Ewing Sarcoma

Ewing sarcoma is an aggressive malignant small round cell sarcoma occurring predominantly in children, adolescents and young adults.

It arises in bone or soft tissue.

Common skeletal sites include:

• Pelvis
• Femur
• Tibia
• Humerus
• Ribs
• Spine

The defining molecular abnormality in most cases involves an EWSR1 rearrangement, most commonly an EWSR1 FLI1 fusion.

Unlike osteosarcoma, Ewing sarcoma is highly sensitive to both:

• Chemotherapy
• Radiotherapy

Even apparently localised Ewing sarcoma should be considered a systemic disease because occult micrometastatic disease is assumed to be present.

Typical presentation includes:

• Progressive bone pain
• Swelling
• Palpable mass
• Functional limitation

Systemic symptoms are more common than in osteosarcoma and can include:

• Fever
• Malaise
• Weight loss
• Raised inflammatory markers

This can lead to initial misdiagnosis as osteomyelitis.

Pelvic tumours can become very large before detection.

Spinal disease can produce neurological compromise.

Plain radiograph: commonly demonstrates an aggressive permeative or moth eaten destructive lesion with aggressive periosteal reaction.

MRI of the entire involved bone: define intramedullary and soft tissue disease.

CT chest: evaluate pulmonary metastases.

PET CT or equivalent systemic staging assesses skeletal and other metastatic disease.

Biopsy

Complete imaging before biopsy.

Use a planned core biopsy tract that can be excised during definitive surgery.

Histology typically demonstrates sheets of small round blue cells.

Molecular confirmation of the characteristic fusion is important because several other round cell sarcomas can mimic Ewing sarcoma morphologically.

Treatment requires multidrug chemotherapy plus local control with surgery, radiotherapy or both.

Systemic chemotherapy

A major current regimen is interval compressed VDC alternating with IE, generally every 14 days when blood count recovery permits.

VDC

Vincristine:

2 mg/m² IV day 1, maximum 2 mg

Doxorubicin:

75 mg/m² IV total per cycle

This can be given as 37.5 mg/m² daily for 2 days.

Cyclophosphamide:

1200 mg/m² IV day 1

with mesna uroprotection according to protocol.

IE

Ifosfamide:

1800 mg/m² IV daily, days 1 to 5

Etoposide:

100 mg/m² IV daily, days 1 to 5

Mesna is administered with ifosfamide.

Growth factor support is routinely required with interval compressed treatment.

Monitor carefully for:

• Myelosuppression
• Febrile neutropenia
• Doxorubicin cardiotoxicity
• Vincristine neuropathy
• Cyclophosphamide and ifosfamide haemorrhagic cystitis
• Ifosfamide encephalopathy
• Ifosfamide renal tubular injury

Local control

Local control usually occurs after induction chemotherapy.

Surgery is preferred when an adequate oncological resection can be achieved without unacceptable functional loss.

Advantages include:

• Histological response assessment
• Defined surgical margins
• No radiation exposure to adjacent growing tissues

Radiotherapy

Radiotherapy is particularly important when:

• Tumour is unresectable
• Surgery would create unacceptable morbidity
• Surgical margins are positive or inadequate
• Tumour spill occurs
• Histological response and local risk justify postoperative treatment

Ewing sarcoma is radiosensitive, unlike conventional osteosarcoma.

Pelvic Ewing sarcoma

Pelvic lesions are difficult because of:

• Large tumour size
• Complex neurovascular anatomy
• Difficulty obtaining wide margins
• Greater metastatic risk

Treatment frequently requires chemotherapy plus a combination of surgery and radiotherapy.

Metastatic disease

Lung only metastatic disease carries a better prognosis than extrapulmonary metastases.

Treat with systemic VDC/IE and appropriate local control of the primary tumour and metastatic sites.

Whole lung irradiation may be incorporated in selected patients with pulmonary metastatic disease.

Bone and bone marrow metastatic disease has a substantially poorer prognosis.

Surgical principles

Resection requires:

• Intact specimen
• Wide tumour margin where anatomically achievable
• Removal of biopsy tract

Reconstruction follows the same general oncological principles as other bone sarcomas.

Recurrent disease

Relapse most commonly involves:

• Lung
• Bone
• Original site

There is no single universally curative salvage regimen.

Active systemic combinations include:

• Cyclophosphamide plus topotecan
• Irinotecan plus temozolomide
• Vincristine, irinotecan and temozolomide

Local surgery or radiotherapy can be useful for limited recurrence.

Longer disease free interval and isolated local or pulmonary relapse generally predict a better outcome than early disseminated relapse.