Journal of Clinical Oncology, Vol 18, Issue 17
(September), 2000: 3108-3114
© 2000 American Society for Clinical Oncology
Prognostic Factors in Ewing’s Tumor of Bone: Analysis of 975 Patients From the European Intergroup Cooperative Ewing’s Sarcoma Study Group
By S.J. Cotterill,
S. Ahrens,
M. Paulussen,
H.F. Jürgens,
P.A. Voûte,
H. Gadner,
A.W. Craft
From the Institute of Child Health, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom; The University of Münster, Münster, Germany; The Emma Kinder Ziekenhuis Academic Medical Center, Amsterdam, the Netherlands; and The St. Anna Children’s Hospital, Vienna, Austria.
Address reprint requests to S.J. Cotterill, MD, Research Associate, Institute of Child Health, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, United Kingdom; email S.J.Cotterill{at}ncl.ac.uk
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ABSTRACT
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PURPOSE: To further elaborate on prognostic factors for Ewing’s sarcoma of bone and to document improvements in relapse-free survival (RFS) and trends in local therapy over the study period (1977 to 1993).
PATIENTS AND METHODS: A retrospective analysis was performed on a combined Gesellschaft Für Pädiatrische Onkologie und Hämatologie/Cooperative Ewing Sarcoma Study and United Kingdom Children’s Cancer Study Group/Medical Research Council data set of 975 patients registered with the respective trial offices before the current collaborative European Intergroup Cooperative Ewing’s Sarcoma Study trial. Both groups independently undertook studies with similar chemotherapy during the period.
RESULTS: The key adverse prognostic factor is metastases at diagnosis (5-year RFS, 22% of patients with metastases at diagnosis v 55% of patients without metastases at diagnosis; P < .0001). For the group with metastases, there was a trend for better survival for those with lung involvement compared with those with bone metastases or a combination of lung and bone metastases (P < .0001). In the group of patients with no metastases at diagnosis, multivariate analysis demonstrated that site (axial v other), age-group (< 15 v  15 years), and period of diagnosis had significant influence on RFS (all P < .005). RFS was superior in the period after 1985 compared with the period before 1985 for nonmetastatic patients (45% v 60%, respectively; P < .0001) and for metastatic patients (16% v 30%, respectively; P = .016). Patients who relapsed within 2 years of diagnosis had a less favorable prognosis than patients who relapsed later (5-year survival after relapse, 4% v 23%, respectively; P < .0001). There were other changes over the period; in particular, radiotherapy or amputation were more common in the period before 1986, whereas endoprosthetic surgery was widely used in the later period.
CONCLUSION: Survival and RFS improved over the period. Prognostic factors are metastases at diagnosis, primary site, and age.
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INTRODUCTION
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EWING’S SARCOMA OF the bone is a rare tumor, and no center or even country, except the United States, can hope to accrue sufficient patients over a reasonable period of time to answer a randomized question. During the late 1970s to the early 1990s patients in the United Kingdom and in Germany were entered onto their respective national protocols. Only nonrandomized studies were undertaken. The protocol in both countries were remarkably similar, as was the philosophy of treatment. In 1990, a decision was taken for the national groups to collaborate with the intention of undertaking randomized studies. The European Intergroup Cooperative Ewing’s Sarcoma Study (EICESS) is the collaborative organization combining the Medical Research Council (MRC)/United Kingdom Children’s Cancer Study Group (UKCCSG) group from the United Kingdom with the Cooperative Ewing Sarcoma Study (CESS) group whose patients were entered from Germany, Austria, and the Netherlands. Since 1992, a joint randomized study, EICESS ’92 has been in progress. The establishment of a common database for the two groups has enabled an analysis to be undertaken of all patients registered since 1977 in the United Kingdom and since 1981 in Germany. A combined analysis has been carried out to determine important prognostic factors that may be used to stratify treatments in future studies.
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PATIENTS AND METHODS
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All 975 patients with Ewing’s sarcoma of the bone registered with either the MRC/UKCCSG or the CESS group before commencement of the EICESS ’92 trial were included in the analysis. In the United Kingdom, patients were entered onto two sequential studies, ET-1 and ET-2; and similarly, the CESS group ran studies, CESS ’81 and ’86. The main features of the protocols and periods of accrual are listed in Table 1. Details of the individual protocols have previously been published.1-4 The data includes both those treated strictly on protocol as well as nonprotocol patients. The nonprotocol patients include those who did not satisfy eligibility criteria for specific studies and patients who were not treated strictly according to protocol (for example, patients for whom the initial intention was to intensify treatment). The aims of including the nonprotocol patients were to afford greater statistical power and to make the sample as representative as possible of the full clinical spectrum of Ewing’s sarcoma of bone.
Tumor volume was only available for the CESS patients because it was not systematically assessed in the United Kingdom. Local therapy in the earlier part of the study period was mainly radiotherapy, but there was an increasing use of either surgery alone or surgery plus radiotherapy. The data was collected in the CESS office in Munster, Germany, and the UKCCSG office in Leicester, United Kingdom. Both data sets were combined and analyzed in Newcastle upon Tyne, United Kingdom. Five-year survival and relapse-free survival (RFS) were calculated using Kaplan-Meier methods5 together with 95% confidence intervals (CI). Group comparisons were made using the log-rank test. RFS was calculated from date of diagnosis to date of first relapse or to death from any cause if there was no relapse. Crude local relapse rates were calculated using Kaplan-Meier estimation from date of diagnosis to date of local relapse (+/- systemic relapse). Multivariate analysis was carried out using Cox’s proportional hazards model.6
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RESULTS
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Nine hundred seventy-five patients, 555 males and 420 females, were registered with the UKCCSG/MRC and CESS groups before the EICESS ’92 trial. Patients were diagnosed between 1978 and 1993 and had a median age of 14 years (range, 8 months to 47 years) (Fig 1). The site of primary tumor is shown in Fig 2. Median follow-up at the time of analysis was 6.6 years (range, 1 to 17 years). Twelve patients (1.2%) died from a treatment-related cause while receiving first-line therapy. The diagnoses were pneumonia (n = 3), sepsis (n = 3), cardiac failure (n = 2), necrotizing enterocolitis caused by clostridium (n = 1), intestinal perforation (n = 1), hemorrhage (n = 1), and cerebral oedema (n = 1). There were 796 patients (81.6%) with no detectable metastases at time of diagnosis and 179 (18.4%) with metastases. Of the 179 patients with metastases, 79 had metastases exclusively in the lungs, 92 in bone with or without lung involvement, eight in other sites, and one with metastatic site unspecified.
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Fig 1. Age distribution of Ewing’s sarcoma patients registered with Gesellschaft für Pädiatrische Onkologie und Hämatologie/CESS and UKCCSG/MRC.
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There was a significant relationship between age and sex, primary site, and tumor volume (Table 2). Compared with patients less than 15 years old, patients aged 15 years at diagnosis had a higher proportion of males (52% v 65%, respectively), a higher proportion of pelvic primaries (21% v 30%, respectively), and greater tumor volume (median, 112 mL v 190 mL, respectively). The proportion of pelvic tumors in males was the same as that in females (25% v 24%, respectively). Pelvic primaries had a higher proportion of metastases at diagnosis compared with other sites combined (25% v 16%, respectively; P < .001, Fisher’s exact test).
Five-year RFS for patients with no detectable metastatic disease at diagnosis was significantly better than for those with metastases (55% v 21%, respectively; P < .0001) (Fig 3). Survival and RFS improved during the period of study. Of those patients who were metastases-free at diagnosis, 282 were entered before 1986 and had a 5-year RFS of 45.6%, whereas the 514 entered after this had a significantly improved RFS of 61.3% (P < .001). The RFS for the 55 patients with metastases diagnosed before 1986 was 15.7%, which improved to 29% for the 123 patients diagnosed after 1986 (P = .02). In univariate analysis restricted to the later period (1986 to 1993), RFS for nonmetastatic patients varied by primary site (axial primaries, 5-year RFS = 50%; 95% CI, 44% to 56% v other primaries, 5-year RFS = 67%; CI, 61% to 73%) and by age group (< 15 years, RFS = 63%; CI, 57% to 69% v 15 years, RFS = 52%; CI, 46% to 59%).
Of those patients free of metastases at diagnosis, the survival varied according to site (Table 3). There was a significant difference in survival between extremity and axial sites (P < .0001) (Fig 4). Tumor volume was available for 454 patients, and survival was better for patients with primary tumors of less than 100 mL (P < .001). The tumor volume varied according to site, and details are listed in Table 4. In particular, pelvic primary tumors were associated with greater tumor volume (median, 309 mL v 107 mL). There was no difference in survival among the 466 patients for whom histologic subtype (Ewing’s sarcoma, atypical Ewing’s sarcoma, or peripheral neuroectodermal tumor) was available (P = .8). In a multivariate analysis of metastasis-free patients, the relative risk (RR) was significantly greater for those with an axial site (RR = 1.38, P < .003), with age 15 years (RR = 1.56, P < .001), and in the study period before 1986 (RR = 1.69, P < .001). Sex (RR = 1.18) and study group, CESS versus MRC/UKCCSG (RR = 1.06), were not significant in this multivariate analysis. Different cutoff points for age were evaluated in univariate analysis of nonmetastatic patients (ages 9 years through 20 years); however, < 15 years versus 15 years was the strongest age predictor of outcome for this combined series (5-year RFS, 58% v 47%, respectively; P < .001).
For the subgroup of patients in whom tumor volume had been recorded (n = 381), a multivariate analysis showed that a tumor size of 100 mL or more was associated with a poorer RFS (P = .001), after taking into account site, age, sex, and study period. Serum lactate dehydrogenase (LDH) was reported for 187 patients, and an elevated level was associated with a worse outcome (P = .03), taking into account site, age, sex, and study period.
Survival according to site of metastases is shown in Fig 5. Patients with exclusively lung metastases had a better prognosis than patients who had bone metastases at diagnosis (with or without lung metastases). Five-year RFS was 29% for those with lung-exclusive metastases, 19% for bone metastases, and 8% for those with combined lung and bone metastases (P < .001). In the period before 1986, none of those patients with bony metastases survived; whereas from the later group, 27% remain alive at time of analysis (5-year survival, 18%; CI, 9% to 25%).
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Fig 5. Survival by site of metastases (figure excludes 1 patient for whom site of metastasis was not specified).
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There was an increasing use of surgery during the study period. The proportion of patients receiving the different modalities of treatment according to site of primary tumor is shown in Fig 6. The local relapse rate for axial-site tumors decreased from 31% to 15% and, for all other sites, the 1 relapse rate decreased from 20% to 4% in those diagnosed before 1986 compared with those diagnosed later.
Survival after first relapse was poor, as shown in Fig 7. There was a significantly worse outcome for those relapsing within 2 years of the original diagnosis (P < .0001). Nine patients have since developed a second malignancy (four acute myelogenous leukemias, two osteosarcomas, one rhabdomyosarcoma, one fibrosarcoma, and one malignant fibroushistiocytoma). Eight of these patients had received radiotherapy as part of their local treatment.
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DISCUSSION
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The formation of the EICESS group has facilitated access to a very large and detailed database of patients with Ewing’s sarcoma treated over the past 20 years. As with many tumor types, the identification of prognostic factors is becoming increasingly important to more effectively tailor the treatment to individual patient characteristics. This retrospective review of almost 1,000 patients with newly diagnosed Ewing’s sarcoma provides an opportunity to analyze prognostic factors with some confidence. It is also important because of its substantial follow-up period, with a median of 6.6 years. Even at 6 years, survival curves in Ewing’s sarcoma have not plateaued, and it is clear from Fig 3 that, in comparison with other pediatric tumors, Ewing’s sarcoma is a late relapsing disease. The United Kingdom and Germany had similar, but not identical, protocols during the study period, but a multivariate analysis showed that outcome was very similar in the two countries, further justifying the combining of the two data sets.
In both groups, there was no evidence of systematic selection bias in terms of patient referral, and it is likely, therefore, that the age (Fig 1) and sex distribution (male:female, 1.3:1) represent Western, largely white populations. Both studies had an upper limit for patient entry of 30 years; therefore, a few older patients may not have been notified (although both groups did register those older than 30 years as nonprotocol patients). The site of primary tumor confirms that 45% occur in the long bones, whereas 55% are in the axial skeleton, which includes pelvis, spine, ribs, clavicle, scapula, and skull. The finding that age was related to sex, primary site, and tumor volume (Table 2) is novel. Compared with younger patients, the older age group had a higher proportion of males (52% v 65%, respectively), a higher proportion of pelvic primaries (21% v 30%, respectively), and greater tumor volume (median, 112 mL v 190 mL, respectively). Although this is not a true population-based study, no reasons for potential selection bias for males or pelvic tumors in the older age group are apparent. It is likely that pelvic tumors are diagnosed later because they can extend into the pelvic cavity and are thus less visibly noticeable than tumors of the extremities. This is consistent with the findings that pelvic primary tumors are associated with greater tumor volume (median, 309 mL v 107 mL) and that patients with pelvic primary tumors, compared with other primary tumors, have a significantly higher proportion of metastases at diagnosis (25% v 16%, respectively).
Although these patients all received intensive chemotherapy as well as surgery and/or radiotherapy, the toxic death rate of 1.2% is remarkably low. Serious infection accounted for half of these deaths.
The key prognostic factor in Ewing’s tumor is the presence of detectable metastases at diagnosis. In particular, those with bony metastases (+/- lung involvement) had a very poor prognosis, although there seem to be modest improvements in outcome over the study period. Before 1986, none of the patients diagnosed with bony metastases survived; whereas, of patients diagnosed with bone metastases after 1986, 27% remain alive at time of analysis.
In a multivariate analysis, site, age group, and study period remained significant once patients with metastases at diagnosis had been excluded. Outcome for patients with no detectable metastases improved significantly; 5-year RFS was 46% for those diagnosed before 1986 and 61% for the subsequent period. The major difference in treatment between the two time periods was the substitution of ifosfamide for cyclophosphamide, which may have been responsible for the improvement, although there were other changes over this time period that may also have contributed, such as improvements in supportive care, centralization of radiotherapy planning for the CESS centers, and moves toward centralization of bone tumor surgery in the United Kingdom. Tumor volume was only available for the CESS patients, but this analysis of a larger sample confirmed their previous reports of a significantly better survival for those with tumors less than 100 mL.7 Data on LDH at diagnosis was available for United Kingdom patients; there was a significantly worse prognosis for those with elevated levels. LDH is correlated with tumor volume.
After 1986, ifosfamide was substituted for cyclophosphamide for all patients in the United Kingdom ET studies but only for patients with tumor volume greater than 100 mL in the CESS group. This retrospective comparison does not prove that ifosfamide is superior to cyclophosphamide but is consistent with the findings of most other recently reported studies.8,9 However, in France,10 they were unable to show any such improvement with ifosfamide given from time of diagnosis. In Bologna, Italy,11 where ifosfamide was given after induction with cyclophosphamide, there was also no benefit seen. The cyclophosphamide given before 1986 was not given in what would now be accepted as maximally tolerable doses. It may well be that given in larger doses, with the benefit of mesna urothelial protection, cyclophosphamide would have been a more effective agent. A randomized trial comparing maximum doses of each drug has not yet been undertaken.
The present study has given an opportunity to look, in a large group of patients, at type of local therapy and subsequent local relapse and outcome. However, it must once again be emphasized that these studies have taken place during an evolutionary phase in the development of bone cancer therapy, and there may be other subtle changes beyond those included in this analysis (eg, changes in timing of local therapy and the influence of preoperative shrinkage on clinical decisions). Recording of local relapse in the presence of systematic relapse may also be a problem, but the systemic relapse rate also decreased with time. There was an increasing use of surgery over the period of study, and this was often combined with radiotherapy for those where excision margins were not tumor-free. This increasing use of surgery seems to be associated with a marked decrease in the local relapse rate. Before 1986, the local relapse rate for nonaxial sites was 24%, and this decreased to 4% in the later period. Even for patients with the high-risk axial sites, the local relapse rate decreased from 31% to 15%. Figure 7 indicates that surgery alone or a combination of surgery and radiotherapy seem to be superior to radiotherapy alone. However, caution must be used in the interpretation of these findings. The type of local therapy is very dependent on other patient factors, which in themselves have a significant effect on outcome. The use of surgery is related to tumor site and size, and, certainly in the earlier part of the study period, surgery was confined to smaller tumors. Outside of a randomized controlled trial, it will never be possible to determine which modality of local therapy is optimal. However, it can be concluded from the present study that the local relapse rate has decreased dramatically for all sites over the period of study and that this has been associated with an increased use of surgery.
Once patients have relapsed, the outcome is poor (Fig 7), particularly for those relapsing within 2 years of diagnosis who almost invariably die of their disease. The site of relapse had no significant effect on outcome. Second-line treatment for relapsed patients using intensified regimens with stem-cell rescue are under evaluation.12
In this series of almost 1,000 patients there have been nine reports of second malignancies. These are mainly other sarcomas that have arisen in the radiation field or acute leukemia. It is likely that the sarcomas were radiation-induced, and it is possible that the alkylating agents cyclophosphamide or ifosfamide were also etiologic agents in the genesis of the leukemias. The second primary tumor has been described as the "Sword of Damocles," which hangs over all patients who have been fortunate enough to survive cancer. The relatively low incidence of primary tumors so far in the present series gives some comfort, but it is likely that more such malignancies will occur in these patients in the future. Further systematic studies of the incidence of second malignancies in relation to radiation dose and specific chemotherapy agents are required for Ewing’s sarcoma. The incidence is lower in this series than that reported in the studies from the Intergroup Ewing’s Sarcoma Study.13
The prognosis for Ewing’s sarcoma of bone has undoubtedly improved. It is now possible to identify patients at the time of diagnosis who are at high risk of a poor outcome. Future treatment protocols will be able to target such patients with more intensive and perhaps novel types of therapy, whereas for patients with standard or average risk, treatment can be modified to reduce the late effects of treatment. As treatments become more stratified according to patient characteristics, there is an increased need for international collaboration to answer randomized questions for rare tumor types.
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ACKNOWLEDGMENTS
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We thank all patients and clinicians who contributed to the CESS and UKCCSG/MRC studies.
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NOTES
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S.J.C. was supported by the North of England Children’s Cancer Research Fund.
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Submitted March 29, 1999;
accepted April 30, 2000.
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TOP
ABSTRACT
INTRODUCTION
