Management of Recurrent Ewing Sarcoma: Challenges and Approaches

Is a tissue diagnosis required to diagnose recurrent Ewing sarcoma?

The most common scenario for relapse is the development of distant metastases in the lungs and/or bones within 2 years of initial diagnosis. In this context, tissue confirmation is not routinely needed. In patients with a solitary site of metastasis, or when the differential diagnosis includes infectious causes of pulmonary nodules, biopsy may be considered. While biopsy/resection may provide definitive diagnosis of relapse as well as tissue for genetic testing for targetable mutations, one drawback is the possible elimination of measurable or evaluable disease that may be required for clinical trial enrollment or assessment of response to therapy. In general, the decision about obtaining a biopsy to confirm relapse should be customized to the individual patient situation.

What is the role of local control measures for relapsed Ewing sarcoma?

For the approximately 15%–20% of patients with isolated local recurrence, further local control measures with either surgery or radiotherapy may improve outcomes and should strongly be considered when feasible.⁸ In general, chemotherapy is also used for local recurrences, given the systemic nature of relapsed Ewing sarcoma and the expected high likelihood of developing additional sites of recurrence if therapy is directed only to local sites.

The role of radiotherapy for recurrent pulmonary metastases is less clear. Most cooperative group studies prescribe 15–18 Gy of whole lung irradiation (WLI) as planned treatment for newly diagnosed patients who have pulmonary metastases that can be cleared with either chemotherapy and/or surgery. Therefore, many physicians would provide similar treatment in the relapse setting for those patients who can achieve a second remission and who had not yet received WLI. According to a retrospective review of 136 Ewing sarcoma patients with pulmonary relapse, 88 (65%) were able to achieve second remission after chemotherapy and/or surgery.¹⁴ The nonrandomized use of WLI (n=44) showed a trend toward improved 3-year progression-free survival (PFS) of 37% vs 21% in this population, but this was not statistically significant (P=0.18).¹⁴ Nevertheless, WLI is generally well tolerated and is often utilized for those patients who can achieve second remission. Larger and more focal radiotherapy doses may be used to treat symptomatic and/or unresectable lesions.

Although local control for patients with localized or oligometastatic disease is often pursued, this approach is not usually feasible for those with widespread metastases. For these unfortunate patients, choosing select lesions for local treatment after administration of salvage chemotherapy may be reasonable. Radiotherapy, including stereotactic body radiotherapy, may be very helpful in palliating painful bone lesions that do not improve with salvage chemotherapy. The timing and extent of local treatment is variable between patients and often is coordinated with chemotherapy decisions. In fact, many patients end up with a customized regimen that incorporates their individual risk factors, tumor burden and sites of disease, and preferences.

What conventional salvage therapies are available outside of a clinical trial?

A variety of commercially available chemotherapy regimens have produced responses in patients with recurrent Ewing sarcoma; however, the superiority of one regimen over another has not yet been established. The rEECur study currently being performed through the Euro Ewing Consortium is designed to address this issue through a multiarm randomized study in which patients aged 2–50 years with recurrent Ewing sarcoma may receive one of the four best-established salvage regimens (ISRCTN 36453794). In this study, patients will receive 1) cyclophosphamide/topotecan (Cy/Topo), 2) gemcitabine/docetaxel (Gem/Doc), 3) high-dose ifosfamide (IFOS), or 4) temozolomide/irinotecan (TEM/IRN). Patients on the IFOS arm will receive four planned cycles, while patients on the other three arms will receive a total of six cycles. Patients with a favorable response may receive additional cycles at the discretion of their oncologist. The design of the study includes sequential elimination of the regimens that produce the lowest objective response rate, which is the primary endpoint of the Phase II portion of the study. Once two regimens have emerged, they will be compared in the Phase III portion of the study, which uses PFS as the primary endpoint. This data will be immensely helpful in defining a more standard approach to recurrent Ewing sarcoma.

Each of the regimens in the rEECur study has been described previously, usually in single-institution retrospective analyses of patients with extensive and often very heavily pretreated disease. Table 1 provides additional data on these four regimens and highlights some differences in expected toxicities. Given that for many patients this therapy will not be curative, understanding the toxicity spectrum and details of treatment administration can become important factors in helping adolescent and young adults make decisions regarding therapy. While all four regimens produce some degree of myelosuppression, this is most pronounced in patients receiving IFOS¹⁵ or Cy/Topo,^16–18 and so prophylactic myeloid growth factor is routinely used in these patients. Nausea is usually manageable for all regimens, although it may be more significant for those receiving IFOS. Patients often ask about alopecia, which is common with all of these regimens but perhaps less with TEM/IRN.^13,19–24Neuropathy has been a problem for some patients receiving GEM/DOC,^25–27 while diarrhea and abdominal pain can be limiting for those treated with TEM/IRN.^13,19–24 Of the four regimens, all are routinely given as outpatients except for IFOS.

(To view a larger version of Table 1, click here.)

TEM/IRN has been the best studied of these four regimens, with a cumulative response rate of 47% reported in seven studies of 166 total patients.^13,19–24 Although both IRN and TOPO act on topoisomerase I, the mechanisms of resistance and spectrum of activity appear different, such that progression with one drug does not preclude response to the other.²⁸ The addition of vincristine (VCR) to TEM/IRN has been reported by some authors,^22,24,29 in an attempt to exploit the synergy seen between VCR and IRN in rhabdomyosarcoma patients.³⁰ However, that synergy has not been formally assessed in patients with Ewing sarcoma, and the benefit of adding VCR to TEM/IRN for relapsed patients is unclear. VCR is not included in the rEECur study, and this drug may be associated with neuropathy, particularly in older adolescents and young adults. As seen in Table 2, a variety of different schedules and doses have been reported. More recent trials have used a 5-day schedule of irinotecan, based on a rhabdomyosarcoma study which showed that efficacy was similar compared to the more prolonged 2-week schedule.³¹

(To view a larger version of Table 2, click here.)