Ewing Sarcoma

ARROCase: Ewing Sarcoma

Jana Kobeissi, MS4

American University of Beirut, Lebanon

Mel Lizaso, MD

University of Cincinnati Cancer Center, Cincinnati, Ohio

Reviewed by: Luke Pater, MD

University of Cincinnati Cancer Center, Cincinnati, Ohio

Case Presentation

• 13 year old boy

• Localized, waxing & waning right leg pain

• 3 weeks duration

• Gradual onset

• Increasing in intensity

• ROS

• Otherwise negative

• No fever, night sweats, fatigue, weight loss

Case Presentation

• History unrevealing

• No history of trauma

• Negative past medical/surgical history

• Family history non-contributory

• No medications or known allergies

• Physical examination

• Afebrile, vital signs within normal range

• Point tenderness on palpation of mid-lateral side of right

leg with mild overlying swelling

• Normal gait and range of motion; Neuro exam non-focal

Imaging

X-ray of the Right Leg

Case courtesy of Dr Samir Benoudina, Radiopaedia.org, rID: 75437

Imaging

X-ray of the Right Leg

Case courtesy of Dr Samir Benoudina, Radiopaedia.org, rID: 75437

Imaging

X-ray of the Right Leg: Codman triangle (Red Arrow)

Sunburst Appearance (Blue Arrow)

Onion-Skin Periosteal reaction (Yellow Arrow)

Case courtesy of Dr Samir Benoudina, Radiopaedia.org, rID: 75437

Biopsy*

Sheets of small, uniform cells with scant cytoplasm, round nuclei, and

small punctate nucleoli

*Open incisional biopsy is preferred so that the biopsy tract can be

removed with definitive surgery.

https://www.webpathology.com/image.asp?n=5&Case=340

EWING SARCOMA

Diagnosis and Workup

Epidemiology

• Aggressive bone and soft-tissue cancer

• Predominant in children and adolescents

• Peak incidence at 15 years of age

• About 2% of all cancers in children

• Around 200 new cases/year

• Second most common bone cancer

• Male > Female

• About 25% present with metastatic disease

Presentation

• Localized pain and swelling

• Most commonly in pelvis and proximal

long bones

• Possible palpation of a firm mass

• Pathological fracture in 10-15% of cases

• Constitutional symptoms

• Fever, night sweats, fatigue, and weight

loss

Diagnosis

TEST RESULT

Plain

radiograph

• Multiple confluent lytic lesions, like “Moth eaten” bone

• Periosteal reaction, giving rise to “onion peel” or Codman’s

triangle

Biopsy

• Sheets of small, round, blue cells with a prominent nucleus and

scant cytoplasm

Blood tests

• May show elevated levels of nonspecific markers of inflammation

and bone remodeling (ESR, Alk Phos)

• Elevated serum LDH

Differential Diagnosis for Small Round Blue

Cell Tumors

• Histologic findings shared with:

• Neuroblastoma

• Desmoplastic small round-cell tumor

• Alveolar rhabdomyosarcoma

• Peripheral neuroectodermal tumor

• Non-Hodgkin’s lymphoma

• Acute lymphoblastic leukemia

• Poorly differentiated synovial sarcoma

• Other rare “Ewing-like” tumors

Molecular Studies

• Fusion of:

• EWS gene (chr. 22)

• Gene of the ETS family

• Most common (85%):

• EWS & FLI-1 fusion; t(11;22)(q24;q12)

• Associated with a better prognosis

• Identification of signature chromosomal

translocation —> Definitive diagnosis

• Consider fusion panels if initial studies -ve

Prognostic Factors

• Favorable

• Distal lesion

• Tumor volume < 100 mL

• Normal LDH level

• Adverse

• Metastatic disease at presentation

• Poor response to initial chemotherapy

Staging

• MRI with or without CT of 1

lesion (with

contrast)

• Head-to-toe PET CT scan and/or bone scan

• In case of high risk disease or concerning

symptoms, consider:

• CT Chest with contrast

• Bone marrow biopsy

• Scanning MRI of spine and pelvis

Staging System

• Localized v.s. Metastatic

• Metastases can be

• Regional (nearby structures/lymph nodes)

• Distant (distant organs; eg, lung)

• TNM staging

• Less commonly used

TNM Staging

Outcomes

• 5-year relative survival rates

• Localized: 82%

• Regional: 70%

• Distant: 39%

• All stages combined: 62%

American Cancer Society statistics: 2010-2016.

Outcomes

• Cure rate in case of metastases in:

• Lung: 30%

• Bone/bone marrow: 20%

• Local control rates:

• Surgery for extremity tumor: >90%

• Surgery for central tumor: 75%

• Radiation therapy: 75-90%

GUIDELINES ON MANAGEMENT

NCCN v2.2022

LOCALIZED EWING SARCOMA

Treatment of Localized Ewing Sarcoma

• In brief:

Induction

Chemotherapy

Local

Treatment

Consolidation

Chemotherapy

Treatment of Localized Ewing Sarcoma

• Induction Chemotherapy

• Alternating VDC & IE

• Vincristine, Doxorubicin, Cyclophosphamide

• Ifosfamide, Etoposide

• Six Cycles

• Re-staging

• Repeat imaging of initial workup

• Stable/improved v.s. progressive

Treatment of Localized Ewing Sarcoma

• If stable or improved —> Local therapy at ~ 15

wks

• Surgery

• Wide local excision or amputation

• Followed by

• Chemo (regardless of surgical margins)

• + RT (if close or positive margins,

consider for pelvic tumors)

• OR Definitive chemoradiation

Treatment of Localized Ewing Sarcoma

• If progressive —> Consider local therapy

• RT or

• Surgery

• For local control or palliation

Treatment of Localized Ewing Sarcoma

• More on local therapy

• Prefer surgery for:

• Younger children (to avoid 2

malignancy)

• Tumors in proximal fibula, lateral clavicle, ribs,

scapular body, iliac wings, small bones of the

hands/feet (i.e. “expendable” bones)

• Prefer definitive chemoRT for:

• Prevention of limb amputation

• Tumors in pelvis/spine (surgery would be debilitating)

Treatment of Localized Ewing Sarcoma

• Consolidation chemotherapy

• To be given after local therapy

• Alternating VDC & IE

• For 11 cycles

METASTATIC EWING SARCOMA

Treatment of Metastatic Ewing Sarcoma

• Primary Treatment: Chemotherapy

• Then:

• Consider local therapy, especially if:

• Oligometastatic

• Good response to chemotherapy

• Otherwise, if widely metastatic, consider:

• Chemo with palliative surgery

• Palliative RT to symptomatic areas

Treatment of Metastatic Ewing Sarcoma

• Special case:

Ewing sarcoma metastatic to lung only

• Treat definitively:

Induction

Chemotherapy

Local

Treatment

Consolidation

Chemotherapy

Consolidation

whole lung RT

RADIATION THERAPY

More on

Radiation Therapy

• Definitive RT

• GTV1: pretreatment bone + soft tissue (45 Gy at 1.8 Gy/fx)

• CTV1: 1-1.5 cm

• PTV1: 0.5-1 cm

• GTV2: post-chemotherapy soft tissue (55.8 Gy at 1.8 Gy/fx)

• CTV2: 1-1.5 cm

• PTV2: 0.5-1 cm

• N.B.

• Anatomically modified CTV so as not to cross nearby borders

• No need to expand into structures which the tumor abutted (but did not invade)

• PTV2 of vertebral body tumors receives 50.4 Gy instead

NCCN v2.2022

Donaldson. Pediatr Blood Cancer. 2004.

Radiation Therapy

• Preoperative RT

• For marginally resectable tumors to improve margin

status

• Eg, R1 —> potential R0

• Goal is not to downstage an un-resectable

tumor (Eg, R2 —> potential R1/R0)

• Initial GTV + 2 cm

• Dose: 36-45 Gy (1.8 Gy/fx)

NCCN v2.2022

Radiation Therapy

• Postoperative RT (Within 60 days) all at (1.8 Gy/fx)

• GTV2 (45 Gy) + CTV1 + PTV1

• R0 resection (No microscopic residual)

• Esp. if unfavorable histology

• R1 resection (Microscopic residual)

• R2 resection (Gross residual)

• With cone down to residual

• Total dose: 55.8 Gy to GTV2 + CTV2 + PTV2

• LN +ve areas

• Resected: 50.4 Gy

• Un-resected: 55.8 Gy

NCCN v2.2022

Donaldson. Pediatr Blood Cancer. 2004.

Radiation Therapy

• Hemithorax Irradiation

• Indication: Chest wall 1

tumor w/ extensive pleural involvement

• Dose:

• 15-20 Gy (1.5 Gy/fx) to ipsilateral whole lung and pleura; THEN

• 21.6 Gy (1.8 Gy/fx) to PTV1; AND

• 14.4 Gy boost to PTV2

• Note: same PTV1 & PTV2 as definitive RT expansions

• Whole Lung Irradiation

• Indication: pulmonary metastases after chemotherapy (even if

complete response) or surgical resection

• Dose: 15 Gy if <14 y.o. or 18 Gy if >14 y.o. (1.5 Gy/fx)

NCCN v2.2022

Radiation Therapy - Some Constraints

• Keep V40 < 66%

• To avoid pathological fracture

• Avoid circumferential RT & add skin strip

• To avoid lymphedema

• Keep in mind:

• Epiphyseal closure at ~ 20 Gy

• Ovarian failure at ~ 8 Gy

• —> Lead shielding or ovarian transposition out of field

• Testicular failure at ~ 2 Gy

• —> Lead shielding

Radiation Therapy - Side Effects

• Secondary malignancy

• Growth abnormalities

• Fibrosis/edema

• Hypoplasia of muscles

• Femoral head necrosis

• Pathologic fractures

• Infertility

Chemotherapy - Side Effects

• Regimen: alternating VDC & IE

• Secondary AML (DC & IE)

• Cardiomyopathy (D)

• Infertility (I &C)

• Renal toxicity (I)

• Cystitis (C)

V: Vincristine, D: Doxorubicin, C: Cyclophosphamide, I: Ifosfamide, E: Etoposide

STUDIES AND TRIALS

Evidence

Induction Chemotherapy

• IESS-I: (VACD) v.s. (VAC) v.s. (VAC +BPR) (Nesbit et al. 1990)

• Localized Ewing sarcoma; N=342

• 5-year RFS: 60% v.s. 24% v.s. 44% (p < 0.001)

• 5-year OS: 65% v.s. 28% v.s. 53% (p < 0.001)

• IESS-II: High-dose intermittent v.s. Moderate-dose

continuous of VACD (Burgert et al. 1990)

• 5-year RFS: 73% v.s. 56% (p=0.03)

• 5-year OS: 77% v.s. 63% (p=0.05)

V: Vincristine; A: Actinomycin D; C: Cyclophosphamide; D: Doxorubicin; BPR: Bilateral pulmonary radiation

Induction Chemotherapy

• INT-0091: (VACD + IE) v.s. VACD (Grier et al. 2003)

• Ewing, PNET or primitive sarcoma of bone; N=398

with non-metastatic dx

• 5-year EFS: 69% v.s. 54% (p=0.005)

• 5-year OS: 72% v.s. 61% (p=0.01)

V: Vincristine; A: Actinomycin D; C: Cyclophosphamide; D: Doxorubicin; I: Ifosfamide; E: Etoposide

Induction Chemotherapy

• INT-0154: VADC/IE in 30 w (dose intensified) v.s. 48 weeks

(Granowetter et al. 2009)

• Ewing sarcoma family of tumors; N=478

• 5-year EFS: 70.1% v.s. 72.1% (p=0.57)

• COG AEWS0031: VDC-IE q2w v.s. q3w (Womer et al. 2012)

• Localized, extradural Ewing sarcoma; N=568

• 5-year EFS: 73% v.s. 65% (p=0.048)

• No increase in toxicity

V: Vincristine; A: Actinomycin D; C: Cyclophosphamide; D: Doxorubicin; I: Ifosfamide; E: Etoposide

Local Modality: Surgery v.s. RT

• COG Meta Analysis of INT-0091, INT-0154, and AEWS0031

(Ahmed et al. 2017)

• Ewing sarcoma; N=956

• Modality: Surgery v.s. RT v.s. (Surgery + RT)

• 5-year LF: 3.9% v.s. 15.3% (p<0.01) v.s. 6.6% (p=0.12)

• Stratified by tumor location and age:

Location

5-year local failure

Surgery

5-year local failure

Definitive RT

Extremity 3.7%

14.8% (p≦0.01)

Pelvic 3.9%

22.4% (p≦0.01)

Axial non-spine No difference

Spine No difference

Extraskeletal No difference

Age 5-year Local Failure

≧18 years

11.9%

< 18 years 6.7% (p=0.02)

* A statistically greater number of patients who underwent surgery had tumors in more favorable locations (ie. Extremity).

Consolidation Treatment

• Euro-E.W.I.N.G.99 and EWING-2008 (Whelan et al. 2018)

• Localized Ewing sarcoma at high risk for relapse; N=240

• VIDE induction (x6) then

(VAI x1 and BuMel HDT)

v.s. (VAI x 8)

• 8-year EFS: 60.7% v.s. 47.1% (HR of event: 0.64;

p=0.026)

• 8-year OS: 64.5% v.s. 55.6% (HR of death: 0.63;

p=0.028)

V: Vincristine; A: Actinomycin D; D: Doxorubicin; I: Ifosfamide; E: Etoposide; BuMel HDT: High dose Busulfan and Mephalan with autologous SCT

High risk for relapse:

• Poor histologic response (≧10% viable cells) after induction chemotherapy (VIDE)

• Large tumor volume at diagnosis (≧ 200 mL) for tumors that were unresected, initially resected, or resected after radiotherapy

Ewing sarcoma + Pulmonary Mets

• Euro-E.W.I.N.G.99 and EWING-2008 (Dirksen et al. 2019)

• Ewing sarcoma + pulmonary/pleural mets only; N=287

• VIDE induction (x6) then

(VAI x8 with WLI)

v.s. (VAI x1 with BuMel HDT)

• 8-year EFS: 43.1% v.s. 52.9% (HR=0.79, p=0.16)

• No difference in OS (HR=1, p=0.99)

• Toxicity-related death: No patients v.s. 4 patients

V: Vincristine; A: Actinomycin D; D: Doxorubicin; I: Ifosfamide; E: Etoposide; BuMel HDT: High dose Busulfan and Mephalan with autologous SCT

WLI: Whole lung irradiation

Proton therapy & Ewing Sarcoma

• Retrospective chart review (Rombi et al. 2012)

• Pediatric Ewing’s sarcoma at different sites; N=30

• Proton + Chemotherapy

• Median dose: 54 Gy RBE (range: 45-58 Gy)

• 3-year LC, EFS, OS: 86%, 60%, 89% respectively

• Adverse effects:

• Scoliosis/kyphosis (x5)

• Eye canalicular stenosis (x1) & corneal ulcer (x1)

• Endocrine deficiency (x2)

• High frequency hearing loss (x1)

• Secondary hematologic malignancies (x4)

Risk of Secondary Malignancy

• Retrospective chart review (Fuchs et al. 2003)

• Ewing’s sarcoma s/p tx; N=397

• Secondary malignancy (29 tumors) in 26 (6.5%) patients

• Mean interval: 9.5 years (range: 1-32.5 years)

• Distribution:

• Hematologic (x8) - Chemo induced

• Sarcoma (x12) - RT induced

• Carcinoma (x9)

• Worse prognosis in case of sarcoma/hematologic

secondary malignancy

Prospective Trial

• NCT00186992: Radiation Therapy to Treat Musculoskeletal

Tumors

• Phase 2 trial, St. Jude Children's Research Hospital

• Single group assignment, active & not recruiting

• MSK tumors, including Ewing’s; N=202

• Intervention: image-guided radiotherapy

• Outcomes:

• Local control (1

)

• RT-related changes in growth and muscle

function

SURVEILLANCE AND RELAPSE

Beyond Treatment

Surveillance

• Physical exam

• CBC

• Imaging

• Intervals

• Initially q2-3 months for at least 2 years

• Annually after 5 years

Relapsed Disease

• 30-40% recurrence

• Very poor prognosis (esp. if within 2 years)

• Management

• Chemotherapy

• +/- RT

• +/- surgery

References

• American Cancer Society. Survival Rates for Ewing Sarcoma. 2022. April 2022. Available from: https://www.cancer.org/cancer/ewing-

tumor/detection-diagnosis-staging/survival-rates.html#references

• Ahmed, S. K., Randall, R. L., DuBois, S. G., Harmsen, W. S., Krailo, M., Marcus, K. J., Janeway, K. A., Geller, D. S., Sorger, J. I., Womer, R. B.,

Granowetter, L., Grier, H. E., Gorlick, R. G., & Laack, N. (2017). Identification of Patients With Localized Ewing Sarcoma at Higher Risk for

Local Failure: A Report From the Children's Oncology Group. International journal of radiation oncology, biology, physics, 99(5), 1286–

1294. https://doi.org/10.1016/j.ijrobp.2017.08.020

• Burgert, E. O., Jr, Nesbit, M. E., Garnsey, L. A., Gehan, E. A., Herrmann, J., Vietti, T. J., Cangir, A., Tefft, M., Evans, R., & Thomas, P. (1990).

Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II. Journal of clinical

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• Dirksen U, Brennan B, Deley M-CL, et al. High-Dose Chemotherapy Compared With Standard Chemotherapy and Lung Radiation in Ewing

Sarcoma With Pulmonary Metastases: Results of the European Ewing Tumour Working Initiative of National Groups, 99 Trial and EWING

2008. J Clin Oncol 2019. DOI: https://doi.org/10.1200/JCO.19.00915

• Donaldson, S. S. (2004). Ewing sarcoma: Radiation dose and target volume. Pediatric Blood & Cancer, 41;42;(5;6;), 471-

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• Fuchs, B., Valenzuela, R. G., Petersen, I. A., Arndt, C. A., & Sim, F. H. (2003). Ewing's sarcoma and the development of secondary

malignancies. Clinical orthopaedics and related research, (415), 82–89. https://doi.org/10.1097/01.blo.0000093900.12372.e4

• Granowetter, L., Womer, R., Devidas, M., Krailo, M., Wang, C., Bernstein, M., Marina, N., Leavey, P., Gebhardt, M., Healey, J.,

Shamberger, R. C., Goorin, A., Miser, J., Meyer, J., Arndt, C. A., Sailer, S., Marcus, K., Perlman, E., Dickman, P., & Grier, H. E. (2009). Dose-

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• Grier HE, Krailo MD, Tarbell NJ, et al. Addition of Ifosfamide and Etoposide to Standard Chemotherapy for Ewing's Sarcoma and Primitive

Neuroectodermal Tumor of Bone. N Engl J Med 2003;348:694-701. DOI: https://doi.org/10.1056/NEJMoa020890

References

• Hornicek, F.J. & Baldini, E.H. (2022). Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family of tumors. In A.S. Pappo, R. Maki, & R.E. Pollock

(Eds.). UpToDate. Available from

https://www-uptodate-com.ezproxy.aub.edu.lb/contents/clinical-presentation-staging-and-prognostic-factors-of-the-ewing-sarcoma-

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• Leavey, P. J., Laack, N. N., Krailo, M. D., Buxton, A., Randall, R. L., DuBois, S. G., Reed, D. R., Grier, H. E., Hawkins, D. S., Pawel, B., Nadel, H., Womer, R. B., Letson,

G. D., Bernstein, M., Brown, K., Maciej, A., Chuba, P., Ahmed, A. A., Indelicato, D. J., . . . Mascarenhas, L. (2021). Phase III trial adding vincristine-topotecan-

cyclophosphamide to the initial treatment of patients with nonmetastatic ewing sarcoma: A children's oncology group report. Journal of Clinical Oncology, 39(36), 4029-

4038. https://doi.org/10.1200/JCO.21.00358

• Ludwig, J. A., Meyers, P. A., Dirksen, U., Blay, J., De Pinieux, G., Gouin, F., Riggi, N., Suvà, M. L., & Stamenkovic, I. (2021). Ewing’s sarcoma. The New England Journal

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Stringham, D., Reed, D. R., Janeway, K. A., Gorlick, R. G., Marina, N., Bernstein, M. L., Krailo, M. D., . . . Bone Sarcoma Committee, Children's Oncology Group. (2020).

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• National Comprehensive Cancer Network. “Bone cancer.” Version 2.2022. Accessed: March 2022. Retrieved from

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• National Library of Medicine (U.S.) (2005, April -) Image guided radiotherapy for the treatment of musculoskeletal tumors: a phase II prospective evaluation of radiation-

related treatment effects. Identifier NCT00186992. https://clinicaltrials.gov/ct2/show/NCT00186992

• Nesbit ME Jr, Gehan EA, Burgert EO Jr, et al. Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the

First Intergroup study. J Clin Oncol 1990;8:1664-74. DOI: https://doi.org/10.1200/JCO.1990.8.10.1664

• Rombi, B., DeLaney, T. F., MacDonald, S. M., Huang, M. S., Ebb, D. H., Liebsch, N. J., Raskin, K. A., Yeap, B. Y., Marcus, K. J., Tarbell, N. J., & Yock, T. I. (2012).

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https://doi.org/10.1016/j.ijrobp.2011.03.038

• Whelan J, Deley M-CL, Dirksen U, et al. High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-

Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008. J Clin Oncol 2018;36:3110-9. DOI: https://doi.org/10.1200/JCO.2018.78.2516

• Womer RB, West DC, Krailo MD, et al. Randomized Controlled Trial of Interval-Compressed Chemotherapy for the Treatment of Localized Ewing Sarcoma: A Report From

the Children's Oncology Group. J Clin Oncol 2012;30:4148-54. DOI: https://doi.org/10.1200/JCO.2011.41.5703

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