3. Identified in 1921 by James Ewing
Ewing sarcoma family tumor (ESFT)
is the second most common primary
tumor of bone in childhood, and also arises in soft tissues.
Ewing’s sarcoma family of tumors:-
Ewing’s sarcoma ( bone- 87%)
Extraosseous Ewing’s sarcoma (8%)
Peripheral PNET (5%)
Askin’s tumour
4. ESFT is uncommon before 8 years of age and after 25
years of age.
In EICESS , the median age was 14 years, with 57%
of the patients male and 43% female although a
majority of the patients below 10 years of age were
female.
Rare in African-Americans and Asians
5. Light microscopy shows a tumor of small round blue
cells that lack markers for
lymphoma, neuroblastoma,
or rhabdomyosarcoma.
Approximately 95% of ESFTs have a translocation
between the EWS gene on chromosome 22 and the
FLI1 gene on chromosome 11 (t[11;22][q24;q12])
or the ERG gene on chromosome 21
(t[21;22][q22;q12]).
6. Also seen:
t(7;22) and t(17;22)
t(1;16) (q21;q13) can be present along with t(11;22)
The c-myc protooncogene is frequently expressed in
Ewing’s.
Strongly express CD99
Cells are periodic acid–Schiff (PAS) positive,
vimentin positive, and also often cytokeratin positive.
7.
8. Locoregional pain (90%)
Pain can be intermittent and variable in intensity. Pain
often does not completely disappear during the night
visible or palpable swelling of the affected site.
May have systemic symptoms:
Fever
Anemia
Weight loss
fatigue
Longest lag time in diagnosis for
any pediatric solid tumour.
9. More common in diaphysis or metadiaphysis
In the EICESS, sites
(23% to 25%) of lesions are located in the pelvis,
(16% to 18%), in the femur,
(10% to 16%) below the knee,
(12% to 13%), in the ribs,
(8%) in the spine,
and (5%) in the humerus.
10. Direct extension into adjacent bone or soft tissue.
Metastases generally spread through bloodstream
20% to 25% present with metastatic disease
◦ Lungs (40%)
◦ Bone (40%)
◦ Bone Marrow (11%)
Nearly all pts. have micromets at diagnosis,
so all Need chemo.
14. CT SCAN
Shows details of radiolucent portion of the lesion
and areas of cortical destruction.
Does not outline the soft tissue extent.
15. 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
16.
17.
18. SYSTEMIC WORKUP
Lab investigations :
ESR
CBC
LDH.
Chest CT Scan,
Bone Marrow Aspirate/Biopsies,
A Bone Scan, whole body MRI Or Better
If Available A FDG-PET-CT.
19. Bone scan :-
◦ To detect polyostotic involvement
◦ to detect bone metastasis Bone Scan: Ewing
Sarcoma of Left
Humerus
demonstrates
Intense Uptake
Fig: bone scan shows
increased activity in the
distal femur.
20. FDG-PET-CT SCAN
It is still an optional staging modality but is used
more and more frequently.
It has demonstrated high sensitivity and specificity
in ESFT.
FDG-PET-CT has been shown to detect more bone
metastases than traditional bone scans do, both at
diagnosis and at recurrence.
21.
22.
23. Disease factors Favorable prognosis Unfavorable prognosis
SITE Distal extremity (tibia, fibula,
radius, ulna, hands, feet)
Central lesions (especially pelvic
bones) less favorable: proximal
extremity (humerus, femur), ribs
SIZE <8 cm in greatest diameter or <200
mL estimated volume
Large tumors
SOFT TISSUE EXTENSION Absence of radiographically
identifiable soft tissue extension
Presence of soft tissue extension by
radiograph or significant extension
by computed tomography
Extentof disease Localized metastatic
Site of Metastasis lung Bone / bone marrow Both Lung
and Bone
Response to chemotherapy Responsive un responsive
24. • Chemotherapy : control of
Micro/macro metastasis
• Surgery :- local control
where possible
• Radiotherapy : local
control where surgery is not
possible or incomplete
Multidisciplinary
approach
25. Effective local and systemic therapy is necessary for the cure.
Induction chemotherapy is often preferred over starting the
systemic therapy and local therapy concomitantly.
There are several advantages to this approach:
Evaluation of the effectiveness of the regimen.
Decrease the vol. of primary tumor for surgery or RT
Some bone healing occur during CT, diminish the risk of
pathological fructure.
28. All patients require chemotherapy
◦ Induction chemotherapy
◦ Maintenance chemotherapy
Response rates to induction chemotherapy are
high, with radiologic complete response and
partial response rates of up to 90% reported
29. Prior to multi agent chemotherapy, long term survival
was less than 10% now increased to 60%-70%
Drugs effective are
Doxorubicin ,
Cyclophosphamide
Vincristine
Actinomycin-
Ifosfamide and
Etopside
30. Name of
regimen
drugs daily dose Administration
day
frequency
VAC Vincristine
Adriamycin
Cyclophosphamide
1.5mg/m2
50mg/m2
750mg/m2
1
1
1
Every 3 weekly
VACA Vincristine
Adriamycin
Cyclophosphamide
actinomycin
1.5mg/m2
60mg/m2
500mg/m2
0.015mg/m2
Weekly(3-7)
Week 7
Weekly(3-7)
1-5(wk1)
Every 3
monthly
AV alternating
with CV
Vincrystine
Adriamycin alternating
with Cyclophasmide
Vincrystine
1.4mg/m2
60mg/m2
1000mg/m2
1.4mg/m2
1-8
1
1
1-8
Alternate each
course every 4
weeks
IA Ifosfamide
G-CSF
Alternating with
Adriamycin,
G-CSF
20mg/m2
480ug
100mg/m2
480ug
1-9
10-16
1-2
3-9
Give 4 such
courses
31. IESS-1and IESS-2 showed 4 drug regimen VACD is
superior to 3drug 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%).
32.
33. DURATION OF CHEMOTHERAPY
Induction Multi agent chemotherapy for at least 12-
14 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 and 49 week depending on the type of
regimen and dose schedule .
34.
35. Indications
Expendable site (fibula, rib, clavicle).
Bone defect able to be reconstructed with modest loss
of function.
Lesion near major epiphysis.
Failed radiation therapy.
Large lesion with irreparable pathological fracture.
36.
37. Limb-salvage surgery is preferred.
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.
38.
39. Radiation responsive tumor.
There are no randomized trials that have directly
compared Radiotherapy to surgery for local controlof
Ewing’s sarcoma.
Radiotherapy can, in combination with chemotherapy,
achieve local control, but complete surgery whenfeasible
has to be regarded as the first choice of local therapy.**
40. Definitive Radiation therapy
Tumor where resection is impossible.
For skull, face, vertebra, or pelvic primary.
Where only a intra lesional resection is achievable.
Patient with poor surgical risks.
Patients refusing surgery.
41. Pre-op RT
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-2003
42. Post op- RT
For gross or microscopic positive margins.
For marginal resection.
For wide resection with poor histological response
to neo-adjuvent chemotherapy ( > 10% viable
tumor cell in the specimen).
43. 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.
44.
45. 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
46.
47. Definitive RT
◦ Phase 1:
Gross tumor in bone and soft tissue (pre chemo ) + 2-4cm longitudinal
margins + 2cm lateral margins.
Dose:45 Gy/180cGy/#
◦ Boost phase :
Reduced 1-2 cm margins(bone and residual tissue)
Up to total dose of 55.8Gy.
49. POST RT DOSE AND VOLUME
Pretreatment gross tumor volume +surgical scar+2cm margin (45Gy)
boost to post op residual +2cm margin.
◦ MICROSCOPIC DISEASE- 45 Gy
◦ MACROSCOPIC RESIDUAL – 55.8 Gy
◦ PRE –OP RT
◦ 45 Gy to original bone and soft tissue
50. For rib primary ,with pleural effusion, RT to
hemithorax.
For lung mets ,whole lung RT(15-18 Gy) or
consider resection if< 4 mets.
51.
52.
53. 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
54. 30-40% of patients develop relapse with 5 year
survival is only 13%.
Early relapse – less than 2 years:
Consider Changing Chemotherapy
Late relapse – more than 2 years:
Continue the previously used chemotherapy
55. 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 induced cardiomyopathy.
Ifosphamide induced renal toxicity
56. 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.
57.
58.
59.
60.
61.
62. 193patients
randomized to 3arms
vincristine,actinomycin-D,cyclophosphamide(VAC),adriamycin(RegimenI);
VACalone (RegimenII);
VACandbilateralpulmonaryirradiation(RegimenIII).
All patients receivedradiationtherapy to localsite.
Localcontrolwasachievedin 96%of the patients in RegimenI,and
86%of the patients in both RegimensIIandIII.
63. Local control wassame (92%) for tumors treated with whole
bone RT with 5cmfree marginaroundthe lesion
Localcontrol was79%when<5mmargin wastaken
Bilateral pulmonary irradiation- lowering the incidence of
lung mets from 38 to 28%.
Lung metastases were similarly decreased (10%) when
adriamycin was added toVACchemotherapy.
64. 214patients
Adriamycin, cyclophosphamide, vincristine, and dactinomycin by
either a high- dose intermittent method (treatment [trt] 1) or a
moderate-dose continuous method (trt 2) similar to the four-
drug arm of IESS-I
Theoverall outcome wassignificantly betterontrt1than ontrt 2
Treatmentfailure for both treatment groups wasthe development
of metastatic disease(lung)
• High-dose intermittent ofVACA at 3weekcyclehasbetter
outcome
67. Addition of ifosfamide and etoposideto a
standard regimen doesnot affect the outcome
for patients with metastatic disease,but it
significantly improvesthe outcome for patients
with nonmetastatic Ewing'ssarcoma,
68.
69. Children’s Oncology Group (COG) has sought to intensify the VDC/IE regimen.
INT-0154 was a randomized trial for newly diagnosed localized Ewing sarcoma.
They were randomly assigned to receive standard doses of VDC/IE over 48 weeks
or a dose-intensified regimen of VDC/IE over 30 weeks.
All patients received same cumulative doses of chemotherapy
A total of 478 eligible patients were randomized.
231 patients received the standard regimen; 247 patients intensified regimen.
The5 year Event free survival (EFS) and overall survival rates for all eligible
patients were 71.1% and 78.6%.
70. There was no statistically significant
difference in event-free survival between
the standard arm and the experimental
arm, demonstrating that higher-dose
therapy did not improve
outcomes.(p=.54)
71.
72. This trial sought to intensify therapy not by dose escalation, but
rather by decreasing the interval between chemotherapy cycles
(interval compression)
Standard and intensified treatment were to chemotherapy every 21
and14 day
Atotal of 568eligible patients wererandomized.
Patients randomized to the interval-compressed arm had a
significantly greater 5-year event-free survival (73%versus 65%for
patients randomized to the standardarmwith p=0.048).
75. Patients aged<30yearswith ESFT,who failed ≥third-line
therapy wereeligible
Enrolled 9patients
Overallmedian PFSwas2.2months (range:0.5-16.9months).
All nine patients had grade 4 neutropenia (100%);grade 3
diarrhea or grade 2/3 neuropathy eachoccurredin two
patients
The Docetaxel +Irinotecan combination may be effective
and tolerable for patients with heavily pre-treatedESFT.
79. All patients with Ewing sarcoma should be treated with
the following protocol:-
Primary treatment followed by local control therapy and
adjuvaprnt treatment.
Primary treatment:- multiagent chemotherapy along wth GF
Support for at least 9 week . (longer duration can be
considered for patient with metastatic disease based on
response).
VAC/IE is preferred regimen for localized disease.
VAdriaC is preferred for metastatic disease.
80. Disease should be restaged with imaging following
primary treatment.
Patients with stable or improved disease should be treated
with local control therapy, that includes option of
Wide excision
Definitive radiation with chemotherapy
Or amputation in selected cases.
The choice of local treatment should be
individualized and is depend on tumor location,
size, response to chemotherapy, patients age,
anticipated morbidity and patients preference.
81. Adjuvant chemotherapy is recommended for all patients
regardless of surgical margins.
Duration should be between 28 and 49 weeks depending
on type of regimen and the dosing schedule.
