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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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  • Biology

    1. 1. Rhabdomyosarcoma
    2. 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. 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. 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. 5. Alveolar RMS
    6. 6. Embryonal RMS
    7. 7. Histological Variants
    8. 8. Clinical features
    9. 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. 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. 11. RMS Staging System Made Simple Raney RB et al. Sarcoma 2001
    12. 12. RMS Grouping Stystem Raney RB et al. Sarcoma 2001
    13. 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. 14. Orbital tumor
    15. 15. Pelvic tumor
    16. 16. Extremity with skip lesions
    17. 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. 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. 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. 20. Cytogenetics: t(2;13)
    21. 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. 22. Pax3 vs. Pax-7 Translocations
    23. 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. 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. 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. 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. 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. 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. 29. Treatment Local Therapy – Surgery – XRT Chemotherapy – Vincristine – ActinoD – Adriamycin – Cytoxan – Ifosfamide – Etoposide – Topotecan/Irinotecan – Melphalan? – CDDP?
    30. 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. 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. 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. 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. 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. 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. 36. IRS IV Results Chemo No difference between VAC vs VAI vs VIE VAC “gold standard”
    37. 37. IRS IV Results (XRT) No apparent benefit of hyperfractionated XRT CWS Study Group (Germany) reported the same finding
    38. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 51. In situ bright field IGF-II
    52. 52. In situ dark field IGF-II
    53. 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. 54. QuickTime™ and a decompressor are needed to see this picture. Variable levels of IGFIR in RMS tumors and cell lines
    55. 55. QuickTime™ and a decompressor are needed to see this picture. Correlation between IGFIR levels and antiproliferative effect of IGFIR Ab
    56. 56. QuickTime™ and a decompressor are needed to see this picture.
    57. 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. 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?