Ewing's Sarcoma in Adults

Natural History

In the past Ewing's sarcoma was associated with poor prognosis. Nearly 80% developed distant mets and died. Multi-agent chemotherapy with neoadjuvant and adjuvant treatment has considerably improved the prognois. Current multi-modal treatment offers progression free survival in 60-75% of localized Ewing's sarcoma. In both Ewing's and osteosarcomas, cure is still achievable even in the setting of metastatic disease at presentation.

Patients with Ewing's sarcoma develop localized pain and edema, and unlike other bone neoplasms, constitutional symptoms are occasionally present. Abnormal labs include elevated LDH and leukocytosis.

The most important prognostic factors are:

Site of disease with distal lower extremity being the most favorable
Normal LDH
absence of metastases.

Nearly 1/4 present with mets which is the most significant adverse prognostic factor in Ewing's and other bone sarcomas. Ewing's metastasizes to the lungs, bones and marrow most commonly. Femur, pelvic bones and bones of the chest wall are most frequently involved, but Ewing's may appear anywhere. When Ewing's arises in the long bones, it most commonly manifests in the diaphysis with periosteal reaction (oinion skinning).

A European Intergroup reported RFS₅ of 22% with M1a/b at diagnosis and 55% with M0 disease.

The results of the Intergroup Ewings Sarcoma Study found that primary pelvic tumors had the lowers survival compared with distal lesions of the extremities. An analysis of 54 patients showwed that pelvic disease and time to local therapy in patients treated with chemotherapy are significant prognostic factors.

Lee determined the following adverse prognostic indicators (OS):

adult age
hispanic race
metastatic disease
large tumor size
low SES

Staging AJCC 7th Ed.

Primary Tumor
T1	Tumor ≤ 8 cm
T2	Tumor > 8 cm
T3	Discontinuous tumor in the primary bone

N -Stage
N0	No nodes
N1	Node positive

M Stage
M0	No distant mets
M1a	Lung mets only
M1b	Other distant sites

Stage Grouping

Grade	T1	T2	T3	N1	M1a	M1b
G1	IA	IB	IB	IVB	IVA	IVB
G2	IA	IB	IB	IVB	IVA	IVB
G3	IIA	IIB	III	IVB	IVA	IVB

Ewing's Sarcoma Diagnosis and Work Up

Ewing's Sarcoma is a malignant "small round blue cell" of the bone or soft tissue. It most commonly occurs in the pelvis, femur, humerus and ribs. A common genetic locus t(11:22) is responsible for a large percentage of Ewing's sarcomas and PNETs. Ewing's occurs most commonly in teens and more commonly in male teens. Ewings presents with an "onion skin appearance on radiographs. Ewings is classified as a bone tumor, but it can have characteristics of both mesodermal and ectodermal origins.

If Ewing's sarcoma is suspect, a complete staging workup should be completed prior to biopsy.

Differentiating Ewings from Osteosarcoma
Ewing's Sarcoma	Osteosarcoma
Lytic, destructive lesion	Sclerotic lesion
Diaphysis (shaft)	Metaphysis
Onion Skin radiograph	Sunburst pattern radiograph

Adult Ewing's Sarcoma Natural History

Ewing's Sarcoma has a genetic component involving t(11:22) transposition and t(7:22) transposition. Ewing's sarcoma differes from typical adult sarcomas as they are considered systemic disease at first presentation. There is no universally accepted staging for Ewings and it is generally staged as bone. Ewing's (and rhabdomyosarcomas) are generally much more chemosensitive in adults. (Osteosarcomas are generally more resistant in adults than peds),

Workup (NCCN)

Plain film radiograph for diagnosis (onion skin lesion)
Imaging: MRI ± CT of primary site; CXR r/o chest mets
PET scan and/or bone scan
Consider BM biopsy or screening MRI of spine and pelvis
Cytogenetics and/or molecular studies
LDH
Fertility consultation

Treatment

Adjuvant or neoadjuvant chemotherapy is considered the standard of care for adults with Ewing's or rhabdomyosarcomas. The NCCN guidelines recommend as Category 1 evidence a minimum of 12 - 24 weeks of neoadjuvant chemotherapy followed by restagingwith chest imaging, and local imaging. If there is a response to chemotherapy (ie stable disease) then proceeding to WLE or pre-op radiation therapy followed by WLE followed by additional chemotherapy (± RT). Additional options include Definitive RT and chemotherapy or amputation in select cases followed by post-op chemotherapy and consideration of adjuvant RT depending on margin status.

Stable Disease

in the event that WLE is chosen after neoadjuvant chemotherapy, then it should be treated with additional adjuvant chemotherapy if there are negative margins. However, if there are positive margins then adding local radiation either after chemotherapy or concurrent with chemotherapy is recommended by the 2011 NCCN guidelines as category I recommendations.

If pre-op RT is given then post-op chemotherapy ± RT after WLE should be considered.

Progressive Disease after neoadjuvant chemotherapy

If there is progressive disease after chemotherapy then RT and/or surgery to the primary site for local control or palliation in recommended. This is generally followed by chemotherapy or best supportive care.

Chemotherapy Regimens

First Line Primary/Neoadjuvant/Adjuvant Chemotherapy VAC/IE (vincristine/adriamycin/cyclophosphamide-alternating with ifosfamide/etoposide) In pediatric (< 18 yo) patients recent evidence from COG supports compressed q2 week treatment v. q3 week treatments VAI (vincristine, doxorubicin, ifosfamide) VIDE (vincristine, ifosfamide, daoxorubicin and etoposide)
Metastatic Disease at Presentation CVD (cyclophosphamide, vincristine, doxorubicin) VAC/IE (vincristine, doxorubicin, cyclophosphamide in alternation with ifosfamide, etoposide VAI (vincristine, doxorubicin and ifosfamide VIDE (vincristine, ifosfamide, doxorubicin, etoposide)
Second Line therapy for relapsed/refractory disease Cyclophosphamide and topotecan Temozolomide and irnotecan ifosfamide and etoposide ifosfamide, carboplatin and etoposide Docetaxel and gemcitabine: Docetaxel and gemcitabine