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Treatment of Ewing’s
Sarcoma
Dr. Rajib Bhattacharjee
MD PGT, IPGMER
May 22nd 2015
Introduction …..
 Identified in 1921 by
James Ewing
 2nd most common
bone tumor in children
 Ewing’s Sarcoma
Family of ...
Pathology
 One of many ‘small
round blue cell’ tumors
seen in pediatrics
(IHC – MIC-2 positive)
 Poorly differentiated
t...
Genetics
Clinical presentation
 Pain & swelling of affected
area
 May also have systemic
symptoms:
 Fever
 Anemia
 Weight loss...
Routes of spread
 Direct extension into
adjacent bone or soft
tissue.
 Metastases generally
spread through
bloodstream
...
Diagnostic & staging work
up
-LDH
-LFT
-CBC, KFT, LFT,
-LDH
AJCC Staging (7th Ed. 2010) Bone
tumors
Prognostic factors
Patient factors
• Age
• sex
Tumor
characteristics
• Site
• Size/volume
• Pretreatment
necrosis
• Metast...
Treatment of Ewing
Sarcoma
Induction
chemotherapy
Local therapy
Surgery
Radiation
Maintenance
chemotherapy
Chemotherapy
1st line agents
 Vincristine (V)
 Actinomycin D (A)
 Cyclophosphamide
(C)
 Doxorubicin (D)
 Ifosfamide (...
Historical perspective
 Pre-chemotherapy era – 5Y OS <10%
 Chemotherapy – 5 Y OS >40%
 1962 - Sutow and Sullivan - use ...
Multiagent chemotherapy
IESS-I (Nesbit et al.)
1973-1978
Schedule 5Y EFS
VAC 24%
VAC+WLI 44%
VACD 60%
CONCLUSION - Additio...
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...
Dose dense approach
Children’s Oncology Group AEWS-0031 study
localized Ewing’s Sarcoma
dose dense therapy standard therap...
Standard Schedule
• IV D1
Vincristine 1.2mg/m2
• IV D1
Doxorubicin 75mg/m2
• IV D1
Cyclophosphamide 1200mg/m2
Ifosfamide 1...
Local control
“ the first indication is for
treatment by radiation in
full doses, and over
considerable periods.
This reco...
Surgery vs RT as local
therapy
Disadvantages of RT
 Secondary
malignancies
 Effect on growth
plates
Advantages of surger...
Choice of local therapy : Surgery vs
RT
Surgery or radiotherapy ???
Local recurrence rate – after surgery - 7.5%
after definitive RT - 26.3%
Unfair bias against RT
 Recurrence rate after RT is
strongly correlated with the
primary site
Extremities – 5 to 10%
Pelv...
Conclusion
Ewing’s sarcoma is a radiation responsive malignancy.
No randomized trials compared Radiotherapy to
surgery f...
Surgery as local therapy
 Surgical Indications
 Expendable bone (fibula, rib, clavicle)
 Bone defect able to be reconst...
Radiotherapy in Ewing’s
Sarcoma
Indications of RT
Definitive Radiation therapy
 Unresectable tumor
 Inaccessible site
 Patient with poor surgical risk
...
Indications of RT
Post-operative Radiation Therapy
 Intra-Lesional Resection
 Marginal Resection
 Wide-resection with P...
Indications of RT
Pre-operative Radiation Therapy
 When Narrow resection margins are expected
Principle : To sterilize th...
Radiotherapy techniques
 Patient position - supine, prone or
lateral.
 Energy – Co-60, 6MV LINAC.
 Tailored portals for...
Schematic depiction of GTV1 (pre-
induction bone and pre-induction
soft tissue extent) and GTV2 (post-
induction soft tiss...
Planning
Definitive RT
◦ PHASE 1:
 Gross tumor in bone and soft tissue (pre chemo ) + 2-4
cm longitudinal margins + 2 cm ...
Post operative RT planning
PHASE 1
Pre chemo GTV + surgical scar + 2cm margin – 45 Gy
PHASE 2
resection histological respo...
Chest wall primaries with
pleural involvement
Phase 1
HEMITHORAX IRRADIATION
15-20 Gy(1.5-1.8Gy/#)
Phase 2
Cone down prima...
Proton beam therapy
Spares normal tissues
No evidence of enhanced
functional outcome or
reduced risk of secondary
malignan...
Surveillance
• Every 2- 3 months
• Increase interval after 24 months
• Annually after 5 years indefinitely
Physical examin...
Relapse
• Median time to relapse – 16-21 months
30% of patients develop
relapse with survival < 20%
• Repeat the same regi...
Metastasis
Metastasis 5 Y RFS
Lung 29%
Bone & bone marrow 19%
Both 8%
Metastatic disease
The addition of Ifosfamide & Etoposide in the
metastatic group provided no survival advantage
# NEJM 20...
Lung bath
Whole lung irradiation
After completion of
chemotherapy/
metastasectomy
>14 years - 18Gy @ 1.5Gy/#
<14 years - 1...
Disseminated metastases
Disseminated disease
Approach 3 Y EFS
Both 47%
Surgery 25%
RT 23%
No local T/t 13%
Conclusion – ad...
Treatment in a
nutshell
Localized disease
Induction chemo (DDVAC/IE)
12 weeks
Surgery or Radiotherapy
Adj RT
Maintenance c...
Extra-osseous Ewing’s Sarcoma
Traditional approach
• Treat EOES as
Rhabdomyosarcoma
• Regimen:-
I - Ifosfamide
V - Vincris...
To Dox or not to Dox; that is the
question !!!
Extraosseous Ewing’s Sarcoma
MMT strategy OET strategy
No Anthracyclin Anth...
Sequelae of treatment
Radiation
 Premature closure of
epiphysis
 Pathologic fractures
 Decrease range of
motion due to ...
Future directions
 Use of 3D-CRT / IMRT as a standard protocol
 PET scan shows potential in both diagnosis and
treatment...
Thank you
Treatment of ewing’s sarcoma
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Treatment of ewing’s sarcoma

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Treatment of ewing’s sarcoma

  1. 1. Treatment of Ewing’s Sarcoma Dr. Rajib Bhattacharjee MD PGT, IPGMER May 22nd 2015
  2. 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. 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. 4. Genetics
  5. 5. Clinical presentation  Pain & swelling of affected area  May also have systemic symptoms:  Fever  Anemia  Weight loss  Pathological fracture
  6. 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. 7. Diagnostic & staging work up -LDH -LFT -CBC, KFT, LFT, -LDH
  8. 8. AJCC Staging (7th Ed. 2010) Bone tumors
  9. 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. 10. Treatment of Ewing Sarcoma Induction chemotherapy Local therapy Surgery Radiation Maintenance chemotherapy
  11. 11. Chemotherapy 1st line agents  Vincristine (V)  Actinomycin D (A)  Cyclophosphamide (C)  Doxorubicin (D)  Ifosfamide (I)  Etoposide (E)
  12. 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. 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. 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. 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. 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. 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. 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. 19. Choice of local therapy : Surgery vs RT
  20. 20. Surgery or radiotherapy ??? Local recurrence rate – after surgery - 7.5% after definitive RT - 26.3%
  21. 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. 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. 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. 24. Radiotherapy in Ewing’s Sarcoma
  25. 25. Indications of RT Definitive Radiation therapy  Unresectable tumor  Inaccessible site  Patient with poor surgical risk  Patient refusing surgery
  26. 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. 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. 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.
  29. 29. Schematic depiction of GTV1 (pre- induction bone and pre-induction soft tissue extent) and GTV2 (post- induction soft tissue extent)
  30. 30. 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#)
  31. 31. 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
  32. 32. 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
  33. 33. 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.
  34. 34. 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
  35. 35. 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)
  36. 36. Metastasis Metastasis 5 Y RFS Lung 29% Bone & bone marrow 19% Both 8%
  37. 37. Metastatic disease The addition of Ifosfamide & Etoposide in the metastatic group provided no survival advantage # NEJM 2003
  38. 38. 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.
  39. 39. 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.
  40. 40. 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
  41. 41. Extra-osseous Ewing’s Sarcoma Traditional approach • Treat EOES as Rhabdomyosarcoma • Regimen:- I - Ifosfamide V - Vincristine A - Actinomycin-D
  42. 42. 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
  43. 43. 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
  44. 44. 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
  45. 45. Thank you

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