Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; P_C [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

INTRODUCTION

From 2001 to 2005, the Children's Oncology Group (COG) conducted AEWS0031, a randomized clinical trial comparing alternating cycles of vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide administered once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (interval-compressed chemotherapy [ICC]) for patients with newly diagnosed localized Ewing sarcoma (ES). At 5 years, patients who received ICC had superior event-free survival (EFS) with no statistically significant increase in toxicity, establishing ICC as the North American standard treatment for patients with localized ES.¹

Although AEWS0031 demonstrated improved outcomes for the localized ES group as a whole, subgroup analyses to determine the differential benefit of ICC in prognostic subgroups defined by age, primary site, tumor volume, and histologic response were not conducted, in part because data on these latter two prognostic factors were not available at the time of the primary analysis.^1-11 The primary objective of this report is to provide long-term outcomes, including relapse, survival, and development of second malignant neoplasms (SMNs) for patients treated on AEWS0031, and thereby determine if the advantage of ICC is maintained with longer follow-up and in known prognostic subgroups.

METHODS

The cohort consisted of patients treated on COG study AEWS0031, with eligibility and treatment details as previously reported.¹ Patient characteristics were analyzed as previously described by Womer et al.¹ The primary outcome of interest in the current analysis was EFS. Overall survival (OS) and cumulative incidence of SMNs were calculated as secondary outcomes. Additional statistical methods are presented in the Data Supplement (Statistical Supplement). Institutional review board (IRB) approval for AEWS0031 was obtained locally by each participating center, with written informed consent obtained for all patients before enrollment. This secondary analysis used deidentified data and was exempt from separate IRB review.

We retrospectively obtained tumor measurements from computed tomography or magnetic resonance imaging reports requested from the treating institution. Tumor volume was calculated only for patients who had three tumor measurements available. Tumor size was analyzed using tumor volume <200 mL versus ≥200 mL. Histologic response data were collected prospectively from institutional pathologists' assessments and reported as (1) no viable tumor (NVT); (2) ≥90% necrosis (<10% viable tumor); and (3) <90% necrosis (≥10% viable tumor). Patients were also analyzed using NVT versus any viable tumor (AVT) groups.

RESULTS

Patient and Clinical Characteristics

Five hundred sixty-eight (568) eligible patients were enrolled on AEWS0031.¹ One patient included in the original analysis had molecular testing at relapse that called into question the original diagnosis of ES and was excluded from the current analysis, leaving 567 patients for this follow-up report. Median potential follow-up for an EFS event was 8.5 years. The distribution of patient demographics and clinical characteristics was well balanced between randomized arms (Table 1). However, there were differences in the distribution of histologic response with a higher percentage of patients in the <10% viable tumor (37% [ICC] v 25% [STC]) and NVT (40% [ICC] v 32% [STC]) groups receiving ICC compared with STC (P_EX = .02).

TABLE 1.

Patient Demographics and Clinical Characteristics

Long-Term Outcomes: EFS, OS, and SMNs

At 10 years, the estimated EFS for patients treated with ICC was 70% versus 61% for STC (P = .03; Fig 1A), and the estimated OS was 76% for patients treated with ICC versus 69% for STC (P = .04; Fig 1B). Of the 13 events first reported in years 6-10 of follow-up, eight were first episodes of relapse/progression (four on each arm of the study), three were SMNs, and two were deaths (Appendix Table A1, online only).

FIG 1.

Comparison of survival by assigned treatment regimen: (A) EFS and (B) OS. EFS, event-free survival; OS, overall survival.

The type of SMN by assigned treatment regimen is shown in Appendix Table A2. Three new SMNs (acute myeloid leukemia, lymphoma, and renal cell carcinoma) were reported since the original publication for a total of 19 SMNs. The 10-year cumulative incidence of all types of SMNs for patients receiving ICC was 3.2% (95% CI, 1.6 to 6.3) versus 4.2% (95% CI, 2.4 to 7.5) for patients receiving STC (P_C [see Data Supplement] = 0.5). Similarly, there was no significant difference in the cumulative incidence risk for either leukemia or nonleukemia SMNs between regimens.

We assessed for potential interactions between randomized arm (ICC v. STC) and known ES prognostic factors (age, primary site, tumor volume, and histologic response) to investigate whether there was a differential benefit to ICC within known prognostic subgroups (Table 2). We did not find evidence for significant interaction in any subgroup except for tumor volume. For patients with tumor volume ≥200 mL, ICC was associated with a relative hazard rate (RHR) of 0.45, which was significantly different than the RHR of 1.2 among patients with tumor volume <200 mL (P_I = .04), suggesting that ICC had increased efficacy in patients with tumor volume ≥200 mL.

TABLE 2.

Relative Hazard Rate for Event by Subgroup

Outcomes according to Randomized Arm by Subgroup

We compared long-term outcomes according to randomized regimen (ICC v STC) on the basis of factors used to stratify the original randomization (age at enrollment and primary site) and known ES prognostic factors (tumor volume and histologic response) analyzed for the first time within the context of this trial. ICC was generally associated with improved outcomes in adverse prognosis subgroups; however, patients age 18 years and older continue to have poor outcomes despite receiving ICC (Data Supplement and Appendix Figs A1-A3). Notably, patients randomly assigned to ICC with NVT at surgery had a 10-year EFS postlocal control of 91%.

DISCUSSION

With longer-term follow-up, ICC for localized ES remains associated with superior EFS and now also demonstrates a statistically significant improvement in OS. There was no difference in the 10-year cumulative incidence of SMNs between treatment regimens, and overall, a limited number of EFS events occurred during years 6-10 of follow-up irrespective of regimen received. Our data demonstrated that ICC was generally associated with improved outcomes for patients with adverse prognostic characteristics. In addition, we observed a statistically significant interaction between randomized arm and tumor volume, indicating greater risk reduction for patients with larger tumors treated with ICC. These results reinforce the routine use of ICC for patients with localized ES, although there remain subgroups with unacceptable outcomes despite the improvements seen with ICC (eg, age ≥ 18 years), and are consistent with the recent results of the Euro Ewing 2012 trial.¹²

Patients in our analysis with a poor histologic response (≥10% viable tumor) who received ICC had a 10-year EFS postlocal control of 73%, which compares favorably with previous studies.¹³ Our analysis also supports previous data suggesting that categorizing tumors as NVT versus AVT may be a better discriminator of outcome.^14,15 The outstanding outcomes for patients with NVT who received ICC should be explored in future studies.

We likewise provide important new data on tumor volume in the context of ICC. Although our data demonstrate that ICC is associated with improved outcomes, it does not completely abrogate the adverse prognostic effect of large tumor volume.¹⁴ We found that ICC was associated with significantly reduced risk of an event in patients with tumors ≥200 mL, but not in patients with tumors <200 mL. The reasons for this differential effect are not clear. The large number of patients with missing data in our analysis limits any further inferences that can be made. This finding should be explored in future studies.

In conclusion, we have demonstrated that ICC for localized ES provides superior EFS and OS that is durable with long-term follow-up. Despite the increased dose intensity of ICC, we did not see an increase in second malignancies in the ICC group even with longer follow-up. We have identified a population of patients with exceptionally good outcomes, those treated with ICC with NVT on excision. Future studies could explore including these patients in a low-risk localized ES group. Although ICC was associated with improved outcomes even for historically adverse prognostic groups, these patients remain at substantial risk for relapse. To improve outcomes for these patients, it will be essential to develop a consensus definition for high-risk localized ES, which incorporates both clinical and molecular features, and to harmonize how patients with ES are stratified internationally.^16-19

APPENDIX

TABLE A1.

Events Occurring During Long-Term Follow-Up (years 6-10) on AEWS0031

TABLE A2.

SMNs Occurring in Patients Treated on AEWS0031

FIG A1.

Comparison of EFS by assigned treatment regimen for patients (A) age <18 years and (B) age ≥18 years, and with (C) nonpelvic primary site and (D) pelvic primary site. EFS, event-free survival.

FIG A2.

Comparison of EFS by assigned treatment regimen for patients with tumor volume (A) <200 mL and (B) ≥200 mL. Comparison of EFS from time of surgical local control by assigned treatment regimen for patients with (C) NVT and (D) AVT. AVT, any viable tumor; EFS, event-free survival; NVT, no viable tumor.

FIG A3.

EFS from time of surgical local control for different histologic response categories (regimens combined). EFS, event-free survival.

AUTHOR CONTRIBUTIONS

Conception and design: Thomas Cash, Mark D. Krailo, Richard Gorlick, Katherine A. Janeway, Steven G. DuBois, Richard B. Womer

Provision of study materials or patients: Mark D. Krailo, Allen B. Buxton

Collection and assembly of data: Thomas Cash, Mark D. Krailo, Allen B. Buxton, Katherine A. Janeway, Steven G. DuBois, Richard B. Womer

Data analysis and interpretation: Thomas Cash, Mark D. Krailo, Allen B. Buxton, Holcombe E. Grier, Patrick J. Grohar, Damon R. Reed, Aaron R. Weiss, Richard Gorlick, Katherine A. Janeway, Steven G. DuBois, Richard B. Womer

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children’s Oncology Group Study AEWS0031

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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