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Dr.

Vandana
Dept of Radiotherapy,
CSMMU, Lucknow
Identified in 1921 by James Ewing
2nd most common bone tumor in children
Ewings Sarcoma Family of tumors:
Ewings sarcoma (Bone 87%)
Extraosseous Ewings sarcoma (8%)
Peripheral PNET(5%)
Askins tumor

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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
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
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 Ewings.
CD 99 ( MIC2)
PAS +ve
1
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
Skull(3.8%)

Scapula (3.8%)

more common in diaphysis or


metadiaphysis

central axis (47%):


pelvis, chest wall, spine, head &
neck

extremities (53%)
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%
No uniform staging system.

The AJCC staging systems for bone or soft-tissue


sarcomas may be used.
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
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
Disease factors Favorable prognosis Unfavorable prognosis
Site Distal extremity (tibia, Central lesions (especially pelvic bones)
fibula, radius, ulna, less favorable: proximal extremity
hands, feet) (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 by
identifiable soft tissue computed tomography
extension
Extent of disease Localized Metastatic

Site of Metastasis Lung Bone / bone marrow


Both Lung and Bone
Response to CT Responsive Unresponsive
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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
Confirmation of diagnosis:
biopsy and histopathologic examination
core needle / open Inx biopsy
Cytogenetics and IHC
X-RAY
Moth eaten lesion
Lytic or mixed lytic-sclerotic areas present
Multi-Layered subperiosteal reaction
(onion skinning)
Lifting of perioteum (codmans triangle)

CT SCAN: bone destruction best seen


Intramedullary space
extraosseous involvement
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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
Bone scan:
To detect polyostotic involvement
to detect bone metastasis

Bone marrow biopsy

CXR/CT of chest: lung mets


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
newer technique
Under evaluation to detect
local and distal extent,
Predictor of outcome and recurrence
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
Multidisciplinary approach

Chemotherapy: control of micrometasis

Surgery: local control where possible

Radiotherapy: local control where surgery not possible or


. incomplete

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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
Local Control Maintenance
Induction Surgery Chemotherapy
Chemotherapy Radiotherapy
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All patients require chemotherapy
Induction chemotherapy
Maintenance chemotherapy

Effective chemotherapy has improved local control


rates achieved with radiation to 85-90%

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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)

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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
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 (6172%) for localized
disease, but not for metastatic disease (25%).
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


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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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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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radiation responsive tumor.

There are no randomized trials that have directely compared


Radiotherapy to surgery for local control of Ewings 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
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.

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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.
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

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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

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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

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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.

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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


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

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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.

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Clinical Situation Total Dose (%) Dose per Fraction (%)
Gross disease (after biopsy
only or intralesional
resection)

1. Treatment once a day Initial Field 45 1.8

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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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.

2030 Gy usually can be given to entire circumference of an


extremity, doesnt cause lymphedema.
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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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

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Functional results : Of all the patients 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.

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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.

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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 antibodiesetc

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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
Ewings sarcoma.

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