The Ewing sarcoma family of tumors is a group of small round cell tumors that includes Ewing sarcoma, primitive neuroectodermal tumor (PNET), Askin’s tumor, PNET of bone, and extraosseous Ewing’s sarcoma.
Ewing’s sarcoma is characterized by the fusion of different members of the ETS gene family (FLI1, ERG, ETV1, ETV4, and FEV) such as the EWS gene (EWSR1) on chromosome 22q12. The EWS-FLI1 fusion transcript is a translocation and fusion of EWS and FLI1 on chromosome 11, t(11;22)(q24;q12) in 85% of Ewing sarcoma cases were identified.
In 5% to 10% of cases, EWS is fused to other members of the ETS gene family. In rare cases, FUS can substitute for EWS to produce fusion gene transcripts when EWS rearrangements are not present.
(FUS-EWS fusion transcription gene translocation t(16;21)(p11;q24) or FUS-FEV fusion transcription translocation from t(2;16)(Q35;p11). Ewing sarcoma is also characterized by high cell surface expression of the glycoprotein MIC2 (CD99). expression of MIC2 may be used in the differential diagnosis of Ewing sarcoma and small round cell tumors such as primitive neuroectodermal tumors, although it is not specific for these tumors.
Typically, ESFT occurs in adolescents and young adults. The most common primary sites are the pelvis, femur, and sternum, although all bones may be affected. The long bone stem is the most common site of involvement, and imaging may show bone spots and the classic periosteal reaction known to radiologists as the “onion skin” reaction. Like most patients with sarcoma of the skeleton, patients with Ewing sarcoma family tumors are usually found due to localized pain or swelling. Unlike some sarcomas, they are detected by systemic symptoms such as fever, weight loss and fatigue. Laboratory test abnormalities include serum LDH and leukocytosis.
Prognostic factors
Important indicators of a good prognosis include a remote end of the primary site at the time of presentation, a tumor volume of less than 100 mL, normal LDH levels, and the absence of metastatic lesions. The prognosis of the Ewing sarcoma family of tumors in the spine and sacrum is worse compared to than other sites. As with other patients with skeletal sarcoma, the most unfavorable prognostic factors were demonstrated when significant metastatic lesions were presented.
In a retrospective analysis of 975 patients in EICESS, a 5-year recurrence survival rate of 22% was found in patients with metastatic lesions at diagnosis, compared to 55% in patients without metastatic lesions at diagnosis. Among patients with metastases, those with pulmonary metastases had better survival compared to those with bone metastases or pulmonary metastases combined with bone metastases.
The prognosis was worse in the 30 patients with metastases to rare sites (brain, liver, spleen). Poor histologic response after chemotherapy has also been identified as a poor prognostic factor in patients with localized tumors without metastatic lesions. In a study by IESS, 303 clinicopathologic features of Ewing sarcoma were identified, and pelvic primary tumors had a lower survival rate compared to distal bone lesions of the extremities. In a recent multivariate analysis of 53 chemotherapy-treated patients with Ewing’s sarcoma (24 adults and 29 children), Gupta et al. found that time to local treatment of pelvic disease was associated with prognosis.
In another retrospective analysis, from a large population-based cancer patient registry, Lee et al. found adult age, Hispanic ethnicity, presence of metastatic lesions, large tumor size and lower socioeconomic status to be poor prognostic factors for short survival time.
Screening
If the diagnosis of Ewing sarcoma family tumors is being considered, patients should have a biopsy including chest CT, MRI or CT of the primary site, PET scan and/or bone scan and bone marrow biopsy or MRI of the spine and pelvis prior to biopsy. in a recent systematic review and meta-analysis Trellia et al. reported that the combination of PET or PET/CT conventional imaging is a valuable tool for staging and restaging Ewing sarcoma family tumors. tool with a sensitivity of 96% and specificity of 92%.
An ongoing comparative diagnostic study attempts to compare whole-body MRI and conventional imaging in pediatric Ewing sarcoma family tumors, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and neuroblastoma, and metastatic lesions such as rhabdomyosarcoma. Cytogenetic and molecular biology studies in biopsy specimens should take into account the evaluation of t(11;22) translocations, and preliminary studies have found that EWS-FLI1 translocations have a better prognosis than other variants in comparison.
However, recent studies from EURO-EWING 99 and the Children’s Oncology Study Group have shown that patients with Ewing’s sarcoma currently have a similar prognosis with effective treatment, regardless of fusion type. In addition, EWS and FUS should be examined together in the molecular diagnosis of fusion genes to identify FUS-ERG or FUS-FEV fusions in rare Ewing sarcoma family tumors. Bone marrow biopsy should be required. Since serum LDH has a role as a tumor marker for prognostic value, this test is something that should be considered. Fertility counseling should also be considered.
Treatment
Local control therapy surgery and radiotherapy are used to control patients with localized lesions. No randomized controlled trials comparing these two treatment modalities have been studied. In the treatment of patients with localized Ewing sarcoma, there was no significant difference in overall survival or tumor-free survival with surgery or radiotherapy or surgery plus radiotherapy. In the CESS 86 clinical trial, although radical surgery and tumor resection plus radiotherapy had slightly better local control rates (100% and 95%, respectively) than radiotherapy alone (86%), there was no improvement in recurrence-free survival or overall survival, which may be related to postoperative metastasis.
In the INT-0091 study, the local failure rate was similar for surgery or radiotherapy alone (25%), but surgery plus radiotherapy may have a lower local failure rate (10.5%). 5-year tumor-free survival was not statistically significantly different between these two groups (42% for surgery, 52% for radiotherapy, and 47% for surgery plus radiotherapy),
47%). Results from other retrospective studies suggest that in patients with localized lesions, local control rates were better in the surgery (postoperative radiotherapy or no radiotherapy) group than in the radiotherapy alone group.
A study of 1058 patients from a combination of CESS 81, CESS 86 and EICESS 92 clinical trials showed that the local failure rate was significantly lower with surgery (postoperative radiotherapy or no radiotherapy) than with radiotherapy alone (7.5% compared to 26.3%), however, the local control rate was better with preoperative radiotherapy than in the surgery alone group.
A recent study in the pediatric oncology group (INT-0091, INT-0154, orAEWS0031) showed a higher risk of local control failure with radiotherapy alone than with surgery plus radiotherapy, but no significant difference in the long term.
Precise radiotherapy may be an effective treatment option, such as in patients in certain anatomical locations where surgery is not feasible to achieve or where the tumor cannot be extensively resected. In a study of Ewing sarcoma of the spine by CESS 81/86 and EICESS 92, precise radiotherapy had a local control rate of 22.6%, a 5-year tumor-free survival and an overall survival of 47% and 58%, respectively, compared to other tumors treated with precise radiotherapy. Tumor size and radiation dose have been shown to be prognostic predictors of tumor control in Ewing’s sarcoma tumors without metastatic lesions with chemotherapy and precision radiotherapy.
Local control therapy also improves the prognosis of patients with initial metastatic lesions. In the EURO-EWING99 clinical trial, patients with local metastatic lesions who did not receive any local control therapy had significantly lower 3-year tumor-free survival than patients with primary tumors but who received local control therapy.
Chemotherapy
Combination chemotherapy regimens including isocyclophosphamide and/or cyclophosphamide, etoposide, adriamycin and/or actinomycin D, and vincristine have been shown to be effective in single and multi-institutional collaborative trials in the United States and Europe for the treatment of limited Ewing’s sarcoma. Preoperative neoadjuvant chemotherapy increases the probability of negative microscopic margins and achieves complete tumor resection. IESS-I and IESS-II showed that radiotherapy combined with neoadjuvant chemotherapy VACD (vincristine, adriamycin, cyclophosphamide, doxorubicin) was superior to radiotherapy combined with neoadjuvant chemotherapy VAC (vincristine, adriamycin, cyclophosphamide) in patients with localized lesions without metastatic lesions.
The 5-year recurrence survival rates were 60% and 24% for VACD and VAC, respectively, and the overall survival rates were 65% and 28%, respectively. Efficacy of isocyclophosphamide, alone or in combination with etoposide, was evaluated in patients with newly diagnosed non-metastatic Ewing’s sarcoma. In the Pediatric Oncology Group-Childhood Cancer Group (POG-CCG) INT-0091 study 398 Ewing sarcoma family tumors without metastasis were found to be randomly assigned to receive either VACD regimen chemotherapy alone or a combination of isocyclophosphamide and etoposide (VACD-IE) for 17 cycles of chemotherapy.
The 5-year tumor-free survival was significantly better in the VACD-IE group than in the VACD group, 69% and 54%, respectively. 5-year overall survival was also significantly better, 72% and 61%, respectively. With the concurrent application of local control therapy, the local control failure rate was lower in the VACD-IE group than in the VACD group, at 11% and 30%, respectively. However, increasing the dose of alkylating agents in the VAC-IE regimen did not improve the prognosis of patients with localized lesions.205 Intensive chemotherapy improved the prognosis of patients with localized lesions by compressing the chemotherapy interval.206 In a randomized controlled trial of 568 patients, all of whom were younger than 50 years and had localized Ewing’s sarcoma, Womer et al. reported that applying VACD-IE chemotherapy once every 2 weeks was more effective than applying VACD-IE every 3 weeks. IE chemotherapy every 2 weeks was more effective than VACD-IE chemotherapy every 3 weeks with no significant increase in toxicity; mean 5-year tumor-free survival was 73% and 65%, respectively.
In all studies, standard chemotherapy with isocyclophosphamide and/or plus etoposide did not improve the prognosis of patients with metastatic lesions. In the INT0091 study, 120 patients with metastatic lesions, there was no significant difference in tumor-free survival and overall survival between patients treated with VACD-IE and VACD regimens.
The 5-year tumor-free survival rate was 22% in both chemotherapy groups, and the 5-year overall survival rates were 34% and 35% in the VACD-IE and VACD groups, respectively. In a study of 68 patients (44 with localized lesions and 24 with distant metastases), Kolb et al. reported 4-year tumor-free survival and overall survival rates of 82% and 89%, respectively, in patients with localized lesions treated with intensive chemotherapy (adriamycin and vincristine with or without high-dose cyclophosphamide) after application of isocyclophosphamide and etoposide.
202 In patients with concomitant distant metastases, the corresponding survival rates were 12% and 18%, respectively.Miser et al. reported similar findings in patients with Ewing’s sarcoma or primitive neuroectodermal tumors of bone with distant metastases.
The EICESS-92 study evaluated whether cyclophosphamide had similar efficacy compared with isocyclophosphamide in Ewing’s sarcoma (small confined tumors) of consistent risk and whether the addition of an isocyclophosphamide-containing regimen with etoposide improved survival in high-risk patients (large tumors or metastatic lesions at diagnosis).208 Seventy-nine patients of consistent risk were randomly assigned to receive VAIA (vincristine, actinomycin D, isocyclophosphamide, and adriamycin).
208 The 3-year tumor-free survival rates were 73% and 74% in the VACA and VAIA regimen groups, respectively, and the results support that cyclophosphamide has similar efficacy to isocyclophosphamide in this group. Patients at high risk were randomly assigned to receive VAIA and EVAIA (VAIA plus etoposide), with 3-year tumor-free survival (DFS) rates of 47% and 52% in the two treatment groups, respectively, with no significant difference in outcomes between the two groups. However, there is some evidence that compared to patients with distant metastases
metastasis-free patients can achieve better survival after additional etoposide treatment.208 The Euro-EWING99-R1 clinical trial, a follow-up study to EICESS-92, demonstrated that treatment with VIDE (vincristine, cyclophosphamide, adriamycin, etoposide) in the presence of vincristine and actinomycin D in 856 patients with risk-consistent Ewing’s sarcoma after combined treatment, cyclophosphamide may be used as an alternative to isocyclophosphamide. VAC is statistically not inferior to VAI, but VAC leads to an increased occurrence of adverse events.
In the VAC group, patients had a slightly higher incidence of hematologic adverse events, but patients in the VAI group had significantly increased renal tubular function impairment.
Hematopoietic stem cell transplantation after high-dose chemotherapy
High-dose chemotherapy followed by hematopoietic stem cell transplantation (HDT/ SCT) has been evaluated in the treatment of patients with localized and metastatic lesions. HDT/ SCT has been shown to be more beneficial in patients with non-metastatic lesions. The EURO-EWING 99 study was the first large randomized clinical trial to evaluate the safety and efficacy of 6 courses of intensive chemotherapy with VIDE, local control (surgery and/or radiotherapy), and HDT/SCT in 281 patients with Ewing’s sarcoma.
After a mean follow-up of 3.8 years, the 3-year tumor-free survival and overall survival rates were 27% and 34%, respectively, in the entire cohort study. recurrence survival rates were 57% and 25%, respectively, after HDT/SCT treatment. Patient age, tumor volume, and degree of metastatic spread were identified as relevant risk factors. Clinical outcomes of patients treated with or without HDT/SCT were not studied due to bias (82% of patients in the non-transplanted HDT/SCT group died at 1 year of follow-up).
NCCN Recommendations
All patients with Ewing sarcoma family tumors should have the following treatment regimen: basal therapy followed by local control therapy and adjuvant therapy.
Primary therapy includes multidrug chemotherapy along with growth factor support therapy for at least 12 weeks. Patients with metastatic disease should continue chemotherapy for longer periods depending on the tumor response. For patients with localized lesions, VAC/IE (vincristine, adriamycin, cyclophosphamide and alternating isocyclophosphamide and etoposide) is the treatment of choice. vAdriaC (vincristine, adriamycin and cyclophosphamide) is the preferred regimen for patients with metastatic lesions.
Additional chemotherapeutic drug regimens are recommended in the bone tumor system for patients with localized and metastatic disease. MRI and chest radiographs need to be redone after basic treatment. PET scan and/or bone scan techniques may be applied at the time of initial examination. Patients with stable or improving disease after basal therapy should be treated with local control therapy. Local control therapy includes extensive resection, precise radiotherapy and chemotherapy, and selective amputation. The choice of local control therapy should be individualized, which is dependent on tumor site, size, response to chemotherapy, patient age, expected morbidity, and patient preference.
Neoadjuvant chemotherapy after wide excision or amputation emphasizes the duration of chemotherapy after wide excision for 28-49 weeks for all patients regardless of negative surgical margins and is strongly recommended, depending on the patient’s lifestyle and treatment dose.195-197 Postoperative radiotherapy combined with chemotherapy is recommended for patients with positive surgical margins or tumors in close proximity to the margins.195-197 Denho et al. recently reported that patients with tumors <8 cm in diameter and negative surgical margins should be treated with postoperative radiotherapy. Denho et al. recently reported that postoperative radiotherapy could be omitted in patients with tumors <8 cm in diameter and negative surgical margins, and did not reduce overall survival. The 15-year prognosis for patients treated with adjuvant radiotherapy was 80% compared to 100% without radiotherapy.
This guideline includes patients with extensive resection and negative margins who receive only neoadjuvant chemotherapy. The primary treatment for patients with progressive disease is planned radiation therapy and/or chemotherapy or best supportive care followed by surgery to the primary site.
Surveillance
Monitoring of patients with ESFT should include: physical examination, CBC and other laboratory tests, and chest and primary site imaging every 2 to 3 months. The monitoring interval may be extended after 2 years postoperatively. Annual examinations may be performed after 5 years postoperatively (level 2B).
Recurrent or refractory disease is experienced by approximately 30-40% of ESFT patients with local and/or distant recurrence and has an extremely poor prognosis. Patients with first relapse have a better chance in terms of survival after relapse. Late recurrence (greater than or equal to 2 years after initial diagnosis), isolated metastatic lesions in the lungs, local recurrence but controllable by radiotherapy, and chemotherapy are the most favorable prognostic factors.
However, early relapse (less than 2 years after initial diagnosis) with multiple pulmonary metastases and/or other metastatic lesions, local or distant recurrence, and LDH elevated at the early stage of diagnosis, early relapse is a poor prognostic factor. In a recent retrospective analysis, site of first recurrence and time to first recurrence were important prognostic factors in adult patients with localized Ewing sarcoma. The 5-year survival rates after recurrence were 50% and 13% for patients with local and distant metastases, respectively. Patients with late recurrence also had a higher 5-year post-recurrence survival rate than patients with early recurrence.
Isocyclophosphamide in combination with etoposide with or without carboplatin for refractory or recurrent sarcoma was evaluated in clinical trials.
In a phase II study, isocyclophosphamide in combination with mesylate and etoposide was highly effective in both recurrent pediatric and adult sarcomas with tolerable toxic effects. In the Pediatric Oncology Group I/II study, an overall tumor response rate of 51% and overall survival rates of 49% and 28% at 1 and 2 years, respectively, were found in patients with recurrent or refractory sarcomas. The overall survival rate was significantly improved and patients had complete or partial remission of symptoms.
Non-isocyclophosphamide based chemotherapy regimens have also been shown to be effective in relapsed or refractory skeletal sarcomas. Docetaxel in combination with gemcitabine was well tolerated, with an objective overall response rate of 29% over a duration of 4.8 months in children and young adults with refractory bone tumors. In relapsed or refractory skeletal sarcomas, topoisomerase I inhibitors (topotecan and irinotecan) in combination with cyclophosphamide and temozolomide also had a good response rate.
In a study of 54 patients with recurrent or refractory Ewing’s sarcoma, cyclophosphamide and topotecan elicited a 44% response in patients (35% in complete remission and 9% in partial remission).229 In a retrospective analysis of a study of 20 patients with recurrent or progressive Ewing’s sarcoma, after a median follow-up of 23 months, irinotecan and temozolomide resulted in an overall objective response rate of 63%, with 26% of patients in sustained remission. The median time to disease progression (TTP) was 8.3 months for all patients (16.2 months for patients with recurrent disease).
Primary disease had a better median TTP compared with recurrent or refractory disease with metastatic disease Ewing’s sarcoma within 2 years. vincristine in combination with irinotecan, and temozolomide treatment also appeared to be effective and well tolerated with an overall efficacy rate of 68.1%. Small sample size studies at a single institution have shown that HDT / SCT improves long-term survival in patients with recurrent or progressive Ewing’s sarcoma. The role of this approach has not been confirmed by definitive prospective randomized studies.
The NCCN recommends
Treatment regimen therapy for patients with relapsed or refractory disease including those participating in clinical trials be chemotherapy with or without radiation therapy. If tumor recurrence is delayed, retreatment with a previously effective regimen may be useful. New treatments from high-level clinical trial studies should be considered for patients with recurrent and metastatic disease.