High-dose chemotherapy improves survival in Ewing sarcoma

A high-dose combination of busulfan and melphalan with autologous stem cell transplant improved survival compared with standard-of-care vincristine, dactinomycin and ifosfamide among patients with Ewing sarcoma, according to an international randomized trial.

“In the subgroup of patients with localized Ewing sarcoma specifically designed for this study, treatment with [busulfan and melphalan] conferred a significant, sustained and clinically meaningful improvement in EFS and OS,” Jeremy Whelan, MD, professor and consultant oncologist at University College Hospital London, and colleagues wrote. “This finding is particularly significant, given the observation that cure rates in this important cancer of children and young people have improved modestly at best over recent decades and that the expanding knowledge of the biology of Ewing sarcoma has, to date, not resulted in the introduction of new agents into standard care.”

The researchers studied 240 high-risk patients (median age, 17.1 years; 61% male) treated between 2000 and 2015. Eligible participants were aged younger than 50 years and had a poor response — defined as at least 10% viable cells — after undergoing six courses of vincristine, ifosfamide, doxorubicin and etoposide, which represented 78% of patients. The other patients had a tumor volume of at least 200 ml if unresected, initially resected or resected after radiotherapy.

Because the role of consolidation high-dose chemotherapy has been controversial in this setting, Whelan and colleagues sought a 15% improvement in 3-year EFS among 122 patients treated with busulfan and melphalan (BuMel) with autologous stem cell transplant compared with 118 patients treated with seven courses of vincristine, dactinomycin and ifosfamide (VAI).

Median follow-up was 7.8 years.

Researchers observed a significant reduction in event risk with BuMel compared with VAI in the intent-to-treat analysis (HR = 0.64; 95% CI, 0.43-0.95).

Three-year EFS was 69% (95% CI, 60.2-76.6) for BuMel vs. 56.7% (95% CI, 47.6-65.4) for VAI.

This trend persisted at 8 years, with an EFS of 60.7% (95% CI, 51.1- 69.6) for the BuMel group and 47.1% (95% CI, 37.7-56.8) for the VAI group.

Patients with an intermediate poor response (10% to 29% viable cells) rather than a very poor response ( 30% viable cells; P = .06) and older patients (25 years or younger vs. older than 25 years) appeared to benefit more from BuMel.

Improvement in EFS with BuMel appeared linked to reduction in risk for metastases (HR = 0.58; 95% CI, 0.37-0.9).

BuMel also had a favorable impact on OS compared with VAI (HR = 0.63; 95% CI, 0.41-0.95).

A greater proportion of patients assigned BuMel achieved OS at 3 years (78%; 95% CI, 69.6-84.5 vs. 72.2%; 95% CI, 63.3-79.6) and 8 years (64.5%; 95% CI, 54.4-73.5 vs. 55.6%; 95% CI, 45.8-65.1).

Two toxicity-related fatalities occurred in the BuMel group and one fatality occurred with standard therapy.

The researchers reported significantly more severe acute toxicities among patients treated with BuMel compared with those treated with VAI.

In an editorial accompanying the study, Richard Gorlick, MD, division head and department chair of pediatrics at The University of Texas MD Anderson Cancer Center, and colleagues called the trial “remarkable,” but expressed caution.

“Importantly, we would caution against adding high-dose chemotherapy and stem-cell rescue to the standard North American treatment approach of intensively timed chemotherapy because the effect on outcome and toxicity of such an approach is not addressed by the Euro-Ewing trial results presented by Whelan et al,” they wrote. “Despite this intercontinental divergence in standard treatment approaches, there is global consensus for the need to develop novel strategies that go beyond dose intensification or introduction of noncross-resistant cytotoxic chemotherapy for treatment of patients with Ewing sarcoma.

“We urge expansion of research efforts that increase our understanding of the fundamental molecular drivers of Ewing sarcoma, which can then translate into the development of more effective therapeutic approaches,” they added. – by Rob Volansky

Disclosures: Whelan reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Gorlick reports no relevant financial disclosures. Please see the editorial for all other authors’ relevant financial disclosures.