Ewing’s Sarcoma

Dr. VandanaDept of Radiotherapy,CSMMU, Lucknow

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

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Introduction

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

Epidemiology

Pathology

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 Ewing’s. CD 99 ( MIC2) PAS +ve

Cytogenetics

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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

Clinical Presentation

Location more common in diaphysis or

metadiaphysis

central axis (47%): ◦ pelvis, chest wall, spine, head &

neck

extremities (53%)

Scapula (3.8%)

Skull(3.8%)

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.

Routes of spread

No mets75%

Lu+Bone/BM 4 %

Lung 13%

Bone/BM 7 %

Other 1 %

No uniform staging system.

The AJCC staging systems for bone or soft-tissue sarcomas may be used.

Staging

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

AJCC Staging (7th Ed. 2010) Bone Tumor

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, 4IVA Any T N0 M1a any GIVB Any T N1 any M any G

Any T any N M1b any G

Stage

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

Larger tumors

Soft tissue extension

Absence of radiographically identifiable soft tissue extension

Presence of soft tissue extension by radiograph or significant extension by computed tomography

Extent of disease

Localized Metastatic

Site of Metastasis

Lung Bone / bone marrowBoth Lung and Bone

Response to CT

Responsive Unresponsive

Prognostic Factors

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Survival

Primary Staging

History & Physical Examination

Histo-pathology -Biopsy-Genetics-IHC

-Bone Marrow

Imaging -X-ray-CT scan-MRI

-CT Thorax-Bone scan-PET scan

Lab Test - Renal – RFT - Cardiac – 2D-ECHO

Diagnostic Work-Up

Confirmation of diagnosis:◦ biopsy and histopathologic examination

core needle / open Inx biopsy

◦ Cytogenetics and IHC

Biopsy

Imaging

X-RAY◦ Moth eaten lesion◦ Lytic or mixed lytic-sclerotic

areas present◦ Multi-Layered subperiosteal

reaction (onion skinning)◦ Lifting of perioteum (codman’s

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

MRI

Bone scan: ◦ To detect polyostotic involvement◦ to detect bone metastasis

Bone marrow biopsy

CXR/CT of chest: lung mets

Fig: bone scan shows increased activity in the distal femur.

Bone Scan: Ewing Sarcoma of Left Humerus demonstrates Intense Uptake

Gross Pathology: Ewing Sarcoma of 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

PET/PET- CT Scan

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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Treatment

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

General Management

Induction Chemotherap

y

Local Control• Surgery• Radiothera

py

Maintenance• Chemother

apy

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Chemotherapy

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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Chemotherapy

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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Chemotherapy

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

Second line therapy (relapse and refractory disease)

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 (61→72%) for localized disease, but not for metastatic disease (25%).

Clinical Studies

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

DURATION

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Surgery

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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Role of Surgery

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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Radiotherapy

radiation responsive tumor.

There are no randomized trials that have directely compared Radiotherapy to surgery for local control of Ewing’s 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

Radiotherapy

Radiotherapy detail 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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Indications for RT: After induction chemotherapy

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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Cont…

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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Cont…

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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Planning

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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Post-op RT Planning

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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Palliative RT

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 poor histologic response at surgery

41.4 – 45 1.8

Preoperative radiotherapy:

45 1.8

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Recommendations for RT Fields & doses

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.

20–30 Gy usually can be given to entire circumference of an extremity, doesn’t 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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Surveillance

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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Relapse

Functional results : 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 cardiomyopathy. Ifosphamide renal toxicity.

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Side Effects

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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Side Effects

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 antibodies…etc

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In the near Future

Overview of Ewing’s tumor treatment

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 Ewing’s sarcoma.

Conclusion

Thank You