Role of High-Dose Chemotherapy Consolidation in Ewing Sarcoma

Role of High-Dose Chemotherapy Consolidation in Ewing Sarcoma

High-dose chemotherapy with busulfan-melphalan followed by autologous stem cell rescue may be an effective treatment for selected patients with localized high-risk Ewing sarcoma but does not provide a significant efficacy benefit in patients with lung metastases, suggest results from two randomized, multinational trials presented during the 2016 Annual Meeting.

Dr. Jeremy Whelan
Both studies were components of the EURO-E.W.I.N.G 99 trials, a series of trials evaluating different treatment approaches in more than 3,000 patients with different clinical presentations of Ewing sarcoma. Both trials compared the efficacy and safety of high-dose chemotherapy with busulfan-melphalan followed by stem cell rescue versus standard chemotherapy with vincristine, actinomycin D, and ifosfamide (VAI) in patients previously treated with induction chemotherapy and surgical resection.

Although high-dose chemotherapy had been evaluated in smaller, uncontrolled studies, the EURO-E.W.I.N.G 99 trials were the first to evaluate the approach in patients with Ewing sarcoma in a randomized fashion. The R2Loc trial, presented by Jeremy Whelan, MD, of University College Hospital, London, enrolled patients with high-risk localized disease after initial localized therapy (Abstract 11000). The R2pulm trial, presented by Uta Dirksen, MD, PhD, of Westfälische Wilhelm’s-Universität Münster, enrolled patients with lung metastases (Abstract 11001). Both trials excluded patients with early or planned radiation to central axial sites due to anticipated busulfan toxicity.

High-Dose Chemotherapy in High-Risk Localized Ewing Sarcoma

The R2Loc trial enrolled 216 patients (61% male, median age 17 years) with high-risk localized disease who were randomly assigned to receive busulfan-melphalan and stem cell rescue (109 patients) or VAI for 7 cycles (107 patients). High-risk factors included poor histological response after chemotherapy alone (79%), high tumor volume (53%), and large tumor size in patients without histologic response data (20%).

In an intention-to-treat analysis of 216 patients, busulfan-melphalan was significantly more effective than VAI as assessed by 3-year event-free survival (67% vs. 53%; hazard ratio [HR] 0.64; 95% confidence interval [CI] [0.43-0.94]; p = 0.024) and 3-year overall survival (78% vs. 70%; HR 0.60, 95% CI [0.39-0.92]; p = 0.019). Investigators attributed the improved efficacy in the busulfan-melphalan arm primarily to a reduction in risk of metastases, noting a 41% reduction in the incidence of metastases with busulfan-melphalan over VAI (HR 0.59, 95% CI [0.38-0.92]; p = 0.02).

“In this selected group,” Dr. Whelan said, “there was a large and significant benefit associated with busulfan-melphalan compared with VAI.” The superiority of high-dose chemotherapy was maintained with long follow-up, after a median of 8 years (range, 0.3 to 15 years).

Researchers reported that the improved efficacy of busulfan-melphalan was observed across relevant subgroups including age, tumor volume, tumor site, and percentage of tumor viable cells, among patients with a poor prior histologic response.

Dr. Whelan noted that the acute toxicity profile of high-dose chemotherapy was as expected and manageable in most cases. However, there were two deaths determined to be related to busulfan-melphalan—one attributed to myelopathy related to radiation therapy and the other attributed to pancytopenia-related acute respiratory distress syndrome. These deaths occurred 9 months and 5 months, respectively, after the end of treatment. A third patient initially assigned to busulfan-melphalan arm died after receiving conventional chemotherapy, which was administered instead of high-dose chemotherapy due to the patient’s limited renal function.

High-Dose Chemotherapy in Ewing Sarcoma with Pulmonary Metastases

The R2pulm trial enrolled 265 patients with Ewing sarcoma with pulmonary or pleural metastases (median age 14 years, 58% male). Patients were randomly assigned to high-dose chemotherapy with busulfan-melphalan followed by stem cell rescue (133 patients) or seven cycles of VAI with whole lung irradiation (132 patients).

Unlike in the localized setting, in patients with pulmonary metastases, high-dose chemotherapy was not superior to standard chemotherapy; 3-year event-free survival rates were 55% with busulfan-melphalan and 51% with VAI plus whole lung radiation (HR 0.82; p = 0.24). Results were similar in per-protocol analyses. Dr. Dirksen noted that the majority of events were due to secondary metastases, the incidence of which was not significantly reduced with the use of high-dose chemotherapy. The 3-year overall survival rate was 68% in both arms.

Subgroup analyses showed no major heterogeneity across groups except for the group of patients with the worst histological response to prior therapy. In this group of patients, VAI plus whole lung irradiation was significantly more effective than high-dose chemotherapy (p = 0.0003).

Dr. Alberto S. Pappo
Although the trial found no significant benefit with high-dose busulfan-melphalan, Dr. Dirksen pointed out that the event-free survival outcomes were 10% better than expected.

High-Dose Chemotherapy Considerations

An analysis of accrual rates suggests that the applicability of high-dose chemotherapy regimen may be limited. Enrollment of both studies closed early due to insufficient enrollment. Moreover, the proportion of patients who met all eligibility criteria, subsequently enrolled, and received the assigned intervention was low. Only 45% of eligible patients with localized disease (216 of 477) and 55% of patients with pulmonary metastases (265 of 480) ultimately enrolled on the trials.

“This might be viewed, perhaps, as the acceptability—both to clinicians and to patients—of the test regimen,” Dr. Whelan said. Even among the 109 patients with localized disease assigned to busulfan-melphalan, only 80% ultimately received the intervention.

During his discussion of the EURO-E.W.I.N.G 99 studies, Alberto S. Pappo, MD, of St. Jude Children’s Research Hospital, highlighted the challenges of interpreting study outcomes, given the low enrollment of eligible patients, the early analysis, and the potential influence of institutional practices.

“For these reasons,” he said, “I cannot recommend busulfan-melphalan as a component of the standard of care for patients with high-risk localized disease but acknowledge that these results are intriguing and need further validation.”

He added that other treatment approaches such as dose-dense scheduling, which does not require stem cell transplantation, may provide similar disease control. However, there are other caveats to other therapies, such as the risk of breast cancer after chest radiation.

–Melinda Tanzola, PhD