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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)
