Annals of Oncology Advance Access originally published online on November 12, 2007
Annals of Oncology 2008 19(4):814-820; doi:10.1093/annonc/mdm521
pediatric malignancies |
Prognostic factors for local and distant control in Ewing sarcoma family of tumors
1 Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA
2 Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA
3 Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, TN, USA
4 Department of Surgery, St Jude Children's Research Hospital, Memphis, TN, USA
* Correspondence to: Dr C. Rodríguez-Galindo, Department of Oncology, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA. Tel: +1-901-495-2203; Fax: +1-901-521-9005; E-mail: carlos.rodriguez-galindo{at}stjude.org
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Abstract |
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Background: Advances in the treatment of Ewing sarcoma family of tumors (ESFT) are the result of improvements in systemic and local therapies. The individual contributions of each treatment component cannot be analyzed separately; improvements in local and systemic control can influence each other.
Patients and methods: We reviewed the records of 220 patients treated on institutional protocols from 1979 to 2004. Factors predictive of local and distant recurrence were analyzed.
Results: The median age at diagnosis was 13.7 years. Ninety-five patients relapsed at a median of 1.6 years. The 5-year overall survival estimate was 63.5% ± 3.5%. The estimated 5-year cumulative incidence (CI) of local failure was 25.1% ± 3.0%. Local failure was associated with treatment era (P < 0.001), tumor size (P = 0.037) and type of local control (P = 0.021). Systemic treatment intensification improved local control. The estimated 5-year CI of distant recurrence was 22.5% ± 2.9%. Patients with localized disease (P < 0.001), smaller tumors (P = 0.018) and those who received surgery ± radiation for local control (P = 0.023) had lower CI of distant failure.
Conclusions: Successful treatment of ESFT requires optimal systemic and local therapy. Both treatment modalities are intertwined and the control of both local and distant disease is the result of the combined approach.
Key words: distant recurrence, Ewing sarcoma, local recurrence, pediatric cancer
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingReferences |
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The term Ewing sarcoma family of tumors (ESFT) defines a group of small round cell neoplasms of neuroectodermal origin that manifests as a continuum of neurogenic differentiation. ESFT comprise 3% of all pediatric malignancies, and represent the second most common malignant bone tumor in children and adolescents, with an estimated incidence in white children <15 years of age of 2.8 per 1 million [1].
The last three decades have witnessed a major improvement in the outcome of patients with ESFT. These advances in the treatment of ESFT have derived largely from cooperative trials and the progress made in the multidisciplinary approach. American and European studies have complemented each other in defining the active agents and their best schedules and combinations; new agents have been incorporated progressively into the treatment armamentarium, and improvements in support measures have allowed for treatment intensification. With most modern treatment regimens, the disease-free survival for patients with localized disease may approach 70%, while the overall survival (OS) may be >80% [2–4].
These advances, however, are also the result of improvements in local control, with better radiation therapy (RT) planning and more aggressive surgical approaches [4]. The optimization of local and systemic therapies for ESFT cannot be analyzed separately as both components are intrinsically intertwined; improvements in local and systemic control may impact each other. We have carried out a comprehensive analysis of the St Jude studies that represent the improvements made over the recent treatment eras and have evaluated the impact made by the different systemic and local control measures on outcome.
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patients and methods |
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patients and treatment
Two hundred and twenty-two ESFT patients treated on five consecutive studies at St Jude Children's Research Hospital from February 1979 to January 2004 were identified. Two patients with diagnosis of undifferentiated neuroectodermal tumor and desmoplastic small round cell tumor were excluded from the analysis; the remainder of the patients had histological confirmation of ESFT. Thus, a total of 220 patients were included in the study. This retrospective study was approved by the Institutional Review Board.
From 1979 to 1986, patients with ESFT were treated on the ES79 protocol, which used vincristine, dactinomycin, cyclophosphamide and doxorubicin; in this protocol, cyclophosphamide was administered on a fractionated schedule (150 mg/m2/day for seven consecutive days) [5]. The ES87 protocol (1987–1991) included ifosfamide and etoposide as a pretreatment window, and added this combination to the continuation phase after local control, alternating with vincristine, fractionated cyclophosphamide and doxorubicin [6]. The EWI92 protocol (1992–1996) evaluated the feasibility of an aggressive early induction with vincristine, cyclophosphamide, doxorubicin, ifosfamide and etoposide, followed by a prolonged maintenance therapy with intensification of alkylating agents and etoposide [2]. Following completion of the EWI92 protocol, patients with localized ESFT were treated on the cooperative POG9354/CCG7942 study [7] until its closure in September 1998; the patients enrolled on that study have not been included in this analysis. After September 1998, patients continued to be treated following similar guidelines to the standard arm of the cooperative study [St Jude best clinical management(SJBCM)], with alternating courses of vincristine, cyclophosphamide and doxorubicin, with ifosfamide and etoposide. Contemporary to these studies were the High Risk Sarcoma Protocol (HIRISA) 1 and 2 protocols (1996–2000), which explored the role of high-dose, short-term intensification regimens and consolidation with myeloablative chemotherapy and autologous hematopoietic stem-cell rescue for patients with high-risk disease (tumors >8 cm, pelvic primaries or metastatic disease). Patients on the HIRISA studies received six courses of vincristine, cyclophosphamide, ifosfamide, etoposide and doxorubicin [8].
Local control varied with the protocol. In ES79 and ES87, patients with completely resected tumors received no RT. In ES 79, 30–35 Gy RT was given for unresected lesions with no computed tomography evidence of gross residual soft tissue tumor, masses biopsy-proven not to contain active tumor, or microscopic residual after surgery. Patients with gross residual soft tissue or evidence of active tumor received 50–55 Gy. In ES87, patients with unresectable small tumors (<8 cm) or microscopic residual after surgery received 35 Gy; patients with unresectable large tumors received 60 Gy. In the EW92 study, the RT dose was determined by tumor location (soft tissue or bone), size (
or <8 cm), response to chemotherapy and extent of resection. Completely resected tumors received either no RT (bone) or 36 Gy (soft tissue). Patients with microscopic residual tumor after surgery received either 36 Gy [after at least a partial response (defined as a >50% reduction in the maximum diameter of all measurable lesions) to chemotherapy] or 60 Gy, hyperfractionated (after a lesser response). Unresectable tumors received either 68.4 Gy, hyperfractionated, or 55.8 Gy (<8 cm and at least a partial response). SJBCM called for 55.8 Gy for unresectable or gross residual and 45 Gy for microscopic residual or inadequate margins. The primary and metastatic sites received 36–68 Gy in the HIRISA trials.
statistical methods
OS was defined as the time interval from the date of diagnosis to the date of death from any cause or to last follow-up date. Event-free survival (EFS) was defined as the time interval from the date of diagnosis to the date of disease progression, recurrence, second malignancy or death from any cause, whichever occurred first, or to date of last follow-up for patients without events. OS and EFS distributions were estimated using the method of Kaplan–Meier.
Local failure was defined as the time interval from the date of diagnosis to the date of local or regional recurrence or progression. Distant failure was defined as the time interval from date of diagnosis to date of distant disease recurrence or progression. Patients with both local and distant recurrence were included as having local recurrence for the analysis of local control and as having distant failure for the analysis of distant disease control. Competing events for local failure included second malignancy, distant failure or death; competing events for distant failure included second malignancy, local failure or death. One patient in the cohort experienced secondary acute myeloid leukemia (AML) 
2 months before locoregional recurrence of primary disease. The locoregional recurrence was used as the event of interest for this patient.
The cumulative incidences (CIs) of local and distant failure were estimated by the methods of Kalbfleisch and Prentice [9]. Gray's test was used to compare CI among groups [10].
Associations among factors were examined using Fisher's exact tests, chi-square tests, Wilcoxon rank sum tests or Kruskal–Wallis tests on the basis of whether the data were continuous or categorical. When an expected count was <5, exact methods were used. No adjustments for multiple comparisons were made in this exploratory study. Statistical analyses were carried out using SAS (version 9.1) and StatXact (version 5) software.
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results |
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patient characteristics and treatment
Patient and disease characteristics are shown in Table 1. Histologic responses were only available in 24% of patients (n = 52) and were thus too limited to use for any analyses. There was evidence of a significant difference in the distribution of type of local control modality across treatment protocols (P = 0.006, Table 2). For ES79, ES87 and EWI92, radiation alone was used in at least half of the patients, whereas it was used in only one-third of the patients treated on the HIRISA and SJBCM studies. The use of surgery and combined surgery and RT appeared to increase with time, and up to two-thirds of patients treated on the most recent regimen (SJBCM) received surgery or a combined approach. The primary site at diagnosis correlated with stage. More patients with axial sites had metastases at diagnosis compared with those with extremity tumors (35% versus 19%, respectively, P = 0.014). Also, less patients with nonpelvic sites had metastasis at diagnosis compared to those with pelvic tumors (25% versus 45%, respectively, P = 0.008). Larger tumors (
8 cm) were associated with metastatic disease (P = 0.002) and marginally associated with older age at diagnosis (P = 0.071). There was no correlation between age and site (P = 0.61) or stage (P = 0.82).
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follow-up and outcome
One hundred and twenty-three (56%) of 220 patients survive with a median follow-up from diagnosis of 11.7 years (range 3.6 months to 25.5 years). Ninety-five patients relapsed or had progressive disease at a median time of 1.6 years (range 50 days to 11.9 years). Of these, failure sites were distant in 37 (39%), local/regional in 41 (43%) or combined in 17 (18%). Nine patients developed second malignancies, including one patient who developed secondary AML
2 months before recurrence of primary disease. Two patients died due to treatment-related toxicity and six other patients died due to unrelated causes. Five- and 10-year estimates of OS were 63.5% ± 3.5% and 56.0% ± 4.1%, respectively. Five- and 10-year estimates of EFS were 55.1% ± 3.6% and 50.3% ± 4.3%, respectively. There was no evidence of a difference in OS or EFS according to the protocol treatment.
prognostic factors for local control
Among all 220 patients, 95 experienced relapse or disease progression. Of these, 41 were local or regional, 37 were distant and 17 were combined local and distant failures. The estimated 5-year (10-year) CI of local failure was 25.1% ± 3.0% (26.8% ± 3.1%). Table 3 summarizes results of analyses investigating potential prognostic factors for local control. Because of the similarity in local control measures between ES79 and ES87, these two studies were compared against the most recent ones, where local control measures were more aggressive. The CI of local failure was associated with protocol treatment, treatment era (ES79 and ES87 versus others), tumor size and type of local control. Pelvic primaries were not associated with an increased CI of local failure when the entire group was considered (P = 0.91). When the group of 156 patients with localized disease was, however, analyzed separately, patients with pelvic tumors had a higher CI of local failure than patients with nonpelvic primaries, although this was not significant at the traditional 0.05 significance level (5-year CI 37.0 ± 9.5 versus 23.3 ± 3.8, respectively, P = 0.095). Finally, the type of local control impacted local failure (P = 0.021): combined treatment with surgery plus radiation showed better results than surgery alone, and surgery alone was better than radiation alone. For patients treated with definitive radiation, the CI of local failure was, however, a function of the radiation dose and tumor size (Table 3). In addition, among patients with localized disease, younger age was associated with lower CI of local failure than older patients (5-year CI estimates for 14 and <14 years were 32.4% ± 5.5% and 19.4% ± 4.5%, respectively, P = 0.075). In a multiple regression model with age at diagnosis, gender, treatment era, tumor size and local control modality, treatment era, tumor size and local control modality remained significant predictors of local failure.
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We also investigated the impact of systemic therapy, in particular the addition of ifosfamide and etoposide, on local control. To this aim, we analyzed the CI of isolated local failure in patients with localized disease that received RT only, with doses >40 Gy, and we compared the patients treated on the ES79 protocol with the other studies. Patients treated after the introduction of ifosfamide and etoposide had a lower incidence of local recurrence than patients treated on the earlier protocols. The 5-year CI of isolated local failure for patients treated with definitive RT with doses
40 Gy on the ES79 protocol was 63.6 ± 15.8, compared with 23.6 ± 8.7 in the later studies (P = 0.007) (Figure 1).
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prognostic factors for distant control
We also investigated potential prognostic factors of distant failure (Table 4). The estimated 5-year (10-year) CI of distant recurrence was 22.5% ± 2.9% (24.2% ± 3.0%). Patients with localized disease (P < 0.001), smaller tumor size (P = 0.018) and those who received surgery with or without radiation for local control (P = 0.023) had lower CI of distant failure. Also, there was a tendency for a higher CI of distant failure among patients with pelvic tumors (P = 0.081). Since pelvic primaries were associated with the presence of metastatic disease at diagnosis, we analyzed the CI of isolated distant recurrence in the group of 156 patients with localized disease at diagnosis. There was no evidence of a significant difference in the CI of distant failure between patients with pelvic (estimated CI 15.1% ± 7.2%) and nonpelvic primary tumors (estimated CI 11.4% ± 2.9%) (P = 0.71). The use of whole-lung irradiation did not appear to improve outcome for the group of patients with isolated or combined lung metastases at diagnosis. In a multiple regression model with gender, stage of disease, primary site (pelvic versus other sites), tumor size and local control modality, stage, size and local control modality remained significant predictors of distant failure after adjusting for the other factors.
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To investigate the impact of local control measures in systemic control of the disease, we compared the CI of isolated distant failure according to the local control approach. The 5-year CI of isolated distant failure was 24.4% ± 4.2% for patients treated with definitive radiation, 7.8% ± 3.8% for patients treated with combined surgery and radiation and 8.1% ± 4.6% for patients treated with surgery only (P = 0.060) (Figure 2). Given the possible bias of less radical surgery for patients with metastatic disease, we then analyzed the CI of isolated distant recurrence according to the local treatment used only for patients with localized disease. There were no significant differences in the 5-year CI estimates of isolated distant failure according to the type of local control for patients with localized disease, although patients receiving definitive radiation still fared worse than patients receiving surgery or surgery plus radiation (5-year CI 10.1% ± 3.7% versus 3.5% ± 3.5% versus 0.0% ± 0.0%, respectively, P = 0.33).
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discussion |
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We have analyzed factors that influence local and distant control in a large series of patients with ESFT treated at St Jude Children's Research Hospital over the last two decades. These five consecutive institutional studies recapitulate the incremental advances made internationally in the management of ESFT [11–14]. Treatments built on the efficacy of the four-drug regimen used in ES79 [5] by first adding the ifosfamide–etoposide (IE) combination (EW87) [6] and then intensifying therapy, adding granulocyte colony-stimulating factor, and improving support measures (EWI92, SJBCM and HIRISA) [2, 15]. As systemic approaches evolved, so did local control. The proportion of patients who received definitive radiation for local control decreased progressively, and now most patients receive surgery or surgery plus radiation. The impact made by improvements in local control appears to be greater than advances in systemic therapy. In a separate analysis, we have evaluated the improvements in overall outcomes for patients with ESFT over the years, and the impact made by increasing chemotherapy intensity is moderate [16].
In our series, local or combined local and distant failures accounted for approximately two-thirds of all recurrences. The importance of achieving good local control cannot be overemphasized; outcome after local failure is very poor [17]. The 5-year CI of local failure was 25.1% ± 3.0%; older patients, patients with larger tumors and patients with pelvic primaries had higher CIs of local failure. Local control, however, was also significantly influenced by treatment variables. First, and more importantly, the type of local control influenced outcome; combined treatment with surgery and RT resulted in lower CI of local failure than surgery alone, and surgery alone resulted in lower CI of local failure than radiation alone. Available data indicate a superior outcome with wide local surgical excision, although bias exists in selecting smaller, more peripheral tumors for definitive surgical resection. With careful selection for surgical therapy, local failure rates are <10% [14, 18, 19]. When surgery is used, the effect of tumor size on local failure is less clear. The combined Cooperative Ewing’s Sarcoma Studies (CESS) and European Intergroup Cooperative Ewing’s Sarcoma Studies did not demonstrate a difference in local failure when surgery was used for tumors <100 versus 100 cm3 (6.1% versus 5.6%, respectively) [18]. Similarly, in a previous analysis carried out at our institution, patients undergoing wide local excision had no difference in local failure on the basis of tumor size <8 or 8 cm (16.7% versus 13.3%), respectively [20]. Postoperative and, more recently, preoperative irradiation have been applied to patients with marginally resected or poorly responding tumors. Despite the selection bias of unfavorable patients treated with combined local therapy, our data and the available literature indicate that there is an equivalent local control compared with surgery alone [18, 21].
The ES79 and ES87 studies added information on the use of low-dose adjuvant RT [22, 23]. Selection of low-dose irradiation has usually been on the basis of young age or favorable tumor characteristics such as small primary size and good response to chemotherapy. Although some centers have reported low local failure rates, low radiation doses are associated with suboptimal local control [18, 22, 24]. As shown by our data, local failure rates for patients managed with RT are consistently higher than those in patients undergoing surgery, with recurrence rates of 30% [14, 18, 19]. Local outcomes for our patients were positively influenced by age <14, tumor size <8 cm and radiation dose 40 Gy. The improvements on the quality of radiation planning and delivery over the years, however, must be considered. Three cooperative group studies have demonstrated the importance of quality RT (CESS 81 and 86 and POG 8346). Central treatment plan review was instituted in CESS 86 following a local failure rate of 50% in CESS 81 for patients undergoing definitive irradiation; subsequent patients treated with definitive RT on CESS 86 had a local failure rate of only 13% [22]. Patients undergoing definitive radiation on POG 8346 had an 84% incidence of local failure if a major deviation in dose or volume of treatment was noted. Even patients with a minor deviation experienced a 52% local failure rate compared with 20% for those with no deviation (P = 0.005) [14]. It is therefore very important to analyze the high historical incidence of local failure rates in patients treated with definitive radiation in the context of evolving and improving techniques.
An important concept confirmed in our analysis is that systemic therapy also influences local control. In patients who received treatment with definitive radiation with doses 40 Gy, the incorporation of ifosfamide and etoposide resulted in better local control rates. It is certainly possible that the improved radiation planning and delivery of the later studies is a confounding factor. Other studies, however, support the notion that systemic therapy impacts local control. In the randomized POG/CCG INT-0091 study, the benefit of more intensive chemotherapy was not only limited to its systemic effects but also to its effect on local control. Using the same local control guidelines, patients treated on the vincristine, actinomycin D, cyclophosphamide and doxorubicin (VACD)/IE arm had less local failures than patients on the VACD arm (7% versus 20%) [25].
The 5-year CI of distant failure in our series was 22.5% ± 2.9%. Distant failure was associated with the presence of metastatic disease at diagnosis, which remains the most important prognostic factor [26]. There is, however, some heterogeneity in patients with metastases. With an appropriately intensive treatment, patients with isolated lung metastases may have a better prognosis, albeit still worse than patients with localized disease, while patients with extrapulmonary metastases have a worse prognosis [27]. In our series, the use of whole-lung radiation did not appear to improve outcome for the group of patients with isolated or combined lung metastases at diagnosis. There was, however, likely an imbalance in the patients selected for lung radiation since in the early studies only patients with persistent lung disease after chemotherapy were irradiated [28]. In our series, distant failures were also associated with large primaries; tumor cell burden probably correlates with micrometastatic disease. With the use of molecular techniques in the staging of ESFT, it is evident that a proportion of patients with localized ESFT (20%–40%) have micrometastatic disease, measured as molecular detection of tumor cells by RT–PCR in peripheral blood or bone marrow [29].
Finally, in order to evaluate the impact of local treatment measures on the control of the distant disease, we compared the incidence of metastatic recurrence among the different local treatment modalities. There was a trend toward better systemic control for patients treated with more aggressive local therapies; the 5-year CI of isolated distant failure was 10.1% + 3.7% for patients treated with definitive radiation, compared with 0% ± 0% for patients treated with combined surgery and radiation.
In summary, successful treatment of ESFT requires a very judicious use of intensive chemotherapy and aggressive local measures. Both treatment modalities are intertwined and the control of the local and the distant disease is the result of the combined approach.
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National Cancer Institute (P30 CA23099 and CA 21765); American Lebanese Associated Charities.
Received for publication May 27, 2007. Revision received October 8, 2007. Accepted for publication October 9, 2007.
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