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Local Control in Pelvic Ewing Sarcoma: Analysis From INT-0091—A Report From the Children's Oncology Group

Torunn I. Yock, Mark Krailo, Christopher J. Fryer, Sarah S. Donaldson, James S. Miser, Zhengjia Chen, Mark Bernstein, Fran Laurie, Mark. C. Gebhardt, Holcombe E. Grier, Nancy J. Tarbell

From the Massachusetts General Hospital; Beth Israel Deaconess Medical Center and Children's Hospital; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Keck School of Medicine, University of Southern California, Los Angeles; Stanford University Medical Center, Stanford; City of Hope National Medical Center, Duarte; COG Statistics and Data Center, Arcadia, CA; British Columbia's Children's Hospital, Vancouver, British Columbia; Hôpital Sainte-Justine, Montréal, Québec City, Canada; and the Quality Assurance Review Center, Providence, RI

Address reprint requests to Torunn I. Yock, MD, MCH, Department of Radiation Oncology, Massachusetts General Hospital, 100 Blossom St, Cox 341, Boston, MA 02114; e-mail: TYOCK{at}PARTNERS.ORG and send a copy to pubs{at}childrensoncologygroup.org

	ABSTRACT

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PURPOSE: The impact of the modality used for local control of Ewing sarcoma is uncertain. We investigated the relationship between the type of local control modality, surgery, radiation (RT) or both (S + RT), and subsequent risk for local failure (LF) in patients with nonmetastatic pelvic Ewing sarcoma treated on INT-0091.

PATIENTS AND METHODS: Patients 30 years with Ewing sarcoma, primitive neuroectodermal tumor or primitive sarcoma of bone were randomly assigned to receive chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin, (VACA) or with these four drugs alternating with ifosfamide and etoposide (VACA-IE). The local control modality, surgery, RT or both was chosen by the treating physicians. The effect of local control modality was assessed after adjusting for the size of tumor (< 8 cm, 8 cm) and chemotherapy type.

RESULTS: Seventy-five patients with pelvic tumors and a median follow-up of 4.4 years (0.6 to 11.4 years) comprised the study population. Twelve underwent surgery, 44 received RT, and 19 received both. The 5-year event-free survival (EFS) and cumulative incidence of LF was 49% and 21% (16%, LF only; 5%, LF and distant failure). There was no significant difference in EFS or LF by tumor size (< 8 cm, 8 cm), local control (LC) modality, or chemotherapy. However, VACA-IE seems to confer an LC benefit (11% v 30%; P = .06).

CONCLUSION: There was no significant effect of local control modality (surgery, RT or S + RT) selected by the treating physicians on rates of local failure or EFS. However, VACA-IE improves LC (11%) compared with previously published results for pelvic Ewing sarcoma.

	INTRODUCTION

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Ewing sarcoma is curable with combined-modality therapy of chemotherapy and or either surgery, radiotherapy (RT), or both (S + RT). Numerous advances and improvements in chemotherapy regimens, RT, and surgical techniques have improved the local control and overall survival. However, there is ongoing debate as to whether surgery and radiotherapy are comparable for local control.^1,2 Many studies fail to reach statistical significance but show a trend favoring surgery for pelvic lesions.^3-5 The choice of local therapy is influenced by multiple clinical characteristics such as tumor location, size, response to chemotherapy, age, availability of surgical or RT resources, anticipated morbidity and patient preference. There has never been a randomized trial of surgery versus RT for local control for pelvic lesions, and this is unlikely to change. However, it has generally been accepted based on retrospective analyses that surgery (with or without radiation) affords better local control.^6-8 Even when pelvic tumors are evaluated separately, it appears that surgery is better than RT for local control.^9-12 These analyses are subject to bias because of the patient characteristics that led to selection of a particular modality, such as location within pelvis, tumor size, response to chemotherapy and surgical resectability, which are also related to risk for subsequent disease progression. The pelvis is the most common primary site in Ewing sarcoma, occurring in approximately 21% of patients¹³ and carries a worse prognosis than tumors in extremity locations. Pelvic tumors also tend to present larger, which further connotes a poor prognosis.^10,14,15 In many cases, the morbidity from definitive RT is expected to be less than the morbidity of extirpative surgery because of involvement of critical structures and difficulty in the placement and durability of allografts in certain parts of the pelvis.

In this study, we look at patients with pelvic Ewing sarcomas treated on the randomized controlled trial INT-0091 testing two forms of chemotherapy, VACA (vincristine, doxorubicin, cyclophosphamide, and actinomycin-D) versus VACA-IE (VACA plus ifosfamide and etoposide), to determine whether local control modality is related to risk for overall treatment failure, or disease progression at the initial tumor site, while accounting for potential confounding factors such as tumor size and chemotherapy regimen.

	PATIENTS AND METHODS

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Patient Population
The patients enrolled onto INT-0091 (CCG-7881 and POG-8850) with nonmetastatic primary tumors of the pelvis constituted the study population. They were enrolled from December 1988 to November 1992, and were age 30 years or younger, with a diagnosis of Ewing sarcoma, peripheral neuroectodermal tumor (PNET) of bone, or primitive sarcoma of bone.

Therapy
The study randomly assigned patients to VACA-IE chemotherapy versus VACA chemotherapy alone.

Details of the treatment plan and timing of local control have been previously published.⁷

RT was planned with diagnostic imaging including computed tomography (CT)/magnetic resonance imaging (MRI)/bone scans but predated the availability of CT-based treatment planning. RT was delivered to the original tumor volume with a 2-cm margin to a dose of 45 Gy with a cone down to a total dose of 55.8 Gy at 1.8 Gy/fraction started during week 12. When administered in the postoperative setting it was most often because of close (< 1 cm) or positive margins, and the dose was 45 Gy. Patients with gross residual disease were treated to 55.8 Gy. All radiation ports and simulation films were reviewed for compliance with radiotherapy guidelines. The protocol allowed for surgery in patients whose tumors were deemed resectable. Surgery was followed with postoperative radiation as described herein depending on the patient's tumor characteristics. The patients with tumors involving the acetabulum or involving S1 or S2 of the sacrum were more likely to be deemed unresectable. A good response to chemotherapy may have improved the resectability of a lesion, but this response was not prospectively measured in this study population.

Definitions
Patients who experienced disease progression, second malignant neoplasm, or death were scored as having experienced an event. Event-free survival (EFS) was defined as the time from completion of all local control measures until the event or last patient contact, at which time the patient was censored. Each event was further classified as (1) local recurrence, (2) systemic recurrence, (3) recurrence concurrently at a local and systemic site, (4) recurrence with insufficient data submitted to determine exact site of recurrence, (5) death, and (6) second malignant neoplasm. Patients with disease progression that had a local component (event 1 or 3), were considered to have experienced local failure (LF).

The classification of local control modality received by each patient was determined according to all interventions performed on the local tumor site up to and including the start of maintenance therapy. Each patient was classified into one of three local control procedures: (1) surgery only; (2) RT only; or (3) surgery and RT (S + RT). Tumor size was assessed from radiographic images done before enrollment onto the study and was categorized into two groups: (1) small tumors—less than 8 cm in longest measurement; and (2) large tumors— 8 cm.

The following definitions of dose and field deviations were used for this analysis. A major field deviation was defined as gross tumor missed or shielded by the radiation ports. A minor field deviation was defined as a tight margin on the primary volume or cone down field. A major dose deviation was defined as underdosing of the tumor by 10% or more.

Statistics
The outcome measures were EFS and LF timed from the completion of local-control therapy. EFS was calculated by the method of Kaplan and Meier.¹⁶ The cumulative incidence (CI) of each type of event was calculated for each method of local control modality and compared by the method proposed by Gray.¹⁷ Where local failure is reported, it is the CI. Nonparametric Wilcoxon's tests and F-tests were used to test for equality of medians and means across multiple groups. Evaluation of the association between RT protocol compliance and risk for event was restricted to the patients who received RT. Patients who received RT were stratified according to compliance with protocol therapy and compared with patients who received surgery only.

	RESULTS

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Patient Population
Ninety-three of the 518 patients enrolled on INT-0091 had localized pelvic primary tumors at presentation. Six patients progressed before the local control phase, leaving 75 patients with sufficient data, including a tumor measurement, to be included in an analysis according to the type of local control they received (surgery, RT or S + RT).

Patient Characteristics
The median follow-up of patients alive at last contact in this cohort was 4.4 years (range, 0.6 to 11.4 years). Disease characteristics of the patients are listed in Table 1 according to local control modality. The groups did not differ significantly by sex, age, race, or lactate dehydrogenase measured before the start of chemotherapy. The majority of the patients (64%) were between 10 and 17 years old, with 19% younger than 10 years and 17% 18 years. However, the groups did differ significantly by tumor size. The choice of local-control measure (surgery, RT or S + RT) is partly dependent on tumor size for patients in this analysis (P = .013). Local control of large tumors was more likely to employ both surgery and RT. Site of pelvic tumor was also recorded as sacrum, ilium, ischium, and pubis.

Analysis by local therapy. The 5-year CI of LF for surgery and RT groups was 25%, and for the S + RT group, 10.5% (P = .46; Fig 1). The 5-year EFS was also not significantly different between the groups, with 42%, 52%, and 47% in the surgery, RT, and S + RT groups, respectively (Table 2; Fig 2). The 5-year CI of LF and EFS were also not different according to tumor size (small v large) at presentation (24% v 18% LF and 49% v 50% EFS, respectively; P = .64, P = .91; Fig 3). A subgroup analysis performed by tumor size, pelvic site, and local-control modality group also failed to show any significant trends with LF or EFS.

View larger version (9K): [in this window] [in a new window]   Fig 1. Cumulative incidence of local progression by the surgery alone, radiation alone, and combined surgery plus radiation.

View larger version (10K): [in this window] [in a new window]   Fig 2. Event-free survival in patients by surgery alone, radiation alone, and surgery and radiation combined.

View larger version (8K): [in this window] [in a new window]   Fig 3. Cumulative incidence of local tumor progression (either alone or in conjunction with distant progression) by size.

View larger version (8K): [in this window] [in a new window]   Fig 4. Cumulative incidence of local progression by chemotherapy, doxorubicin, vincristine, cyclophosphamide, and dactinomycin, (VACA) versus VACA alternating with ifosfamide and etoposide (VACA-IE).

Late Sequelae
There were no second malignancies recorded in this group to date. In the surgery group, there were seven patients who had disease progression, and all patients died. In the RT group, there were 21 patients who progressed, and 19 had died at the time of analysis. Of the patients who received S + RT, 10 progressed and nine have died. In summary, of the 75 assessable patients with pelvic Ewing sarcoma enrolled onto this trial, 38 have progressed and all but 8% of these patients with relapse have died.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
This analysis of 75 patients with pelvic Ewing sarcoma treated on INT-0091 did not demonstrate a significant difference in local control between the different local control measures: surgery, RT, and S + RT. Because the assignment to local control therapy was not random, we conclude that the local control measure, when used according to the treating physician's best judgment, was not significantly related to risk of LF or DF in this patient group. Although not significant, surgery and RT seemed to have comparable LF rates at 5 years of 25% each, in contrast to patients treated with both, whose LF rate at 5 years is 11%. Other investigators have suggested that better local control is obtained by using combined surgery and radiotherapy,^18,19 and this combined approach warrants investigation in future studies.

This analysis also revealed the importance of chemotherapy in achieving local control. Ewing sarcoma patients treated with VACA-IE had lower rates of LF (11%) than those treated with VACA (30%). This benefit appears to persist irrespective of local control modality. The number in each surgical subgroup is small and should be interpreted with caution, but the LF rates by local-control modality group in the VACA-IE treatment arm range from 0% to 14% compared with 11% to 36% in the VACA treatment arm. For patients treated with RT alone, the trend of VACA-IE to improve local control did not translate into a significant benefit in EFS. This failure to show a significant benefit in EFS may be a result of small patient numbers. In the report of all nonmetastatic patients from INT-0091, VACA-IE significantly reduced the risks of treatment failure and death.¹⁴

Other studies, including the initial report, have shown tumor size to be an important prognostic factor for risk of treatment failure.^4,14 We did not find size to be important in this group of patients, which is also consistent with another large series of pelvic Ewing sarcoma.²⁰ Initial tumor size was related to the type of local control that was performed. Because patients with large tumors were more likely to receive combined-modality therapy for local control, this may have negated any deleterious effects of large tumors.

The European Cooperative Group (CESS81/86, and EICESS 92) and the Pediatric Oncology Group (POG 8346) demonstrated the importance of a radiotherapy quality-assurance program and showed a statistically significant benefit in local control outcome when there were no radiotherapy protocol violations.^18,21-23 This analysis of pelvic patients from INT-0091 did not show a statistically significant benefit in the patients with no radiotherapy deviations. However, the numbers of deviations and events were small. When normal tissue constraints allow, it is imperative to deliver protocol-prescribed RT doses to the appropriate volume, and central review of RT is an important component of trials.

A further difficulty is that there is no similar quality-assessment (QA) review for the surgically treated patients. Although close or positive margins may suggest an inadequate resection, these pelvic tumors are often close or involving critical structures that are not fully appreciated before the time of surgery by imaging. Because of these unknown factors before and during the operation, a similar kind of QA analysis with a designation of a surgical protocol violation cannot be made with as much certainty, rendering the QA analysis somewhat incomplete.

In CESS81/86 and EICESS 92, the overall local failure rates for all sites of disease were significantly different for patients treated with surgery (with or without RT) 7.5% compared with RT alone 22.5%.¹⁸ However, there exists a bias that the surgically resectable tumors tend to be the tumors with a better prognosis because they are located more often in the extremities, respond better to the chemotherapy, and are often smaller. These combined data from the CESS and EICESS studies demonstrated a difference between surgery and RT LF rates only in patients with large tumors. Our analysis fails to demonstrate a difference in LF or EFS rates by tumor size. However, this analysis of the pelvic patients differs from the original report including all sites where size was found to be an important prognostic factor.¹⁴ This lack of association with tumor size could be attributable to the small numbers of patients with pelvic tumors when compared with the entire study population.

Although a strength of this analysis is that the data were prospectively collected as part of a randomized trial, we are retrospectively analyzing the data and the analysis is therefore subject to unintended bias. We tried to determine whether the known prognostic factors such as age and tumor size could account for associations or their lack when attempting to determine whether local-control modality was important for local control and EFS outcome. We did not find any such associations, but there may be other biases for which we have not accounted that remain unknown. The prognostic factor of response to chemotherapy either histologically or by imaging^24,25 was not collected in a reliable manner, and therefore we did not look at this variable to see if it had an effect on this patient population. However, it is likely that the response rates to VACA-IE were superior to VACA alone, which is why it translated into better local control. Response to chemotherapy has been an important prognostic factor in other studies^5,26-28 and must be a component of the next Intergroup study.

In summary, this analysis showed that there was a local control benefit to VACA-IE chemotherapy and that this benefit appeared to persist irrespective of the local control modality used. For all nonmetastatic pelvic patients who received VACA-IE, the 5-year LF incidence was 11%, which is better than the 20% to 30% or more that is commonly quoted in the literature.^4,5,9,29 In contrast to all patients enrolled onto INT-0091, there was no statistically significant benefit in EFS in this subset, but the absolute difference was 9% in favor of VACA-IE. Radiotherapy or surgery alone appeared to provide similar incidences of LF (25%), but the combination may decrease LF (11%), warranting further investigation.^18,19 Additionally, this study demonstrates that chemotherapy plays an important role in attaining local control. The combined relative benefit of S + RT may not be seen in a population treated with the now standard combination of chemotherapy such as VAC-IE. Furthermore, in the modern era of CT-based planning with regular use of MRI to assist in target delineation, improved RT targeting is likely to further improve outcomes. Additional investigation delineating both the disease control and the morbidity of surgery, RT, or both will yield worthwhile information for clinicians faced with making an optimal treatment recommendation.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Torunn I. Yock, Mark D. Krailo, Christopher J. Fryer, Sarah S. Donaldson, James S. Miser, Zhengjia Chen, Mark C. Gebhardt, Holcombe E. Grier Provision of study materials or patients: Christopher J. Fryer, Sarah S. Donaldson, Holcombe E. Grier Collection and assembly of data: Mark D. Krailo, Sarah S. Donaldson, Zhengjia Chen, Fran Laurie, Mark C. Gebhardt, Holcombe E. Grier Data analysis and interpretation: Torunn I. Yock, Mark D. Krailo, Christopher J. Fryer, Sarah S. Donaldson, Zhengjia Chen, Mark L. Bernstein, Fran Laurie, Mark C. Gebhardt, Holcombe E. Grier Manuscript writing: Torunn I. Yock, Mark D. Krailo, Christopher J. Fryer, Sarah S. Donaldson, Zhengjia Chen, Mark L. Bernstein, Mark C. Gebhardt, Holcombe E. Grier, Nancy J. Tarbell Final approval of manuscript: Torunn I. Yock, Mark D. Krailo, Christopher J. Fryer, Sarah S. Donaldson, James S. Miser, Zhengjia Chen, Mark L. Bernstein, Mark C. Gebhardt, Holcombe E. Grier

 

	ACKNOWLEDGMENTS

 
We thank the clinical research assistants, nurses, and doctors who assisted with the research, as well as the patients and their families.

	NOTES

 
Supported by the National Cancer Institute (National Institutes of Health, Bethesda, MD) through its support of Children's Oncology Group (CA 98543), which brought the Pediatric Oncology Group (CA 30969) and the Children's Cancer Group (CA 13539) together to make this trial possible.

Presented in part at the Annual Meeting of the American Society for Therapeutic Radiology and Oncology, Atlanta, GA, October 3-7, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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26. Burdach S, Meyer-Bahlburg A, Laws HJ, et al: High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: Results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 21: 3072-3078, 2003[Abstract/Free Full Text]

27. Shankar AG, Pinkerton CR, Atra A, et al: Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma. United Kingdom Children's Cancer Study Group (UKCCSG). Eur J Cancer 35: 1698-1704, 1999[CrossRef][Medline]

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Submitted January 25, 2006; accepted June 12, 2006.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yock, T. I. Articles by Tarbell, N. J. Search for Related Content PubMed PubMed Citation Articles by Yock, T. I. Articles by Tarbell, N. J.