Treatment of Ewing’s Sarcoma

Dr. Rajib BhattacharjeeMD PGT, IPGMER

May 22nd 2015

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

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

Genetics

Clinical presentation

Pain & swelling of affected area

May also have systemic symptoms: Fever Anemia Weight loss

Pathological fracture

Routes of spread Direct extension into

adjacent bone or soft tissue.

Metastases generally spread through bloodstream

25% present with metastatic diseaseLungsBoneBone Marrow

Nearly all pts. have micro-metastasis at diagnosis, so all need chemotherapy.

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•Metastasis•Serum LDH•Cytogenetics •Molecular characteristics•2nd malignancy

Treatment related issues

•Response to induction•“surgery not a part of local treatment”

Treatment of Ewing Sarcoma

Induction chemotherapy

Local therapySurgery

Radiation

Maintenancechemotherapy

Chemotherapy

1st line agents Vincristine (V) Actinomycin D (A) Cyclophosphamide

(C) Doxorubicin (D) Ifosfamide (I) Etoposide (E)

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%

Multiagent chemotherapyIESS-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

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

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

Standard Schedule

Vincristine 1.2mg/m2

• IV D1

Doxorubicin 75mg/m2

• IV D1

Cyclophosphamide 1200mg/m2

• IV D1

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

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

Surgery vs RT as local therapy

Disadvantages of RT Secondary

malignancies Effect on growth

plates

Advantages of surgery Limb salvage Structural bone

function preservation

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%

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)

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

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.

Radiotherapy in Ewing’s Sarcoma

Indications of RTDefinitive Radiation therapy Unresectable tumor

Inaccessible site

Patient with poor surgical risk

Patient refusing surgery

Indications of RTPost-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

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

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.

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

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#)

Post operative RT planningPHASE 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

Chest wall primaries with pleural involvement

Phase 1HEMITHORAX IRRADIATION15-20 Gy(1.5-1.8Gy/#)

Phase 2Cone down primary siteDose based on resection margins

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.

Surveillance

Physical examination, CXR

• Every 2- 3 months• Increase interval after 24 months• Annually after 5 years indefinitely

CBC & other lab works as indicated

Bone scan & FDG-PET

# NCCN

Relapse

30% of patients develop relapse with survival < 20%

• Median time to relapse – 16-21 months

Late relapse ( >2 years)

• Repeat the same regimen

Early relapse ( <2years)• Survival <10%• No established salvage regimen• Cyclophosphamide & Topotecan; Irinotecan &

Temozolomide; Ifosfamide, Carboplatin & Etoposide; Gemcitabine & Docetaxel

• Myeloablative chemotherapy

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 2003

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.

Disseminated metastasesDisseminated 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.

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

Extra-osseous Ewing’s Sarcoma

Traditional approach

• Treat EOES as Rhabdomyosarcoma

• Regimen:- I - Ifosfamide V - Vincristine A - Actinomycin-D

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

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

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

Thank you