatic
•   Renal
•   Pregnancy
•   Cardiac
•   Secondary
    Malignancy




                              9
                        St. Jude Solid Tumor Board
                             27 February 2009
                                                         PET Scanning of Wilms Tumors
                                 PET Scanning            • Shulkin BL, Chang E, Strouse PJ et al. PET FDG studies
                                                           of Wilms tumors. J Pediatr Hematol Oncol.
                                                           1997;19(4):334-338.
                                                            – Metabolic activity
                                                         • Misch D, Steffen IG, Schonberger S et al. Use of
                                                               it      i i tomography f staging, preoperative
                                                           positron emission t        h for t i             ti
                                                           response assessment and posttherapeutic evaluation in
                                                           children with Wilms tumour. Eur J Nucl Med Mol
                                                           Imaging. 2008;35(9):1642-1650
                                                            – 9 patients with newly diagnosed Wilms’ tumor and
                                                            – perfect concordance between the PET-CT and conventional
     Barry L. Shulkin, MD, MBA
              Shulkin,                                        imaging studies
                                                            – None of the patients had metastatic disease




PET Scanning of Wilms Tumors                             PET Scanning of Wilms Tumors
• AKM Moinul Hossain MD PhD                              • 27 patients
• 3 institutions                                         • 58 scans
  – St. Jude Children’s Research Hospital                   – 1 at diagnosis
    Cincinatti Children’s Hospital
  – Ci i tti Child ’ H        it l                              following
                                                            – 1 f ll i surgery
  – Vancouver Children’s Hospital                           – 56 relapse, progressive disease, monitoring of
                                                              therapy




PET Scanning of Wilms Tumors                             PET Scanning of Wilms Tumors
• 34 scans abnormal                                      • Two of 8 patients with lung metastases
  – 8 patients (24 scans) had pulmonary metastases
    larger than 10 mm in diameter
                                                           had variable uptakes.
  – 10 patients (12 scans) had hepatic metastases        • Lung lesions 10 mm or smaller were not
  – 11 patients (11 scans) had regional nodal                                              scans.
                                                           consistently visualized on PET scans
    involvement
  – 3 patients (3 scans) had bone metastases             • One patient with liver metastasis showed
  – 1 patient (1 scan) had chest wall involvement          no uptake on PET scan after treatment
  – 2 patients (2 scans) had pancreatic metastasis         (size decreased from 45 mm to 15 mm)
  – 5 patients (5 scans) had abdominal and pelvic soft
    tissue involvement




                                                                                                                        10
        8-year-old girl with recurrent Wilms’ tumor showing                          9-year-old girl with bilateral lung metastases
       focal uptake in the liver




                                                                                                                   11 year old
                                                                                                                   11-year-old girl with recurrent
                                                                                                                   Wilms’ tumor showing focal
                                                                                                                   uptake and sclerotic process in the
                                                                                                                   left proximal tibia; consistent with
                                                                                                                   bony metastatic disease



     7-year-old girl with newly diagnosed right sided Wilms’ tumor
     showing extensive metastatic disease in the chest, abdomen and
     pelvis




                                                                                  PET Scanning of Wilms Tumors
                                                                                  • 27 patients
                                                                                  • 58 scans
                                                                                    – 1 at diagnosis
                                                                                        following
                                                                                    – 1 f ll i surgery
                                                                                    – 56 relapse, progressive disease, monitoring of
                                                                                      therapy


10-year-old girl with left sided recurrent Wilms’ tumor showing two liver
metastases (yellow arrows) on contrast enhanced CT and three foci on MRI not
detectable on PET-CT fusion image (without intravenous contrast). The lesion in
the pancreatic tail area (red arrows) is evident in all images.




                                                                                                                                                          11
           Patient Followup                                                                 Conclusion
• Per Fariba Navid MD                                                            • FDG PET CT useful in Wilms
                                                                                   tumors
                                                                                   – Staging +/-
                                                                                   – Recurrent disease
                                                                                   – Monitoring during and following
                                                                                     therapy
                                                                                   – Lung metastases < 1 cm better
                                                                                     visualized with CT




                        Thanks
                                                                                                         ?
             Jesse Jenkins, MD
             Andrew Davidoff, MD
             Atman Pai, MD
             Moinul Hossain, MD                                                          Questions and Answers
             Najat Daw, MD                                                              Some questions were asked without
                                                                                              a microphone nearby
                                                                                           and may be difficult to hear.




                                      End

                                Shulkin,
                          Barry Shulkin, MD
                        Jesse Jenkins, III, MD
                         Andrew Davidoff, MD
                              Pai-Panandiker,
                     Atmaram Pai-Panandiker, MD



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