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Treatment of Ewing sarcoma

Treatment of Ewing sarcoma
Literature review current through: Jan 2024.
This topic last updated: May 03, 2023.

INTRODUCTION — Ewing sarcoma (ES) is a rare malignancy that most often presents as an undifferentiated primary bone tumor; less commonly, it arises in soft tissue (extraosseous ES). Advances in multidisciplinary management have markedly improved long-term survival. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Prognostic factors'.)

This topic will discuss the management of ES. The pathology and molecular genetics; the clinical presentation, diagnosis, and prognosis; and radiation therapy for ES are discussed separately.

(See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma".)

(See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma".)

(See "Radiation therapy for Ewing sarcoma family of tumors".)

GENERAL TREATMENT PRINCIPLES — Despite the fact that fewer than 25 percent of patients have overt metastases at the time of diagnosis, ES is considered a systemic disease. Because of the high relapse rate (80 to 90 percent) in patients undergoing local therapy alone, it is surmised that the majority of patients have subclinical metastatic disease at the time of diagnosis, even in the absence of overt metastases.

Chemotherapy can successfully eradicate these deposits, and modern treatment plans all include chemotherapy, usually administered prior to and following local treatment. For patients with localized disease, the addition of intensive multiagent chemotherapy to local therapy has had a dramatic impact on survival, and reported five-year survival rates are now approximately 70 percent [1-10].

A subset of patients with advanced disease may be cured by multimodality therapy, although the long-term survival rates are clearly lower than for patients with localized disease [11]. Approaching a patient who has metastatic ES with noncurative intent is rarely, if ever, appropriate since it is not possible to predict a priori which patients will be cured. Because of these issues, clinicians experienced in the treatment of ES must direct the surgery and radiation therapy (RT), and coordination with the medical/pediatric oncologist is essential [5,12,13].

Adult patients — Treatment of adults with ES should generally be guided by the same general principles as those used for younger individuals. However, few clinical trials address treatment in adults since most studies have excluded older individuals.

Less than 5 percent of cases of ES arise in adults over the age of 40. Some studies have defined "older" patients as those over the age of 15 at initial diagnosis, while others have used a cutpoint of 18 years. Although some studies suggest that older age is an adverse prognostic factor in ES, it is not clear if the worse prognosis in older individuals is due to biological differences or differences in treatment regimens (ie, regimens used in pediatric versus those used in adult medical oncology).

In general, adults who are treated with contemporary adjuvant and neoadjuvant chemotherapy for localized ES may do as well as children [14-16]. Observational studies also suggest that survival rates for adults with ES are similar to those of children [14,16-24]. As an example, one retrospective series of 102 adult patients ≥18 years of age treated between 1977 and 2005 showed an overall survival (OS) of 69 percent and an event-free survival (EFS) of 52 percent [22]. A subsequent cohort (treated between 1993 and 2007) had better outcomes (five-year OS and EFS of 73 and 60 percent, respectively). This cohort routinely had the addition of ifosfamide and etoposide, similar to pediatric treatment protocols.

TREATMENT FOR LOCALIZED DISEASE

Neoadjuvant chemotherapy — Most modern treatment plans utilize initial (neoadjuvant or induction) chemotherapy followed by local treatment and additional chemotherapy. Reduction of local tumor volume is accomplished in the majority of patients, and this can facilitate resection. This is particularly important with regard to limb-sparing procedures for extremity lesions, but it may also be important for rib, chest wall, and vertebral primaries [25-27]. Initially, chemotherapy was used in the adjuvant setting to control metastatic disease, but it is now administered prior to local therapy (neoadjuvant therapy) to treat micrometastatic disease earlier and to improve local control [28]. Since most treatment failures are attributable to systemic metastatic disease, local therapy considerations should be planned to avoid complications that might compromise the administration of effective systemic therapy. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management".)

Although patients with extraosseous ES (EES) have been treated in the past on protocols for rhabdomyosarcoma and have a similar response to multimodality therapy [7], EES responds to the same chemotherapy regimens as osseous ES and patients with these tumors should be treated similarly [29-32]. Data suggest that patients with EES have slightly superior outcomes compared with patients with osseous ES [33].

Selection of therapy — For patients with localized ES, we recommend initial chemotherapy with alternating cycles of vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (VDC/IE) rather than vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). The VDC/IE regimen improved overall survival (OS) in a randomized trial, and is shorter in duration with less toxicity [34].

Different chemotherapy regimens have been used internationally for the treatment of localized ES. The VDC/IE regimen, which is used in the United States, was developed based on data from the Intergroup Ewing sarcoma studies (IESS-I, IESS-II, and IESS-III) [3,35,36]. The VIDE regimen used in Europe was based on data from the (Euro-EWING) 99/EWING 2008 trial [37]. (See 'Other strategies' below.)

The superiority of VDC/IE over VIDE was established in an open-label phase III trial (EE2012) conducted in Europe. In this study, 640 patients with ES were randomly assigned to initial treatment with VDC/IE administered on an interval-compressed schedule (every two weeks with hematopoietic growth factor support) or the vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) regimen [34]. At median follow-up of 47 months, VDC/IE improved EFS and OS compared with VIDE (three-year EFS 67 versus 61 percent, HR 0.71, 95% CI 0.55-0.92; three-year OS 82 versus 74 percent; HR 0.62, 95% CI 0.46-0.85). While grade ≥3 toxicity rates were similar between the two treatment arms (90 versus 91 percent), the risk of grade ≥3 febrile neutropenia was lower for VDC/IE compared with VIDE (58 versus 74 percent). The duration of therapy for VDC/IE was also shorter by approximately two months.

However, combining interval-compressed VDC/IE with chemotherapy effective in relapsed disease (eg, topotecan/cyclophosphamide) does not appear to confer additional clinical benefit. In a separate randomized phase III COG trial (AEWS1031) conducted in 629 patients with localized treatment-naïve ES, the addition of vincristine/topotecan/cyclophosphamide to the interval-compressed VDC/IE regimen did not improve EFS or OS [38,39].

Interval-compressed VDC/IE — For patients age <18 years with localized ES, we recommend interval-compressed therapy with alternating cycles of vincristine/doxorubicin/cyclophosphamide (VDC) and ifosfamide/etoposide (VDC/IE) given every two weeks with hematopoietic growth factor support (table 1), rather than every three weeks without growth factor support. In a phase III trial (AEWS0031), this approach improved event-free survival (EFS) and OS in this population without increased toxicity or higher risk of second (subsequent) malignant neoplasms [40,41].

For patients age ≥18 years, we offer VDC/IE either every two weeks with hematopoietic growth factor support or every three weeks without growth factor support. A subgroup analysis of this population in AEWS0031, which mainly enrolled younger patients, did not demonstrate a difference in EFS between the two treatment arms.

For patients receiving interval-compressed VDC/IE, we typically administer four to six cycles of chemotherapy followed by local therapy in the absence of disease progression. We then administer additional cycles of the same chemotherapy in the postoperative setting, for a total of 14 to 17 cycles. Clinical evidence that chemotherapy is effectively treating the tumor include relief of tumor-related pain, decrease in tumor size, fall in lactate dehydrogenase (LDH) level, radiologic improvement, and evidence of necrosis in the resected specimen.

Treatment for localized ES can be intensified with interval compression, in which chemotherapy cycles are administered every 14 days instead of every 21 days [42]. A randomized phase III trial (AEWS0031) from the Children's Oncology Group (COG) conducted in North America established interval-compressed therapy with alternating cycles of VDC/IE as the preferred initial chemotherapy regimen for children with localized ES (table 1) [40,41]. In this study, 587 patients with localized ES were randomly assigned to receive 14 alternating cycles of VDC/IE every 21 or 14 days. A majority of patients enrolled (88 percent) were age <18 years. In preliminary results available in abstract form, interval-compressed VDC/IE given every 14 days improved ten-year EFS (70 versus 61 percent) and ten-year OS (76 versus 69 percent) compared with VDC/IE given at 21-day intervals [41]. In subgroup analyses, compared with chemotherapy every three weeks, interval compressed VDC/IE also improved ten-year EFS in patients with pelvic primary tumors (67 versus 43 percent), large tumor volume ≥200 mL (74 versus 46 percent), those with the presence of viable tumor at the time of surgery (75 versus 47 percent), and those age <18 (73 versus 64 percent, HR 0.71, 95% CI 0.52-0.99). However, among patients age ≥18 years, the study did not demonstrate a difference in ten-year EFS for interval-compressed therapy over every three-week therapy (53 versus 37 percent, HR 0.75, 95% CI 0.38-1.47).

The toxicity of both regimens was similar [40]. There was also no difference in the ten-year cumulative incidence of second (subsequent) malignant neoplasms between treatment every 14 days (3.2 percent) and treatment every 21 days (4.2 percent).

Other strategies

High-dose chemotherapy with hematopoietic cell transplantation – The role of consolidative high-dose chemotherapy with autologous hematopoietic cell transplantation is uncertain. This approach improved outcomes for children with high-risk localized disease who were treated with the VIDE induction regimen [37]. However, high-dose chemotherapy with autologous hematopoietic cell transplantation has not been used with interval-compressed VDC/IE chemotherapy because the efficacy and toxicities of such an approach have not been addressed in prior trials [43]. Additionally, in a phase III trial (EE2012), interval-compressed VDC/IE improved OS over VIDE among the subgroup of patients with high-risk localized disease (tumor volume ≥200 mL at diagnosis) [34]. (See 'Interval-compressed VDC/IE' above.)

The role of consolidative high-dose chemotherapy followed by autologous hematopoietic cell transplantation for localized high-risk disease was evaluated in the European Ewing Tumour Working Initiative of National Groups (Euro-EWING) 99/EWING 2008 trial. High-risk disease was defined as a poor histologic response after receiving six cycles of VIDE (76 percent of the cohort) or tumor volume at diagnosis ≥200 mL if unresected, initially resected, or resected after radiation therapy (RT) [37] In this study, 240 patients with high-risk localized ES were treated with six courses of VIDE plus one course of consolidation vincristine, dactinomycin, and ifosfamide (VAI). Patients were then randomly assigned to either one course of busulfan plus melphalan followed by autologous hematopoietic cell rescue or seven courses of standard chemotherapy with VAI. At a median follow-up of 7.8 years, high-dose chemotherapy followed by hematopoietic cell transplantation improved both EFS (eight-year EFS 61 versus 47 percent) and OS (eight-year OS 65 versus 56 percent).

Severe acute toxicities were more common in the high-dose chemotherapy group, and three patients died in this group, two of treatment-related toxicity; the third patient did not receive dose-intense chemotherapy or high-dose chemotherapy because of renal dysfunction. The risk of secondary malignancies in long-term survivors was not reported.

Dose escalation of VDC/IE – We do not use a dose-escalated VDC/IE as initial chemotherapy of ES. In a randomized phase III clinical trial conducted by the COG, dose escalation of VDC/IE without hematopoietic cell support did not improve outcomes in patients with newly diagnosed localized disease [43]. Furthermore, concerns for an increased risk of secondary malignancies in patients receiving dose-intense therapy have tempered enthusiasm for this approach.

Local treatment — Following initial systemic therapy, local control for ES can be achieved by surgery, RT, or both. The choice between RT and surgery is based on patient characteristics, the potential harm and benefit of the treatment options, and patient preference. In most cases of extremity ES of bone, limb-salvage resections and reconstructions similar to those used for osteosarcomas have been used most frequently if it is anticipated that a wide margin can be achieved. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management".)

Surgery — Patients who might lose function from surgical procedures because of tumor location (such as the periacetabular region of the pelvis) or extent may be offered RT as an alternative. However, advances in endoprosthetic reconstruction such as 3D printed, custom prostheses even for the periacetabular area have become available to reconstruct surgical defects [44-46]. Data are limited for the long-term outcomes of these prosthetic reconstructive procedures. One observational study of 35 patients with pelvic ES suggested that preoperative radiotherapy and surgical resection was associated with better histologic response and OS than either surgery alone or in combination with postoperative radiation [47]. The functional outcomes were better with hip transposition (ie, no implant used in the reconstruction) than if an implant were used, likely due to a much lower incidence of infection in those patients without an implant. However, this study is limited by the small number of patients.

Surgery is preferred for potentially resectable lesions and for those arising in dispensable bones (eg, fibula, rib, small lesions of the hands or feet) for the following reasons:

It avoids the risk of secondary radiation-associated sarcomas. (See "Radiation therapy for Ewing sarcoma family of tumors".)

An analysis of the degree of necrosis in the excised tumor can permit refinements in the estimate of prognosis. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management".)

In the skeletally immature child, resection may be associated with less morbidity than RT, which can retard bone growth and cause deformity.

Technical advances in the endoprostheses used for limb reconstruction of other bone sarcomas have led to improved long-term outcomes and can be applied to patients with ES as well. (See "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management", section on 'Reconstruction techniques'.)

Although there are no randomized trials comparing surgery with RT for local control, multiple retrospective series and a systematic review suggest superior local control and, in some cases, EFS for surgery compared with RT alone [13,48-51]. However, selection bias accounts for at least some of these results (ie, smaller, more favorably situated peripheral tumors or those that respond well to chemotherapy are more likely to be resected, while larger, axial lesions are radiated). The difference in local control between RT and surgery has been abrogated in some series when age and primary tumor site were controlled for [52-54]. Radiation dose and proper field planning are also important factors in local control. The role of RT in the local management of ES is discussed separately. (See "Radiation therapy for Ewing sarcoma family of tumors".)

For primary tumors of the spine, complete surgical resection with negative margins is rarely feasible. In most patients and at most treatment centers, definitive RT is usually the preferred mode of local control in these cases [55].

However, improved resection and fusion techniques have made it possible to resect spinal ES in selected patients. For the rare patients who are treated with surgery, the majority will also require postoperative RT to achieve local control. There is also weak evidence to suggest that a complete resection in combination with chemotherapy and/or radiation can potentially improve local control and survival [56-59]. (See 'Adjuvant radiation therapy' below.)

Patients with pelvic primaries have a high complication rate if treated surgically and poorer function if the acetabulum is resected [60], but some studies suggest superior survival with surgical resection. Local control of pelvic primaries must be individualized. There have been improvements in implants and spine fixation techniques that have potentially improved functional outcome following resection of selected primary tumors of the spine and pelvis. The experience in resecting other tumors of the spine and pelvis may be applied to ES, but it requires careful selection of patients and a specialized center with experience in these reconstructions.

The surgical principles that apply to resection of the primary tumor and reconstruction are similar to those in patients with osteosarcoma and are discussed elsewhere (see "Bone sarcomas: Preoperative evaluation, histologic classification, and principles of surgical management"). However, there are three main differences between ES and osteosarcoma:

ES is radiosensitive, while osteosarcoma is much less so.

ES tends to occur in a younger population, where skeletal immaturity and concern for radiation-induced growth inhibition must be considered.

ES tends to arise in different areas of the long bones than osteosarcoma (the diaphysis compared with metaphysis (figure 1 and figure 2)) [61].

Adjuvant radiation therapy — RT is usually avoided in patients without residual disease (ie, resected with negative margins) to avoid exposing them to the risk of a radiation-induced malignancy. However, RT is an essential component of therapy for patients undergoing resection if the surgical margins are inadequate, although effective chemotherapy can also reduce the risk of local failure in such patients [3,9]. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Adjuvant radiation therapy'.)

TREATMENT FOR METASTATIC DISEASE — Patients with overt metastatic disease at presentation have a significantly worse outcome than do those with localized disease. However, aggressive multimodality therapy can relieve pain, prolong the progression-free interval, and cure some patients of their disease. In a review of 13 different series in which patients with metastatic ES were predominantly treated with chemotherapy, five-year event-free survival (EFS) and overall survival (OS) rates averaged 25 (range 9 to 55) and 33 (range 14 to 61) percent, respectively [1,5,62-72]. The small numbers of patients in each series and the heterogeneity in location and extent of metastatic disease probably account for these wide variations in outcome. (See "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Disease extent'.)

In particular, the site of metastatic disease is an important variable. For children with isolated lung and pleural metastases, EFS rates up to 40 percent are reported with multimodality therapy; for metastases involving bone or bone marrow, EFS rates fall to 10 to 20 percent and, for combined sites, to less than 15 percent [70]. Because it can be difficult to predict which patients with metastatic disease will be long-term relapse-free survivors [63], treatment should be administered with curative intent. (See 'General treatment principles' above.)

Several issues are pertinent to patients with metastatic ES:

What is the optimal initial chemotherapy regimen?

Does dose intensification or interval compression provide benefit in the initial treatment phase?

Is there a role for high-dose chemotherapy with hematopoietic cell transplantation as consolidation after initial therapy?

Is radiation therapy (RT) to sites of metastatic involvement of any benefit?

How should control of the primary site be approached?

Chemotherapy — Patients with disseminated disease at diagnosis often respond well to the same type of systemic chemotherapy as is used for localized disease. Randomized trials are limited in this population as it accounts for only 25 to 30 percent of patients with ES. Whenever possible, patients with newly diagnosed metastatic ES should be offered enrollment in open clinical trials evaluating novel approaches. In the absence of a clinical trial, regimens similar to those used for the treatment of patients with newly diagnosed localized disease are commonly used (see 'Neoadjuvant chemotherapy' above):

VDC plus standard-dose I/E – In contrast to the experience for patients with nonmetastatic disease, specific benefit for the addition of ifosfamide plus etoposide (I/E) to the vincristine, doxorubicin, and cyclophosphamide (VDC) backbone (VDC/IE) has not been shown for patients with metastatic disease at diagnosis [36,65,66,73-75]. Nevertheless, the combination of VDC/IE is commonly employed for this group of patients. An alternative approach of equal validity based on these data is to administer VDC until disease progresses, then switch to I/E.

Dose-intensified VDC/IE – In a nonrandomized trial, patients with newly diagnosed metastatic ES were treated with VDC/IE with augmented alkylator doses [76]. Outcomes were similar to patients treated with non-intensified therapy. As a result, this approach has not been propagated in further trials for this population. (See 'Other strategies' above.)

Other approaches – There is little experience with interval-compressed VDC/IE in the context of metastatic ES, although this regimen is frequently used in this context(see 'Interval-compressed VDC/IE' above).

In patients with recurrent or refractory ES, initial studies suggested activity for antibodies that target insulin-life growth factor-1 receptor (IGF-1R), such as ganitumab [77-81]. However, in a randomized phase III trial of patients with treatment-naïve metastatic Ewing sarcoma, the addition of ganitumab to interval-compressed chemotherapy with VDC/IE did not improve event-free survival and increased toxicity [82].

High-dose chemotherapy with hematopoietic cell transplantation also remains investigational in patients with metastatic disease. (See 'Role for high-dose chemotherapy with hematopoietic cell transplantation?' below.)

Surgery and radiation therapy — Outcomes are best when chemotherapy is combined with optimal local therapy, including radiation and sometimes resection of sites of gross metastatic disease [71,83-85]. This multimodality approach has been most successful for patients with limited pulmonary metastases.

Pulmonary metastases — For patients with pulmonary metastases, we offer a multimodality approach that includes chemotherapy and supplemental low-dose whole-lung irradiation, with surgical resection reserved for lung metastases that do not resolve with chemotherapy.

Patients with a limited number of lung metastases do not share the same dismal prognosis as patients with metastatic disease at other sites (ie, bone or bone marrow). Surgical resection may be undertaken in selected patients [86]. Although complete resection may be possible, chemotherapy is a necessary component of therapy, and five-year survival between 20 and 40 percent can be achieved [70,87,88].

Supplemental whole-lung radiation also appears to provide a benefit as a consolidation approach for patients with pulmonary metastatic disease, even after a complete response to chemotherapy. Most of the available data supporting radiation in this setting are from nonrandomized series, and patient selection factors confound interpretation of the data. Nevertheless, in patients with a complete response to chemotherapy, low-dose bilateral whole-lung irradiation (12 to 18 Gray [Gy] in daily 1.5 to 2 Gy fractions) may provide added disease control in the lungs without significant pulmonary toxicity. Patients may be evaluated for this approach on an individual basis. This topic is discussed in detail separately. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Pulmonary metastases'.)

Bone and soft tissue metastases — Patients with solitary or circumscribed bone or soft tissue lesions can be irradiated at those sites, usually to doses of 45 to 56 Gy, in addition to local control of the primary tumor. However, the likelihood of long-term survival is considerably lower than for patients with isolated pulmonary metastases. More attention has focused on the role of stereotactic body radiation therapy (SBRT) to oligometastatic sites of disease [89]. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Bone and soft tissue metastases'.)

Local control of the primary tumor — Local control can pose major issues for patients with metastatic disease. The complete response rate to initial chemotherapy can be increased with subsequent RT or selected excision for all sites of evident disease; however, long-term relapse-free survival is still only achieved in the minority of patients [63].

The presence of diffuse metastatic disease can make it difficult to justify a large resection, which would necessitate a lengthy period off systemic chemotherapy. For selected patients, resection of the primary tumor may be reconsidered if chemotherapy results in significant volume reduction, particularly if areas of small-volume metastatic disease are also amenable to surgical resection. On the other hand, RT, which is more often considered in patients with metastatic disease, will usually provide adequate local control with acceptable morbidity. If substantial amounts of bone marrow will need to be included in the radiation treatment volume, then radiating the primary tumor may occur first, followed by metastatic site radiation, delayed until the end of systemic therapy to avoid interfering with chemotherapy. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Management of the primary site'.)

Role for high-dose chemotherapy with hematopoietic cell transplantation? — High-dose chemotherapy with hematopoietic cell transplantation does not have a significant role in the treatment of patients who present with metastatic disease, and we do not offer this approach. In randomized studies, the addition of high-dose chemotherapy with hematopoietic cell transplantation did not significantly improve EFS or OS and was associated with significant toxicity [90-92]. Patients who present with metastatic disease should be encouraged to participate in clinical trials that evaluate the use of novel therapeutic approaches.

Previous observational data were mixed regarding the efficacy and toxicity of high-dose chemotherapy with hematopoietic cell transplantation in this population [93-106], mostly due to variability in the definitions of high-risk patients, in metastatic disease sites, and in regimens. As examples, several prospective observational studies reported EFS rates as high as 50 percent with high-dose chemotherapy and hematopoietic cell transplantation among patients with either isolated pulmonary metastases or multifocal disseminated disease [99,100]. In contrast, other studies evaluating this approach in patients with bone or marrow metastases showed less favorable results, with EFS ranging between 14 and 36 percent [101-106].

High-dose chemotherapy with hematopoietic cell transplantation was subsequently evaluated in a randomized clinical trial (European Ewing Tumour Working Initiative of National Groups [Euro-EWING] 99 and EWING 2008) [90]. In this trial, 287 patients with isolated pulmonary (lung or pleural) metastatic disease received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one cycle of vincristine, dactinomycin, and ifosfamide (VAI). Subsequently, patients were randomly assigned to receive either one course of busulfan plus melphalan high-dose chemotherapy followed by autologous hematopoietic cell transplantation, or seven cycles of conventional chemotherapy with VAI followed by whole-lung irradiation. At a median follow-up of approximately eight years, there was no statistically significant difference in EFS between the two groups (eight-year EFS 53 versus 43 percent, hazard ratio [HR] 0.79, 95% CI 0.56-1.1), and OS results were comparable (eight-year OS 55 versus 54 percent, HR 1, 95% CI 0.7-1.44). Additionally, rates of infection as well as gastrointestinal and liver toxicities were higher in the high-dose chemotherapy group and included four deaths versus no deaths in the conventional chemotherapy group.

Similar results were demonstrated in a separate randomized trial. In an open-label phase III trial (Ewing 2008R3), 109 patients with metastatic ES (excluding those with pulmonary metastases only) were treated with six cycles of VIDE and consolidation therapy with eight cycles of vincristine, actinomycin D, and cyclophosphamide. Patients were then randomly assigned to either treosulfan plus melphalan high-dose chemotherapy followed by hematopoietic cell transplantation or no further treatment. At median follow-up of 3.3 years, the addition of high-dose chemotherapy with hematopoietic cell transplantation did not improve three-year EFS (21 versus 19 percent, HR 0.85, 95% CI 0.55-1.32) [92]. However, in a posthoc analysis of the subset of 41 patients less than 14 years of age, a potential EFS benefit for this approach was demonstrated (three-year EFS 39 versus 9 percent, HR 0.4, 95% CI 0.19-0.87). Given the limited sample size and lack of preplanned analysis for this subgroup, these results should be interpreted with caution.

POSTTREATMENT SURVEILLANCE — There are no prospective data that address the appropriate schedule or selection of tests for surveillance for patients with ES after initial treatment for localized disease. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [107] and from the Children's Oncology Group (COG) [108] recommend physical examination, a complete blood count, chest imaging, and surveillance imaging for primary site and distant recurrences every three months for two years, every six months for years 3 to 5, and annually thereafter (table 2) [107,109].

Local imaging of the primary site depends upon the specific site and prior local therapy. For example:

Patients with a metal endoprosthesis are usually imaged with plain radiographs. Magnetic resonance imaging (MRI) of the primary site may offer little in the way of diagnostic information if a metal endoprosthesis is present. In addition, some patients treated with extendible endoprostheses cannot have an MRI. MRI and computed tomography (CT) techniques with metal subtraction are available but may not be necessary for most patients.

For patients treated with prior radiation therapy (RT), MRI may continue to be used.

For patients with chest wall primary tumors, a chest CT scan or chest radiograph may be used, depending upon level of concern for risk of recurrence.

For surveillance imaging of potential distant metastases, we perform a chest radiograph, with subsequent evaluation using chest CT for abnormal imaging. Patients with symptoms or abnormal imaging or those who are planning surgical interventions may also be offered fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT. A meta-analysis study showed that FDG-PET and PET-CT have a high accuracy in detecting distant metastases and postoperative recurrences in patients with ES [110].

The appropriate duration of follow-up is unknown. Given the possibility of late relapse (although the vast majority of recurrences are observed within 10 years) and late development of treatment-related complications such as second neoplasms, some suggest that the patient be followed indefinitely [111]. There are no definite protocols for this, but the authors suggest that survivors have ongoing surveillance for late effects or late relapse. (See 'Evaluation' below.)

Physicians performing posttreatment surveillance must be cognizant of concerns for radiation exposure and the risk for secondary malignancies, particularly in younger individuals. (See 'Complications in long-term survivors' below and "Radiation-related risks of imaging".)

RECURRENT DISEASE — The majority of relapses occur within two years of initial diagnosis, but late relapse is not uncommon [112-114]. In a report from the Childhood Cancer Survivor Study (CCSS), the 20-year cumulative incidence of a late recurrence among five-year survivors of ES was 13 percent [114]. For this reason, it is advisable that patients be followed for the potential of late relapse indefinitely. (See 'Posttreatment surveillance' above.)

In general, survival after an early relapse is poor, with few survivors among those who relapse within two years of therapy. In contrast, up to 15 to 20 percent of those who relapse later may survive long-term [115,116]. Other prognostic factors for death in patients with recurrent ES include recurrence at combined local and distant sites, and an elevated lactate dehydrogenase (LDH) at initial diagnosis [115,116].

Evaluation — Symptoms at the primary site or elsewhere should raise concern and be appropriately investigated. Patients with a suspected recurrence should undergo evaluation both of the primary site and for the presence of metastatic disease before a treatment plan is formulated. The majority of patients with a local recurrence have either gross or microscopic metastatic disease.

The documentation of a local recurrence can be difficult. In patients with metallic endoprostheses, MRI and CT evaluation can be distorted by metal artifact, although this is improved with contemporary MRI and CT imaging technology. In patients who are treated with certain extendable "growing" prostheses, MRI may be contraindicated. The interpretation of irradiated areas on imaging studies can be challenging because of the changes in bone caused by the radiation. Soft tissue masses may represent residual fibrosis rather than recurrent tumor. The evaluation of intraosseous sites is even more difficult since the response to prior therapy and the variability in reossification complicate the interpretation of radiographic studies. Progressive cortical destruction or increasing radiolucent areas suggest local recurrence, as do bone scans that demonstrate increased radiotracer uptake. Positron emission tomography (PET) scans may be useful to assess the likelihood of recurrence at a site that is suspicious on cross-sectional radiographic imaging. Ultrasound can also be useful to assess for soft tissue masses around an endoprosthesis. The decision to biopsy a site of suspected recurrent local or metastatic disease depends upon patient history and the level of evidence from imaging studies. Open bone biopsies can be associated with local morbidity (ie, wound complications and bone fracture), and needle biopsies may suffice.

Treatment — Although the prognosis for patients with recurrent disease is poor, some patients can be successfully salvaged, particularly patients with late relapses [117,118]. Sites of recurrence, prior treatment, and relapse-free interval affect remaining treatment choices. Most patients with recurrent disease will receive systemic therapy prior to attempts at additional local control measures. Patients relapsing after a lengthy disease-free interval off chemotherapy may respond again to the same agents used as part of initial therapy

Chemotherapy — For patients with an initial recurrence of ES, we suggest either high-dose ifosfamide or irinotecan plus temozolomide (IT) rather than topotecan plus cyclophosphamide (TC). For patients who decline or are ineligible for either of these regimens due to potential toxicities, TC is an appropriate alternative. Since treatment intent is generally palliative and each chemotherapy regimen carries a different toxicity profile, clinicians should discuss the risks and benefits of each treatment with their patients.

Based on data from initial studies [119-124], an international randomized phase II/III trial (rEECur) was conducted in 439 patients with recurrent or primary refractory ES [125]. In this study, patients were randomly assigned to one of four different chemotherapy regimens: high-dose ifosfamide; TC; IT; and gemcitabine plus docetaxel (GD). During the first two interim analyses, IT and GD were dropped from further study as these regimens were predicted to have a lower probability of superiority compared with the remaining arms. Continued recruitment for this trial is ongoing for other regimens including carboplatin plus etoposide and evaluation of targeted therapy (ifosfamide plus lenvatinib).

The phase III portion of the trial compared high-dose ifosfamide with TC in 146 patients. At a median follow-up of 40 months, high-dose ifosfamide demonstrated higher event-free survival (EFS; median 5.7 versus 3.5 months; six-month EFS 47 versus 37 percent, hazard ratio [HR] 0.73, 95% CI 0.51-1.05) and overall survival (OS; median 15.4 versus 10.5 months; one-year OS 55 versus 45 percent, HR 0.73, 95% CI 0.50-1.08); this difference, while potentially clinically significant, was not statistically significant. In this Bayesian trial design, there was a 96 percent probability that high-dose ifosfamide was superior to TC. Objective response rates were also higher for high-dose ifosfamide compared with TC (30 versus 21 percent). In a subgroup analysis, high-dose ifosfamide conferred a higher EFS benefit versus TC for children (age <14 years) compared with adolescents and adults (age ≥14 years). However, compared with TC, high-dose ifosfamide had higher rates of grade ≥3 neurotoxicity (7 versus 0 percent), nephrotoxicity (8 versus 0 percent), and infection (14 versus 8 percent), leading to higher rates of treatment discontinuation. Other grade ≥3 toxicity rates were similar between the two treatment arms including febrile neutropenia (25 versus 26 percent), vomiting (1 percent each), nausea (3 versus 0 percent), and diarrhea (1 percent each).

Due to the trial design of rEEcur, it is difficult to compare the efficacy of high dose ifosfamide with IT. These two regimens were not directly compared in the randomized phase III portion of the study, and the dropping of the IT treatment arm implies that its efficacy was inferior to high-dose ifosfamide. However, in preliminary results of an interim analysis of rEEcur, at median follow-up of 9 months, among the 127 patients treated with IT arm, median EFS and OS were 4.7 and 13.9 months, respectively, which were only slightly lower than that seen with high-dose ifosfamide (5.7 and 15.7 months, respectively) but higher than that seen with TC (3.5 and 10.5 months, respectively) [126]. Grade ≥3 toxicity for IT were diarrhea (17 percent), nausea, vomiting (6 percent each), fatigue, and febrile neutropenia (3 percent each). Since data on patient-reported outcomes are limited, toxicity profiles are different for each regimens, and treatment is generally palliative in this situation, both IT and TC remain reasonable options in patients with recurrent ES.

Targeted therapies — Cabozantinib, an inhibitor of the vascular endothelial growth factor receptor (VEGFR) and MET signaling pathways, is an alternative option for subsequent-line therapy in patients with relapsed/refractory or metastatic disease. Cabozantinib has demonstrated activity in patients with advanced ES, with an objective response rate of 26 percent and median progression-free survival of five months in one phase II trial (CABONE) [127].

Local therapies — Local management of a local recurrence usually includes surgery (and possibly an amputation if the local recurrence involves an irradiated extremity), radiation therapy (RT), or both. RT to bone lesions usually provides pain relief, while surgery can eradicate disease in some cases with limited isolated lung metastases [87]. As an example, one study of 26 patients with local recurrence showed that the survival at five years post local recurrence was 28 percent. Better survival outcomes were seen in those who did not have metastases at diagnosis of the recurrence, had a surgical treatment for the recurrence, and had complete eradication of all disease [128].

Investigational agents — Patients with recurrent or advanced ES should be encouraged to participate in clinical trials, where available. Future therapies will likely emerge as the fundamental biology of the fusion oncoproteins driving this disease is better understood [11,129]. (See "Epidemiology, pathology, and molecular genetics of Ewing sarcoma" and "Clinical presentation, staging, and prognostic factors of Ewing sarcoma", section on 'Prognostic factors'.)

In a phase II study of adults with relapsed ES, lurbinectedin demonstrated an objective response rate of 14 percent [130].

Examples of other drugs under investigation include agents targeting cyclin D1/CKD4 inhibitors [131], lysine specific demethylase 1 (LSD1) [132], and RNA helicase [133].

COMPLICATIONS IN LONG-TERM SURVIVORS — Although the survival of patients with ES has improved steadily since the 1970s, long-term survivors have considerable burden of the late effects of their therapy [10,52,111,134-136]. These include subsequent primary cancers, pathologic fractures, other radiation-associated complications (wound complications, pulmonary fibrosis, neuropathy, limb leg discrepancy, femoral head necrosis), and chemotherapy-related complications (subsequent primary cancers, reduced fertility, renal insufficiency, and cardiomyopathy) [134,137].

Secondary myelodysplasia (MDS) and leukemia are particular concerns for this population [103,106,138-140]. This was illustrated in a report from the Children's Oncology Group (COG) of 578 children with ES who were treated with three different regimens over a six-year period [138]. Overall, 11 children developed secondary MDS/acute myeloid leukemia (AML), and the cumulative risk was significantly higher among children treated with a regimen incorporating higher doses of doxorubicin, cyclophosphamide, and ifosfamide as compared with those receiving standard-dose vincristine, doxorubicin, cyclophosphamide, and dactinomycin (VDCA) with or without ifosfamide plus etoposide (11, 0.9, and 0.4 percent at five years, respectively).

The health status of long-term (≥5 years) survivors was addressed in a cohort study of 568 individuals who were diagnosed with ES before age 21 from 1970 to 1986, including a subset of 403 patients who were participating in the Childhood Cancer Survivor Study (CCSS) [136]. Cumulative mortality among all survivors was 25 percent at 25 years after diagnosis, and the cumulative incidence of secondary malignancy was 9 percent. Disease progression/recurrence accounted for 60 percent of all deaths, while other causes included secondary neoplasms, cardiac disease, other medical causes, and pulmonary disease. The cumulative mortality attributed to subsequent malignant neoplasms and cardiopulmonary disease potentially attributed to treatment was 8.3 percent at 25 years. In addition, compared with their siblings, survivors had significantly higher rates of severe, disabling, or chronic health conditions, significantly lower fertility rates, and higher rates of self-reported moderate to extreme adverse health status.

It is anticipated that the adoption of tailored radiation ports in the last 15 years (as opposed to whole-bone ports used in the period 1960 to 1980), the use of lower and risk-adopted radiation therapy (RT) doses, an appreciation of the rise in radiation-induced subsequent primary cancer risk with doses above 60 Gray (Gy), and the increased use of surgical resection in the population with nonmetastatic disease will all reduce the risk of late effects. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Late effects'.)

Nevertheless, the relatively high complication rates seen with many of these earlier treatment approaches, the delayed nature of many of the complications, and the possibility that trends in chemotherapy intensification may alter the pattern of secondary malignancies [135] underscore the need for long-term follow-up. Long-term follow-up guidelines after treatment of childhood malignancy are available from COG.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma" and "Society guideline links: Bone sarcomas".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Ewing sarcoma (The Basics)" and "Patient education: Bone cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

General treatment principles – Patients with Ewing sarcoma (ES) require referral to centers that have multidisciplinary teams of sarcoma specialists. With rare exception, systemic combination chemotherapy and definitive local therapy are required in all patients, and care should be coordinated among the medical/pediatric oncologist, surgeon, and radiation therapist. (See 'General treatment principles' above.)

Treatment of adults with ES should be guided by the same general principles as are used for younger individuals. (See 'Adult patients' above.)

Initial therapy (chemotherapy) – For patients with localized ES, we recommend initial chemotherapy with alternating cycles of vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (VDC/IE) rather than vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) (Grade 1B), as this regimen improves overall survival (OS) and is shorter in duration with less toxicity. (See 'Selection of therapy' above.)

Patients age <18 years – For patients age <18 years with localized ES, we recommend interval-compressed VDC/IE given every two weeks with hematopoietic growth factor support (table 1), rather than every three weeks without growth factor support (Grade 1B), as this approach improved event-free survival (EFS) and OS without increased toxicity or higher risk of second (subsequent) malignant neoplasms in a phase III trial (AEWS0031). (See 'Interval-compressed VDC/IE' above.)

Patients age ≥18 years – For patients age ≥18 years, we offer VDC/IE either every two weeks with hematopoietic growth factor support or every three weeks without growth factor support. A subgroup analysis of this population in AEWS0031, which mainly enrolled younger patients, did not demonstrate a difference in EFS between the two treatment arms.

Local control – Local control for ES can be achieved by surgery, radiation therapy (RT), or both. The choice between RT and surgery is decided based on patient characteristics, potential harm and benefit of the treatment options, and patient preference. (See 'Local treatment' above.)

For most patients with nonmetastatic disease, surgical resection is preferred if it is anticipated that a complete resection with negative margins can be achieved and a functional reconstruction is possible. Patients who lack a function-preserving surgical option because of tumor location or extent may be offered RT as an alternative to resection. Surgery is also preferred for lesions arising in dispensable bones (eg, fibula, rib, small lesions of the hands or feet) and to avoid the risk of secondary radiation-associated sarcomas.

A combination of radiation and surgery is reserved for cases in which negative margins cannot be achieved while still preserving function. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Adjuvant radiation therapy'.)

Following local treatment, chemotherapy is usually continued (the same alternating VDC/IE regimen), typically for several months (table 1). (See 'Interval-compressed VDC/IE' above.)

Metastatic disease – Patients with clinically detectable metastatic disease at initial presentation also require multimodality therapy. Patients with advanced disease typically should be approached with potentially curative treatment. Up to 40 percent of children with limited pulmonary metastatic disease who undergo intensive chemotherapy and pulmonary resection with or without RT may be long-term survivors. The prognosis for other subsets of patients with advanced disease is less favorable. (See 'Treatment for metastatic disease' above.)

For children with pulmonary-only metastases, we offer a multimodality approach that includes chemotherapy and supplemental low-dose whole-lung irradiation, with surgical resection for lung metastases that do not resolve completely with chemotherapy. Adults with pulmonary-only metastases may be treated similarly, but data for this approach are limited. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Pulmonary metastases'.)

High-dose chemotherapy with hematopoietic cell transplantation does not have a significant role for patients with metastatic ES, and we do not offer this approach as standard of care in the United States. (See 'Role for high-dose chemotherapy with hematopoietic cell transplantation?' above.)

Posttreatment surveillance – The majority of relapses occur within two years of initial diagnosis, but later relapses have been observed. For all ES of bone or soft tissue, there are no prospective data that address the appropriate schedule or selection of tests for surveillance after initial treatment for localized disease. (See 'Posttreatment surveillance' above.)

Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) and from the Children's Oncology Group (COG) (table 2) recommend physical examination, a complete blood count, chest imaging, and local imaging of the primary site every three months for two years, every six months for years 3 to 5, and annually thereafter.

Long-term follow-up (lifelong) is needed following therapy because disease relapse, treatment-related complications, and second malignancies all occur beyond five years after treatment is initiated.

Recurrent disease – Although the prognosis for patients with recurrent disease is poor, some patients can be successfully salvaged. The sites of recurrence, prior treatment, and relapse-free interval affect the remaining treatment choices. Most patients with recurrent disease will receive systemic therapy prior to attempts at additional local control measures. (See 'Recurrent disease' above.)

For patients with an initial recurrence of ES, we suggest either high-dose ifosfamide or irinotecan plus temozolomide (IT) rather than topotecan plus cyclophosphamide (TC) (Grade 2C). For patients who decline or are ineligible either of these regimens due to potential toxicities, TC is an appropriate alternative. Since treatment intent is palliative and each chemotherapy regimen carries a different toxicity profile, clinicians should discuss the risks and benefits of each treatment with their patients. (See 'Chemotherapy' above.)

Cabozantinib is an alternative option for subsequent-line therapy in patients with relapsed/refractory or metastatic disease. (See 'Targeted therapies' above.)

Long term toxicities in survivors of ES – The survival of patients with ES has steadily improved; however, long-term survivors have considerable burden of the late effects of their therapy. These include subsequent primary cancers, pathologic fractures, other radiation-associated complications (wound complications, pulmonary fibrosis, neuropathy, limb leg discrepancy, femoral head necrosis), and chemotherapy-related complications (subsequent primary cancers, reduced fertility, renal insufficiency, and cardiomyopathy). (See 'Complications in long-term survivors' above.)

Long-term follow-up guidelines after treatment of childhood malignancy are available from the COG. (See "Radiation therapy for Ewing sarcoma family of tumors", section on 'Late effects'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David C Harmon, MD, who contributed to earlier versions of this topic review.

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Topic 7740 Version 53.0

References

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