Ewing Sarcoma
WORKUP/STAGING
What is the annual incidence of Ewing sarcoma (EWS) in the U.S.? How common is it relative to other bone tumors?
200 cases/yr of EWS in the U.S.; 2nd most common bone tumor (osteosarcoma #1)
What is the median age of presentation of EWS?
The median age of EWS is 14–15 yrs.
Is EWS associated with congenital Dz?
No. However, it can occur as a 2nd malignant neoplasm secondary to chemotherapy (i.e., VP16) or radiation.
What is the racial and gender predilection?
EWS is more common in whites (>90% of cases) and among males (1.5:1).
What is the embryologic tissue and cell of origin in EWS?
Neuroectodermal tissue is the embryonic tissue of origin for EWS and it is derived from a primordial bone marrow mesenchymal stem cell.
What is the most common genetic change seen in EWS?
1. t(11;22) in 90%, FLI1(11): EWS(22). Other minor translocations include
2. t(21;22) in 10% of cases and
3. t(7;22).
What other neoplasms are associated with the EWS translocation?
PNET, malignant melanoma of soft parts, and desmoplastic small round cell tumor (DSRCT)
Which exon fusion in t(11,22) is most common, and why is this important?
The most common fusion is exon 7 of EWS and exon 6 of FLI1 in 60% of cases. It is associated with a lower proliferative rate and better prognosis.
What type of cell morphology is expected to be seen in EWS?
Small round blue cells should be seen in EWS.
What constitutes the Ewing family of tumors?
EWS (osseous and extraosseous), PNET, DSRCT, and Askin tumor
What other tumors also have small round blue cells?
Lymphoma
Ewing
Acute lymphoblastic leukemia
Rhabdomyosarcoma
Neuroblastoma (NB)
Neuroepithelioma
Medulloblastoma
Retinoblastoma
(Mnemonic: LEARN NMR)
What markers help differentiate EWS from other small round blue tumors?
Markers that differentiate EWS:
1. Vimentin
2. HBA-71
3. β2-microglobulin
4. ↑c-myc (vs. n-myc in NB)
How is PNET similar to and different from EWS histologically?
PNET and EWS have similar translocations and are both CD99 (MIC2)+ and vimentin+. However, PNET is neuron-specific enolase (NSE)+, S100+, more differentiated, and has more neuroendocrine features. EWS is NSE− and S100 variable.
What major factors have been classically associated with a poor prognosis in EWS?
Male gender
Age >15 yrs (>17 yrs in some)
Pelvic/axial Site or rib origin
Size (>8 cm per St. Jude or >100 cc per CESS-81 [Cooperative Ewing Sarcoma Studies])
Stage (presence/absence of metastatic Dz is strongest prognostic factor)
↑LDH
Poor response to chemo (>10% viable tumor)
(Mnemonic: MASSSive LDH response) (Jürgens H et al., Klin Padiatr 1988)
What is Askin tumor?
Askin tumor is nonosseous PNET of the chest wall (worse prognosis than other sites).
What % of EWS pts present with mets?
25% of EWS pts present with mets. Mets typically occur in the lung (40%–50%) > bone.
Where do mets typically occur?
(25%–40%) ≥ BM (∼25%) and LNs (<10%).
What % of pts with localized Dz vs. lung mets have BM micromets?
25% (localized) vs. 40% (lung mets)
What is the typical clinical presentation with EWS?
Pain (96% of cases) and swelling (63% of cases) are most common → fever (21%) and fractures (16%).
What Sx at presentation portends a particularly poor prognosis in EWS?
Pts who present with fever (21% of cases) tend to have a poor prognosis.
What is the most commonly involved site in EWS at presentation?
Extremities (53%) > axial skeleton (47%). The lower extremity is the most common region (41%), and the femur is most common site (∼20% of cases) followed by the pelvis (26%), chest wall (16%), upper extremity (9%), spine (6%), and skull (2%).
If an EWS tumor presents centrally, what is the most common site?
The pelvis (26% of cases) is more common than the axial skeleton (12% of cases).
List the general workup for a pt who presents with an extremity mass.
Extremity mass workup: H&P, plain x-ray, MRI/CT primary, and core needle Bx or incisional Bx. Once a Dx of a sarcoma (EWS) is confirmed, complete the workup with CBC, BMP, LDH, ESR, LFTs, CXR, CT chest, bone scan, or PET/CT (preferred), and bilateral BM Bx.
What are the characteristic findings on plain x-ray in EWS? How does this compare to osteosarcoma?
Classically, EWS shows an “onion skin” reaction on plain films, whereas osteosarcoma is associated with a “sunburst” appearance. The Codman triangle, an area of new subperiosteal bone as a result of periosteal lifting by underlying tumor, can be seen in both EWS and osteosarcoma.
How is EWS staged?
No standard staging system exists. Tumors are either localized or metastatic.
In EWS, what is meant by expendable bones? Name 3.
Expendable bones are ones that can be resected with minimal morbidity, such as:
1. Proximal fibula
2. Ribs
3. Distal four fifths of clavicle
4. Body of scapula
5. Iliac wings
TREATMENT/PROGNOSIS
Summarize the current Tx paradigm for EWS.
EWS Tx paradigm: induction VAdriaC (vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide/etoposide (IE) → local therapy at wk 12 (surgery ± RT or definitive RT with non-Adria chemo given during RT, usually 2 cycles) → further adj chemo to wk 48. Surgery when possible, give PORT when necessary, and whole lung irradiation (WLI) for lung mets.
Estimate the 5-yr OS for localized and metastatic EWS.
5-yr OS for localized EWS is 60%–80% (60% for pelvic, 80% extremities) and 20% for metastatic EWS (bone mets 5 yrs 30%; lung mets 5 yrs 50%).
What are the RT doses given for EWS in the definitive vs. the postop setting?
Definitive: 55.8 Gy (45 Gy to prechemo volume with 1.5–2-cm margin with boost to postchemo volume to 55.8 Gy).
Postop: 50.4 Gy for microscopic/tumor spill and 55.8 Gy for gross residual; 45 Gy for vertebral body involvement because of spinal cord tolerance.
What is the LF rate for EWS after definitive RT?
Overall, 5%–25%; worse with pelvic sites (LF 15%–70%); worse with large (>8 cm) lesions (LF 20%)
What are considered adequate surgical margins in EWS?
Per COG protocol AEWS0031, adequate margins are >1 cm for bone, >0.5 cm for soft tissue, and >0.20 cm for fascia. (Womer RB et al., JCO 2012)
What are 3 indications for adj RT after surgery in EWS?
+Margin, tumor spill, and >10% viable tumor after induction chemo (poor chemo response)
Is there a difference in LC between EWS pts who rcv preop RT vs. postop RT vs. definitive RT?
Yes. Schuck et al. performed a secondary analysis of 1,085 pts in CESS-81 and -86 and EICESS 92 (European Intergroup CESS) and found no difference in LF between preop and postop RT (5.3% vs. 7.5%), but LF was significantly worse in the definitive RT arm (26%). However, there was a strong negative selection bias against the definitive RT cohort. There was no difference in LF between RT alone and surgery + post-RT if only partial resection was achieved. Preop RT may improve LC if STR is deemed likely. (IJROBP 2003)
When is surgery preferred to RT as a local therapy in EWS?
Surgery is preferred when expendable bones are involved, if there is a pathologic fracture, and when there is a lower extremity lesion in a child (<10 yo).
What Tx were compared in IESS-1? Summarize the study’s major results (OS, RFS, and LR).
IESS-1 compared induction vincristine/actinomycin D/Cytoxan (VAC) alone vs. vincristine/actinomycin D/Cytoxan/doxorubicin (VACAdr) vs. VAC + prophylactic WLI. 5-yr OS was significantly worse in the VAC alone arm (28%) compared to VACAdr (65%) or VAC + whole-lung irradiation (WLI) (53%). 5-yr OS was not significantly different between VACAdr and VAC + WLI. However, the VACAdr arm had an improved 5-yr RFS (60%) compared to VAC + WLI (44%). 5-yr LR was not significantly different between arms (∼15%). (Nesbit ME et al., JCO 1990)
In IESS-1, which site had the worst prognosis?
In IESS-1, pts with pelvic primaries had significantly worse 5-yr OS (pelvic 34% vs. nonpelvic 57%). (Nesbit ME et al., JCO 1990)
What Tx were compared in IESS-2? Summarize the study’s major results (OS).
IESS-2 randomized 214 patients between induction high-dose intermittent (HDI) VACAdr to moderate-dose continuous (MDC) VACAdr in nonpelvic localized tumors. HDI given q3wks vs. MDC given weekly. 5-yr OS favored the HDI arm (77% vs. 63%). (Burgert EO et al., JCO 1990)
What Tx were compared in INT-0091 (IESS-3)? Summarize the study’s major results (OS and LR).
INT-0091 randomized patients to induction VACAdr vs. VACAdr alternating with IE. The study enrolled 518 pts with EWS, PNET of bone and primitive sarcoma of bone, and pts with both localized and metastatic Dz. In pts with nonmetastatic Dz, induction VACAdr alternating with IE improved 5-yr OS (72% vs. 61%) and 5-yr LR (5% vs. 15%). There was no 5-yr OS advantage with adding IE for pts with metastatic Dz at presentation (∼34%). (Grier HE et al., NEJM 2003)
When was local therapy given in INT-0091?
In INT-0091, local therapy (surgery +/– PORT or RT alone) was given at wk 12.
How was RT given in INT-0091 compared to IESS-1–2?
INT-0091: definitive RT was given with IE to GTV + 3-cm margin to 45 Gy → CD to postchemo volume to 55.8 Gy. For PORT: if R0, then no PORT; if R1, then 45 Gy (initial GTV + 1 cm); if R2, then 55.8 Gy.
IESS-1–2: definitive RT to whole bone to 45–50 Gy → CD to 55–60 Gy
In INT-0091, what pt characteristics were associated with the largest benefit from the addition of alternating IE?
In INT-0092, benefit from the addition of alternating IE was associated with pelvic tumors, large tumors, and age <17 yrs.
In INT-0091, for pts with pelvic primaries, did LR differ between surgery alone, surgery + PORT, and definitive RT?
LR did not differ by local therapy for pts with pelvic primaries (∼15%). (Yock TI et al., JCO 2006)
What RT Tx techniques were compared in POG- 8346? Summarize the study’s major results.
In POG-8346, osseous EWS pts who rcv definitive RT for local therapy after induction chemo were randomized to whole bone RT (39.6 Gy → 55.8 Gy boost to GTV +2 cm) vs. involved-field RT (GTV +2 cm to 55.8 Gy). All pts then rcv maintenance chemo. The RT Tx techniques had similar 5-yr EFS (∼41%) and LC (∼53%). (Donaldson SS et al., IJROBP 1998)
What are 2 Tx options in EWS pts with lung mets?
In addition to chemo, consider WLI or surgical resection (if <5 mets) in EWS pts with lung mets.
What 2 key retrospective studies support the use of WLI in pts with metastatic EWS?
EICESS secondary analyses: Paulussen et al. reviewed the outcomes of EWS pts with (a) isolated pulmonary mets or (b) combined lung + bone/BM mets who were treated +/– WLI as part of a series of protocols from the EICESS. WLI was associated with improved EFS in both subgroups. (Ann Oncol 1998)
St. Jude’s retrospective study: Rodriguez-Galindo et al. reviewed outcomes in EWS pts with isolated pulmonary recurrence. Pts who rcv WLI had improved 5-yr postrecurrence survival (30% vs. 17%). (Cancer 2002)
What doses and technique are used for WLI in EWS?
The WLI dose in EWS depends on age: if <14 yo, then 15 Gy (1.5 Gy/fx); if ≥14 yo, then 18 Gy (mostly in European protocols, but U.S. protocols still use 15 Gy).
Describe the field borders used in WLI for EWS.
Superior-Inferior: 1 cm above 1st rib to L2
Lateral: 1 cm lat rib cage
Block PA kidney at 7.5 Gy.
Is there a difference in prognosis for metastatic EWS pts who present with isolated lung mets, bone-only mets, or both?
Yes. Metastatic EWS pts who present with either isolated pulmonary mets or skeletal mets have a similar EFS. However, EFS is significantly worse in pts with both.
5-yr OS for metastatic EWS:
Lung mets: ∼35%
Bone/BM mets: ∼25%
Lung 1 bone/BM mets: ∼15%
(Paulussen M et al., Ann Oncol 2009)
What evidence supports the use of hemithorax RT in chest wall EWS?
Schuck A et al. retrospectively reviewed 138 pts with localized chest wall EWS treated in CESS-86 and EICESS 92. 42 pts rcv hemithorax RT. If <14 yo, then 15 Gy; otherwise, 20 Gy at 1.5 Gy/fx or 1.25 Gy bid. All RT pts rcv a boost to the primary site of 45–60 Gy. Despite worse baseline prognostic factors in the hemithorax RT cohort, 7-yr EFS trended in its favor (63% vs. 46%). Improvements in EFS appeared to be due to reductions in pulmonary mets. A major criticism of this study is that the RT group had superior chemo. (IJROBP 2002)
Does hyperfractionation improve outcomes in EWS?
No. CESS-86 randomized localized osseous EWS pts being treated with definitive RT to conventional fractionation (60 Gy in 1.8–2.0 Gy/fx) during a chemo break or split-course hyperfractionated RT concurrently with chemo. Hyperfractionated RT was 1.6 Gy bid to 60 Gy with a 12-day break after the initial 22.4 Gy and 44.8 Gy. LC was somewhat higher in the hyperfractionation arm (86% vs. 76%), but the difference was not SS. Benefits of this altered fractionation may have been lost due to the Tx breaks. (Dunst J et al., IJROBP 1995)
In EWS, how are the Tx volumes defined, and what are the margins used for the following scenarios?
1. Bone-only lesion
2. Bone lesion with soft tissue extension
3. Postop setting
In EWS, RT volumes depend on the chemo response.
1. Bone only: treat prechemo GTV + 2 cm to block margin (1-cm CTV, 0.5-cm PTV) to 55.8 Gy.
2. Bone with soft tissue extension: treat prechemo GTV + 2 cm to 45 Gy, then CD to initial/prechemo bone and postchemo soft tissue extent + 2 cm to 55.8 Gy.
3. Postop setting: treat preop, prechemo volume (except pushing borders in areas of lung or intestines) + 2 cm to 45 Gy, then CD to postop residual + 2 cm to 55.8 Gy.
In EWS pts with resected node + Dz, what RT dose is used to treat the nodal bed?
In EWS pts with resected node+ Dz, treat the nodal bed to 50.4 Gy.
Based on the SFOP (France) metastatic EWS protocol, what was the 5-yr EFS with the addition of high-dose busulfan and melphalan as consolidation?
High-dose oral busulfan and melphalan were used → stem cell rescue as consolidation after 5 cycles Cytoxan/Adr and 2 cycles IE → local therapy (surgery and/or RT). 5-yr EFS was 52% for lung-only mets and 36% for bone-only mets (no BM involvement). With BM involvement, survival was 4%. (Oberlin O et al., JCO 2006)
Based on the SFOP (France) metastatic EWS protocol, how was local therapy delivered?
Local therapy was delivered either before or after consolidative high-dose chemo. RT was given alone or after incomplete resection (55–60 Gy).
RT after R0 resection was given if >5% viable cells were seen (40 Gy). If <5% viable cells were seen, no RT was given. (Oberlin O et al., JCO 2006)
TOXICITY
What is the 20-yr cumulative risk of 2nd malignancies in pts treated for EWS?
Kuttesch et al. retrospectively reviewed 266 EWS pts treated at St. Jude’s Hospital. 20-yr cumulative incidence was 9.2% for any malignancy and 6.5% for sarcoma. There appeared to be a RT dose–response relationship with a 2nd malignancy RR of 40 if RT was >60 Gy. ( JCO 1996 )
What GU side effect is of particular concern when treating pelvic EWS tumors?
Since EWS pts are typically treated with ifosfamide and cyclophosphamide, RT cystitis is of particular concern.
What dose causes premature epiphyseal closure?
>20 Gy causes premature epiphyseal closure. Decreased bone growth can occur at ∼10 Gy.
How can lymphedema be minimized in the extremities when treating with RT?
Attempt to spare a 1–2-cm strip of skin on the extremity or minimize the circumferential RT dose to 20–30 Gy.
What are some factors that influence fracture risk?
Total dose, extent of cortical disruption at Dx, younger age, and 2nd bone malignancy in the RT field.
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