# Presentation: 420774

## Rhabdomyosarcoma

## 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.**

## 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**

## RhabdomyosarcomaSubtypes

## Alveolar RMS

## Embryonal RMS

## Histological Variants

## Clinical features

##  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**

## 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**

## RMS Staging System Made Simple

**RMS Staging System Made Simple**

- Raney RB et al. Sarcoma 2001

## RMS Grouping Stystem

**RMS Grouping Stystem**

- Raney RB et al. Sarcoma 2001

## Prognostic Stratification for Rhabdomyosarcoma

## Orbital tumor

## Pelvic tumor

## Extremity with skip lesions

## 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**

## 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**

## 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)**

## Cytogenetics: t(2;13)

## Identification of Pax-3-FKHRPositive Alveolar RMS

**Pax3 Probe**

## Pax3 vs. Pax-7 Translocations

## 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**

## 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                           **

## Impact of Age on Survival

- 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

- Probability

- <1 year

- 1-9 years

- 10+ years

## 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**

## 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**

## 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?**

## Treatment

**Local Therapy**
**Surgery**
**XRT**

**Chemotherapy**
**Vincristine**
**ActinoD**
**Adriamycin**
**Cytoxan**
**Ifosfamide**
**Etoposide**
**Topotecan/Irinotecan**
**Melphalan?**
**CDDP?**

## 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**

## 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**

## 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**

## 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**

## Slide 34

## 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**

## IRS IV ResultsChemo

**No difference between VAC vs VAI vs VIE**
**VAC “gold standard”**

## IRS IV Results (XRT)

**No apparent benefit of hyperfractionated XRT**
**CWS Study Group (Germany) reported the same finding**

## 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

- Percent Alive

- IRS-I

- IRS-II

- IRS-III/IVP

- IRS-IV

- by Study

## 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

- Percent Alive

- Group I

- Group II

- Group III

- Group IV

## Fig 3. Failure-free survival for 370 patients with nonmetastatic alveolar rhabdomyosarcoma or undifferentiated sarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV

**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**

## Fig 4. Failure-free survival for 88 patients with nonmetastatic embryonal rhabdomyosarcoma enrolled onto Intergroup Rhabdomyosarcoma Study-III and -IV

**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**

**Notes:**
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

## Survival by Histology

- 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

- Probability

- Sarcoma-NOS

- Alveolar

- Emb/Spind/Botr

- Undifferentiated

## Chemotherapy in IRS V

**High Risk Stage IV patients-Irinotecan (Daily x5 x2 20 mg/M****2****) + 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 **

## 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**

## Survival after relapse in RMS-IRSG

## 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**

## 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**

## 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**

## 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**

## 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**

## In situ bright field IGF-II

## In situ dark field IGF-II

## Slide 53

## Variable levels of IGFIR in RMS tumors and cell lines

**Variable levels of IGFIR in RMS tumors and cell lines**

## Correlation between IGFIR levels and antiproliferative effect of IGFIR Ab

**Correlation between IGFIR levels and antiproliferative effect of IGFIR Ab**

## Slide 56

## IGF-1R/InR

**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

## 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?**