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Keywords:

  • sarcoma;
  • Ewing;
  • Asian Continental Ancestry Group;
  • treatment outcome

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND.

Ewing sarcoma family of tumors (ESFT) of bone is extremely rare in Japan. The objectives of the current study were to assess the clinical outcome and prognostic factors of patients with ESFT of bone in Japan and to compare them between Euro-American and Japanese populations.

METHODS.

The authors conducted a retrospective analysis of 243 patients who were treated for ESFT of bone in Japan between 1981 and 2003. Local therapy was surgery in 35% of patients, surgery combined with radiotherapy in 40% of patients, radiotherapy alone in 22% of patients, and no local treatment in 3% of patients. All but 3 patients received various regimens of multidrug chemotherapy.

RESULTS.

The median patient age was 16 years. The primary disease sites were the trunk in 53% of patients and the extremities in 47% of patients. Forty-one patients had metastases at presentation. The median follow-up was 66 months. A univariate survival analysis demonstrated that patients who had metastases at presentation, primary site in the trunk, age ≥16 years, tumor size ≥10 cm, tumor that responded poorly to induction chemotherapy, and local treatment with radiotherapy alone had a significantly worse event-free survival (EFS). A multivariate analysis further verified that the former 3 factors were significant adverse prognostic factors. Of 201 patients with localized disease, 45 patients who received current chemotherapy regimens that included ifosfamide and etoposide had a significantly better 5-year EFS rate (67.6%) compared with other patients.

CONCLUSIONS.

The clinical outcome of patients with localized ESFT of bone in Japan has improved markedly with the use of current chemotherapy regimens that include ifosfamide and etoposide and has become comparable to the outcomes observed in other major series of Euro-American patients. The prognostic factors are also almost identical. Cancer 2007 © 2007 American Cancer Society.

Ewing sarcoma family tumors (ESFT) are highly malignant, small, round cell tumors of neuroectodermal origin arising from bone and soft tissue. ESFT of bone is the second most common primary malignant bone tumor after osteosarcoma in children and adolescents. It is well known that there is an interracial variation in the incidence of ESFT. The incidence is remarkably lower in black populations and in East and Southeast Asians compared with the incidence in Euro-American populations.1–3 Therefore, in the past, there was no clinical study targeting large populations of patients with ESFT in Japan and other Asian countries. These facts inspired the Japanese Musculoskeletal Oncology Group (JMOG) to conduct a multi-institutional, retrospective study. The objectives of the current study were 1) to assess the clinical outcome of patients with ESFT of bone in Japan, 2) to identify prognostic factors from which to develop a therapeutic strategy for future studies, and 3) to determine whether there are any differences in patients' characteristics, clinical outcome, or prognostic factors between Euro-American and Japanese populations.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patients

This study was designed as a multi-institutional, retrospective analysis by the JMOG, which consists of representative Japanese tertiary referral hospitals and cancer centers for musculoskeletal tumors. For this study, the JMOG conducted a survey of clinical outcomes of patients who had primary bone tumors that were diagnosed histologically as ESFT of bone and were treated at the institutions of the JMOG between January 1981 and May 2003. Patients who had received previous anticancer therapy for Ewing sarcoma were excluded from the study. Two hundred forty-three patients from 29 institutions finally were enrolled into the study. Clinical staging was determined based on diagnostic imaging examinations according to the Musculoskeletal Tumor Society surgical staging system.4 Primary tumor size was based on the greatest tumor dimension on radiographic images, including computed tomography scans and magnetic resonance imaging.

Treatment

Although treatment strategy varied to some extent according to the time of referral and the policy of the institution, fundamentally, it was a combination of systemic chemotherapy and localized, definitive surgery and/or radiotherapy. Patients and/or their guardians were informed and consented to their treatment. Of the 243 patients in this study, 183patients underwent definitive surgery as primary local treatment. The primary lesions were excised with a wide margin in 145 patients, with a marginal margin in 17 patients, with an intralesional margin in 19 patients, and with unspecified surgical margins in 2 patients. Of those 183 patients, 96 patients (52.5%) also received radiotherapy. The modes of combined radiotherapy were preoperative for 70 patients, postoperative for 21 patients, both postoperative and preoperative for 3 patients, intraoperative and postoperative for 1 patient, and not specified for 1 patient. Fifty-three patients received local radiotherapy alone. Carbon ion beam radiotherapy was applied to 4 patients. The total dose of radiotherapy ranged from 14 grays (Gy) to 95.5 Gy (mean, 47.9 Gy, not including the dose of carbon ion beam radiotherapy). Seven patients received only systemic chemotherapy without local treatment.

All but 3 patients received chemotherapy, and those 3 patients were excluded from the survival analysis. Although the majority of chemotherapy was administered according to regimens that have been reported previously in major prospective studies, some regimens were unique to an institution. The regimens that were applied are listed in Table 1.5–19 High-dose chemotherapy (HDC) with hematopoietic stem cell rescue was received by 51 patients, including 48 patients who received autologous peripheral blood stem cell transfusion (PBSCT) and 3 patients who underwent autologous bone marrow transplantation.

Table 1. Chemotherapy Regimens
RegimenAgentsNo. of patients
  • VACD indicates vincristine (VCR), actinomycin D (ACT), cyclophosphamide (CYC), and doxorubicin (DOX); IE, ifosfamide (IFO) and etoposide (ETO); NCI, National Cancer Institute; CCG, Children's Cancer Group; POG, Pediatric Oncology Group; CCCH; PBSCT, peripheral blood stem cell transfusion; THP, therarubicin; CDDP, cisplatin; BLM, bleomycin; MTX, methotrexate; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosurea; CBDCA; carboplatin; DTIC; dacarbazine.

  • *

    VCR (1.5 mg/m2), DOX (60 mg/m2/48 h), CYC (900 mg/m2 × 2 d), and IFO (16 g/m2/8 d) repeated twice and local treatment followed by VCR, DOX, CYC, and IFO (16 g/m2/8 d) repeated 3 times (for good responders) or VCR, DOX, CYC, and IFO (9 g/m2/5 d) and ETO (500 mg/m2) repeated 4 times (for poor responders).

  • VCR (2 mg/m2), THP (80 mg/m2/48 h), CYC (2.2 g/m2), and IFO (14 g/m2/5 d), ETO (600 mg/m2/5 d) repeated 5 times with or without ACT (600 μg/m2 × 2) and CYC (600 mg/m2 × 2).

  • IFO (10 g/m2/5 d), ETO (360 mg/m2/3 d), DOX (60 mg/m2 48 h), CYC (2500 mg/m2 × 2 d), and IFO, ETO, DOX repeated 4 times.

  • §

    ETO (500 mg/m2/5 d), CDDP (125 mg/m2/5 d), THP (40 mg/m2), IFO (4.2 g/m2/3 d).

VACD+IE-based regimens 41
 NCI protocol (Wexler et al., 19965; Grier et al., 20036)VCR,DOX,CYC+IFO,ETO10
 CCG 7942/POG 9354 Regimen A (Granowetter et al., 20017)VCR,DOX (ACT),CYC+IFO,ETO7
 P6 (Kolb et al., 20038)VCR,DOX,CYC+IFO,ETO3
 SE 91-CNR (Rosito et al., 19999)VCR,DOX,CYC+VCR,ACT,IFO+IFO,ETO2
 CCCH (for poor responders) (Kimura et al., 200210)*VCR,DOX,CYC+IFO,ETO2
 Protocol of the PBSCT Study GroupVCR,THP,CYC (+ACT,CYC)+IFO,ETO9
 Other VACD+IE-based regimens 8
T-16IFO,ETO,DOX+CYC+IFO,ETO,DOX11
EVAIA (Paulussen et al., 199811)ETO,VCR,DOX,IFO,ACT3
KS-1§ETO,CDDP,THP,IFO7
T-6 (Rosen et al., 198112)ACT,CYC,BLM,VCR+MTX,CYC,DOX+CYC,BCNU4
T-11 (Rosen, 198213) and modified T-11CYC,DOX,MTX,VCR+BLM, CYC,ACT+CYC,DOX,MTX47
VAC (Nesbit et al., 198114) and modified VACVCR,ACT,CYC6
VACA (Burgert et al., 199015; and Jurgens et al., 198816) and modified VACAVCR,ACT,CYC,DOX22
VAIA (Paulussen et al., 200117)VCR,ACT,IFO,DOX22
CCCH (for good responders) (Kimura et al., 200210)*VCR,DOX,CYC+IFO8
K2 (Tsuchiya et al., 199818)DOX,CDDP,caffeine9
VCD-based regimensVCR,CYC,DOX, etc10
VCD+I-based regimensVCR,CYC,DOX,IFO, etc12
CDDP- or CBDCA-based regimensCDDP or CBDCA, etc10
CYVADIC (Bramwell et al., 199419)CYC,VCR,DOX,DTIC2
DOX+CDDP-based regimensDOX,CDDP, etc12
Others 12
Not specified 2
No chemotherapy 3
Total 243

Evaluation of Response to Chemotherapy

Resected tumor specimens were examined specifically to evaluate the surgical margins and the rate of necrosis by induction chemotherapy. For 126 tumors, the extent of viable tumor cells was evaluated histologically, and the response to chemotherapy was graded according to the modified criteria of Rosen et al.20, 21 as follows: grade 3, 100% tumor necrosis; grade 2, <10% area of viable tumor; grade 1, from 10% to 50% area of viable tumor; grade 0, from 50% to 100% area of viable tumor.

The mass-reductive effect of chemotherapy with or without radiotherapy was evaluated radiographically for 190 primary lesions. The effectiveness of chemotherapy was defined according to the criteria of the Japanese Orthopedic Association (JOA) Committee of Tumors21 as follows: A complete response was defined as the disappearance of extraosseous mass that continued for ≥3 weeks, a partial response was defined as a reduction ≥30% of extraosseous mass that continued for ≥3 weeks, no change was defined as from 10% expansion to 30% reduction of extraosseous mass that continued for ≥3 weeks, and progressive disease was defined as expansion >10% of extraosseous mass or other newly emerged lesions.

Statistical Analysis

Event-free survival (EFS) and overall survival (OAS) rates were estimated by using the Kaplan-Meier method.22 Both EFS and OAS were calculated from the date of initial treatment. An event against EFS was defined as disease recurrence or progression; onset of a secondary, therapy-related neoplasm; or death from any other causes. A terminal point of OAS was defined as the time of death from disease or from chemotherapy-related toxicity. Deaths from concurrent causes were estimated as censored deaths in the OAS analysis. Local control rates also were calculated by using Kaplan-Meier estimation based on the period from the initiation of treatment to the date of local recurrence. Log-rank tests and generalized Wilcoxon tests were used to evaluate the significance of differences between groups of patients. A Cox proportional hazards model was used to identify independent factors that were predictive of survival for multivariate analysis. Patient age also was evaluated as a continuous variable in the Cox regression model. These statistical analyses were performed using the JMP version 5.01 statistical analysis software package for personal computers (SAS Institute Inc., Cary, NC).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this study, 243 patients (136 men and 107 women) from 29 institutions were enrolled. The patients' characteristics are summarized in Table 2. The median patient age at diagnosis was 16 years (range, 0–49 years). At the time of this analysis, the median follow-up for the survivors was 66 months (range, 4–248 months). There were 41 patients (16.9%) who had metastases at presentation. The primary site was the extremities in 115 patients (47.3%) and the trunk in 128 patients (52.7%).

Table 2. Patient Characteristics
CharacteristicPatients (N = 243)
No.%
Sex
 Men13656.0
 Women10744.0
Age at diagnosis, y
 Median16 
 Range0–49 
Primary tumor site
 Extremity11547.3
  Humerus239.5
  Radius31.2
  Ulna31.2
  Hand41.6
  Femur4317.7
  Tibia197.8
  Fibula135.3
  Foot72.9
 Trunk12852.7
  Skull52.1
  Clavicle93.7
  Scapula156.2
  Rib cage249.9
  Thoracic spine93.7
  Lumbar spine41.6
  Pelvis6225.5
Disease extension at diagnosis
 Localized20283.1
  Stage IIA (intracompartmental)156.2
  Stage IIB (extracompartmental)17672.4
  Not specified114.5
 Metastatic4116.9

Local Control

Local control was evaluated in 229 patients; the other 14 patients were excluded either because they received no chemotherapy (3 patients) or because they had incomplete records (11 patients). Of the 229 evaluable patients, 180 patients (78.6%) underwent definitive surgery with or without combined radiotherapy as local treatment, and 25 patients (13.9%) developed local recurrences during follow-up. Conversely, of 49 patients who received treatment with radiotherapy alone, 14 patients (28.6%) developed local recurrences; this difference in the local recurrence rate was statistically significant (P = .015; chi-square test). There was no difference in the rate between patients who underwent surgery alone and patients who underwent surgery combined with radiotherapy. However, of the 49 patients who received radiotherapy alone as local treatment, 36 patients (73.5%) had primary tumor sites in the trunk. The ratio of axial sites in the radiotherapy group was significantly higher compared with the ratio in axial sites among patients who underwent surgery (81 of 180 patients; 45.0%; P < .001; chi-square test). With regard to surgical margins, the rate of local recurrence was 38.9% (7 of 18 patients) for those who had intralesional margins, 35.3% (6 of 17 patients) for those who had marginal margins, and 8.4% (12 of 143 patients) for those who had wide or radical margins (including amputations). The rate was significantly lower for patients who had tumors excised with wide or radical margins compared with patients who had tumors excised with intralesional or marginal margins (P < .001; chi-square test).

The local recurrence-free rate also was calculated by using the method of Kaplan and Meier for 224 assessable patients (another 5 patients were excluded because of unspecified periods to local recurrence). The cumulative local recurrence-free rate for patients who underwent surgery with or without combined radiotherapy was significantly higher for patients who received radiotherapy alone (5-year local recurrence-free survival rate, 87.4% vs 68.2%, respectively; P = .0016 [log-rank test] and P = .0006 [Wilcoxon test]).

Survival Rate

Of 243 patients who were enrolled in the current study, 3 patients were excluded from the survival analysis because they did not receive chemotherapy. Of the remaining 240 patients, 97 patients (40.4%) remained continuously free of disease during follow-up. Four patients (1.7%) died of chemotherapy-related toxicity (3 patients died of sepsis, and 1patient died of rhabdomyolysis). Of 202 patients who did not have any metastatic disease at presentation, 27 patients (13.4%) developed local recurrences, and 97 patients (48.0%) developed distant recurrences. In 1 patient, secondary chronic myeloid leukemia developed at an interval of 50 months after HDC with autologous PBSCT rescue. This patient was treated with further chemotherapy and had no evidence of disease at the time of final follow-up.

The 5-year OAS and EFS rates, which were estimated by using the Kaplan-Meier method, were 48.7% and 40.7%, respectively (Fig. 1a). In patients without metastasis at presentation, the 5-year OAS and EFS rates were 54.9% and 46.6%, respectively (Fig. 1b). Conversely, the 5-year OAS and EFS rates for patients who had metastatic disease at presentation were 13.2% and 6.8%, respectively; both rates were significantly less favorable than the rates for patients without metastasis (P < .0001; log-rank test and Wilcoxon test).

thumbnail image

Figure 1. Kaplan-Meier estimated overall survival (dotted line) and event-free survival (solid line) are illustrated for all patients (n = 240 patients) (a) and for patients without metastatic disease at presentation (n = 201 patients) (b).

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Univariate Analysis for Survival

The clinical variables and their prognostic impact on EFS are listed in Table 3. With regard to pretreatment factors, extent of tumor (metastatic), primary tumor site (trunk or pelvis), age (≥16 years), and tumor size (≥10 cm) were significantly predictive of poor survival. For the age variable, a cut-off age of 16 years was chosen. When it was evaluated as a continuous variable, older age was predictive of poor EFS in the Cox regression model with a relative risk of 1.029 (95% confidence interval, 1.008–1.048; P = .006). For the tumor size variable, different cut-off sizes (5 cm, 10 cm, and 15 cm) were tested, but differences were observed only for tumor sizes of 5 cm and 10 cm. The number of patients who had tumors ≥15 cm, however, was very small (14 patients) in the current analysis.

Table 3. Univariate Analysis for Event-free Survival
VariableNo. of patients (N = 240)5-Year EFS, %P
Log-rankWilcoxon
  1. EFS indicates event-free survival.

Disease extension
 Localized20146.6<.0001<.0001
 Metastatic396.8  
Primary tumor site
 Trunk12630.3.0001<.0001
 Extremities11451.7  
Primary tumor site
 Pelvic6222.3<.0001<.0001
 Extrapelvic17847.1  
Tumor size, cm
 <1015143.9.019.0057
 ≥106831.8  
Age at diagnosis, y
 <1611950.1.0024.0081
 ≥1612131.1  
Sex
 Men13539.4.53.27
 Women10541.8  
Histologic response to chemotherapy
 Grade 3 (100% necrosis)5958.0.013.0083
 Grade 2–0 (necrosis <100%)6737.7  
Histologic response to chemotherapy
 Grade 3–2 (necrosis >90%))9050.1.093.022
 Grade 1–0 (necrosis ≤90%)3639.2  
Radiographic response to chemotherapy
 Complete response4852.8  
 Partial response10640.4<.0001<.0001
 No change2230.3  
 Progressive disease140.0  
Local treatment
 Surgery with or without radiotherapy18144.8.0025.0002
 Radiotherapy alone5227.7  

With regard to treatment-related variables, both histologic and radiographic responses to induction chemotherapy and local treatment were significant factors. The histologic response was assessable in 126 patients. Patients who had tumors with a grade 3 response (good responders; n = 59) had a significantly higher EFS rate compared with other patients (poor responders; n = 67) (Table 3). Patients who had tumors with grade 3 and 2 responses were defined as good responders (n = 90 patients) and had a significantly higher EFS rate compared with poor responders (n = 36 patients) according to the Wilcoxon test (P = .022) but not according to the log-rank test (P = .093). The radiographic response was assessable in 190 patients. It was apparent statistically that poorer tumor responses, from the best response (complete response) to the worst response (progressive disease), resulted in worse EFS rates (P < .0001; both log-rank test and Wilcoxon test) (Table 3).

Patients who received local treatment with radiotherapy alone (n = 52 patients) had a significantly lower EFS rate compared with patients who underwent surgery with or without radiotherapy (n = 181 patients) (Table 3), but the distribution of patients in each group was biased with regard to the primary tumor site. When the analysis was conducted exclusively among patients who had nonmetastatic tumors that were located in the extremities (n = 102 patients), there was no significant difference in the rate of EFS between the 2 groups.

Chemotherapy regimens varied according to the treatment period and the policy of each institution. Recently, it was reported that the addition of ifosfamide and etoposide (IE) to previous standard chemotherapy regimens contributed significantly to improvements in clinical outcome for patients with nonmetastatic ESFT of bone.6 Of 202 patients without metastasis at presentation, 201 patients received chemotherapy. Of these, 45 patients who received chemotherapy regimens that included (IE) (vincristine, actinomycin D, cyclophosphamide, and doxorubicin [VACD] plus IE-based regimens; T-16, EVAIA, KS-1) (see Table 1) had significantly better EFS (5-year EFS rate, 67.6%) compared with the other patients (n = 156 patients; 5-year EFS rate, 41.2%; P = .0054 [log-rank test] and P = .010 [Wilcoxon test]) (Fig. 2). Moreover, of the various chemotherapy regimens, we compared outcomes of nonmetastatic patients who received 2 typical regimens, the T-11 protocol (see Table 1) and VACD plus IE-based regimens. The results indicated that patients who received VACD plus IE-based regimens had significantly better EFS (n = 32 patients; 5-year EFS rate, 67.3%) than patients who received the T-11 protocol (n = 43 patients; 5-year EFS rate, 41.6%; P = .032 [log-rank test] and P = .041 [Wilcoxon test]).

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Figure 2. Kaplan-Meier estimated event-free survival is illustrated for patients without metastatic disease at presentation by chemotherapy regimens. Comparison between chemotherapy regimens that included ifosfamide and etoposide (IE) (n = 45 patients; solid line) and regimens that did not include IE (n = 156 patients; dotted line) (see Tables 1 and 5).

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Multivariate Analysis for Survival

Based on the results from the univariate analyses, we performed multivariate analyses using a Cox proportional hazards model. Among the parameters that were identified in the univariate analyses, response to chemotherapy was excluded, because the number of assessable patients was small. The type of local treatment also was excluded, because the distribution of patients in each group was biased. The model (n = 219 patients) indicated that the risk of an event increased when a patient had the following characteristics: metastatic disease at presentation, primary tumor located in the trunk, and age ≥16 years. Tumor size lost its statistical significance in this set of multivariate analyses (Table 4).

Table 4. Multivariate Analysis for Event-free Survival
VariableRR95% CIP
  1. RR indicates relative risk; 95% CI, 95% confidence interval.

Disease extension
 Localized1 <.0001
 Metastatic1.811.46–2.24 
Primary tumor site
 Extremities1 .0357
 Trunk1.221.01–1.47 
Tumor size, cm
 <101 .0617
 ≥101.200.99–1.44 
Age at diagnosis, y
 <161 .0393
 ≥161.211.01–1.46 

A second multivariate analysis was performed that included only the 181 assessable patients who did not have metastases at presentation. In that analysis, the parameters chemotherapy regimen, primary tumor site, age, and tumor size were estimated. The results indicated that not only primary tumor site in the trunk and age ≥16 years but also chemotherapy regimens that did not include IE (Table 1) had an adverse prognostic impact on EFS (Table 5).

Table 5. Multivariate Analysis for Event-free Survival in Patients Without Metastatic Disease
VariableRR95% CIP
  • RR indicates relative risk; 95% CI, 95% confidence interval; IE, ifosfamide and etoposide.

  • *

    Vincristine, actinomycin D, cyclophosphamide (VAC), and doxorubicin (VACD)- and IE-based regimens; T-16, EVAIA, and KS-1 (see Table 1).

  • T-6, T-11, and modified T-11; VAC and modified VAC, VACA and modified VACA; VAIA, CCCH (for good responders), K2; VDC-based regimens; VDC+I-based regimens; CDDP- or CBDCA-based regimens; CYVADIC; DOX+CDDP-based regimens, and others (see Table 1).

Primary tumor site
 Extremities1 .0109
 Trunk1.311.06–1.62 
Tumor size, cm
 <101 .0656
 ≥101.230.99–1.53 
Age at diagnosis, y
 <161 .0085
 ≥161.321.07–1.64 
Chemotherapy regimen
 Including IE*1 .0033
 Not including IE1.501.14–2.06 

HDC with Hematopoietic Stem Cell Rescue forHigh-risk Patients

In the multivariate survival analysis, when high-risk patients were defined as patients with metastatic disease at presentation, primary tumors located in the trunk, or age ≥16 years, 178 patients were classified into this group. Of those, 39 patients received HDC followed by hematopoietic stem cell rescue. However, those patients did not have a significantly better EFS than the other patients in the high-risk group (P = .86 [log-rank test] and P = .85 [Wilcoxon test]).

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

It has been noted that ESFT is very rare in black populations and in East and Southeast Asian1 or Chinese and Japanese populations.2 According to the Japanese annual registry of primary malignant bone tumors by the JOA,21 only 156 patients with Ewing sarcoma of bone were registered for the 6 years between 1989 and 1994. Previously, the extreme rarity of the disease may have prevented a large mass clinical study, which may have led to improvements in clinical outcome among patients with ESFT in Japan. The current study, however, revealed that the clinical outcome of patients with localized ESFT who received current chemotherapy regimens that included IE attained 67.6% of the 5-year EFS rate. This result was comparable to the reports from other major series in ESFT of bone among Euro-American populations.6, 8, 9, 23–27

Compared with the international variation in incidence, there was no considerable difference in the ratio of men to women, age distribution, or site distribution between Japanese patients and Euro-American patients (Table 2). Parkin et al. also noted that there was no suggestion of any geographic or ethnic difference in the site distribution.1

In the current study, the factors that were associated with decreased EFS were similar to those identified in previous retrospective studies.27–29 It has been well confirmed that ESFT patients with larger tumors have a poorer outcome.6, 17, 27, 29, 30 However, recent studies have demonstrated that this classic prognostic factor may become less critical when it is accompanied by the application of more aggressive treatment, such as EW-92,25 SE 91-CNR,9 and P68 (see Table 1).

Although the histologic response to initial chemotherapy was among the most reliable predictive factors,16, 17, 28, 31, 32 even with the limitation that tumors had to be resected to determine response, we also used simple radiographic evaluations based on changes in extraosseous tumor size. These evaluations also demonstrated sufficient predictive value.

The most advantageous local treatment for Ewing sarcoma of bone remains controversial. Although some studies demonstrated no significant differences in the rates of local recurrence and/or survival between patients who received radiotherapy alone and patients who underwent surgery,9, 26, 33 other studies demonstrated that surgery improved clinical outcomes significantly.34, 35 Results from 1058 patients who were treated on Cooperative Ewing Sarcoma Study 81 (CESS 81), CESS 86, and European Intergroup Cooperative Ewing Sarcoma Study 92 demonstrated that local control and EFS among patients who received definitive radiotherapy was significantly lower than EFS among patients who underwent surgery with or without receiving additional radiotherapy, although the former subgroup of patients represented a negatively selected population with unfavorable tumor sites.35 Similar results were obtained in the current study. To eliminate such a selection bias, Bacci et al. retrospectively evaluated patients with tumors located exclusively in the extremities. Their study demonstrated the significant superiority of local surgical treatment.34 These results indicate that surgery should be considered primarily in the local treatment of ESFT if the tumor is resectable with an adequate surgical margin.

In the current study, we observed that Rosen's T-11 protocol was used widely used in 1980s, and the 5-year EFS rate of patients without metastasis at presentation who received the T-11 protocol was only 41.6%. The St. Jude Children's Hospital study, EW-87,36 showed that the combined administration of IE was very active in untreated patients with ESFT. Similarly, the Pediatric Branch of the National Cancer Institute's pilot study demonstrated the efficacy of adding IE to the core regimen of vincristine, cyclophosphamide, and doxorubicin.5 Furthermore, the first Pediatric Oncology Group (POG)-Children's Cancer Group (CCG) randomized study (POG 8850/CCG 7881)6 demonstrated that the addition of IE to a standard regimen improved outcomes significantly among patients with nonmetastatic ESFT of bone. In the current study, the majority of JMOG institutions introduced chemotherapy regimens that included IE in and after 1990. Although progress in surgical and radiation expertise also contributed in part to the recent improvement in clinical outcome of patients with nonmetastatic ESFT of bone in Japan, it is believed that this improvement resulted mostly from the application of these newer chemotherapy regimens.

For patients with high-risk ESFT, more aggressive treatment with HDC followed by hematopoietic stem cell rescue have been used to achieve better survival. Many studies have been conducted to assess the benefit of this megachemotherapy. Some studies suggested an improvement in clinical outcomes,37–39 whereas others did not.40, 41 In the current study, HDC with hematopoietic stem cell rescue failed to improve EFS significantly among high-risk patients. Precise assessment of the utility of HDC for patients with high-risk ESFT will require massive prospective, controlled studies.

In conclusion, this is the first report to our knowledge of a large series of patients with ESFT of bone in Japan as a representative cohort of East Asians. The current results demonstrated that 1) the incidence of ESFT is remarkably lower in Japan than in Western countries, 2) the recent clinical outcome of patients with localized ESFT of bone in Japan was virtually comparable to outcomes reported in other major series of Euro-American patients with ESFT, 3) the identified prognostic factors also are almost the same, and 4) the recent improvement in clinical outcome resulted mostly from the application of current chemotherapy regimens that included IE. In the future, for the establishment of highly effective therapy against ESFT, a large-scale, prospective study also will be required in Japan, even if it is conducted in collaboration with the major Euro-American group studies.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  • 1
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    Stiller CA,Bunch KJ,Lewis IJ. Ethnic group and survival from childhood cancer: report from the UK Children's Cancer Study Group. Br J Cancer. 2000; 82: 13391343.
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    Wolf RE,Enneking WF. The staging and surgery of musculoskeletal neoplasms. Orthop Clin North Am. 1996; 27: 473481.
  • 5
    Wexler LH,DeLaney TF,Tsokos M, et al. Ifosfamide and etoposide plus vincristine, doxorubicin, and cyclophosphamide for newly diagnosed Ewing's sarcoma family of tumors. Cancer. 1996; 78: 901911.
  • 6
    Grier HE,Krailo MD,Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003; 348: 694701.
  • 7
    Granowetter L,Womer R,Devidas M. Comparison of dose intensified and standard dose chemotherapy for the treatment of non-metastatic Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) of bone and soft tissue: a Pediatric Oncology Group-Children's Cancer Group Phase III trial. SIOP XXXIII meeting, Brisbane. Med Pediatr Oncol. 2001; 37: 172.
  • 8
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