High-Dose Chemotherapy and Blood Autologous Stem-Cell Rescue Compared With Standard Chemotherapy in Localized High-Risk Ewing Sarcoma: Results of Euro-E.W.I.N.G.99 and Ewing-2008

Abstract

Purpose For over 30 years, the place of consolidation high-dose chemotherapy in Ewing sarcoma (ES) has been controversial. A randomized study was conducted to determine whether consolidation high-dose chemotherapy improved survival in patients with localized ES at high risk for relapse. Methods Randomization between busulfan and melphalan (BuMel) or standard chemotherapy (vincristine, dactinomycin, and ifosfamide [VAI], seven courses) was offered to patients if they were younger than 50 years of age with poor histologic response (≥ 10% viable cells) after receiving vincristine, ifosfamide, doxorubicin, and etoposide (six courses); or had a tumor volume at diagnosis ≥ 200 mL if unresected, or initially resected, or resected after radiotherapy. A 15% improvement in 3-year event-free survival (EFS) was sought (hazard ratio [HR], 0.60). Results Between 2000 and 2015, 240 patients classified as high risk (median age, 17.1 years) were randomly assigned to VAI (n = 118) or BuMel (n = 122). Seventy-eight percent entered the trial because of poor histologic response after chemotherapy alone. Median follow-up was 7.8 years. In an intent-to-treat analysis, the risk of event was significantly decreased by BuMel compared with VAI: HR, 0.64 (95% CI, 0.43 to 0.95; P = .026); 3- and 8-year EFS were, respectively, 69.0% (95% CI, 60.2% to 76.6%) versus 56.7% (95% CI, 47.6% to 65.4%) and 60.7% (95% CI, 51.1% to 69.6%) versus 47.1% (95% CI, 37.7% to 56.8%). Overall survival (OS) also favored BuMel: HR, 0.63 (95% CI, 0.41 to 0.95; P = .028); 3- and 8-year OS were, respectively, 78.0% (95% CI, 69.6% to 84.5%) versus 72.2% (95% CI, 63.3% to 79.6%) and 64.5% (95% CI, 54.4% to 73.5%) versus 55.6% (95% CI, 45.8% to 65.1%). Results were consistent in the sensitivity analysis. Two patients died as a result of BuMel-related toxicity, one after standard chemotherapy. Significantly more BuMel patients experienced severe acute toxicities from this course of chemotherapy compared with multiple VAI courses. Conclusion BuMel improved EFS and OS when given after vincristine, ifosfamide, doxorubicin, and etoposide induction in localized ES with predefined high-risk factors. For this group of patients, BuMel may be an important addition to the standard of care.

Figures

Fig 1.

Trial profile. A total of 111 patients with disease classified as localized high-risk disease assessed for eligibility did not meet eligibility criteria: insufficient diagnosis criteria or diagnosis rejected (n = 14); persisting toxicity related to previous treatment and/or contraindication to planned treatment (n = 78), including contraindication to busulfan and melphalan (BuMel) because of planned radiotherapy to an axial site (n = 36); early radiotherapy (n = 13); psychological problems (n = 6); 123 patients meeting eligibility criteria were not enrolled because of other reasons. HDT, high dose therapy; R2Loc, selected high-risk population; VAI, vincristine, dactinomycin, and ifosfamide.

Fig 2.

(A and B) Event-free survival (EFS) and (C) overall survival. (A) Kaplan-Meier estimates of EFS by treatment group, on the intention-to-treat (ITT) population. At the time of this analysis (cutoff date, Jan 1, 2016), 105 events were reported: 60 in the vincristine, dactinomycin, and ifosfamide (VAI) group and 45 in the busulfan and melphalan (BuMel) group. (B) Forest plot of EFS according to subgroups. The hazard ratio of events by subgroup were estimated in a Cox proportional hazards model, on the ITT population including all patients, except for the (1) assessment of treatment effect according to tumor volume: we excluded one patient with missing data; (2) assessment of treatment effect by the high-risk group definition (poor response v large tumor): we excluded 10 patients who were not classified as high risk (listed in the Data Supplement) and two patients who entered the trial for a small tumor with exclusive radiotherapy, but poor clinical response (too small category); and (3) assessment of treatment effect according to the grading of histologic response in patients with poor response: we focused the analysis on the 188 patients who entered the trial because of a poor histologic response and excluded four patients with poor response not otherwise specified. French group: French Society of Pediatric Oncology/French Sarcoma Group/Unicancer. Concerning the interaction between treatment effect and age, the P value was .12 when age was considered in two categories using the cutoff of 25 years as defined at the design stage to stratify the randomization. (C) Kaplan-Meier estimates for overall survival by treatment group on the ITT population. EORTC, European Organization for Research and Treatment of Cancer; GPOH, Gesellschaft für Pädiatrische Onkologie und Hämatologie; UKCCLG, UK Children’s Cancer and Leukaemia Group

Fig 3.

Adverse events. The panel on the left is a butterfly plot showing the proportion of patients experiencing an adverse event, whatever the grade (gold for busulfan and melphalan [BuMel] and blue for the vincristine, dactinomycin, and ifosfamide [VAI] arm), and a severe adverse event (dark gold for BuMel and dark blue for VAI arm) according to the randomization group. The panel on the right displays the relative risk of a severe adverse event in patients with BuMel relative to patients with VAI, with 95% CIs for a 2 × 2 table. The acute toxicity related to chemotherapy was assessed after each course, using a list of 22 selected items from the National Cancer Institute Common Toxicity Criteria version 2.0. A modified list of items was used to evaluate toxicity after radiotherapy, using Radiation Therapy Oncology Group classification for eight types of specific toxicities. A free text area was available to document other adverse reactions. The toxicity items were then pooled by category: bladder toxicity, cardiac toxicity, GI toxicity, general deterioration, hematologic toxicity, infection, liver toxicity, lung toxicity, neurologic toxicity (including mood alteration), renal toxicity, and skin toxicity. The respiratory tract toxicity (larynx, pharynx, salivary gland) reported after radiotherapy was pooled within the category GI toxicity because of small numbers and because they were usually associated. Details are provided in the Data Supplement. For each adverse event type, the analysis is based on the maximum grade observed over the whole maintenance treatment duration. A grade 4 hematologic toxicity and a grade ≥ 3 nonhematologic toxicity were classified as severe toxicities. The categories of adverse event are ordered by decreasing value of the relative risk of severe toxicity. This analysis was performed on the safety set (116 VAI patients and 93 BuMel patients), excluding patients who did not receive the treatment allocated by randomization, similar to the as-treated population. The number of chemotherapy courses followed by toxicity over the whole maintenance treatment duration is detailed in the Data Supplement.