# Presentation: 896745

## Ewing’s SarcomaJames Ewing, 1921

- Diffuse Endothelioma of Bone
- Sheets of small round blue cells, absence of intracellular material, PAS+
- Distinguished from osteosarcoma
- Diaphyseal/flat bone involvement
- No new bone, therefore honeycombed on xray
- Susceptible to radium

## Peripheral NeuroepitheliomaStout, 1918

- Small round blue cells with rosetting (Homer-Wright rosettes), some lobules
- Histologically similar to neuroblastoma
- Neurosecretory granules/neurites by EM
- Clinically distinct from neuroblastoma
- Adolescents, young adults
- Tumor of soft tissue often with peripheral nerve involvement (e.g. Askin tumor:  malignant small cell tumor of the thoracopulmonary region)

## t(11;22)(q24,q12)

**Ewing’s Sarcoma**

**Primitive Neuroectodermal Tumor (PNET)/Peripheral Neuroepithelioma (PN)**

- 1983, Aurias et al.,
- 1983, Turc-Carel et al.

- 1984, Whang-Peng et al.

## ESFT Specific Translocationt(11;22)(q12,q14)

- 5’ end of EWS on chromosome 22 fuses with 3’ end of Fli-1 on chromosome 11
**EWS**:  poorly characterized, regulatory
- Fli-1:  **Ets** family of transcription factors, DNA binding, highly conserved
- Alternative translocations EWS-ERG t(21;22), EWS-ETV t(7;22),t(17;22), EWS-FEV t(2:22) all involve **Ets family proteins**
- Protein displays enhanced transactivating activity of Fli-1 but retains specificity
- Downstream effects responsible for neoplastic transformation remain elusive

## SPECTRUM OF EWING’S SARCOMA FAMILY OF TUMORS

**EWING’S**
**SARCOMA**

**ATYPICAL**
**EWING’S **
**SARCOMA**

**•****PNET (Primitive Neuroectodermal Tumor)**
**•****PN (Peripheral Neuroepithelioma)**
**•****ASKIN TUMOR (Malignant tumor of the thoraco-pulmonary region)**

***NEURAL DIFFERENTIATION***

## ESFT Immunohistochemistry

| 25 CONSECUTIVE EWING'S SARCOMA OF BONE
(Fellinger, Am J Surg Path, 1992) |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Mic-2/CD99 | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + | + |
| Vimentin | + | + | + | - | - | + | + | - | + | - | - | - | + | + | + | - | + | - | + | + | + | - |
| NSE | + | - | - | +  | - | - | + | + | + | - | + | + | - | + | + | + | - | - | + | + | - | - |
| Desmin | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |
| Leukocyte Common Ag | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - | - |

***Primary use for Mic-2 in the dx of ESFT is to rule out neuroblastoma***

## Epidemiology/Clinical Presentation

- Second most common bone tumor in children
- ~200 new cases/year in the U.S.
- Predominantly white adolescent males
- 64% second decade
- 59% male
- 96% white
- Presentation
- Pain and swelling
- Protracted symptoms common
- Fever 20%
- Site:  bone or soft tissue

## Prognostic Factors in Ewing’s Sarcoma

**Overt metastatic disease (lungs, bone, bone marrow)**
- Approximately 25% of patients

## Metastatic Disease:  Primary Prognostic Factor in ESFTNCI POB Results: 86-C-169

## Prognostic Factors in Ewing’s Sarcoma

**Overt metastatic disease (lungs, bone, bone marrow)**
- Approximately 25% of patients
- Tumor size
- Maximal diameter (> or < 8 cm.)
- Tumor volume
- >100 ml vs. < 100 ml
- LDH
- Tumor Site
- Non-metastatic:  distal > proximal > axial
- Metastatic:
- Pleural disease > pulmonary only > bone/bone marrow

**Tumor Site and Tumor Size are Interrelated, and Both Convey Prognostic Impact**

## CESS-81: 

**Axial**

**Proximal extremity**

**Distal extremity**

**1300**
**1200**
**1100**
**1000**
**900**
**800**
**700**
**600**
**500**
**400**
**300**
**200**
**100**
**0**

**Volume (ml)**

**CESS-81:**** **
**	****REMISSION**
**	****RELAPSE **
**Adapted from Gobel et al. JCRCO, 1987**

## Prognostic Factors (cont’d)

**Response to chemotherapy**
- 79% vs. 31% DFS < or > 10% viable tumor in CESS-81
- Institute Rizzoli
- Macroscopic nodules vs. microscopic nodules vs. no viable tumor
- Surgical resection as local therapy
- Age
- Fever, increased ESR
- NOT Histology
- Chromosomal breakpoint
**p53 and/or p16/p14ARF deletion**
- Evidence for minimal residual disease following chemotherapy

## Variant EWS/Fli1 Fusion Transcripts

- Type I EWS/Fli1 (7/6) is an independent positive predictor of overall survival in patients with localized disease (Zoubek et al. JCO 1996, de Alava et al. JCO, 1998)

**7**

**7**

**7**

**7**

**7**

**7**

**7**

**7**

**8**

**9**

**1**

**0**

**8**

**8**

**8**

**8**

**9**

**9**

**9**

**9**

**1**

**0**

**1**

**0**

**9**

**2**

**3**

**%**

**2**

**%**

**2**

**%**

**2**

**%**

**4**

**%**

**6**

**%**

**2**

**%**

**EWS EXONS**

**FLI-1 EXONS**

**57%**

**23%**

**8**

- Type I EWS/Fli1 (7/6) is an independent positive predictor of overall survival in patients with localized disease (Zoubek et al. JCO 1996, de Alava et al. JCO, 1998)
- Modest effects overall

## FISH for p16/p14ARF

**Non-translocation molecular markers as prognosticators in ESFT**
*Ladanyi et al, MSKCC*

- p53 mutations (approx. 10% of Ewing’s sarcoma)
- p16/p14ARF mutations
- p16 blocks cell cycle progression: deletion should increase cell cycling
- p14ARF inhibits MDM2, a p53 antagonist: deletion should inhibit p53 function

**FISH for p16/p14ARF**

*Huang, JCO, Jan 2005*

## p53 and/or p16/p14ARF Show Strong Negative Prognostic Value

- In Multivariate Analyses, *Huang, JCO 2005*

## Detection of Minimal Residual Disease for Prognosis

- RT-PCR+ bone marrow or circulating tumor in approx 25% of patients with localized disease (Schleiermacher, JCO, Jan 2003 )
- ?independent predictor
- Telomerase (telomerase activity and hTERT)
- Expressed by most tumors
- Induced by EWS-Ets (Takahashi, Can Res 2003)
- Combined identification of telomerase activity and RT-PCR for EWS-Ets may be highly predictive of recurrence (Ohali, JCO, 2003)

**Low TA**

**high TA**

**survival**

**Low TA +/- RTPCR+**

**High TA - RTPCR**

**High TA + RTPCR**

## Ewing’s Sarcoma:  Early StudiesEstablished Ewing’s sarcoma as a disseminated, but chemosensitive disease

- 1967: 10-25% DFS at 5 years, amputation or radiation therapy (Falk et al.)
- 1960s-70s:  20-30% DFS with vincristine, actinomycin D and cyclophosphamide (VAC) at progressively shorter intervals (6 wk, 4 wk, 3 wk)
- 1970:  Doxorubicin
- 41% response rate in Phase II trials

## IESS-I:  1972-78 (Nesbit, 1990)

- Non-metastatic patients: VACA vs. VAC+pulm. XRT vs. VAC
- RFS at 5 yr. 60% VACA > 44% pulm. XRT > 24% VAC
- 15% local recurrence, 44% distant recurrence
- No significant difference among regimens for pelvic tumors
- 34% vs. 57% RFS for pelvic tumors vs. non-pelvic tumors

***Adriamycin Moved into Frontline Management***

## Survival Correlates Positively with Adriamycin DI and Negatively with Actinomycin D DI in IESS-II (adapted from Smith et al., JNCI 1991)

**5-YEAR DFS**

**70**

**60**

**40**

**50**

**70**

**60**

**50**

**40**

**4**

**8**

**10**

**12**

**14**

**6**

**0.0**

**0.1**

**0.2**

**DOXORUBICIN DOSE INTENSITY (mg/m2/wk)**

**ACTINOMYCIN D DOSE INTENSITY (mg/m2/wk)**

**Survival Correlates Positively with Adriamycin DI and Negatively with Actinomycin D DI in IESS-II ***(adapted from Smith et al., JNCI 1991)*

## IESS-II:  1978-1992 (Burger et al., 1990)

- Question:  Compare dose intensive VACA vs. less intensive VACA
- 68% DFS dose intensive vs. 48% less intensive
- Cardiovascular toxicity observed
- 3 deaths in intensive arm

***Dose Intensity is Important***

## Adriamycin in Ewing’s Therapy:  Implications

- Limits on cumulative dose (generally < 450 mg/m2)
- Is there a “safe” dose?
- “Cardioprotection”
- Prolonged infusion regimens
- ICRF-187, Wexler et al., 1996, JCO
- diminished incidence of acute subclinical cardiotoxicity (22% vs. 67%)
- Could receive a higher cumulative dose (310 mg/m2 vs. 410 mg/m2)
- No difference in response rate or overall survival

## 1980’s:  Two New Active Agents:Ifosfamide/Etoposide

- 1985, 86 (Pinkerton et al,.Magrath et al.): Phase II Study of Ifosfamide in recurrent solid tumors
- 45% response rate in ESFT (9/20)
- All had previously received cyclophosphamide
- 1987, (Miser et al.):Ifosfamide + VP-16 in recurrent pediatric sarcomas
**16/17 PR or CR in ESFT**
- Meyer et al. 1992, Phase II window of Ifosfamide+VP16 in ESFT
- 96% RR

## IESS-III (1988-1992):  NEJM 2003All Ewing’s Patients Receive “Five Drug Therapy”

- Alternated VAdCA and VP-16/Ifosfamide for 1 year
- 61% survival in VAdCA vs. 72% for VAdCA + I/E
- (p=0.01)
- Most notable improvement observed in patient with poor prognosis, non-metastatic disease
- No improvement for patients with metastatic disease

## Recently Completed COG Trial AEWS0031Non-metastatic Ewing’sIncrease Dose Intensity via Cycle Compression

**DIAGNOSIS**
**EWS/PNET/Askin**

**VAdriaC/VPIfos**
**Q3 wk. X 4 cycles**

**VAdriaC/VPIfos**
**Q2 wk. X 6 cycles**

**LOCAL THERAPY:  RADIATION AND/OR SURGERY**

**10 CYCLES/30 WKS**

**8 CYCLES/16 WEEKS**

**A**

**B**

## Results Released July 20, 2007

**AEWS0031 accrued 564 eligible patients from 2001 to 2005, and randomized them between every-three-week (Regimen A) and every-two-week (Regimen B) chemotherapy cycles.  The Data Safety Monitoring Committee has authorized the release of the results of an analysis performed on July 6, 2007.**
**The every-two-week regimen (B) is superior to the control regimen (A) in both event-free and overall survival: 76 v. 65 percent EFS at 4 years (p=0.029), and 91 v. 85 percent survival at 4 years (p=0.026).  There is no difference in toxicity between the two regimens.  A variety of other analyses are underway or pending.**
**Patients with localized Ewing sarcoma should be treated with every-two-week chemotherapy using vincristine-doxorubicin-cyclophosphamide alternating with ifosfamide-etoposide, as per AEWS0031 Regimen B, unless they are enrolled in another clinical trial.  The successor study from the Bone Tumor Committee, AEWS07P1, will also use every-two-week therapy."**

## EWINGS’ SARCOMA FAMILY OF TUMORS

- Controversies
- Extraosseous Ewing’s Sarcoma
- Radiation vs. Surgery for Local Control
- Metastatic Disease
- Pulmonary XRT
- Role of high dose therapy and stem cell rescue

## Extraosseus Ewing's SarcomaIRS-I, -II, -III(Raney et al. JCO, 1997)

- 130/2792 patients enrolled on IRS trials from 1972-1991 had extraosseus Ewing’s sarcoma
- 10 yr. Survival:  62%-77%
- No difference with or without adriamycin (62% vs. 65%) in clinical group III patients

## Adriamcyin in Extraosseous Ewing’sCastex, M.-P. et al. J Clin Oncol; 25:1176-1182 2007

**EWS93: French Society of Pediatric Oncology (SFOP) (n = 31) **
**ALL PATIENTS:**
**Cyclophosphamide (150 mg/m2/d d1-7); **
**Doxorubicin (35 mg/m2 day 8);**
**DEPENDING UPON RESPONSE:**
**Vinc/ActD or Ifos/Etop**

**MMT89: International Society of Pediatric Oncology (SIOP) (n = 32)**
**ALL PATIENTS **
**Vincristine (1.5 mg/m2/d 1, 8, 16, 22; **
**Actinomycin (1.5 mg/m2 day 1);**
**DEPENDING UPON RESPONSE**
** ****Ifosfamide (3 g/m2 days 1 to 3)/ Vin/ActD**

- Adriamcyin in Extraosseous Ewing’s*Castex, M.-P. et al. J Clin Oncol; 25:1176-1182 2007*

##  Overall survival (OS) and event-free survival (EFS) of patients with extraosseous Ewing tumor (EOE) according to treatment (n = 63)

**Castex, M.-P. et al. J Clin Oncol; 25:1176-1182 2007**

** ****Overall survival (OS) and event-free survival (EFS) of patients with extraosseous Ewing tumor (EOE) according to treatment (n = 63)**

## Local Therapy for ESFT: Evolution in Technology

- 1970s:  limited imaging
- Most patients received radiation therapy
- Exceptions were an expendable bone, growth plate
- Field encompassed the entire medullary cavity of the bone and all soft tissue extensions, hemi-pelvis for pelvic tumors
- Dosed by age 5500-6500 Gy
- 1980s:  neoadjuvant chemotherapy/improved imaging
- Smaller field size: 3 cm margin in current trials
- Improved technique/better machinery
- Dose:  4500-6500 Gy
- New surgical options available
- Modular prosthetics developed for osteosarcoma

## Controversy regarding Surgery in ESFT:  Retrospective Reviews

- Patients who undergo primary surgery have a better prognosis than patients who receive XRT (Pritchard et al. Mayo 1912-1968, 1975 and Wilkins Mayo 1969-1982, 1986)
- Selection bias:  patients with smaller tumors and better prognostic sites are more likely to have surgery
- Patients who receive surgery/XRT have better prognosis than XRT alone (Sailer, MGH 1988)
- 92% survival with surgery vs. 37% survival without surgery, significant in univariate analysis
- In multivariate analysis, only primary site was significant

## Selection Bias: Smaller, Less Bulky Tumors are Treated 

|  | RT |  | Surgery + RT |  | Surgery |  | Total |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | Bulky | No | Bulky | No | Bulky | No | Bulky | No |
| Extremities | 11 | 11 | 3 | 7 | 7 | 20 | 21 | 38 |
| Axial | 16 | 2 | 5 | 2 | 0 | 0 | 21 | 4 |
| Other | 1 | 1 | 6 | 4 | 3 | 1 | 10 | 6 |
| Total | 28 | 14 | 14 | 13 | 10 | 21 | 52 | 48 |

***Barbieri et al., Int J Rad Onc Bio Physics, 1990***

- Selection Bias: Smaller, Less Bulky Tumors are Treated
- with Surgery Whereas Large Bulky Tumors
- are Treated XRT

## Surgery in ESFT:  Facts

- Many patients now with a surgical option
- Effective neoadjuvant chemotherapy
- Progress in limb salvage techniques
- Curative surgery requires wide local excision and negative margins
- Still with significant distant relapse
- IESS-I:  4/7 amputees with distant mets
- Surgery is often combined with XRT

## Radiation Technique is of Critical Importance in the Treatment of Ewing’s Sarcoma (CESS-81)(Sauer et al., Radiotherapy and Oncology, 1987)

## Radiation  Dose is a Central Factor in Determining Risk of Second Malignant Tumors in ESFT

***Adapted from Kuttesch, JCO, 1997***

**P=0.002**

## Local Therapy and Outcome in Pelvic Ewing’s (INT91) Yock, T. I. et al. J Clin Oncol; 24:3838-3843 2006

**	****	****	****(5 yr)****	****	****	****(5 yr)**
_**Modality**_**	****	****	****	**
**    ****Surgery alone ****	****12 ****	****25.0 ****	****(0-51.2) ****	****	****41.7 ****	****(13.8 -70.0) ****	**
**    ****RT alone ****	****	****44 ****	****25.0 ****	****(12.0-38.0) ****	****	****52.0 ****	****(37.1- 66.9) ****	**
**    ****S + RT ****	****	****19 ****	****10.5 ****	****(0-24.8) ****	****	****47.4 ****	****(25.0-69.8) ****	**
_**Size **_**	****	****	**
**    ****Small (≤ 8 cm) ****	****37 ****	****24.3 ****	****(10.2-38.4) ****	****	****48.7 ****	****(32.6-64.8) ****	**
**    ****Large (> 8 cm) ****	****38 ****	****18.4 ****	****(5.9-30.9) ****	****	****50.0 ****	****(34.1-65.9) ****	**
_**Chemotherapy**_** ****	****	****	****	**
**    ****VACA ****	****	****40 ****	****30.1 ****	****(15.6- 44.6) ****	****	****44.7 ****	****(29.2-60.2) ****	**
**    ****VACA-IE ****	****	****35 ****	****11.4 ****	****(0.7 - 22.1) ****	****	****54.0 ****	****(37.3 - 70.7) ****	**
_**Large tumors **_**	****	****	****	**
**    ****Surgery alone ****	****6 ****	****16.7 ****	****(0 -49.4) ****	****	****50.0 ****	****(10.0 -90.0) ****	**
**    ****RT alone ****	****	****17 ****	****23.5 ****	****(2.6-44.4) ****	****	****58.8 ****	****(35.4-82.2) ****	**
**    ****S + RT ****	****	****15 ****	****13.3 ****	****(0-31.4) ****	****	****40.0 ****	****(15.2 -64.8) ****	**
_**Small tumors **_**	****	****	****	**
**    ****Surgery alone ****	****6 ****	****33.3 ****	****(0 -77.8) ****	****	****33.3 ****	****(0 -71.0) ****	**
**    ****RT alone ****	****	****27 ****	****25.9 ****	****(8.9-42.9) ****	****	****48.5 ****	****(29.6- 67.4) ****	**
**    ****S + RT ****	****	****4 ****	****0.0 ****	****(NA) ****	****	****75.0 ****	****(32.6-100.0) **
_**VACA **_**	****	****	****	**
**    ****Surgery alone ****	****9 ****	****33.3 ****	****(0 -67.1) ****	****	****44.4 ****	****(11.9-76.9) ****	**
**    ****RT alone ****	****	****22 ****	****36.4 ****	****(15.6- 57.2) ****	****	****50.0 ****	****(29.1 -70.9) ****	**
**    ****S + RT ****	****	****9 ****	****11.1 ****	****(0 -34.0) ****	****	****33.3 ****	****(2.5 -64.1) ****	**
_**VACA-IE **_**	****	****	****	**
**    ****Surgery alone ****	****3 ****	****0.0 ****	****(NA) ****	****	****33.3 ****	****(0 -86.7)****	**
**    ****RT alone ****	****	****22 ****	****13.6 ****	****(0 -28.4) ****	****	****53.7 ****	****(32.5 -74.9)**
**    ****S + RT ****	****	****10 ****	****10.0 ****	****(0 -29.6) ****	****	****60.0 ****	****(29.6-90.4) ****	**

- Local Therapy and Outcome in Pelvic Ewing’s (INT91) *Yock, T. I. et al. J Clin Oncol; 24:3838-3843 2006*

## Local Therapy and Outcome in Pelvic Ewing’s (INT91) Yock, T. I. et al. J Clin Oncol; 24:3838-3843 2006

- Local Therapy and Outcome in Pelvic Ewing’s (INT91) Yock, T. I. et al. J Clin Oncol; 24:3838-3843 2006

## Take Home Message: Individualized Approach to Local Therapy in ESFT

- With good technique, no clear evidence that XRT is less effective than surgery.  XRT is very effective in surgically approachable tumors.
- Most patients recur distantly, rather than locally, therefore systemic therapy should not be compromised.
- Long term morbidity is the primary issue, especially radiation induced sarcoma.
- Surgery most appropriate for pathologic fractures, expendable bones and in patients who require XRT of unfused epiphyses
- Surgery is preferred if:
- Clear margins are predicted
- Not disfiguring
- Complications which will delay systemic therapy are not likely
- Local expertise with either therapy is critical for outcome
- Many institutions have made greater use of combined surgery/XRT, especially in large pelvic primaries

## Pulmonary Metastases in Ewing’s Sarcoma

- Overall survival improved compared to extrapulmonary metastases
- Prognostic factors
- Unilateral metastases
- Good response of primary tumor
- Surgery
- No data showing a survival advantage

## Whole Lung Irradiation
Biologic effect observed in randomized trials following 1500-1800 rads in non-metastatic patients in IESS-1
5 yr. RFS VACA 60%>VAC + pulm XRT 44%>VAC 24% (Nesbit 1990)
Dose response effect reported between 12-21Gy (Dunst, 1993) using historical, non-randomized analyses
Retrospective Analysis of CESS 81,CESS 86,CESS 92 (Paulssen, JCO 1998)
Improved survival in patients with metastatic disease who receive whole lung irradiation
Independent prognostic factor in Cox analysis but not logistic regression analysis
Long term morbidity not well defined
Standard treatment arm on current EuroEwing’s Trial for patients with pulmonary metastases

- Biologic effect observed in randomized trials following 1500-1800 rads in non-metastatic patients in IESS-1
- 5 yr. RFS VACA 60%>VAC + pulm XRT 44%>VAC 24% (Nesbit 1990)
- Dose response effect reported between 12-21Gy (Dunst, 1993) using historical, non-randomized analyses
- Retrospective Analysis of CESS 81,CESS 86,CESS 92 (Paulssen, JCO 1998)
- Improved survival in patients with metastatic disease who receive whole lung irradiation
- Independent prognostic factor in Cox analysis but not logistic regression analysis
- Long term morbidity not well defined
- Standard treatment arm on current EuroEwing’s Trial for patients with pulmonary metastases

- Management of Pulmonary Metastases in Ewing’s Sarcoma

## Role of High Dose Therapy with Stem Cell Rescue in Ewing’s Sarcoma (selected series)

| Author | # pts. | Event free survival | Median f/u |
| --- | --- | --- | --- |
| Kushner, 2001 | 11 | 9% | N/a |
| Ladenstein, 1995 | 63 | 21% CR1/32% CRs | 4 yrs. |
| Horowitz, 1993 | 91 | 14% (intent to treat) | 8 yrs. |
| Burdach, 1993 | 17 | 45% | 4 yrs. |
| Chan, 1997 | 6 | 16% | N/a |
| Atra, 1997 | 11 | 55% | 2 yrs. |
| Stewart, 1996 | 6 | 16% | N/a |

## Euro-E.W.I.N.G. 1999Only Randomized Trial to Assess Role of High Dose Therapy in Ewing’s

- All receive induction with VIDE
- Good prognosis: compare VAI vs. VAC consolidation
- Poor prognosis, localized (>200 ml or poor histologic response)
- Randomize VAI consolidation vs. Bu/Mel based HD therapy with PBSC rescue
- Lower than expected accrual to this arm
- “Good” prognosis, metastatic (lung and/or pleural only)
- Randomize VAI + pulmonary XRT consolidation vs. Bu/Mel based HD therapy with PBSC rescue
- Currently open in the US as a COG trial
- “Bad” prognosis, metastatic (bone and/or bone marrow)
- All get HD therapy, Options remain to be defined

## Late Effects in ESFT Survivors

- Second malignant neoplasms
- Radiation Induced Sarcoma
- dose related
- much less frequent < 48 Gy
- Alkylator Induced Leukemia
- alkylator dose more important than the addition of etoposide
- Adriamycin cardiomyopathy
- Ifosfamide:  renal toxicity
- Gonadal failure
- Chronic pain/musculoskeletal dysfunction related to local therapies
- Psychological Trauma - adolescents

## Risk of Subsequent Primary Cancer by Age at Dx and Histology

| Histologic Type | Age at initial dx (yr) | Number of patients | Age at initial dx (mean) | Radiation (%) | Surgery (%) | Observed # | Observed/Expected | Excess Absolute Risk |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| All bone sarcomas | All ages | 4,807 | 37.4 | 26.5 | 73.5 | 223 | 1.24* | 13.27 |
| Ewing’s | All ages | 789 | 17.9 | 62.1 | 44.7 | 23 | 6.45* | 41.04 |
| Osteosarcoma | <18 | 750 | 13.3 | 6.5 | 80.4 | 10 | 5.15* | 15.11 |
|  | 18-29 | 376 | 22.8 | 10.1 | 82.4 | 6 | 2.51 | 13.44 |
|  | >30 | 578 | 55.5 | 25.1 | 70.8 | 36 | 1.42 | 39.29 |
| Chondrosarcoma | <30 | 243 | 21.9 | 12.8 | 87.7 | 2 | 0.86 | -1.29 |
|  | >30 | 1,106 | 55.6 | 14.6 | 86.3 | 104 | 1.09 | 10.76 |
| Other histologies | All ages | 965 | 49.9 | 37.2 | 71.5 | 42 | 0.85 | -12.16 |
|  |  |  |  |  |  |  |  |  |
| All soft tissue sarcomas | All ages | 12,448 | 50.2 | 40.8 | 84.8 | 1,006 | 1.19* | 19.81 |
| Rhabdomyosarcoma | <18 | 361 | 7.8 | 65.9 | 60.4 | 5 | 8.25* | 17.94 |
|  | >18 | 320 | 48.1 | 50.3 | 72.2 | 19 | 1.37 | 36.72 |
| Fibrosarcoma | <18 | 248 | 10.8 | 21.8 | 90.7 | 7 | 8.35* | 25.25 |
|  | 18-29 | 421 | 24.5 | 33.7 | 91.4 | 15 | 3.60* | 27.85 |
|  | >30 | 3,821 | 61.1 | 43.9 | 90.4 | 402 | 1.18* | 26.23 |
| Neuroblastoma | All ages | 342 | 6.2 | 34.2 | 71.1 | 0 | 0 | -4.14 |
| Liposarcoma | All ages | 2,158 | 56.9 | 39.0 | 91.9 | 259 | 1.04 | 5.95 |
| Leiomyosarcoma | All ages | 1,299 | 58.4 | 28.4 | 83.2 | 103 | 1.17 | 21.27 |
| Other histologies | All ages | 3,478 | 45.9 | 42.4 | 78.5 | 196 | 1.31* | 24.77 |

- Bone and Soft Tissue Sarcomas
- SEER 1973-2000

## Future Vision:EWINGS’ SARCOMA FAMILY OF TUMORS

- Challenge: Identify agents which can overcome chemoresistance
- ?Biologically based therapy

## Xan & Helman, The Oncologist, 2007 

**Xan & Helman, The Oncologist, 2007 **

## Multiply relapsed Ewing’s Sarcoma

- Status Post standard five drug therapy, salvage therapies

- Prior to anti-IGF1R moAb

- Following one month of weekly
- dosing of anti-IGF1R moAb

*Courtesy of Larry Baker, Univ. of Michigan*

**Roche Announces Positive Results in Solid Tumors Using Human Monoclonal Antibody against IGF-1R (R1507) and Plans for Future SARC Studies**
**Embargoed Until Oct. 23, 2007 at 1:15 p.m. EDT**
**NUTLEY, NJ – October 23, 2007 – Today, Roche announced positive results from a Phase I trial of R1507, a human monoclonal antibody to target IGF-1R (insulin-like growth factor receptor), in patients with solid tumors. IGF-1 is one of the most potent natural activators of the AKT and MAPK signaling pathways, which promote cell growth and cell survival. The IGF-1R pathway has also been shown to have an important role in mediating the resistance to cytotoxic drugs and EGFR/HER2-targeted agents. The results were reported during the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held in San Francisco.**
**Study Results**
**In the Phase I study, R1507 was administered by intravenous infusion. Nine of 34 adult patients with advanced solid tumors experienced disease stabilization. ****Four of the seven heavily pretreated patients with Ewing’s sarcoma demonstrated clinical benefit with two of these patients achieving durable, objective partial responses. **

## 16 yo with multiply relapsed Ewing’s Sarcoma:

**16 yo with multiply relapsed Ewing’s Sarcoma:**
**Previously received standard 5 drug therapy, salvage therapies**

**April 29, 2008**
**Pre-anti-IgF1 MoAb**

**June 12, 2008**
**Following 5 weekly doses **
**of anti-IgF1 MoAb**

***No significant side effects***

## Compounds that target the insulin-like growth factor I receptor in clinical development

**Copyright ©2008 AlphaMed Press**

**Ryan, P. D. et al. Oncologist 2008;13:16-24**

**Compounds that target the insulin-like growth factor I receptor in clinical development**

## The Effectiveness of mTOR Inhibition is Limited by Feedback Loops

**Xan, Oncogene, 2007**

******IgF1**

**Death of RD Rhabdomysarcoma**

## Insulin-like Growth Factor (IGF) System Complexity: 

**Copyright ©2008 AlphaMed Press**

**Ryan, P. D. et al. Oncologist 2008;13:16-24**

**Insulin-like Growth Factor (IGF) System Complexity: **
***Receptors are Ubiquitous, Multiple ligands, multiple cell surface receptors, and multiple IGF binding proteins (IGFBPs)***

**Signal**

##            PERIPHERAL BLOOD LYMPHS

**METASTATIC RECURRENCE**

**6 MONTHS**

**12 MONTHS**

**18 MONTHS**

**           ****PERIPHERAL BLOOD LYMPHS**

**CD3**

**CD4**

**CD8**

**0**

**200**

**400**

**600**

**800**

**1000**

**1200**

**DX**

**PRIMARY THERAPY**

**(cells/mcl)**

## NCI POB 97-C-0052: n=52

**Metastatic or Late Recurrence of Translocation+ ESFT or ARMS underwent apheresis for cell harvest**

## Survival Outcomes of Pediatric Sarcoma Patients Treated with Consolidative Immunotherapy

***Clin Canc Res, 2008***

## Ewing’s Sarcoma Tumor Lysate Contains Tumor Antigens

**Tumor infiltrating lymphocytes in a patients with ESFT**
**Expanded with artificial antigen presenting cells expressing anti-CD3/4-1BBL**
**Lysis of tumor lysate pulsed autologous DCs vs. control lysate pulsed DCs**

## A Pilot Study Of Autologous T Cell Transplantation With Vaccine Driven Expansion Of Anti-Tumor Effectors After Cytoreductive Therapy In Metastatic Pediatric Sarcomas (NCI-97-C-0052)

## Ewing’s Sarcoma Conclusions

- Early dramatic progress resulted from the use of multimodal therapy and the conduct of carefully controlled clinical trials
- Plateau in progress within the last 15 years awaiting new therapies based upon biologic insights
- EWS/Fli1 remains an attractive yet elusive target
- Early promising results with anti-IGF-1R therapies
- requires Phase II studies to clarify the true response rate
- Plethora of available agents could make study prioritization/interpretation of results challenging
- Given an available active biologic agent in the future, how best to incorporate it into frontline therapy?

## Tumor Dormancy:  Clinical Examples in Ewing’s Sarcoma

- Median time to metastatic recurrence is 17 mos. following completion of primary therapy (Hawkins, JCO)
- Fizazi et al, J Clin Onc 1998
- 9% of relapses occur > 4 years after completion of therapy
- KM: Ewing’s sarcoma of chest well at age 34
- pulmonary mets at dx
- remained NED until presented for late effect study 18 years after therapy
- Pulmonary Ewing’s on CXR
- Treated with chemotherapy, progressive dz, died
- TH: Diagnosed with Ewing’s sarcoma of chest wall at age 25
- non-metastatic at dx
- Remained NED until 14 years after therapy when he presented with pulmonary metastases
- Remains alive 9 years later after several recurrences
- KS:  diagnosed with Ewing’s sarcoma at age 9
- Multiple recurrences
- Now 37 years of age, last recurrence approximately 2 yrs. ago