Identified in 1921 by James Ewing 2nd most common bone tumor in children Ewing’s Sarcoma Family of tumors: Ewing’s sarcoma (Bone –87%) Extraosseous Ewing’s sarcoma (8%) Peripheral PNET(5%) Askin’s tumor

1. Dr. Vandana
Dept of Radiotherapy,
CSMMU, Lucknow

2.  Identified in 1921 by James Ewing
 2nd most common bone tumor in children
 Ewing’s Sarcoma Family of tumors:
◦ Ewing’s sarcoma (Bone –87%)
◦ Extraosseous Ewing’s sarcoma (8%)
◦ Peripheral PNET(5%)
◦ Askin’s tumor
2

3. Epidemiology
 2% of cancer childhood malignancy
 Occurs most commonly in 2nd decade
◦ 80% occur between ages 5 and 25
 M:F 1.3:1 < 10 yrs
1.6:1 > 10 yrs
 Rare in African-Americans and Asians

4.  One of many ‘small round
blue cell’ tumors seen in
pediatrics
 Poorly differentiated
tumor
 Unknown origin, Thought
to be of neural crest
progenitor cells origin

5.  Consistent cytogenetic abnormality, t(11;22)(q24;q12) present in
90-95%
◦ resultant fusion gene is EWS/FLI-1
 Also seen:
◦ t(21;22)(q22;q12)  5-10%
EWS/ERG
◦ t(7;22) and t(17;22)  the remainder
EWS/ETV1 and EWS/E1AF respectively
◦ t(1;16)(q21;q13)
present along with t(11;22)
 The c-myc protooncogene is frequently expressed in Ewing’s.
 CD 99 ( MIC2)
 PAS +ve

6. 1

7.  Pain & swelling of affected area
 May also have systemic
symptoms:
◦ Fever
◦ Anemia
◦ Weight loss
◦ Elevated WBC & ESR,LDH
 Longest lag time in diagnosis for
any pediatric solid tumor (mean of
146 days)
 Pathological fracture

8. Skull(3.8%)
Scapula (3.8%)
 more common in diaphysis or
metadiaphysis
 central axis (47%):
◦ pelvis, chest wall, spine, head &
neck
 extremities (53%)

9.  direct extension into adjacent bone or soft tissue.
 Metastases generally spread through bloodstream
 25% present with metastatic disease
◦ Lungs (38%)
◦ Bone (31%)
◦ Bone Marrow (11%)
 Nearly all pts. have micromets at diagnosis, so all Need
chemo.
Lung 13%
Bone/BM 7 %
Lu+Bone/BM 4 %
Other 1 %
No mets
75%

10.  No uniform staging system.
 The AJCC staging systems for bone or soft-tissue
sarcomas may be used.

11. Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor 8 cm or less in greatest dimension
T2 Tumor more than 8 cm in greatest dimension
T3 Discontinuous tumors in the primary bone site
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Note: Because of the rarity of lymph node involvement in bone sarcomas, the
designation NX may not be appropriate and cases should be considered N0 unless
clinical node involvement is clearly evident.
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
M1a Lung
M1b Other distant sites

12. IA T1 N0 M0 G1,2 low grade, GX
IB T2 N0 M0 G1,2 low grade, GX
T3N0 M0 G1,2 low grade, GX
IIA T1 N0 M0 G3, 4 high grade
IIB T2 N0 M0 G3, 4 high grade
III T3 N0 M0 G3, 4
IVA Any T N0 M1a any G
IVB Any T N1 any M any G
Any T any N M1b any G

13. Disease factors Favorable prognosis Unfavorable prognosis
Site Distal extremity (tibia, Central lesions (especially pelvic
fibula, radius, ulna, bones) less favorable: proximal
hands, feet) extremity (humerus, femur), ribs
Size <8 cm in greatest Larger tumors
diameter or <200 mL
estimated volume
Soft tissue Absence of Presence of soft tissue extension by
extension radiographically radiograph or significant extension
identifiable soft tissue by computed tomography
extension
Extent of Localized Metastatic
disease
Site of Lung Bone / bone marrow
Metastasis Both Lung and Bone
Response to CT Responsive Unresponsive

14. 14

15. Primary Staging
History & Physical Examination
Histo-pathology -Biopsy -Bone Marrow
-Genetics
-IHC
Imaging -X-ray -CT Thorax
-CT scan -Bone scan
-MRI -PET scan
Lab Test - Renal – RFT
- Cardiac – 2D-ECHO

16.  Confirmation of diagnosis:
◦ biopsy and histopathologic examination
 core needle / open Inx biopsy
◦ Cytogenetics and IHC

17.  X-RAY
◦ Moth eaten lesion
◦ Lytic or mixed lytic-sclerotic areas
present
◦ Multi-Layered subperiosteal reaction
(onion skinning)
◦ Lifting of perioteum (codman’s
triangle)
 CT SCAN: bone destruction best
seen
 Intramedullary space
 extraosseous involvement

18. 18

19.  Involvement detected by MRI extends
beyond the anticipated area seen on plain
X-ray
 Intra-medullary extent
 Soft tissue extension
 Skip lesions
 Relation Adjacent structures, vessels ,
nerves
 Multi-planar

20.  Bone scan:
◦ To detect polyostotic involvement
◦ to detect bone metastasis
 Bone marrow biopsy
 CXR/CT of chest: lung mets

21. Bone Scan: Ewing Sarcoma of
Left Humerus demonstrates
Intense Uptake
Fig: bone scan shows increased Gross Pathology: Ewing Sarcoma of
activity in the distal femur. Metadiaphysis of Proximal Humerus. (Top
arrow) Permeative Marrow Lesion.
(Bottom arrow) Surrounding Soft Tissue
Mass

22.  newer technique
 Under evaluation to detect
◦ local and distal extent,
◦ Predictor of outcome and recurrence

23.  Laboratory tests:
◦ CBC, Alkaline phosphatase, liver/kidney function tests,
◦ LDH:
 useful as gauge of tumor burden
 Falls with effective therapy and rises with disease recurrence

24.  Multidisciplinary approach
◦ Chemotherapy: control of micrometasis
◦ Surgery: local control where possible
◦ Radiotherapy: local control where surgery not
possible or . incomplete
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25.  Effective local and systemic chemotherapy
necessary for cure.
 Induction chemotherapy preferred over starting
the systemic and local therapy
 Advantage of this approach:
◦ Evaluation of effectiveness of the regimen
◦ Decreases the vol. of local therapy for surgery or RT
◦ Some bone healing occurs during CT, diminish the risk of
pathological fracture

26. Local Control Maintenance
Induction • Surgery • Chemotherapy
Chemotherapy • Radiotherapy

27. 27

28.  All patients require chemotherapy
◦ Induction chemotherapy
◦ Maintenance chemotherapy
 Effective chemotherapy has improved local
control rates achieved with radiation to 85-90%
28

29.  First Line therapy:
◦ VAC/IE
 Vincristine 2.0 mg/m2 on D1
 Adriamycin 75 mg/m2 on D1
 Cyclophosphamide 1.2 gm/m2 on D1
 Ifosphamide 1.8 gm/m2 on D1-5
 Etoposide 100 mg/m2 on D1-5
◦ **Substitute adriamycin with dactinomycin (1.2 mg/m2 on D1) after
375 mg/m2
◦ VAI (Vincristine, Adriamycin, Ifosphamide)
◦ VIDE ( Vincristine, ifosphamide, Doxorubicin, Etoposide)
29

30.  Cyclophosphamide (250 mg/m2)and
topotecan(0.75 mg/m2) D1-D5
 Temozolomide and irinotecan
 Ifosfamide and etoposide
 Ifosfamide ,etoposide and carboplatin
 Docetaxel and gemcitabine

31.  IESS-1and IESS-2 showed 4 drug regimen VACD is superior to 3
drug VAC in terms of RFS and OS.
 INT-OO91:Adding IE improved 5-year OS (61→72%) for localized
disease, but not for metastatic disease (25%).

33.  Induction Multiagent chemotherapy for at least 12-
24 weeks prior to local therapy.
 Maintenance (adjuvant chemotherapy) with or
without Radiotherapy is recommended following
local control treatment and the duration of
chemotherapy should be between 28-49 weeks.
**NCCN guidelines version 2.2012

34. 34

35.  Development of Innovative Surgical Techniques:
Limb preservation & Structural bone function
preservation
 Chemo - cytoreduction makes resection
possible
 Local failure rates with RT in historical series :
9 - 25% *
 Concern over second malignancies
* Horonitz et al, Pediatr Clin Nor Am, 1991
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36.  Surgical Indications
◦ Expendable bone (fibula, rib, clavicle)
◦ Bone defect able to be reconstructed with modest loss of function
◦ May consider amputation if considerable growth remaining
◦ After pre-op RT
 Limb-salvage surgery is preffered.
 Curative surgery requires wide local excision and negative
margin
◦ Bony margins of at least 1 cm, with a 2 to 5 cm margin recommend.
◦ Soft tissue at least 5mm in fat or muscle , with 2mm through fascial
planes.
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37. 37

38.  radiation responsive tumor.
 There are no randomized trials that have directely
compared Radiotherapy to surgery for local control of
Ewing’s sarcoma.
 Radiotherapy can, in combination with chemotherapy,
achieve local control, but complete surgery when feasible
has to be regarded as the first choice of local therapy.**
**ESMO clinical practice Guidelines for diagnosis, treatment and follow-up for Bone sarcomas. Ref.
Annals of Oncology 21 (Supplement 5) 13,2010

39.  Patient may be treated in supine ,prone, or lateral
position site dependent.
 6MV of energy used
 For limb, opposing fields normally used.
 Tailored portals for every patient.
 Field should not cross joints unless essential.
 Entire Medullary cavity need not be included in the
RT portal.
 Try and spare a strip(1-2cm) of normal tissue for
lymph drainage.
39

41. FIG. Changes in treatment volume. (A) Field
encompassing the entire length of the medullary cavity
for a tumor involving the proximal left humerus. (B)
Tailored field encompassing only the proximal aspect of
the leg for a limited tumor of the left tibia.

42.  Definitive Radiation Therapy:
◦ Tumors where Resection is Impossible
◦ For skull, face, vertebra, or pelvic primary
◦ where only an intra-lesional resection is achievable
◦ Patient with poor Surgical risk
◦ Patient refusing surgery
 Note: Surgery is the preferred arm where wide or marginal
resection is possible
42

43.  Pre-operative Radiation Therapy
◦ Indicated when narrow resection margins are expected
◦ Principle :
 To sterilize the tumor compartment before surgery & to
potentially reduce the risk of dissemination during surgery
◦ Local recurrence with pre-op RT
 <5%
EI-CESS-92 : Schuck et al – IJROBP-1998 & 2003
43

44.  Post-operative Radiation Therapy
◦ For gross or microscopic positive margin
◦ For marginal Resection
◦ For wide-resection with Poor Histological response to Neo-
adjuvant Chemotherapy
 (>10% viable tumor cells in the specimen)
Based on CESS-81, CESS-86, EICESS-92 Studies : Schuck et al,IJROBP-1998 & 2003
44

45.  Definitive RT
◦ Phase 1:
 Gross tumor in bone and soft tissue (pre chemo ) + 2-4 cm longitudinal
margins + 2 cm lateral margins.
 Dose:45 Gy/180cGy/#
◦ Boost phase :
 Reduced 1-2 cm margins(bone and residual tissue)
 Up to total dose of 55.8Gy.
Note: - In case of no soft tissue involvement, the proximal and distal margins in
bone are not changed.
45

46. Figure: Schematic depiction of
GTV1 (pre-induction bone and pre-
induction soft tissue extent) and
GTV2 (pre-induction and post-
induction soft tissue extent)
Pre-chemotherapy tumor Post-chemotherapy tumor

47.  Pretreatment gross tumor volume +surgical scar+2cm
margin(45 Gy) boost to post op residual +2cm margin.
 Dose:
◦ MICROSCOPIC DISEASE- 45 Gy
◦ MACROSCOPIC RESIDUAL – 55.8Gy
Pre op RT
 45 Gy to original bone and soft tissue
47

48.  For rib primary ,with pleural effusion, RT to hemithorax
 For lung mets ,whole lung RT(15-18 Gy) or consider
resection if< 4 mets.
 Pain palliation– advanced disease.
 Isolated bone secondaries.
48

49. Clinical Situation Total Dose (%) Dose per Fraction
(%)
Gross disease (after
biopsy only or intralesional
resection)
1. Treatment once a Initial Field 45 1.8
day
Boost field 10.8 1.8
After marginal resection or 41.4 – 45 1.8
poor histologic response at
surgery
Preoperative radiotherapy: 45 1.8
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50.  If disease extension into pre-formed body cavities e.g.
lung & pelvis, radiotherapy volume includes post
induction volume with 2cm margin in order to reduce
treatment related toxicity.
 Lesion of vertebral body treated with 45Gy to 50.4Gy
 More than 20 Gy can prematurely close epiphysis.
 20–30 Gy usually can be given to entire circumference
of an extremity, doesn’t cause lymphedema.

51. Physical Exam, Local and Chest
Imaging:
• Every 2- 3 months
• Increase interval after 24 months
• Annually after 5 years indefinitely
CBC and other lab studies as
indicated
Consider Bone Scan or Pet scan
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52.  30-40% of patients develop relapse with
<20% survival
 Early relapse – less than 2 years:
 Consider Changing Chemotherapy
 Late relapse – more than 2 years:
 Continue the previously used chemotherapy
52

53.  Functional results : Of all the patient’s treated
with RT
◦ 60 % have good functional activity
◦ 20 % have mild morbidities
◦ 20 % have significant morbidities
 Risk for Post treatment Fractures
 Lymphedema
 Dermatitis; recall reaction may occur with doxo,
dactinomycin.
 Adriamycin cardiomyopathy.
 Ifosphamide renal toxicity.
53

54.  Second malignancy after RT
◦ Cumulative risk at 15yrs = 6 – 6.7%
( CESS-81 & CESS-86; IJROBP:1997; 39)
◦ No secondary sarcomas seen at doses <48 Gy
( Kutterch et al; JCO:1996, 14 )
◦ Risk increased by anthracycline and alkylating agent
chemotherapy
◦ Osteosarcoma most common.
◦ Leukemia can also occur.
54

55.  Use of 3D-CRT / IMRT as a standard protocol
 Incorporation of functional imaging modalities e.g. PET-
CT / PET-MRI for Target Volume delineation, Boost
treatment and IMRT
 TARGATED therapy :Molecular agents like Apoptosis
directed targeted therapies e.g. TRAIL therapy (TNF
Related Apoptosis Inducing Ligand),anti IGF-1R
antibodies…etc
55

57.  Second most common childhood bone tumor.
 Small round cell tumor with CD99 (MIC2), PAS
positive
 Lytic lesion with onion peel appearance on X-Ray
 Overall survival with localized disease (55%) and
metastatic disease 22%
 Multimodal treatment approach
 Induction Chemotherapy for 3-6 cycles and another 6-
10 cycles for maintenance.
 Surgery when feasible first choice of local therapy
 Radiation responsive tumor
 There are no randomized trials that have directely
compared Radiotherapy to surgery for local control of
Ewing’s sarcoma.