Keywords: relapsed Ewing sarcoma, adolescent and young adult oncology, AYA, irinotecan, topotecan


Ewing sarcoma is a high-grade sarcoma arising in bone or soft tissue and occurs most commonly in adolescent and young adult patients. The primary tumor is treated with surgery and/or radiation, depending on the feasibility of resection. Because of the high rate of dissemination even in patients with apparently localized disease, patients are also treated with chemotherapy in an effort to eradicate microscopic disease that could lead to distant metastases and death. Three strategies for initial chemotherapy are most commonly used, depending in part on institutional preferences and patient age. For example, younger patients in North America typically receive the combination of vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE), using an intensively timed schedule with planned chemotherapy administration every 2 weeks.1 In Europe, a common approach is to use vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) as the initial chemotherapy regimen.2 For adult patients, some centers have simplified the regimen down to vincristine, ifosfamide, and doxorubicin (VID).3 Therapy is administered for up to 14 total cycles, and the vast majority of patients achieve remission by the completion of treatment.

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Despite this extensive therapy, at least one-fourth of patients with initially localized disease will relapse after completing all planned therapy. The recurrence rate is even higher for those with initially metastatic disease, with treatment failure seen in 50%–80% of patients depending on the site of metastases.4 For patients in whom relapse is detected, or for those few who are unable to achieve an initial remission, the chance of long-term survival is low. In addition, there is no standard management for this group of patients, raising many questions about how best to proceed. In this review, we address common management issues and discuss current and upcoming strategies for the treatment of this complex disease.

When and where is Ewing sarcoma most likely to recur?

Over 70% of relapses occur within 2 years of initial diagnosis,5–10 and these patients are designated as having “early relapse”. The median time of recurrence for patients with initially localized disease treated on Children’s Oncology Group protocols was 1.4 years from diagnosis, with a median of 1.0 year for those who presented initially with metastases.5 For patients with late relapses, most occur within 2–3 years from initial diagnosis, although very late relapses even 5 or more years from diagnosis have occasionally been reported.11

At least two-thirds of first relapses occur at distant sites, usually the lungs and/or bones. This pattern of recurrence is particularly common in patients who initially presented with metastatic disease. In contrast, isolated local recurrence occurs in about one-fifth of patients, develops later than systemic relapse, and is more typical in patients who initially had localized tumors.6

Of interest, about one-half of relapsed patients in one large retrospective study were identified by scheduled surveillance imaging, while one-half were symptomatic at the time recurrence was noted, with new pain or swelling being the most common complaints.12

What prognostic factors can facilitate risk stratification and patient counseling?

As a group, only one in five patients with recurrent Ewing sarcoma is expected to achieve long-term survival. The disease-free interval (DFI) between diagnosis and first relapse is the single most important prognostic factor, as patients with a DFI >2 years have an estimated 5-year overall survival of approximately 30%. In contrast, 5-year survival is only 7% for the more common group of patients with DFI <2 years.5,6 In terms of median survival, Shankar et al reported that for a group of 61 relapsed patients, the median survival for DFI <1 year was 3 months, compared with 8 months for those with DFI of 12–24 months, and 24 months for those with DFI >2 years.9

In addition to DFI, the site of recurrence is also prognostic. Patients with combined local and distant relapse have the worst outcomes, while those with isolated local recurrences appear to fare better.5,6This is understandable given that these patients may have less total burden of disease at recurrence and may be amenable to further local therapies in addition to systemic treatment. More debatable is the prognostic impact of isolated pulmonary recurrence, as some series have reported that these patients did better than those with other distant metastases,6,7,10 while others did not find such an association.5

Additional factors that have been associated with improved outcomes in retrospective cases series include normal levels of lactate dehydrogenase and favorable performance status.13 Younger age has been shown to be associated with improved outcome in some case series,10 but results have been variable.13 Some of this variability may relate to the intensity of the initial treatment regimens in younger versus older patients. Understanding the relevance of key prognostic factors such as DFI and relapse site provides important guidance for clinical trial design and interpretation of results, given the substantial differences in survival between patients with favorable vs unfavorable features. Another factor to be considered is the extent of prior therapies, as relapsed patients will typically experience progressively shorter progression-free periods with subsequent lines of therapy.

The prognostic factors may also help guide patient decisions regarding further therapy. As detailed in the sections below, there are several regimens utilizing commercially available drugs that can result in response and/or disease stabilization for some period of time. However, given the very low likelihood of cure with these regimens, and the desperate need for innovative therapies, strong consideration should be given to enrollment on clinical trials testing new strategies when possible.