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  • Subset A: Stage I group I or Iia, Stage II group I and Stage III orbit
    Subset B: Stage I group IIB/Iic, Stage I group III non orbit, Stage II group II, andd stage III group I or II
    Subset C: remaining stage II or III group III
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Transcript

  • 1. Rhabdomyosarcoma
  • 2. Rhabdomyosarcoma Most common soft-tissue sarcoma of childhood Incidence: four to seven cases per million Approximately 250 newly diagnosed cases a year in U.S.
  • 3. Pathology Small blue round cell tumor Myogenic lineage – MyoD Two major histologic subtypes – Embryonal (LOH 11p15) » Botryoid, leiomyomatous – Alveolar t(2;13)(q35;q14) t(1;13) (p36;q14) » Solid
  • 4. Rhabdomyosarcoma Subtypes EMBRYONAL ALVEOLAR Histology Spindle cell, stroma-rich Small round blue cell tumor Cytogenetics LOH at 11p t(2;13) Location Head & neck, GU Extremities/trunk Age group Younger (4-6 yrs) Older (>10 yrs)
  • 5. Alveolar RMS
  • 6. Embryonal RMS
  • 7. Histological Variants
  • 8. Clinical features
  • 9. Diagnostic Evaluation Determine extent of primary and presence or absence of metastases Staging system - evolved from surgical to nonsurgical staging Biopsy-adequate tissue for routine path, cytogenetics, and molecular studies
  • 10. Diagnostic Evaluation (cont.) Radiologic studies – CT/MR of primary lungs – Bone scan – Role of PET?? » Several recent published studies suggest it depicts additional important information when combined with CT/MR Other studies – Bone marrow exam (evolving 12/901 isolated + in IRS IV) – CSF evaluation for parameningeal
  • 11. RMS Staging System Made Simple Raney RB et al. Sarcoma 2001
  • 12. RMS Grouping Stystem Raney RB et al. Sarcoma 2001
  • 13. Prognostic Stratification for Rhabdomyosarcoma Prognosis (Event-free survival) Stage Group Site Size Age (Years) Histology Metastasis Regional Lymph Nodes 1 I favorable a or b <21 ERMS MO NO Excellent (> 85%) 1 II favorable a or b <21 ERMS MO NO 1 III orbit only a or b <21 ERMS MO NO 2 I unfavorable a <21 ERMS MO NO or NX 1 II favorable a or b <21 ERMS MO N1 1 III orbit only a or b <21 ERMS MO N1 Very Good (70-85 %) 1 III favorable (excluding orbit) a or b <21 ERMS MO NO or N1 or NX 2 II unfavorable a <21 ERMS MO NO or NX 3 I or II unfavorable a <21 ERMS MO N1 3 I or II unfavorable b <21 ERMS MO NO or N1 or NX 2 III unfavorable a <21 ERMS MO NO or NX 3 III unfavorable a <21 ERMS MO N1 Good (50-70%) 3 III unfavorable a <21 ERMS MO NO or N1 or NX 1 or 2 or 3 I or II or III favorable or unfavorable a or b <21 ARMS MO NO or N1 or NX 4 I or II or III or IV favorable or unfavorable a or b <10 ERMS M1 NO or N1 Poor (<30%) 4 IV favorable or unfavorable a or b >10 ERMS M1 NO or N1 4 IV favorable or unfavorable a or b <21 ARMS* M1 NO or N1 Definitions. Favorable orbit/eyelid, non-parameningeal head and neck; non bladder/non prostate genitourinary tract Unfavorable = bladder, prostate, extremity, parameningeal other (trunk, retroperitoneal, etc) a = tumor size < 5 cm in diameter b = tumr size > 5 cm in diameter ERMS = embryonal subtype (or botryoid or leiomyomatous variant) ARMS = alveolar subtype (or solid variant) or undifferentiated sarcoma NO = regional nodes not clinically involved N1 = regional nodes clinically involved NX = node status unknown ARMS* - preliminary data suggest that variant-translocation ( PAX7-FKHR ) positive metastatic ARMS has a more favorable prognosis, with estimated 4-year overall survival of 75% (see text).
  • 14. Orbital tumor
  • 15. Pelvic tumor
  • 16. Extremity with skip lesions
  • 17. Biology Multiple Genetic Abnormalities Ubiquitous overexpression of IGFII in both ARMS and ERMS LOH at 11p15 in ERMS, LOI IGFII in ARMS Other described alterations – Ras mutations – p53 mutations – p16-CDK4-Rb pathway alterations – Overexpression of Met (HGF receptor) – 13q31 amplification in 20% – IGFIR amplicfication – Loss at 9q22-PTH locus
  • 18. Biology (cont) t(2;13)(q35;q14) fuses Pax-3 with FKHR Variant t(1;13) fuses Pax-7 with FKHR Allows for RT-PCR diagnosis A target for therapy? Prognostic significance
  • 19. Mouse Models Heterozygous PTC KO INK4a KO/HGF transgenic p53KO/Her2 transgenic P53/FOS KO All develop embryonaly type histology Most recently alveolar RMS model (conditional knock-in (Pax-3-FKHR and knock-out p53 or Ink4a)
  • 20. Cytogenetics: t(2;13)
  • 21. Identification of Pax-3-FKHR Positive Alveolar RMS GAPDH Pax3-FKHR Pax3-FKHR Pax3/7-FKHR Pax3/7-FKHR GAPDH Pax3-FKHR Pax3/7-FKHR MM Tumor 1 (+) Control Pax3 Probe
  • 22. Pax3 vs. Pax-7 Translocations
  • 23. Evolution of biology of fusions Most recent analysis of all RMS showed increasing number of fusion negative tumors (from 20% to over 40%) Recently found that solid alveolar variant frequently lacked fusion For ARMS, best outcome in those with <50% alveolar histology, intermediate outcome for P7-FKHR or fusion negative and > 50% alveolar histology, worst outcome for P3-FKHR
  • 24. Age is a risk factor For IRS 1-4, 5-yr FFS 72% for 1-10 yo, 51% for adolescents, and 53% for infants While adolescents have tumors with known negative prognostic features (i.e. alveolar histology), infants do not
  • 25. Log Rank Test: p<0.001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure-free survival, years 0 1 2 3 4 5 6 Proba <1 year 1-9 years 10+ years Impact of Age on Survival
  • 26. Epidemiology Approximately 250 new cases diagnosed yearly Among extracranial solid tumors, third most common after NB and WT In US, incidence in African-American females half that for Caucasian females; incidence in males similar for both groups Incidence appears to be lower in Asian populations
  • 27. Epidemiology (cont.) Risk of genetic predisposition 7-33% Index case in Li-Fraumeni (LFS) – Clustering of RMS and other STS, adrenocortical carcinoma, early onset breast cancer, neurofibromatosis – Associated with germline mutation of p53 – Study of 33 cases “sporadic” RMS – 3/13 cases in children <3 had germline p53 mutations – 0/20 >3 had germline p53 mutations
  • 28. Epidemiology (cont.) Associated with BWS-paternal disomy of 11p15 Should all patients <3 with RMS be screened for germllne p53 mutations? Should those patients be treated differently? How should patents with germline mutations be followed?
  • 29. Treatment Local Therapy – Surgery – XRT Chemotherapy – Vincristine – ActinoD – Adriamycin – Cytoxan – Ifosfamide – Etoposide – Topotecan/Irinotecan – Melphalan? – CDDP?
  • 30. Treatment (cont.) Surgery – Major conclusion of IRSI-complete resection had major influence on overall survival – Probably due to inadequate (pre- CT guided XRT) – Currently recommend complete surgical resection if not mutilating or cosmetically damaging » Should re-excise for a whoops surgical resection
  • 31. Second-Look Surgery Document pathologic evidence of CR after induction therapy-NO – 50% recurrence after documented CR (SIOP) » Biopsy only Resect residual viable tumor after local therapy-maybe – CGIII patients in IRS III » 64% in PR found to be in CR » 52% with less that PR converted to CR
  • 32. Treatment XRT – General principles to evolve » 4000-4500cGy for microscopic disease Contrast to European approach » 4500-5000cGy for gross residual disease and >5cm tumor » Parameningeal tumors 4500-5500cGy to well-defined field Whole brain or craniospinal XRT and IT therapy not indicated n absence of overt disease
  • 33. Treatment (cont.) XRT in IRS IV – Defined by clinical group – Group I- No XRT – Group II- 4140cGy conventional two months into Rx to original tumor volume – Group II- 5040cGy conventional over five-six weeks vs 5940cGy hyperfractionated
  • 34. Table 3 Number of Patients Entered and Eligible by Treatment in IRS-IV IRS-IV Clinical Subgroups Treatment Entered Eligible Paratesticular (Group I) or Orbit/Eyelid (Groups I, II) VA (36 weeks) 144 134 Stages 1-3 with significant renal abnormalities VAC (1 year) 61 56 Stage 1 (except Paratesticular Group I and Orbit/Eyelid Groups I,II) and Stages 2 and 3 without renal abnormalities) VAC VAI VIE Total 263 254 267 784 235 222 236 693 Group III Conventional RT Hyperfractionated RT Total 280 279 559 251 239 490
  • 35. IRS IV Results Local/regional embryonal tumors- some improvement compared to IRS-III – 3-yr FFS 83% vs 74% IRS-III – CTX 2.2 gm vs 1.0 gm Alveolar-no difference in FFS – 3-yr FFS 64% vs. 70% IRS-III for non- metastatic
  • 36. IRS IV Results Chemo No difference between VAC vs VAI vs VIE VAC “gold standard”
  • 37. IRS IV Results (XRT) No apparent benefit of hyperfractionated XRT CWS Study Group (Germany) reported the same finding
  • 38. Log Rank Test: p<0.001 Survival, IRS-I through IV Patients 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Overall survival (years) 0 2 4 6 8 10 PercentAlive IRS-I IRS-II IRS-III/IVP IRS-IV by Study
  • 39. Log Rank Test: p<0.001 Survival, IRS-I through IV Patients by Group 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Overall survival (years) 0 2 4 6 8 10 PercentAlive Group I Group II Group III Group IV
  • 40. Copyright © American Society of Clinical Oncology Meza, J. L. et al. J Clin Oncol; 24:3844-3851 2006 Fig 3. Failure-free survival for 370 patients with nonmetastatic alveolar rhabdomyosarcoma or undifferentiated sarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV
  • 41. Copyright © American Society of Clinical Oncology Meza, J. L. et al. J Clin Oncol; 24:3844-3851 2006 Fig 4. Failure-free survival for 88 patients with nonmetastatic embryonal rhabdomyosarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV
  • 42. Log Rank Test: p<0.001 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Failure-free survival, years 0 1 2 3 4 5 6 Probab Sarcoma-NOS Alveolar Emb/Spind/Botr Undifferentiated Survival by Histology
  • 43. Chemotherapy in IRS V High Risk Stage IV patients- Irinotecan (Daily x5 x2 20 mg/M2 ) + Vincristine window , followed by VCPT/VAC in responders vs. VAC alone in non-responders Intermediate Risk Stage III patients- VAC vs. VAC/VTC Low Risk Stage I patients and Stage II group I patients-VA for embryonal and VAC for alveolar + XRT for group II and III
  • 44. Treatment of Recurrent Disease Localized Recurrence – Complete surgical resection offers best hope – Potentially followed by adjuvant XRT and chemotherapy » Long-term survival well described (vaginal, paratesticular) Disseminated Recurrence – Chemotherapy is primary therapeutic modality
  • 45. Survival after relapse in RMS- IRSG No. of Patients Est. 5-Yr. Survival Favorable Risk 117 51% Botryoid 18 60% Embryonal Stage I or Group I 83 50% Alv/Und Group I 16 42% Others 492 <20%
  • 46. Late Effects Bladder, Prostate and Paratesticular Tumors – Bowel obstruction (surgical), enteritis (XRT), poor bladder function or hemorrhagic cystitis, sex hormone deficiency – Ifosfamide based Rx » Renal damage – Adriamycin-based Rx » Cardiomyopathy
  • 47. Late Effects (cont.) Second malignancies 22 SMNs out of 1770 patients on IRS-I/II – Eleven bone sarcomas (XRT fields), five ANLL median seven months off therapy – Etoposide induced leukemias
  • 48. Outcome Summary 60%-70% of newly diagnosed patients with nonmetastatic disease can be cured with combined modality Rx Less than 30% of metastatic disease currently cured-Cy/Topo alternating with VAC does not improve OS or EFS in this group of patients
  • 49. Challenges Detection of MRD by RT-PCR – What is its significance? – What can we do? Identification of “higher risk” and “lower risk” in localized patients Identification of factors that contribute to metastases
  • 50. Challenges (cont.) Development of less toxic therapy for “good risk”localized patients – Decrease long-term morbidity – Decrease incidence of second tumors New therapeutic approaches for metastatic patients
  • 51. In situ bright field IGF-II
  • 52. In situ dark field IGF-II
  • 53. IRS-1 PI3K PIP2 PIP3 PTEN PDK1 PKB/Akt T308 S473 TSC1 TSC2 Rheb mTOR Raptor mLST8 mTOR Rictor mLST8 LKB1 AMPK Rapamycin FKBP12 Nutrents GF(insulin/IGF) S6K1 4E-BP1 elF4B elF4ErpS6 Top-dependent translation (e.g. IGF-II) Cap-dependent translation (e.g. Cyclin D1, c-MYC, HIF-1α, VEGF) Actin cytoskeleton RTK
  • 54. QuickTime™ and a decompressor are needed to see this picture. Variable levels of IGFIR in RMS tumors and cell lines
  • 55. QuickTime™ and a decompressor are needed to see this picture. Correlation between IGFIR levels and antiproliferative effect of IGFIR Ab
  • 56. QuickTime™ and a decompressor are needed to see this picture.
  • 57. IGF-1R/InR IRS-1 PI3K Akt TSC1/2 mTORC1 S6K1 4E-BP1 Rheb Rapalogs mTORC2 LY294002 Akt inhibitors mTORC1and mTORC2inhibtion with kinase inhibitors ? IGF-1R Ab TK inhibitors PI3K/mTOR inhibitors
  • 58. Must Study Biology Clinical studies should be designed to test a hypothesis related to biology How can we set up clinical studies so outcome is not the only endpoint?