James Ewing, 1921

Endothelial origin

14 yr Girl

Ewings Family Tumors

• Ewings

Sarcoma of BONE• Extra-skeletal ES• Askins

Tumor

• Peripheral PNET

• Share –

Immunological And Genetic traits

Dellatre et al – NEJM 94;33:294-299

SPECTRUM OF ESFT

EWING’SSARCOMAEWING’SSARCOMA

ATYPICALEWING’S SARCOMA

ATYPICALEWING’S SARCOMA

•PNET

•Peripheral Neuroepithelioma

•ASKIN TUMOR (thoraco-pulmonary)

•PNET

•Peripheral Neuroepithelioma

•ASKIN TUMOR (thoraco-pulmonary)

NEURAL DIFFERENTIATION

least Well

Genetics

Most Consistent : Pathognomic

of EFT

85 % : Reciprocal Translocation t(11;22) (q24;q12)

20 % : Gain 1p & Loss 16q -

[ der(1;16)]

t(11;22) (q24;q12) resuls

EWS-FLI1 gene

-similar histological appearance

-response to therapy and prognosis

-majority (>90%) –

same

chromosomal

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

West DC et al ‘ Curr Opin Oncol , 2000;12(4):323–329

EFT

Epidemiology

2 nd most common primary osseous malignancy in children

Incidence is 2.1 / million (U.S.)

Males > Females

65% in the 2nd decade of life

Rare in blacks and Asians

Age distribution of Ewing’s sarcoma patients registered with CESS and UKCCSG/MRC

S.J. Cotterill et al, JCO: 18;2000, 3108-3114

Median age -14 years

S.J. Cotterill et al, JCO: 18;2000, 3108-3114

Ewings’ sarcoma

Investigations

Radiology

Primary

-X-ray-CT scan-MRI

Staging

-CT Thorax-Bone scan-PET scan

Histo-pathology -Biopsy-Genetics-IHC

-Bone Marrow

Therapy -

Renal –

RFT -

GFR-

Cardiac –

2D-ECHO

Imaging

Plain Radiograph : 2 planes

Malignant :-

Osteolysis

, Periosteal

detatchmentCalcification spicules,

CT scan : Cortical lesions

MRI : Relation Adjacent structures, vessels , nervesIntra-medullary

extent

X-ray

Periosteal lamellation

(circular)

Massive swelling of soft tissue

Diaphyseal tumour

•

Intraossous extension

•

Soft tissue extension

•

Skip lesions

• Relation Adjacent structures,

vessels , nerves

• Intra-medullary

extent

• Multi-planar

MRI

Extent of lesion

Involvement detected by MRI extends beyond the anticipated area seen on plain X-ray

PET scan

Biopsy

-Multiple core / open Inx biopsy-Longitudinal-Soft tissue extension

Tissue processing

-Cytogenetics (Karyotyping)-Molecular RT-PCR & immuno-cytochemical studies-Flow Cytometry – DNA ploidy

IHCEwing’s sarcomas MIC2 positivePAS-positive & reticulin

negative

lymphomas PAS-negative and reticulin-positive positive for leukocyte common antigen and other T and B cell markers

Embryonal rhabdomyosarcomapositive for desmin, myoglobin

and muscle-specific actins.

small-cell metastatic carcinomas & melanomasexpress detectable cytokeratin.

primitive neuroectodermal tumors, PNETNeural differentiation by light microscopy (Homer Wright rosettesin more than 20% of tumor tissue) and immunohistochemicalstaining for neuron-specific enolase

(NSE), S-100protein, Leu-7

Lu+Bone/BM 4 %Other 1 %

Bone/BM 7 %

Lung 13%

No mets75%

Ewing tumours Primary dissemination

Prognostic factors

Site

Stage : localised / metastatic

Size

Age

Molecular prognostic factors

Response to chemotherapy (Necrosis)

Minimal residual diease

S.J. Cotterill et al, JCO: 18;2000, 3108-3114

SITE

67 % 67 %50 % 50 %

S.J. Cotterill et al, JCO: 18;2000, 3108-3114

S.J. Cotterill et al, JCO: 18;2000, 3108-3114

Stage : localised / metastatic

Overt metastatic disease (lungs, bone, bone marrow)

Approximately 25% of patients metastatic

S.J. Cotterill et al, JCO: 18;2000, 3108-3114

Stage : localised

/ metastatic

55 % 55 %

21 % 21 %

S.J. Cotterill et al, JCO: 18;2000, 3108-3114

Site of metastasis

2 9 2 9 1919

88

(P .001)

Response to chemotherapy

Grade Necrosis % 5 yr EFS % Responders %

I <50 0 19II 50 -90 37 22III 90-99 84 18IV 100 84 42

Huvos

grading system

Grade Necrosis (%) OS – 3 yrs (%)I 0 30II A – 1 to 10

B – 11 to 9030

III 91-99 49IV 100 73

POG-CCG (Modified Huvos

system)

p53 and/or p16/p14ARF Strong Negative Prognostic Value

I Huang, JCO 2005

Detection of Minimal Residual Disease for PrognosisRT-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 tumorsInduced 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)

Management is multi-disciplinary treatment with close co-operation

Current standard treatment

Primary induction chemotherapy

Followed by local therapy (Surgery / radiotherapy)

Maintenance chemotherapy

Treatment

Chemotherapy

1960 – Sutow & Pinkel – Cyclophosphamide- ¾ response

1966 – Jenkin – N2 mustard – 3/3 responseVAC

1968 – Hustu – comb – V+C & RT- sustained resp-5 pt

1976 – Jaffee- sup survival – VAC vs Single agent

1976 – Rosen MSKCC- RT+ VACD comb- long term survival

1990 – Nesbitt- VACD vs VAC – improved EFS & LC

Paulussen et al. The Oncologist 2006;11:503–519

Paulussen et al. The Oncologist 2006;11:503–519

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

Benefit only in localised disease

NOT in metastaic disease

Add I+E to VACD ?

Holcombe E. et al N Engl J Med 2003;348:694-701

n = 518 pt

≤

30 years

398 –nonmetastatic

120 -

metastatic

398 –nonmetastatic

200 –standard therapy VACD198 –

experimental therapy VACD alt I+E

120 –

metastatic

62 –

standard arm58 –

experimental arm

Primary end-pt –

Event free survival

Randomise

Randomise

Randomise

Methods

Chemo every three weeks for a total of 17 coursesThe duration of chemotherapy 49 weeks

Local therapy ay 12 weeks

Surgery ±RT / Radical RT –

inoperable

Gross residual –

55.8 Gy@ 1.8 Gy/#Microscopic residual –

45 Gy

@ 1.8 Gy/#

Holcombe E. et al N Engl J Med 2003;348:694-701

Without MetsThe 5 year EFS exper

group -

69 %Standard -

54 %

With MetsThe 5 year EFS exper

-

22 ±

5 %Standard -

22 ±

6 %

Results

Addition of I+E to VACD improved outcomes in patients with nonmetastatic

Ewing’s sarcoma,

BUT not with metastatic disease

Improvement greatest with large primary tumors or primary tumors of the pelvis

Local Therapy for ESFT: Evolution in Technology

1970s: limited imagingMost patients received radiation therapyField encompassed the entire medullary cavity of the bone and all soft tissue extensions, hemi-pelvis for pelvic tumorsDosed by age 5500-6500 Gy

1980s: neoadjuvant chemotherapy/improved imagingSmaller field size: 3 cm margin in current trialsImproved technique/better machineryDose: 4500-6500 GyNew surgical options available

Modular prosthetics

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 analysisIn multivariate analysis, only primary site was significant

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 4Other 1 1 6 4 3 1 10 6Total 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

Many patients now with a surgical optionEffective neoadjuvant chemotherapyProgress in limb salvage techniques

Curative surgery requires wide local excision and negative margins

Still with significant distant relapseIESS-I: 4/7 amputees with distant mets

Surgery is often combined with XRT

ANDREAS SCHUCK, et al ; IJROBP, 55(1),168–177, 2003

LOCAL THERAPY IN LOCALIZED EWING TUMORS: RESULTS OF 1058PATIENTS TREATED IN THE CESS 81, CESS 86, AND EICESS 92 TRIALS

Definitive RT significantlyreduced EFS compared with all other local therapy

EFS: studies

Study % 5yr EFS

local therapy in %==================================================

all

Sx

Sx+RT RT

Sx

Sx+RT

RT==================================================CESS 81

54 ±

10%

55 ±

18%

67 ±

17%

44 ±

17%

34

32

34

CESS 86

61 ± 7%

62 ±

15%

63 ±

10%

58 ±

15%

22

53

25

EICESS 92

64 ± 6%

72 ±

13%

66 ± 7%

46 ±

13%

15

65

20

RT- Indications

Definitive

RT

-Location –

Unfavourable-

axial-Intralesional

resection expected

Post-op adjuvant RT

-

Gross or microscopic positive margin-

Poor histological response to chemo

Surgical Margins

In Children’s Oncology Group protocols, negative margins are defined as

bony margins of at least 1 cm, with a 2-

to 5-cm margin recommended. soft tissue, at least 5 mm in fat or muscle is required, with 2 mm through fascial

planes

Target volume

Initial phase (45 Gy):pre-chemotherapy tumor volume on MRI with 1.5–2 cm margins

Appropriate modifications into cavities or the lung

Boost phase (10.8 Gy): post-operative gross residual disease with 1.5–2 cm margins

Post-op adjuvant RT DOSE

45 Gy

to the pre-chemotherapy volume

10.8 Gy

boost to areas of gross tumor residual

Surg .margins

Necrosis 100 %

Necrosis <100 %

Boost

Negative NO RT 45 Gy ----

Close (< 1cm)

45 Gy 50 Gy 5.4 Gy

Micro R1 45 Gy 50 Gy 5.4 Gy

Gross R2 50 Gy 55-60 Gy 5.4-10-8

Definitive RT Borderline / Un-resectable

Ph-I : 45 Gy/25 #

Ph-II : CR : No BoostPR : 10.8 Gy (> 50 % regression)Poor : 14.4 Gy (< 50 % regression)

178 eligible patients

141 (79%) had localized disease and 37 (21%) had metastatic disease

37 of the localized patients underwent resection of whom 16 (43%) required postoperative radiotherapy

Remaining 104 localized patients wereeligible for randomization to receive radiotherapy

104 localized patients10 patients were taken off study with progressive metastatic disease,lost to follow-up, and/or refused radiotherapy.

Thus, only 94 patients actually proceeded to radiotherapy.Forty patients were randomized to receive either Whole bone (n = 20) versus Involved field (n = 20) RT

The remaining 11 patients received IF RTIF would have been equivalent to whole bone RT

Outcome by treatment fieldNo difference between 5-year EFS forpatients receiving Whole bone 37% and IF 39%

Timing of Post-Operative Radiation

In an analysis of patients receiving PORT in the CESS 86and EICESS trials,

Schuck

et alno significant difference in the local control and survival who received RT within 60 days of surgery or later.

Dunst

J,et

al -improved local control in CESS 86 over CESS 81 timing of RT was brought forward from the 18th week to the 10th week

Dunst J, Results of CESS 81 and CESS 86. Cancer 1991;67:2818–2825

Schuck A,. Strahlenther Onkol 2002;178:25–31.

Does PORT actually benefit patients with poor response to chemotherapy?

The EICESS 92 –

first cooperative group include poor histologic

response (<90% necrosis) as an indication for PORT even with clear surgical margins.

reduction in local failures (5% vs. 12%) in the poor responders if they received PORT

Schuck A: Results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. IJROBP 2003;55:168–177.

Laskar S ,Mallick I. et al. Pediatr Blood Cancer 2008;51:575–580

RT lung mets

Good TX resultsAnalysis EI-CESS 92 trial

lung mets

with WLI EFS 47% 5 yrs/ 24 % without WLI

Management of Pulmonary Metastases in Ewing’s Sarcoma

Whole Lung IrradiationBiologic effect observed in randomized trials following 1500-1800 radsin 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 analysesRetrospective Analysis of CESS 81,CESS 86,CESS 92 (Paulssen, JCO 1998)

Improved survival in patients with metastatic disease who receive whole lung irradiationIndependent prognostic factor in Cox analysis but not logistic regression analysis

Long term morbidity not well definedStandard treatment arm on current EuroEwing’s Trial for patients with pulmonary metastases

Second Malignancies after Radiotherapy

The incidence range of 2–10% in these reports. 50–60% of these have been sarcomas induced by RT, hematological malignancies, mainly acute myeloid leukemia and myelodysplastic

syndromes, induced by chemotherapy.

In a radiation dose-dependency analysis from a multi-institutional database of patients with EFT, Kuttesch

et al. found no second cancersamong patients receiving less than 48 Gy.

Most of the patients receiving PORT receive doses of about 45 Gy

that may be safe from this viewpoint.

Moreover, in the CESS experience, most secondary bone sarcomas could be easily resected

and did not contribute to mortality.

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

0 5 10 15 20 25 30 35

0

10

20

30No radiation4800-5999>6000 cGy

time (yrs.)

Adapted from Kuttesch, JCO, 1997

P=0.002

EICESS 92 - Second malignancies

Second malignancies after Ewing tumor treatment in 690 patients from a cooperative German/Austrian/Dutch study

Paulussen M, Ahrens S, Lehnert M, Taeger D, Hense HW, Wagner A, Dunst J, Harms D, Reiter A, Henze G, Niemeyer C, Göbel U, Kremens B, Fölsch UR, Aulitzky WE, Voûte PA, Zoubek A, Jürgens H

Annals of Oncology 12:1619-1630, 2001

EICESS 92 - Second malignancies

6 / 690 pts

2 / 6 MDS/AML2 / 6 ALL/NHL1 / 6 Squamous cell carcinoma1 / 6 Liposarcoma

Paulussen et al, Annals of Oncology 12:1619-1630, 2001

EICESS 92 - Second malignancies

Paulussen et al, Annals of Oncology 12:1619-1630, 2001

Second cancer risk

EICESS 92 - Second malignancies

Second leukemia/lymphoma risk

Paulussen et al, Annals of Oncology 12:1619-1630, 2001

Late Effects in ESFT Survivors

Second malignant neoplasmsRadiation Induced Sarcoma

dose relatedmuch less frequent < 48 Gy

Alkylator Induced Leukemiaalkylator dose more important than the addition of etoposide

Adriamycin cardiomyopathyIfosfamide: renal toxicityGonadal failureChronic pain/musculoskeletal dysfunction related to local therapiesPsychological Trauma - adolescents

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

0 10 20 30 40 50 60 700

102030405060708090

100With central planningWithout centralplanning

TIME (months)