1. Treatment of Ewing’s
Sarcoma
Dr. Rajib Bhattacharjee
MD PGT, IPGMER
May 22nd 2015

2. Introduction …..
 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% of all childhood
malignancies
 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

3. Pathology
 One of many ‘small
round blue cell’ tumors
seen in pediatrics
(IHC – MIC-2 positive)
 Poorly differentiated
tumor
 Unknown origin, Thought
to be of neural crest
progenitor cells origin

4. Genetics

5. Clinical presentation
 Pain & swelling of affected
area
 May also have systemic
symptoms:
 Fever
 Anemia
 Weight loss
 Pathological fracture

6. Routes of spread
 Direct extension into
adjacent bone or soft
tissue.
 Metastases generally
spread through
bloodstream
 25% present with
metastatic disease
 Lungs
 Bone
 Bone Marrow
 Nearly all pts. have
micro-metastasis at
diagnosis, so all need
chemotherapy.

7. Diagnostic & staging work
up
-LDH
-LFT
-CBC, KFT, LFT,
-LDH

8. AJCC Staging (7th Ed. 2010) Bone
tumors

9. Prognostic factors
Patient factors
• Age
• sex
Tumor
characteristics
• Site
• Size/volume
• Pretreatment
necrosis
• Metastasis
• Serum LDH
• Cytogenetics
• Molecular
characteristics
• 2nd malignancy
Treatment
related issues
• Response to
induction
• “surgery not a
part of local
treatment”

10. Treatment of Ewing
Sarcoma
Induction
chemotherapy
Local therapy
Surgery
Radiation
Maintenance
chemotherapy

11. Chemotherapy
1st line agents
 Vincristine (V)
 Actinomycin D (A)
 Cyclophosphamide
(C)
 Doxorubicin (D)
 Ifosfamide (I)
 Etoposide (E)

12. Historical perspective
 Pre-chemotherapy era – 5Y OS <10%
 Chemotherapy – 5 Y OS >40%
 1962 - Sutow and Sullivan - use of
cyclophosphamide
 Hustu et al. - Vincristine and
Cyclophosphamide.
 1974 - Rosen et al.(MSKCC) – VACD
Regimen
5 Y OS (‘73-’77) – 36%
5 Y OS (‘93-’97) – 59%

13. Multiagent chemotherapy
IESS-I (Nesbit et al.)
1973-1978
Schedule 5Y EFS
VAC 24%
VAC+WLI 44%
VACD 60%
CONCLUSION - Addition of
Doxorubicin provides clear
survival advantage
IESS-II
1978-1982
schedule 5Y EFS
VACD-HD 68%
VACD-MD 48%
CONCLUSION – Intermittent
high dose VACD is
superior to continuous
moderate dose therapy

14. American Intergroup Ewing’s
trial
(INT-0091 - POG-8850/CCG-7881)
localized Ewing’s Sarcoma
VD(A)C/IE VD(A)C
69% 5 Y EFS 54%
CONCLUSION – Addition of IE has advantage in:-
localized disease
large tumors
pelvic primary

15. Dose dense approach
Children’s Oncology Group AEWS-0031 study
localized Ewing’s Sarcoma
dose dense therapy standard therapy
VD(A)C/IE VD(A)C/IE
q 14 days q 21 days
73% 5 Y EFS 65%
CONCLUSION – Dose dense VD(A)C/IE with G-CSF support is the
standard of care in localized Ewing’s sarcoma

16. Standard Schedule
• IV D1
Vincristine 1.2mg/m2
• IV D1
Doxorubicin 75mg/m2
• IV D1
Cyclophosphamide 1200mg/m2
Ifosfamide 1800mg/m2
• IV D1-D5
Etoposide 100mg/m2
• IV D1-D5
• Alternate 2 week cycle
• G-CSF support
• Total duration of chemotherapy is 30 weeks
• Local therapy after 12 weeks
• Replace Doxorubicin by Actinomycin-D(1.2mg/m2) on
11th cycle

17. Local control
“ the first indication is for
treatment by radiation in
full doses, and over
considerable periods.
This recommendation is
based on the reported
cure of certain cases….by
radiation alone, and on
the clinical disappearance
of the disease by variable
periods in many more
cases. The response to
radiation also confirms
the diagnosis….”
James Ewing, 1940
“ Neoplastic Diseases”, 4th Edn

18. Surgery vs RT as local
therapy
Disadvantages of RT
 Secondary
malignancies
 Effect on growth
plates
Advantages of surgery
 Limb salvage
 Structural bone
function
preservation

19. Choice of local therapy : Surgery vs
RT

20. Surgery or radiotherapy ???
Local recurrence rate – after surgery - 7.5%
after definitive RT - 26.3%

21. Unfair bias against RT
 Recurrence rate after RT is
strongly correlated with the
primary site
Extremities – 5 to 10%
Pelvis – 15 to 70%
 Tumor size is strongly related
to Recurrence rates
< 8cms = ≤ 80%
> 8cms = 90 %
 Combined modality trials are
designed to evaluate
[RT Vs Surgery + RT] not
[Surgery Vs Surgery + RT]
 Quality of the RT delivered in
some negative trials is
doubtful
 Surgical series always select
patients at low-risk (e.g.
Extremity lesions with low
volume disease)
 Second malignancies are
related not to RT alone but to
chemotherapy as well
(Anthracyclines & alkylating
agents)

22. Conclusion
Ewing’s sarcoma is a radiation responsive malignancy.
No randomized trials compared Radiotherapy to
surgery for local control of Ewing’s sarcoma.
Radiotherapy can 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

23. Surgery as local therapy
 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 preferred.
 Curative surgery requires wide local excision and
negative margin
 Bony margins of at least 1 cm.
 Soft tissue margin of at least 5mm.

24. Radiotherapy in Ewing’s
Sarcoma

25. Indications of RT
Definitive Radiation therapy
 Unresectable tumor
 Inaccessible site
 Patient with poor surgical risk
 Patient refusing surgery

26. Indications of RT
Post-operative Radiation Therapy
 Intra-Lesional Resection
 Marginal Resection
 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

27. Indications of RT
Pre-operative Radiation Therapy
 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

28. Radiotherapy techniques
 Patient position - supine, prone or
lateral.
 Energy – Co-60, 6MV LINAC.
 Tailored portals for every patient.
 Field should not cross joints unless
essential.
 Strip(1-2cm) of normal tissue spared
for lymph drainage.

30. Schematic depiction of GTV1 (pre-
induction bone and pre-induction
soft tissue extent) and GTV2 (post-
induction soft tissue extent)

31. Planning
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 @1.8Gy/#.
◦ PHASE 2 :
 Cone down to original bony extent + 2 cm margins
 Complete response - 45 Gy (no boost)
 Chemotherapy response > 50% - 55.8 Gy (10.8Gy/6#)
 Chemotherapy response < 50% - 59.4 Gy (14.4Gy/8#)

32. Post operative RT planning
PHASE 1
Pre chemo GTV + surgical scar + 2cm margin – 45 Gy
PHASE 2
resection histological response boost dose
R0 100% no Adj RT
< 100% no boost
R1 100% no boost
< 100% 5.4 Gy/3#
R2 100% 5.4 Gy/3#
< 100% 10.8 Gy/6#
---------------------------------------------------------------------------------------------
Pre operative RT planning
Pre chemo GTV + 2 cm margin – 36-45 Gy

33. Chest wall primaries with
pleural involvement
Phase 1
HEMITHORAX IRRADIATION
15-20 Gy(1.5-1.8Gy/#)
Phase 2
Cone down primary site
Dose based on resection
margins

34. Proton beam therapy
Spares normal tissues
No evidence of enhanced
functional outcome or
reduced risk of secondary
malignancy
Effect on local recurrence
uncertain
Rombi, Barbara, et al. "Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical
outcomes." International Journal of Radiation Oncology* Biology* Physics 82.3 (2012): 1142-1148.

35. Surveillance
• Every 2- 3 months
• Increase interval after 24 months
• Annually after 5 years indefinitely
Physical examination, CXR
CBC & other lab works as
indicated
Bone scan & FDG-PET
# NCCN

36. Relapse
• Median time to relapse – 16-21 months
30% of patients develop
relapse with survival < 20%
• Repeat the same regimen
Late relapse ( >2 years)
• Survival <10%
• No established salvage regimen
• Cyclophosphamide & Topotecan; Irinotecan &
Temozolomide; Ifosfamide, Carboplatin &
Etoposide; Gemcitabine & Docetaxel
• Myeloablative chemotherapy
Early relapse ( <2years)

37. Metastasis
Metastasis 5 Y RFS
Lung 29%
Bone & bone marrow 19%
Both 8%

38. Metastatic disease
The addition of Ifosfamide & Etoposide in the
metastatic group provided no survival advantage
# NEJM 2003

39. Lung bath
Whole lung irradiation
After completion of
chemotherapy/
metastasectomy
>14 years - 18Gy @ 1.5Gy/#
<14 years - 15Gy @ 1.5Gy/#
< 6 years – 12 Gy@ 1.5Gy/#
Paulussen, M., et al. "Primary metastatic (stage
IV) Ewing tumor: survival analysis of 171 patients
from the EICESS studies." Annals of oncology 9.3
(1998): 275-281.

40. Disseminated metastases
Disseminated disease
Approach 3 Y EFS
Both 47%
Surgery 25%
RT 23%
No local T/t 13%
Conclusion – adequately treat
primary and all the
metastasis.
Disseminated bone mets
Approach 3Y EFS
RT to mets site 35%
No local therapy 16%
Conclusion – treat all lesions in
disseminated bone
metastases. (whole body MRI
f/b compartmental irradiation
upto 54 Gy)
# Haeusler, Julia, et al. "The value of local treatment in patients with primary,
disseminated, multifocal Ewing sarcoma (PDMES)." Cancer 116.2 (2010): 443-450.

41. Treatment in a
nutshell
Localized disease
Induction chemo (DDVAC/IE)
12 weeks
Surgery or Radiotherapy
Adj RT
Maintenance chemo
(DDVAC/IE)
18 weeks
Metastatic disease
Treatment of primary (Local T/t)
local T/t of the metastatic site
(bone irradiation, WLI)
___________________________
Follow up
Relapse
2nd line chemo
Myeloablative therapy

42. Extra-osseous Ewing’s Sarcoma
Traditional approach
• Treat EOES as
Rhabdomyosarcoma
• Regimen:-
I - Ifosfamide
V - Vincristine
A - Actinomycin-D

43. To Dox or not to Dox; that is the
question !!!
Extraosseous Ewing’s Sarcoma
MMT strategy OET strategy
No Anthracyclin Anthracyclin
59% OS 83%
44% EFS 75%
CONCLUSION – The regimen of
osseous Ewing’s sarcoma may
be used in extraosseous
Ewing’s sarcoma

44. Sequelae of treatment
Radiation
 Premature closure of
epiphysis
 Pathologic fractures
 Decrease range of
motion due to fibrosis
 Skin changes
 Lymphoedema
 Infertility
 Second malignancies
Chemotherapy
 Secondary leukemia
 Bladder toxicity
 Cardiotoxicity
 SIADH

45. Future directions
 Use of 3D-CRT / IMRT as a standard protocol
 PET scan shows potential in both diagnosis and
treatment
 Proton therapy needs further evaluation
 TARGETED therapy : against IGF1 or IGF1R
 Small molecule therapy – Mithramycin inhibits EWS-
FLI1 downstream targets (including c-myc)
YK-4-279 stops EWS-FLI fusion protein from sticking
to RNA Helicase A

46. Thank you