Dr. parvez patel

Hemat-oncology activity.

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

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

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

1

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

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.

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.

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

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, 4

IVA Any T N0 M1a any G

IVB Any T N1 any M any G

Any T any N M1b any G

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 marrow

Both Lung and Bone

Response to CT Responsive Unresponsive

14

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

Confirmation of diagnosis:◦ biopsy and histopathologic examination

core needle / open Inx biopsy

◦ Cytogenetics and IHC

X-RAY◦ Moth eaten lesion

◦ Lytic or mixed lytic-sclerotic areas

present

◦ Multi-Layered sub periosteal reaction

(onion skinning)

◦ Lifting of periosteum (Codman's

triangle)

CT SCAN: bone destruction best

seen Intramedullary space

extra osseous involvement

18

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

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

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

24

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

All patients require chemotherapy◦ Induction chemotherapy

◦ Maintenance chemotherapy

Effective chemotherapy has improved local

control rates achieved with radiation to 85-90%

26

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)

27

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

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%).

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

32

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

33

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.

34

35

radiation responsive tumor.

There are no randomized trials that have directly 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

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

39

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

40

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

41

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.

42

• Every 2- 3 months

• Increase interval after 24 months

• Annually after 5 years indefinitely

Physical Exam, Local and Chest Imaging:

CBC and other lab studies as indicated

Consider Bone Scan or Pet scan

43

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

44

Functional results : Of all the patient’s treatedwith 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.

45

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.

46

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

47

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.