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Prognostic Factors in Nonmetastatic Ewing’s Sarcoma of Bone Treated With Adjuvant Chemotherapy: Analysis of 359 Patients at the Istituto Ortopedico Rizzoli

From the Departments of Musculo-Skeletal Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy.

Address reprint requests to Gaetano Bacci, MD, Sezione di Chemioterapia, Istituto Ortopedico Rizzoli, via Pupilli 1, 40136, Bologna, Italy; email chemioterapia{at}ior.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The identification of prognostic factors in patients with nonmetastatic Ewing’s sarcoma could allow the use of risk-adapted therapeutic strategies of treatment.

PATIENTS AND METHODS: Data on 359 patients with nonmetastatic Ewing’s sarcoma of bone treated at a single institution between January 1979 and April 1995 were retrospectively considered. The influence of clinical, hematologic, therapeutic, and histologic parameters on event-free survival was assessed.

RESULTS: By univariate analysis, the following features were found to be associated with a poor prognosis: male sex (P < .02), age older than 12 years (P < .006), fever (P < .0001), anemia (P < .0025), high serum lactate dehydrogenase (LDH) level (P < .0001), axial location (P < .04), radiation therapy only for local control (P < .009), type of chemotherapy regimen (P < .0001), and poor chemotherapy-induced necrosis (P < .001). After multivariate analysis, the adverse independent prognostic factors were male sex (P < .04), age older than 12 years (P < .001), fever (P < .0002), anemia (P < .02), high serum LDH level (P < .0003), axial location (P < .02), and type of chemotherapy regimen (P < .0003). When the multivariate analysis was restricted to surgically treated patients, the adverse independent prognostic factors were poor chemotherapy-induced necrosis (P < .0001), fever (P < .015), anemia (P < .02), and high serum LDH level (P < .025).

CONCLUSION: The prognosis in cases of nonmetastatic Ewing’s sarcoma is influenced by many different clinical and hematologic variables, all of which are to be considered when patients are being stratified according to the risk of relapse. In surgically treated patients, the most important prognostic factor is chemotherapy-induced necrosis.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
EWING’S SARCOMA of bone is an aggressive tumor whose prognosis is critically determined by the adequacy of the local control of the primary lesion (through surgery, radiation therapy, or both) and by the efficacy of the systemic chemotherapy treatment aimed at the control of micrometastatic disease.

Local therapy alone, as used before the 1970s, was associated with an approximately 10% 5-year event-free survival (EFS) rate. With the addition of multidrug chemotherapy regimens in the last 20 years, the prognosis has significantly improved,^1-13 but metastases and/or local recurrences still develop in approximately 30% to 50% of cases. Ewing’s sarcoma patients who develop metastases almost invariably die of their disease, despite second-line treatments. Intensified first-line chemotherapy regimens could further improve prognosis but at the risk of overtreating patients who could benefit from less aggressive regimens. Therefore, the identification of risk factors for relapse would be of major importance in the development of new and differentiated strategies of treatment.

In previous articles, we reported the prognostic significance of serum lactate dehydrogenase (LDH) levels¹⁴ and of the histologic response to chemotherapy in patients who had been locally treated by surgery for tumors located in their extremities.^15,16

The aim of this study was to assess the influence of a larger series of clinical, hematologic, and histologic parameters on EFS in a larger, continuous series of patients with nonmetastatic Ewing’s sarcoma of bone treated at a single institution over a 16-year period.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Criteria for inclusion onto this retrospective study were a diagnosis of Ewing’s sarcoma of bone, age younger than 40 years, absence of metastases at diagnosis, no previous treatments, less than a 4-week interval between the time a biopsy was performed and the beginning of treatment, and chemotherapy treatment according to the protocols listed in Table 1.

Pretreatment Evaluation
The diagnosis of Ewing’s sarcoma was made on representative specimens obtained from an open biopsy for each patient. Each histopathologic diagnosis was based on the presence of a small round cells occurring in the bone, with no histologic, cytologic, ultrastructural, or immunohistochemical features of lymphoma, rhabdomyosarcoma, or neuroblastoma. No attempts were made to differentiate Ewing’s sarcoma from peripheral neuroectodermal tumors.

The histology of all the cases included onto the study and the histologic response to induction chemotherapy were reviewed by two pathologists with special expertise in bone tumors (F.B., P.B.).

A complete history, thorough physical examination, and several chemical laboratory tests, including serum LDH level measurements, were performed in all patients. Patients’ primary tumors were staged by use of plain x-rays, technetium-99 bone scan, computed tomography (CT), and, in recent years, magnetic resonance imaging. Tumor size was estimated, using plain x-rays or CT-scan measures of the three diameters of the lesion, and calculated according to the method used by Göbel et al.¹⁷ Tumor size was estimated using plain x-rays in 22 patients and CT in 238. Bone scintigraphy and CT scans of the lungs were used to investigate the presence of metastases.

Chemotherapy
Chemotherapy was administered according to four sequentially activated consecutive protocols (Table 1) that have previously been reported in detail.^4,12,18

In the first protocol, REA-2 (protocol study period, January 1979 to December 1982; n = 59 cases), chemotherapy comprised 45 weeks of treatment with a four-drug regimen (vincristine [VC], dactinomycin [AC], cyclophosphamide [CP], and doxorubicin [AD]). In this study, local treatment involved surgery (before chemotherapy) or radiation therapy (concurrently with chemotherapy).

In the second protocol, REN-1 (protocol study period, March 1983 to April 1988; n = 108 cases), patients received 2 months of induction chemotherapy with three cycles of VC, AD, and CP (VAC). After local treatment, patients received maintenance chemotherapy with five cycles of VC/AD, six cycles of VC/AC, and six cycles of VC/CP.

In the third protocol, REN-2 (protocol study period, May 1988 to October 1991; n = 82 cases), two cycles of VAC were administered as induction chemotherapy, and four cycles of VAC were administered as maintenance chemotherapy, intercalated with three cycles of VC-ifosfamide-AC, followed by three cycles of etoposide-ifosfamide and two cycles of VC/AC/CP.

In the last protocol, REN-3 (protocol study period, November 1991 to April 1995; n = 110 cases), induction chemotherapy consisted of two cycles of VAC intercalated with one cycle of VC-ifosfamide-AC. The maintenance chemotherapy was similar to that used in the REN-2 protocol. Patient compliance with the protocol was good: 315 (88%) patients received a treatment dose intensity greater than 90% of the planned one, and only four patients had a less than 50% dose intensity.

Local Treatment
Local treatment consisted of surgery only, surgery followed by radiation therapy, or radiation therapy only. For each patient, the choice of local treatment was based on patient age, the site and size of the tumor, and the presence of pathologic fractures. Complete local control was also associated with the need to retain the greatest level of function of the tumor-affected site.

Strategies for local control changed over the years. Although surgery was performed in the first study only on tumors located in expandable bones, it then became the primary strategy for local treatment and as treatment for lesions that were located in sites which required reconstruction with prostheses, allografts, or autografts after tumor resection. Amputation was performed only in patients in whom radiation therapy would probably have caused worse functional results because of age or tumor site. For local control, radiation therapy alone was given at a dose of 60 Gy. Before 1991, patients received conventionally fractionated irradiation, whereas hyperfractionated irradiation was used after 1991. Patients who had had prior surgical treatment but inadequate surgical margins were treated with additional radiation therapy at a dose of 44 Gy, in cases of marginal surgical margins, or 60 Gy, in cases of intralesional resection. In the remaining patients who underwent surgery, radiation therapy at a dose of 44 Gy was given when it was not contraindicated by the patient’s age or type of surgical reconstruction.

The type of local treatment is listed in Table 2 according to the primary tumor site. The mean age of patients treated with radiation therapy was 17.3 years (SD, 7.7), those treated with surgery was 13.4 years (SD, 7.2), and those treated with surgery plus radiation therapy was 17.4 years (SD, 8.9).

Histologic Response to Chemotherapy
After surgery, all specimens were carefully studied, and surface-labeled histologic sections were created. Surgical margins were evaluated according to Enneking et al.¹⁹ The extent of viable tumor that survived preoperative chemotherapy was evaluated according to a previously described method, and the response to chemotherapy was graded according to the classification of Picci et al¹⁵: grade I, macroscopic foci of viable tumor cells, as identified either by individual nodules that are larger than a x10 magnification field or by smaller scattered nodules that, taken together, occupy an area greater than a x10 field; grade II, isolated microscopic nodules of viable tumor cells that, taken together, occupy an area smaller than a x10 field; and grade III, no viable tumor cells at all. The histologic response was evaluated in 174 of the 193 patients who were surgically treated after induction chemotherapy: 67 (38.5%) responses were classified as grade III, 42 (24%) were classified as grade II, and 65 (37.5%) were classified as grade I.

Follow-Up
With follow-up periods ranging between 3.5 and 19 years (mean, 10.5 years), 201 (56.3%) patients remained continuously free of disease, whereas 150 (42%) patients relapsed. The mean time to relapse was 25.5 months (range, 2 to 110 months). Two (0.6%) patients died of chemotherapy-related toxicity (sepsis during myelodepression and doxorubicin cardiomyopathy during remission). In four (1.1%) patients, a radiation-induced osteosarcoma developed at intervals of 4 to 20 years after the beginning of radiation therapy. The 3-, 5-, and 10-year cumulative probabilities of EFS were 66%, 60%, and 55%, respectively. Forty-two (12%) patients developed local recurrences that, in all but one case, were associated with metastases.

With regard to type of local treatment, the rate of local recurrence was 19% (26 of 135 patients) for patients treated only with radiation therapy, 6% (eight of 130 patients) for those treated with surgery only, and 8.5% (eight of 94 patients) for those treated with surgery and radiation therapy. Local recurrence developed in 15 (7%) of the 207 patients who had undergone surgical resection and in one (6%) of the 17 patients who had undergone amputations. With regard to surgical margins, the rate of local recurrence was 14% ( three of 22 patients) for patients with marginal surgical margins, 14% (one of seven patients) for those with intralesional surgical margins, and 6% (12 of 195) for those with wide surgical margins. In 19 patients, local recurrence was the first adverse event; in 16 patients, local recurrence and metastasis occurred contemporaneously; and in six patients, local recurrence occurred after metastases appeared. In all of these patients, metastases first appeared in the lungs in 22 cases and in the bones in 19.

One hundred eight patients (30.1%) relapsed with metastases. In 47 of these patients, metastases appeared in the lung; in 45 patients, in the bones; in 14 patients, in both sites; and in two patients, in the CNS.

With regard to the postrelapse outcomes for the 150 relapsed patients, eight patients were alive without evidence of disease 0.5 to 14 years after the last postrelapse treatment (six patients for more than 5 years), six were alive with uncontrolled disease, and 136 had died of their cancer. In these 136 patients, the mean time to death was 35 months (range, 4 to 118 months) from the beginning of treatment.

Statistical Analyses
Because of a lack of uniformity in the therapeutic regimen performed after relapse, and considering that all but eight of the patients who relapsed died or are alive with disease, the prognostic significance of the variables investigated was evaluated only as it pertained to EFS. Four patients who developed a second neoplasm were censored at the time that the second tumor was diagnosed.

EFS was established from the date of diagnosis to the date of recurrence (local recurrence or metastases). EFS curves were calculated according to the Kaplan-Meier method and compared by means of the log-rank test. A Cox multivariate analysis was performed to identify factors predictive of EFS. In the multivariate analyses, only the factors that proved significant in the univariate analysis were investigated.

The following variables were considered: sex, age (> 12 years v 12 years), tumor volume ( 100 mL v < 100 mL), presence of fever (temperature > 38°C that lasted for at least 2 weeks before the beginning of treatment), presence of anemia (for patients 12 years of age or younger, hemoglobin values below 11.5 x g/dL; for older patients, males 13 x g/dL, females 12 x g/dL), interval between the onset of symptoms and diagnosis ( 3 months v < 3 months), serum LDH level (normal [ 460 U/L] v elevated [> 460 U/L]), and tumor site (extremity v pelvis v other sites).

For tumor volume, we used a cutoff of 100 mL to allow a comparison of our data with those of other authors.¹⁷ For the same reason, we chose an interval of 3 months between the onset of symptoms and diagnosis.^6,7 For the age variable, we chose a cutoff of 12 years of age because none of the patients who were 12 years of age or younger had a body surface area greater than 1.33 m². Patients with a smaller body surface area would have required a dose reduction because of the VC and AC maximum dose of 2 mg defined in the protocol. With regard to anemia, we referred to normal values -2 SDs, as reported by Berliner et al.²⁰ Further variables related to the type of treatment were type of local therapy (surgery v radiation therapy or surgery followed by radiation therapy), chemotherapy regimen (REA-2 v REN-1 v REN-2 v REN-3) and, in patients who had been locally treated with surgery, histologic response to chemotherapy. In contrast to the results reported in previous articles,^15,16 in which only extremity tumors had been considered, the larger series presented here showed no differences in terms of EFS between grade III and grade II responses (5-year EFS, 82% v 74%; P .31). For this reason, we decided to have only two categories: grades II and III together ("good responders") versus grade I ("poor responders"). Data regarding time to recurrence were compared by means of an unpaired t test.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Univariate Analysis
The parameters investigated and their prognostic significance on EFS are listed in Table 3.

Age
Patients 12 years of age or younger had a higher probability of EFS than did those older than 12 years of age (62.9% v 51.3%; P < .006). The mean time to relapse was significantly longer for patients 12 years of age or younger than in older patients (33 months v 22.6 months; P = .006). For patients who died of their cancer, the length of survival was significantly longer in younger patients (40.5 months v 32.6 months; P = .04). Different cutoff points were investigated (13, 14, 15, 16, 17, 18, 18+ years), and the strongest predictor of outcome was 12 years of age.

Fever at Presentation
The rate of EFS was significantly lower in patients who had a fever at presentation (26.8% v 60.2%; P < .0001). Similarly, the time to relapse (15.7 v 28.8 months; P = .0009) and the survival time for patients who died (26.4 v 37.8 months; P = .003) were both significantly shorter in patients who had a fever at the time of diagnosis.

Anemia
The presence of anemia at the time of diagnosis was significantly correlated with EFS (37.9% v 58.2%; P < .0025). For relapsed patients, however, the presence of anemia did not significantly influence the time to relapse (20.4 v 26.7 months; P = not statistically significant) or the survival time for patients who died of their cancer (33 v 35.1 months; P = not statistically significant).

Serum LDH Level
Initial pretreatment serum LDH levels were strongly predictive of outcome. The cumulative probabilty of EFS was 62.2% for patients with a normal serums LDH value and only 41.7% for patients with a high level of the enzyme (P < .0001). Relapsed patients’ serum LDH levels significantly correlated with their time of relapse (18 v 31.9 months; P = .0001) as well as with survival time for patients who died of their cancer (28.2 v 40.5 months; P = .0004).

Location of the Tumor
The site of primary tumor correlated with EFS (P < .04). The most favorable EFS rates were determined to be those relating to tumors in the extremities (EFS, 60.6%), whereas the worst results were those in cases of pelvic/sacral tumors (EFS, 43.2%). The heterogeneous group of patients with tumors located neither in the extremities nor in the pelvis showed an EFS that was close to the rate for patients with pelvic lesions (EFS, 47.6%). Time to relapse and time to death were both longer in the "other site" group (30.6 and 45.1 months, respectively) than in the group of patients with tumors located in the extremities (25.2 and 32.8 months, respectively) or in the pelvis (23 and 31.6 months, respectively).

Volume
Patients whose tumor volume was more than 100 mL had the same probability of EFS as did those with smaller tumors, but patients with larger tumors relapsed significantly earlier (17.6 v 25.6 months; P = .03). In addition, the survival time in patients who died was significantly shorter in those patients who had larger tumors (27.4 v 35.3 months; P = .03). Different cutoff points were investigated, but only at a cutoff of 700 mL was a significant difference in prognosis found (53.5% v 26%; P < .002). Because of the small number of patients in the group of patients with tumor volumes greater than 700 mL (18 patients), the variable volume at this cutoff was not analyzed in the multivariate analysis.

Local Treatment
Patients treated with local radiation therapy alone had a significantly lower rate of EFS than did patients treated with surgery or surgery followed by radiation therapy (47.5% v 64.7% and 55.7%, respectively; P < .009). In the three groups, there were no differences regarding the time to relapse and the survival time for patients who relapsed and for those who died of their cancer.

Among patients who underwent surgery, no differences were seen between those who underwent resection and those who underwent amputation (EFS, 59% v 60%). In addition, the quality of surgical margins did not influence EFS in our series (EFS by surgical margin: wide, 62%; marginal, 50%; intralesional, 54%).

Chemotherapy Protocol
Regarding chemotherapy protocol, the best results were achieved in patients treated with the last protocol (REN-3) than in patients treated with the first three protocols (EFS: 78.8% for REN-3 v 55.8%, 43.9%, and 59.7% for REA2, REN-1 and REN-2, respectively; P < .0001). No significant differences were found when comparisons were made among patients treated according to the first three protocols. Because of the different times that the protocols were initiated, it was not possible to compare the relapse times and the survival times of all patients.

Histologic Response
Of the 223 patients treated by surgery (alone or followed by radiation therapy), 193 received preoperative chemotherapy. In 174 of these patients, it was possible to assess the histologic response to chemotherapy (these data were not available for the other 19 patients). A strict correlation between the histologic response and EFS was found. In fact, the EFS for good responders was 77.2%, versus only 28% for poor responders (P < .001). Moreover, in patients who relapsed and died of their cancer, the survival time was significantly longer in good responders than in poor responders (51 v 32.6 months; P = .03).

Multivariate Analyses
Through the use of univariate analyses, nine covariates seemed to be predictive of EFS: sex, age, fever, anemia, serum LDH level at presentation, site of tumor, histologic response to chemotherapy, type of local treatment, and regimen of chemotherapy applied. Using the Cox proportional hazards model, multivariate analyses were performed to determine the variables that were predictive of EFS.

In the first analysis (Table 4), the histologic response to chemotherapy was excluded because it was available for only 174 (49%) patients in our series. The model indicated that the risk of relapse increased when the following characteristics were present: male sex, age older than 12 years, fever, anemia, high level of serum LDH at presentation, and tumor located outside the extremities. In addition, chemotherapy regimen was an independent prognostic factor.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Moreover, a number of clinical and pathologic features have been recently been reported to have a prognostic significance in nonmetastatic Ewing’s sarcoma treated with chemotherapy, including the site^{2,4,7,11,23,24} and size^3,5,10,17,25 of the lesion, the age^10,24,26 and sex⁹ of the patient, the serum LDH level,^{11,14,24,27,28} the presence of anemia,²⁶ the interval between the onset of symptoms and diagnosis,^6,7,29,30 the presence of fever,⁸ the number and type of drugs used in chemotherapy,^6,9,10,12 the histologic response of the tumor to primary chemotherapy,^{3,8,13,15,16,26} and the type of local treatment (surgery, radiation therapy, or both).^3,4,9,23 Unfortunately, it is difficult to determine the true prognostic effect of the variables evaluated because of the number of major variations in the methodologies used in these studies. The basic differences are (a) that not all factors have been evaluated in single studies; (b) the lack of standard values in reporting measurable variables, such as age, tumor size, and necrosis; and (c) the small amount of patients considered in most of these series.

Our analysis evaluated a large number of patients treated in a single institution and all the previously reported prognostic variables. Our study showed that eight of these variables had an influence on the EFS of patients with nonmetastatic Ewing’s sarcoma of bone. In fact, in multivariate analyses, a significant adverse effect on prognosis was found for patient age greater than 12 years, male sex, presence of fever and anemia at the time of diagnosis, high serum LDH level, tumor location outside of the extremities, type of chemotherapy applied, and, in patients treated with local surgery, a poor histologic response to preoperative chemotherapy. In contrast with other reports, tumor volume, at least at the 100 mL cutoff, the interval between the onset of symptoms and diagnosis, and the type of local treatment did not correlate with prognosis.

Because our study included a cohort of patients who were treated over a 16-year period, it is possible that strategies for local treatment and changes in supportive care, diagnostic methodologies, and chemotherapy had some impact on the outcome. In addition, the histologic response to chemotherapy cannot be properly defined as a true prognostic factor because it is unpredictable before treatment and not assessable for patients who did not undergo surgery for local treatment (in the study presented here, approximately 40% of the total number of patients).

With regard to the type of local treatment, the univariate analysis showed a statistical significance for this factor, which disappeared in the multivariate analysis; in our series, the mean age of patients treated only with surgery was lower than that of patients treated with radiation therapy with or without surgery. This might have interfered with the results of the multivariate analysis. It is possible that the strong statistical significance of age could have concealed the importance of local treatment.

It is interesting to note that in our series, some of the factors that influenced EFS (age, primary tumor site, serum LDH level, fever, histologic response to chemotherapy) also influenced the pattern of relapse and the length of survival for patients who died of their cancer. For instance, patients 12 years of age or younger not only had a higher probability of EFS, but in the relapsing patients in this age group, the time to relapse, as well as the time to death, were significantly longer than those observed in the group of patients older than 12 years of age.

Because 30% to 50% of patients with nonmetastatic Ewing’s sarcoma of bone relapse and then die of the disease despite current management techniques (chemotherapy combined with surgery and/or radiation therapy for local control), patients in two previous multicenter studies were divided into two groups—standard risk and high risk of relapse—and treated with different chemotherapy protocols in an attempt to perform risk-adapted treatment. In the American Intergroup Ewing’s Sarcoma Study-II⁶ study, patients with primary tumors located in the pelvis were considered to be at high risk, whereas in the Cooperative Ewing’s Sarcoma Study 86,¹⁰ patients with tumors located outside the extremities and tumors of the extremity with a volume greater than 100 mL were considered to be "high risk."

On the basis of our results, the criteria used in these two studies to classify patients as high risk seem questionable. In fact, in our study, tumor volume, at least at a cutoff of 100 mL, does not seem to be a significant prognostic factor, and the tumor site is only one, and not the most important, of the eight prognostic factors detected in patients.

In future clinical trials for nonmetastatic Ewing’s sarcoma, appropriate therapeutic strategies (or chemotherapeutic protocols) for different risk groups of patients should be selected in an attempt to gain the greatest benefit from treatment while reducing the morbidity to patients. The criteria to be used to stratify patients according to the risk of relapse should not be based on a single prognostic factor but should include all the variables that resulted in prognostic significance in this study.

Furthermore, new prognostic factors, determined by molecular analysis, have recently been reported. These new prognostic factors could prove to be useful in the detection of tumor-specific markers derived from the gene fusions which result from chromosome translocations in Ewing’s sarcoma.^31,32 These innnovative tumor-specific markers could possibly contribute to a better prognostic stratification of patients with Ewing’s sarcoma and could contribute toward an explanation of the biologic basis for the clincally evident prognostic factors that are analyzed in this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted June 15, 1999; accepted August 18, 1999.

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