Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma

doi:10.1016/S0959-8049(99)00144-6

European Journal of Cancer

Volume 35, Issue 12, November 1999, Pages 1698-1704

https://doi.org/10.1016/S0959-8049(99)00144-6 Get rights and content

Abstract

Relapse patterns have been documented in 191 children with localised Ewing's sarcoma treated with the United Kingdom Children's Cancer Group (UKCCSG) Ewing's Tumour regimen ET2. All received chemotherapy comprising ifosfamide, vincristine, doxorubicin and actinomycin D. Local treatment modality was excision and or radiotherapy depending on tumour site and response to primary chemotherapy. Although not strictly comparable, due to the clinical indications used for each modality, local relapse rates were very low and were similar, irrespective of the type of local treatment modality: radiotherapy (3/56), surgery (7/114) or a combination (0/20). Combined relapse (local + distant) rates were similarly low irrespective of the type of local therapy: radiotherapy (4/56), surgery (4/114) or a combination (0/20). Overall survival was lower in females (P=<0.04), older children (P=<0.002) and those with primaries at sites other than long bones (P=<0.02). It is concluded that with effective intensive chemotherapy combined with either radiotherapy or surgery, local control in this study was excellent at sites other than the pelvis. Preventing distant relapse, predominantly to lung and bone, remains the major challenge.

Introduction

Aggressive multi-agent combination chemotherapy combined with adequate local treatment, surgery and or radiotherapy, has dramatically improved survival in patients with localised Ewing's sarcoma 1, 2. For many years radiation treatment has been the local treatment of choice especially for inoperable bulky pelvic and spinal tumours. Its role is less clear in the light of advances in orthopaedic surgery and with the use of effective multi-agent chemotherapy. There are conflicting reports in the literature regarding the effectiveness of irradiation in local disease control 3, 4, 5, 6, 7, 8. Another important consideration is the risk of second malignancies within the radiation field for patients with Ewing's sarcoma, 9, 10 although with lower doses and less extensive irradiation fields the incidence is likely to be lower than reported in the past [11].

Surgery is increasingly the preferred modality of local treatment in Ewing's sarcoma with many reports in the literature suggesting improved local control and survival 12, 13, 14. It must be recognised, however, that those patients undergoing surgical resection tend to have smaller tumours and/or have shown a good response to chemotherapy, both factors which could account for the favourable outcome.

In this study, we examined the impact of local treatment modality on local control, overall relapse pattern and survival in an unselected, national series of patients with localised Ewing's sarcoma treated on a standardised ifosfamide-based chemotherapy protocol combined with surgery and/or radiotherapy.

Section snippets

Patients and methods

From January 1987 to November 1993, 201 patients with localised Ewing's sarcoma of the bone were registered on the Ewing's Tumour Study-2 (ET-2) of the United Kingdom's Children's Cancer Study Group (UKCCSG). 10 patients were excluded due to major protocol violations (n=7) or due to insufficient clinical details (n=3). Hence 191 patients were available for analysis. For this analysis the median follow-up period was 5.5 years (range 2 months–10 years). Of the 139 living patients, 114 had been

Results

Patients characteristics for the entire group are listed in Table 2.

Discussion

This study has evaluated a number of factors which could contribute to local control in patients with Ewing's tumour. Tumour bulk rather than site (although these are often related) was not documented consistently in this trial. Similarly, histological response to preoperative chemotherapy, which has been shown to correlate with event-free survival, was not available for inclusion in the analysis.

These results show that using a four-drug ifosfamide-based chemotherapy regimen and applying a

Acknowledgements

On behalf of the joint UKCCSG and MRC Bone Tumour Working Party. The UKCCSG and CRP are supported by the Cancer Research Campaign. We would like to thank all clinicians and patients who participated in the study. We also thank Ms Jane Neil for her secretarial support.

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Citation Excerpt :
Choice of modality for local control of pelvic ES tumors has not been associated with a significant effect on rates of local progression.5,13 The United Kingdom Children’s Cancer Study Group found that rates of local relapse were both low and similar regardless of local treatment modality.14 In contrast, a later COG study of localized ES of bone concluded that risk of local failure was higher with radiation alone compared to surgery.10
Ewing sarcoma, a malignancy originating from the bone or soft tissues most commonly diagnosed in adolescents, requires multimodality therapy. Although both surgical resection and radiation therapy are effective local control modalities, there are limited data comparing outcomes in patients treated with surgery versus radiation. We sought to determine whether there were differences in 5-year local failure-free survival, event-free survival, and overall survival based on the modality used for local control.
Patients treated for Ewing sarcoma at a single tertiary pediatric hospital between 2010 and 2020 were included for retrospective analysis. Patient and tumor demographics, treatment information, and patient response to therapies were collected from the medical record. Outcome measures were local failure-free survival, event-free survival, and overall survival at 5 years from diagnosis.
Sixty-one patients met inclusion criteria. All patients received chemotherapy, and 68.9% of patients presented with localized disease. Of these, 23.8% were treated with radiation alone; the remaining 76.2% underwent resection ± radiation. A total of 52.4% of patients with localized disease achieved R0 resection. Only 3 patients experienced local progression; there was no difference between treatment groups. There was no significant association between local control modality and event-free survival or overall survival in patients with localized disease, regardless of margin status.
There was no significant difference in 5-year local failure-free survival, event-free survival, or overall survival in Ewing sarcoma patients treated with radiation versus surgery ± radiation, regardless of whether or not R0 resection was achieved. Future directions include a multi-institutional study to allow for further subgroup analysis and increased sample size.
A nomogram to predict prognosis in Ewing sarcoma of bone
2019, Journal of Bone Oncology
Citation Excerpt :
Treatment in relation with survival was evaluated by several studies which showed discordant results. Radiation therapy has been controversial, because current knowledge is based on conflicting results from observational studies [31,32,33]. Lee et al. [7] specifically demonstrated that patients who accept radiotherapy have a better OS compared to who don't accept.
This study was designed to develop a nomogram for assessing the survival of patients with Ewing sarcoma (ES).
Data from patients diagnosed with ES between 2004 and 2013 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Based on patient registration, the primary cohort was divided into a training set (n = 479, data from 17 cancer registries) and a validation set (n = 137, data from 1 cancer registry). Then, the prognostic effects of variables were analyzed using Kaplan–Meier method and Cox proportional hazard model. Moreover, nomograms were established for estimating 3- and 5-year overall survival (OS) and cancer-special survival (CSS) based on Cox regression model. Last, nomogram was validated by training set and validation set.
According to the multivariate analysis of training set, nomogram which combined age, race, stage, tumor site, tumor size and chemotherapy was identified. The internal bootstrap resampling approach suggested the nomogram had sufficient discriminatory power with the C-index of OS: 0.754 (95% CI, 0.705–0.802) and CSS: 0.759 (95% CI, 0.700–0.800). The calibration plots also demonstrated good consistence between the prediction and the observation.
Our nomogram is a reliable and powerful tool for distinguishing and predicting the survival of ES patients, thus helping to better select medical examinations and optimize treatment options in collaboration with medical oncologists and surgeons.
Pediatric Ewing sarcoma of the head and neck: A retrospective survival analysis
2019, International Journal of Pediatric Otorhinolaryngology
To determine the demographics, treatment modalities, and overall survival of pediatric Ewing sarcoma of the head and neck.
The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify cases of pediatric Ewing sarcoma of the head and neck between 1973 and 2015. Additional variables collected included age, gender, ethnicity, tumor grade, staging, treatment modality, and follow-up time. Kaplan-Meier survival curves were generated and overall survival was calculated.
One hundred and twenty-seven cases of pediatric Ewing sarcoma were identified. The majority of patients were male (52.8%), white (88.2%), and non-Hispanic (75.6%), and the mean age at diagnosis was 10.5 years. The most common tumor sites were bones and joints of the skull and face (45.5%), followed by soft tissue of the head, face, and neck (25.2%), followed by the mandible (13.4%). Most patients (69.2%) had some type of surgery, 70.0% received radiation, and 92.1% received chemotherapy as part of their treatment. Overall 1-, 5-, and 10-year survival was 91.1%, 72.9%, and 68.2%, respectively. There was no significant difference in survival based on patient gender, age, tumor location, radiation, or chemotherapy treatment.
This study demonstrates that pediatric patients with Ewing sarcoma of the head and neck most commonly have stage II disease, no distant metastasis, and are treated with chemotherapy, with or without radiation. One, five, and ten-year survival are 91.1%, 72.9%, and 68.2%, respectively, and age, gender, and radiation do not seem to affect prognosis.
Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group
2017, International Journal of Radiation Oncology Biology Physics
To identify clinical and treatment variables associated with a higher risk of local failure in Ewing sarcoma patients treated on recent Children's Oncology Group protocols.
Data for 956 patients treated with ifosfamide and etoposide–based chemotherapy on INT-0091, INT-0154, and AEWS0031 were analyzed. Local treatment modalities were defined as surgery, definitive radiation therapy (RT), or surgery plus radiation (S+RT). Five-year cumulative incidence of local failure was determined.
The local failure rate for the entire cohort was 7.3%, with a 3.9% rate for surgery, 15.3% for RT (P<.01), and 6.6% for S+RT (P=.12). The local failure incidence was 5.4% for extremity tumors, 13.2% for pelvis tumors (P<.01), 5.3% for axial non-spine tumors (P=.90), 9.1% for extraskeletal tumors (P=.08), and 3.6% for spine tumors (P=.49). The incidence of local failure was 14.8% for extremity tumors and 22.4% for pelvis tumors treated with RT, compared with 3.7% for extremity tumors and 3.9% for pelvis tumors treated with surgery (P≤.01). There was no difference in local failure incidence by local treatment modality for axial non-spine, spine, and extraskeletal tumors. The local failure incidence was 11.9% in patients aged ≥18 years versus 6.7% in patients aged <18 years (P=.02). Age ≥18 years (hazard ratio 1.9, P=.04) and treatment with RT (hazard ratio 2.40, P<.01) remained independent prognostic factors for higher local failure incidence on multivariate analysis. Tumor size (</≥ 8 cm) was available in 40% of patients and did not correlate with local failure incidence.
Local tumor control is excellent and similar between surgery and RT for axial non-spine, spine, and extraskeletal tumors. Age ≥18 years and use of RT, primarily for pelvis and extremity tumors, are associated with the highest risk of local failure. Further efforts should focus on improving outcomes for these patients.
Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E.W.I.N.G group
2016, European Journal of Cancer
The role of postoperative radiotherapy (PORT) in Ewing sarcoma (ES) is unclear. We assessed the impact of PORT on local control in patients with localised ES and good histological response to chemotherapy (<10% cells).
All randomised patients in the EE99-R1 trial (comparing two consolidation chemotherapy regimens) undergoing surgery after induction chemotherapy were included. Local relapse (LR) cumulative incidence was estimated using a competing risk approach. Impact of PORT was assessed in multivariable models, adjusted for country, age, tumour site and volume, quality of resection and histological response. We also evaluated the heterogeneity of PORT effect by patient and tumour characteristics.
One hundred forty-two (24%) of the 599 patients included from 1999 to 2009 received PORT (median dose: 45 Grays). With median follow-up of 6.2 years, 67 patients had an LR (with concomitant metastases in 28), leading to an 8-year LR-incidence = 11.9% (standard error [se] = 1.4%). Overall survival (OS) = 21% (se = 5%) 3 years after LR (31% in isolated LR). Controlling for possible confounders, we observed a statistically significant reduction of LR in patients treated by surgery + PORT compared to surgery alone (subdistribution-hazard ratio = 0.43, 95% confidence interval, 0.21–0.88, p = 0.02). The benefit of PORT was particularly marked for tumours larger than 200 ml at diagnosis and 100% necrosis. We observed a non-significant trend for benefit associated with PORT for disease-free, event-free and OS.
Radiotherapy appears to improve local control. We now recommend PORT in case of incomplete removal of the tissues involved by the pre-chemotherapy tumour volume. Further studies are required to assess the balance between benefit and risks.
Evidence-based guideline recommendations on treatment strategies for localized Ewing's sarcoma of bone following neo-adjuvant chemotherapy
2016, Surgical Oncology
(1) To provide recommendations regarding the choice of surgery, radiation therapy (RT), or the combination of surgery plus RT in patients with localized Ewing's sarcoma of bone following neoadjuvant chemotherapy. (2) To determine the appropriate surgical planning imaging (pre-chemotherapy magnetic resonance imaging [MRI] or post-chemotherapy MRI) to identify optimal resection margins in patients with localized Ewing's sarcoma who undergo surgery following neoadjuvant chemotherapy.
MEDLINE, EMBASE, the Cochrane Library (1999 to February 2015), main guideline websites, and relevant annual meeting abstracts (2012 to January 2015) were searched. Internal and external reviews were conducted.
1. Recommendation (1) – In patients with localized Ewing's sarcoma of bone following neoadjuvant chemotherapy: (a) Surgery alone or RT alone are two reasonable treatment options; the combination of surgery plus RT is not recommended as an initial treatment option. (b) The local treatment for an individual patient should be decided by a multidisciplinary tumour board together with the patient after consideration of the following: (1) patient characteristics (e.g., age, tumour location, tumour size, response to neoadjuvant chemotherapy, and existing comorbidities), (2) the potential benefit weighed against the potential complications from surgery and/or toxicities associated with RT, and (3) patient preferences. 2. Recommendation (2) – In patients with localized Ewing's sarcoma who will undergo surgery: (a) Both pre-chemotherapy and post-chemotherapy MRI scans should be taken into consideration for surgical planning. In certain anatomic locations with good chemotherapy response, the post-chemotherapy MRI may be the appropriate imaging modality to plan surgical resection margins.

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Original PaperLocal therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma

Abstract

Introduction

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Eur. J. Cancer. Clin. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Eur. J. Cancer

Lancet.

Late follow-up of a short term intensive regimen for Ewing's sarcoma

Am. J. Clin. Oncol.

Multimodal therapy for management of non-pelvic localised Ewing's sarcoma of boneintergroup study IESS-II

J. Clin. Oncol.

Local control of Ewing's sarcomaan analysis of 67 patients

Br. J. Radiat.

Treatment of femoral Ewing's sarcoma

Cancer

Multimodal therapy for the management of localised Ewing's sarcoma of pelvic and sacral bonesa report from the second intergroup study

J. Clin. Oncol.

Local treatment of Ewing's sarcomaRadiation therapy versus surgery

Cancer. Treat. Rep.

Bone sarcomas linked to radiotherapy and chemotherapy in children

N. Engl. J. Med.

Long term outcome of patients with mono-ostotic Ewing's sarcoma treated with combined modality

Med. Ped. Oncol.

Risk of radiation related subsequent malignant tumours in survivors of Ewing's sarcoma

J. Natl. Cancer Inst.

Long term results in 14.4 localised Ewing's sarcoma patients treated with combined therapy

Cancer

Significance of surgical margin on the prognosis of patients with Ewing's sarcoma

Cancer

Ewing's sarcoma of boneexperience with 140 patients

Cancer

Ifosfamide containing chemotherapy in Ewing's sarcomaThe second United Kingdom Children's Cancer Study Group and Medical Research Council Ewing's Tumour Study (ET-2)

J. Clin. Oncol.

Non-parametric estimation from incomplete observation

J. Am. Stat. Assoc.

Original Paper
Local therapy and other factors influencing site of relapse in patients with localised Ewing's sarcoma