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Ewing's Sarcoma of the Pelvis: Long-Term Survival and Functional Outcome

Sucato, Daniel, J.*; Rougraff, Bruce**; McGrath, Brian, E.*,†; Sizinski, Joseph§,*; Davis, Mary; Papandonatos, George††; Green, Daniel; Szarzanowicz, Thaddeus*; Mindell, Eugene, R.*,†

Clinical Orthopaedics and Related Research: April 2000 - Volume 373 - Issue - p 193-201
Section II: Original Articles: Tumor
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Fifty patients with Ewing's sarcoma of the pelvis were treated using a multidisciplinary approach; followup of surviving patients averaged 137 months (range, 40-276 months). The addition of surgical resection to the multidisciplinary treatment for all patients was associated with improved survival compared with survival of patients treated with chemotherapy and radiation therapy alone; the addition of surgery to the treatment regimen of 37 patients without metastases also was associated with improved survival. There were no significant differences between the surgical and nonsurgical groups in terms of tumor size, stage of disease, patient age, duration of symptoms before diagnosis, or anatomic site. Surgery was used more often in recently treated patients, but the year of diagnosis and treatment did not significantly affect overall survival, secondary to large confidence intervals. The Short Form-36 and the Musculoskeletal Tumor Society functional evaluation instruments showed a superior level of function in the nonsurgical group, but this difference was not statistically significant. There have been many advances in the treatment of patients with Ewing's sarcoma during the past 3 decades, resulting in improved survival for patients with Ewing's sarcoma of the pelvis. The addition of surgery significantly improved survival and did not show a significant difference in functional outcome.

From the Department of *Orthopedic Surgery and ††Statistics, State University of New York at Buffalo and Roswell Park Cancer Institute; Departments of **Orthopedic Surgery and Pathology, Indiana University School of Medicine, Bloomington; the §Department of Orthopedic Surgery, Henry Ford Hospital; and the Department of Pediatric Hematology and Oncology, Children's Hospital of Buffalo, and Roswell Park Cancer Institute, Buffalo, NY.

Reprint requests to Brian E. McGrath, MD, B-280, Buffalo General Hospital, 100 High Street, Buffalo, NY 14203.

Received: June 9, 1998.

Revised: April 9, 1999; August 30, 1999.

Accepted: October 9, 1999.

Ewing's sarcoma of bone is a potentially curable, malignant, round cell tumor whose treatment has improved significantly during the last 3 decades. The pelvic ring represents one of the most common primary sites for Ewing's sarcoma of bone; it also is one of the most difficult locations to obtain local and systemic control of the disease.1,2,7,11,13,15,17,19 Some authors have reported their results of patients with Ewing's sarcoma of the pelvis who were treated with surgery (in addition to chemotherapy and radiation therapy) to improve their otherwise dismal prognosis.3,5,8,10,15,19 These studies have had conflicting conclusions; some suggest that surgery improves survival, whereas others do not. There are several variables that must be identified before evaluating whether the results of patients treated with surgery are comparable with those of patients treated without surgery, including tumor site, size, and stage of disease. The effects of improved chemotherapy protocols and imaging studies also should be addressed.

The purported functional loss of a pelvic resection and the inconsistent oncologic outcome of pelvic resection reported previously raises the question of whether surgery offers any benefit to patients with Ewing's sarcoma of the pelvis. The current report concentrates on the prognostic variables that affect oncologic and functional outcome, and compares these findings with conflicting conclusions described in recently published reports.

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MATERIALS AND METHODS

Between 1966 and 1993, 50 patients were referred to either the Roswell Park Cancer Institute or Riley Hospital for Children for treatment of Ewing's sarcoma of the pelvis; 37 patients had localized, nonmetastatic disease at presentation, whereas 13 patients had metastatic disease (Tables 1, 2). Each of these patients had Ewing's sarcoma proven by biopsy. All of these patients were treated with intravenous chemotherapy; 48 of 50 patients received external beam radiation, and 23 of the 50 patients underwent surgical resection of their primary disease.

Table 1

Table 1

TABLE 2

TABLE 2

The average age of the patients was 14.2 years (range, 2-28 years). Nineteen patients were female and 31 were male. All patients sought medical attention because of pain. The length of symptoms before the beginning of treatment averaged 4 months (range, 1-12 months). All but one patient had a soft tissue mass associated with the lesion. At the time of diagnosis, a multidisciplinary conference was held to discuss local control modalities and the status of national chemotherapy protocols. During the 1960s and 1970s, surgery rarely was used to control the primary disease; patients treated in the 1980s and 1990s were considered for surgery unless the family refused or the patient had metastatic disease at presentation. Surgery was used to control the primary disease in two patients who presented with metastatic disease. The chemotherapy used was determined by national protocols and reflected the most up to date chemotherapeutic regimens.

Twenty-seven patients received radiation therapy without surgical resection. Twenty-three patients underwent an attempted surgical resection; all but the two patients who presented with metastatic disease also received radiation therapy. No patients in the current series underwent surgical resection as a salvage therapy for failure of radiation therapy to control their disease. All 23 pelvic resections were limb preserving operations. A complete resection with uninvolved surgical margins was performed successfully in 15 patients, whereas margins were considered less than wide in eight patients. These eight patients had microscopic involvement of structures such as the acetabulum (three), sacral nerve (two), or pelvic viscera (three). All patients received postoperative external beam radiation, except for one patient (Patient 41) who received 5040 cGy of preoperative external beam radiation. The radiation dose ranged from 4000 to 7000 cGy, with an average of 5500 cGy.

The site of primary disease is shown in Table 3. The stage and size of the disease are reported in Table 4. The size of the primary tumor was based on the pathologic examination or the most accurate radiographic study available and was recorded as the single largest dimension before treatment. Because cross sectional imaging was not available in the earliest cases, the single greatest dimension was estimated from the patient's plain radiographs.

TABLE 3

TABLE 3

TABLE 4

TABLE 4

Followup information was available for all patients (except for Patient 20, who was lost to followup after 40 months but who had no evidence of disease). Systemic and local control of disease were monitored carefully by routine clinical examination and appropriate radiographic studies. A local recurrence was tabulated for any patient who had recurrence in the original tumor bed.

The average length of followup for the surviving patients was 137 months (range, 40-276 months), and all surviving patients had no detectable disease at the time of the current report. The Musculoskeletal Tumor Society functional evaluation instrument4 and the Short Form-3618 were used to evaluate all available surviving patients.

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Statistics

Continuous data were analyzed using t tests. Categorical data were analyzed using chi square tests and Fisher's exact test. The survival experience of patients treated with surgery and those without surgery were compared with Kaplan-Meier survival curves.9

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RESULTS

The estimated 5- and 10-year overall survival for these 50 patients was 44%. Table 5 shows the oncologic results of 37 patients without metastases at diagnosis. Sixteen of the 37 patients were treated without attempted surgical resection, and only three (18%) are alive. In contrast, 16 of the 21 (76%) patients without metastases who underwent surgical resection as part of their therapy are alive without evidence of disease. This difference in survival was statistically significant (p = 0.005). The survival curves of all patients and those patients with localized disease treated with surgery and those treated without surgery (radiation and chemotherapy alone) are shown with Kaplan-Meier survival curves in Figures 1 and 2, respectively. There were no differences between the surgical and nonsurgical groups in terms of patient age, size of tumor, patient gender, or stage of the disease. There were no discernible survival differences between patients with one pelvic bone or more than one pelvic bone involved with tumor. However, the addition of surgery to the subgroup of patients with more than one pelvic bone involved resulted in a statistically significant improvement in survival than in patients treated with chemotherapy and radiation therapy alone (p = 0.01).

Table 5

Table 5

Fig 1

Fig 1

Fig 2

Fig 2

Twenty-one patients without metastasis underwent surgical resection. Thirteen of the 21 patients had microscopically negative margins. Eight of these 21 patients had contaminated margins after an attempted wide resection. Eleven of the 13 patients with negative surgical margins are alive without evidence of disease, and five of the eight patients with contaminated margins are alive without evidence of disease; both groups have a minimum 57 months of followup. This difference in survival was not significant.

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Local Control

Local recurrence of disease was identified in seven of 37 (19%) patients who presented without metastases and is reported in Table 6. Two of the seven local recurrences were in patients who had combined chemotherapy, radiation therapy, and surgery, whereas the remaining five local recurrences were in the patients who underwent chemotherapy and radiation alone. There is no significant difference between the groups regarding the rate of local recurrence (p = 0.2). The average time to local recurrence was 9 months (range, 2-17 months), whereas the average time to death was 14 months in the 22 patients who died of their disease. No patient with local recurrence survived, but 21 of 30 (70%) patients who obtained local control of their disease were disease free at latest followup. This was statistically significant (p = 0.001).

TABLE 6

TABLE 6

Three of the 13 patients with metastases at the time of diagnosis currently are alive without evidence of disease 54, 87, and 276 months after diagnosis. Two of the three patients surviving after presentation with multiple bone and pulmonary metastases underwent resection of their primary disease, pulmonary wedge resection, and chemotherapy. The third patient was treated with local radiation and systemic chemotherapy. Two of the 28 patients in whom metastatic disease developed during therapy are alive, 151 and 89 months after diagnosis (121 and 37 months after relapse).

The study period of this series spanned 3 decades, which saw many improvements in the care of patients with cancer. There was a trend toward improved survival with successive decades of treatment, but this improvement was not statistically significant (p = 0.141). During the 1980s and 1990s, the surgical group achieved a 75% 5-year overall survival, whereas the nonsurgical group achieved only a 40% 5-year overall survival. This difference in survival was not statistically significant (p = 0.28). Figure 3 shows the improvement in survival between the earliest and more recent decades of treatment, and the improvement in survival between the surgical and nonsurgical groups treated during the 1980s and 1990s.

Fig 3

Fig 3

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Functional Evaluation

Functional evaluations of 16 of the 21 patients who were alive at the latest followup were used to compare patients who had surgical resection with those who had nonsurgical treatment (Table 7). The Musculoskeletal Tumor Society functional evaluation score average was 71% for the surgical group and 83% for the nonsurgical group. This difference was not statistically significant. The Short Form-36 functional evaluation is a multiitem scale that assesses eight health concepts. Overall, the nonsurgical group scored better in five categories (physical function, role physical, bodily pain, general health, and vitality), whereas the surgical group scored slightly better in the category of mental health. Although the numbers were small with only two surviving patients who did not have surgery, the general trend was an overall better functional outcome for patients in the nonsurgical group.

TABLE 7

TABLE 7

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DISCUSSION

Surgery as part of the multidisciplinary treatment plan for patients with Ewing's sarcoma of the pelvis resulted in improved survival compared with survival of patients who were treated with radiation therapy and chemotherapy alone. Many previously reported studies that focused on Ewing's sarcoma of the pelvis show a trend toward improved local control and survival in patients treated with surgery.6,10,12,15

Several authors have been interested in a rationale for the improvement in oncologic outcome for patient's with Ewing's sarcoma who were treated with surgery. Picci et al12 reported their histologic experience in patients who had neoadjuvant chemotherapy without radiation. They found that 2/3 of patients had viable tumor present at the time of resection, despite receiving systemic chemotherapy, and 1/3 had macroscopic disease. Telles et al16 reported that autopsy specimens of patients with Ewing's sarcoma treated with radiation and chemotherapy also contained persistent viable cancer in nearly 2/3 of cases. It would seem logical that if surgery could remove the primary lesion, particularly in the central avascular region, it would enhance the local control that could be obtained with radiation alone. Thus, improved local control may be associated with improved survival.

Local control data in Ewing's sarcoma can be deceiving. The current study shows a statistically significant increase in survival in patients who achieved local control, but the study did not show a difference in local recurrence between the surgical and nonsurgical groups. It is possible that this study is underreporting subclinical recurrences in the early nonsurgical group, which had a short mean survival of 14 months; autopsies were not done routinely on these patients. However, it is unlikely that any local recurrence was missed in the patients who were treated with surgery who otherwise are free of disease at an average followup of 137 months.

Local recurrence was associated with poor oncologic outcome. Previously reported series generally have not reported the size of the pelvic primary tumor. It is possible that the patients who undergo surgery are those with a smaller primary tumor. Because patients with small primary Ewing's sarcoma may have a better prognosis, these surgical candidates with smaller masses may have had superior oncologic outcome, even if they had not had the surgery.14 There was no significant difference in the size of the tumor treated in the surgical and nonsurgical groups in the current series. In fact, the size of the tumors in the surgical group was slightly larger than those in the nonsurgical group.

The issue of adequate surgical margins in Ewing's sarcoma deserves comment. The small number of patients in the current study did not show a difference in survival based on the quality of surgical resection. The current approach to Ewing's sarcoma in the pelvis at the authors' institutions is to resect the entire lesion, including the soft tissue mass, based on the pretreatment studies. If a margin is contaminated or close, radiation is recommended. Debulking surgery is not recommended, although its virtue was not addressed by the current study.

Yang et al20 reported differences in oncologic outcome between patients who had two parts of the pelvic ring involved with the disease versus those with only one. Although the current study did not show a significant difference in survival between patients with two parts of the pelvic ring involved with the disease and those with only one, it did show a statistically significant improvement in survival between patients with two or more parts of pelvic ring involved with tumor who were treated with surgical resection versus those who were treated with chemotherapy and radiation alone (p = 0.01).

Functional outcome was assessed using two instruments: the Musculoskeletal Tumor Society's functional evaluation form and the Short Form-36. Both instruments revealed a better functional outcome for the nonsurgical group, but the difference was not statistically significant. The superior functional outcome seen with nonoperative treatment must be weighed against significantly improved 5- and 10-year survival of patients who had operative treatment.

The strength of this study is also its greatest weakness: long-term followup. This study spans 3 decades, in which advances in imaging studies, radiation therapy, and chemotherapy have improved the diagnosis and treatment of patients with Ewing's sarcoma. An internal control for the expected improvement in survival from these advances can be seen in a comparison of the nonsurgical groups of the 1960s and 1970s (19% 5-year survival) and the non-surgical group of the 1980s and 1990s (45% 5-year survival). This improvement in the rate of survival does not explain the much greater survival observed in the combined surgical and nonsurgical groups treated in the 1980s and 1990s (75% 5-year survival). Clearly, the patients treated in the 1980s and 1990s benefited from the increased incidence of surgical resection of their pelvic Ewing's sarcoma.

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References

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