Ewing's Sarcoma

The role of radiotherapy and/or surgery in the local treatment of Ewing's sarcoma has still to be

determined. The outcome of Ewing's sarcoma may differ according to its location and a selection bias towards surgery limits the ability to compare methods of local treatment. We have carried out a retrospective review of 91 consecutive patients treated for non-- metastatic Ewing's sarcoma of the femur. They received chemotherapy according to four different protocols. The primary lesion was treated by surgery alone (54 patients), surgery and radiotherapy (13) and radiotherapy alone (23). One was treated by chemotherapy alone.

At a median follow-up of ten years, 48 patients (53%) remain free from disease, 39 (43 %) have relapsed, two (2%) have died from chemotherapeutic toxicity and two (2%) have developed a radio-induced second tumour.

The probability of survival without local recurrence was significantly (p = 0.01) higher in patients who were treated by surgery with or without radiotherapy (88 %) than for patients who received radiotherapy alone (59%). The five- and ten-year overall survival rates were 64% and 57%, respectively. Patients who were treated by surgery, with or without radiotherapy, had a five- and ten-year overall survival of 64%. Patients who received only radiotherapy had a five- and ten-year survival of 57% and 44%, respectively.

Our results indicate that in patients with Ewing's sarcoma of the femur, better local control is achieved by surgical treatment (with or without radiotherapy) compared with the use of radiotherapy alone. Further studies are needed to verify the impact of this strategy on overall survival.

J Bone Joint Surg [Br ] 2003;85-B: 107-14.

Received 30 August 2001Accepted after revision 2 April 2002

A major advance in the treatment of non-metastatic Ewing's sarcoma of bone occurred during the 1970s with the introduction of multiagent chemotherapy in combination with local treatment. The addition of chemotherapy improved the rate of cure from approximately 10% to 50%, 1-9 but the correct local treatment for this tumour remains controversial. In some series surgical treatment has given an improved rate of survival and local control when compared with radiotherapy.1,2,56,10,11 Other studies have not shown any improvement or only improvement in local control.3,8,12 These included patients with tumours located at all sites and therefore may be selection-biased. In Ewing's sarcoma the prognosis differs according to the anatomical site of the tumour, and patients in whom surgery is appropriate usually have a tumour which is located in a limb.4, 13 These have a better prognosis, regardless of the type of local treatment. For this reason, the best local treatment for Ewing's sarcoma can only be decided after an analysis of the results from separate sites.

Until recently, there have been few specific site analyses for a tumour located in a limb, comparing the results of surgical resection and radiotherapy. For the femur, the bone which is most frequently involved in Ewing's sarcoma, the results of two multicentre studies were conflicting.14,15 We have therefore retrospectively analysed the outcome in 91 patients with Ewing's sarcoma of the femur treated with combined chemotherapy in a single institution in order to determine the role of surgery and radiotherapy.

Patients and Methods

Patients. Between January 1970 and July 1996, 91 consecutive patients with a non-metastatic Ewing's tumour located in the femur, were treated by four protocols of adjuvant and neoadjuvant chemotherapy. There were 56 men (61%) and 35 women (39%) with a median age at diagnosis of 16.3 years (1.5 to 59).

Inclusion criteria were: a histological diagnosis of Ewing's sarcoma, a lesion located in the femur, age less than 60 years, no metastases at the time of diagnosis, no previous treatments, and a time from biopsy to the beginning of treatment of no more than four weeks.

Diagnosis and pretreatment assessment. The diagnosis of Ewing's sarcoma was made on a sample obtained by open biopsy. A standard histological investigation and appropriate immunohistochemistry studies were undertaken. The initial assessment included the medical history, physical examination, haematological studies, and several chemical laboratory tests, including the measurement of serum lactic dehydrogenase (LDH). The primary tumour was staged by standard radiographs, CT and, in the 58 most recent patients, by MRI. Metastases were excluded by chest CT and wholebody technetium bone scanning. Bone-marrow aspiration from sites distant to the tumour was not carried out. The size of the tumour was estimated from CT scans of three diameters of the lesion and calculated according to the method reported by Gobel et al.16

The median duration of symptoms before diagnosis was 4.7 months (0.5 to 24). Fever was present at the time of diagnosis in ten patients and anaemia in 11. After histological examination, 73 tumours were classified as typical Ewing's sarcoma (TES) and 18 as primitive neuroectodermal tumours. The serum LDH was normal in 57 patients and high in 34. In 39 patients the tumour involved the proximal femur, in 36 the diaphysis and in 16 the distal femur. There was a pathological fracture at the time of diagnosis in 16 femora (18%). The median tumour volume was 276 ml (13 to 2184). In 35 patients it was smaller than 100 ml and 56 patients had a tumour volume equal to or more than 100 ml.

Chemotherapy and local treatment. The four different protocols used for the chemotherapy, reported in detail previously, are shown in Table 1.',2',to The first protocol, REA-2 (January 1979 to December 1982), involving 12 patients was adjuvant therapy. The local treatment was carried out before (in the event of surgery) or concurrent (in the event of radiotherapy) with chemotherapy. The three other protocols, REN-I (March 1983 to April 1988), REN-2 (May 1988 to October 1991) and REN-3 (November 1991 to July 1996) involved 20, 24 and 30 patients, respectively. These were neoadjuvant therapies and the local treatment was scheduled after two or three cycles of induction chemotherapy. In the first two protocols a four-drug regimen, vincristine, doxorubicin, cyclophosphamide and actinomycin D (VAC Ac) was used, while the final two protocols also included ifosfamide and etoposide.

All patients were offered surgery as a local treatment. Amputation was recommended for pathological fractures which otherwise could not be treated, and for lesions of the distal femur in young, growing children. In these patients radiotherapy would cause an unacceptable limb-length discrepancy with worse functional impairment than an amputation. Postoperative radiotherapy was given to all patients with inadequate surgical margins at full dose. The grade of histological response was not considered when making the decision whether or not to use postoperative radiotherapy. Radiotherapy was given in doses which ranged between 4480 and 6080 cGy. In patients who were treated surgically, those with inadequate surgical margins always received postoperative radiotherapy at full dose (6080 cGy). In patients with adequate surgical margins, radiotherapy at a reduced dose (4480 cGy) was given if compatible with the surgical reconstruction.

Before 1991, patients received conventional fractionated radiotherapy,1,2 whereas hyperfractionated irradiation was used after 1991.17

Pathological assessment of surgery. After surgery, all gross specimens were carefully observed and surface labelled. Histological sections were also taken. Surgical margins were assessed according to Enneking, Spanier and Goodman.18 Radical and wide margins were considered to be adequate, whereas marginal and intralesional margins were inadequate. The response to chemotherapy was determined by histological examination of an entire coronal section of the tumour and classified as grade I (evidence of macroscopic foci of viable tumour cells), grade II (only isolated microscopic nodules of viable tumour cells), and grade III (no nodules of viable cells).19

Follow-up. During and after the combined treatment, patients were reviewed with physical examination and standard radiographs of the chest and of the involved bones. These were undertaken every three months for four years, and twice a year thereafter. Additional studies, including biopsies, were undertaken if indicated by the clinical and radiological examinations.

Statistical analysis. The results of treatment were evaluated in terms of event-free survival (EFS), overall survival and local recurrence-free survival. Relapses were classified as local (only local recurrence), systemic (only metastases) and combined (local recurrence and metastases). EFS was calculated from the first day of treatment until relapse or death from toxicity. Overall survival was calculated from the first day of treatment until local recurrence.

The Kaplan-Meier product limit estimate was used to calculate EFS and overall survival. The frequency distribution of different variables was compared between groups of patients by means of the chi-squared test or Fisher's exact test when appropriate. The log-rank test was used in order to investigate the effect of surgical margins on EFS. Significance was set at p

Results

Local therapy and the histological response to chemotherapy. Local treatment included surgery in 54 patients (59%), radiotherapy in 23 (25%) and surgery followed by radiotherapy in 13 (14%). In the remaining patient, a child aged 1.5 years with a tumour located in the proximal femur and a pathological fracture, his parents refused surgery, which was the only possible local treatment, and he only received chemotherapy (REN-2 protocol).

In the 67 patients treated surgically, this comprised limb salvage in 62 (93%). Amputation was carried out in two patients with large tumours involving major neurovascular structures and presenting with a pathological fracture. Rotationplasties were undertaken in three young children aged 5, 6 and 6 years. In the patients who underwent a resection, reconstruction was accomplished by using a modular prosthesis in 41 patients, a composite (allograft prosthetic composite) in eight, a biological reconstruction (allograft only or with vascularised fibula) in ten and a temporary reconstruction in three. Two patients who had a temporary reconstruction required an arthrodesis to restore function.

Surgical margins were intralesional in one patient, marginal in six, wide in 59, and radical in one. The histological response to chemotherapy in patients treated by neoadjuvant chemotherapy was grade I in 24 patients (36%), grade II in 14 patients (21 %), and grade III in 28 (42%). The frequency distribution of different variables according to local treatment is shown in Table II.

Event-free survival. On October 31, 2001, with a median follow-up of ten years (5 to 22) 48 patients (53%) were event-free, 39 had relapsed (43%), two had died from chemotherapy-related toxicity and two had developed a radio-induced sarcoma. The five-year and ten-year EFS was 56% (95% CI 46 to 66) and 53% (95% CI 43 to 64), respectively.

Relapses. There were 23 systemic and 16 combined relapses. The median time to relapse was 22 months (3 to 108). For those with a combined relapse, eight patients had concurrent metastases and a local recurrence, seven had local relapse and after three to 12 months developed metastases, and in one patient a local recurrence was diagnosed six months after the appearance of metastases. The first site for metastases was the lung in 15 patients (38%), other bones in 13 patients (33%), and both bone and lung in 11 patients (28%). There was no first systemic relapse outside the lung or bones.

Influence of variables. Because of a lack of uniformity in the treatments after relapse, and the fact that all except three of the patients who relapsed, had died or were alive with uncontrolled disease, the prognostic significance of variables was evaluated only in respect of EFS.

Gender, age, tumour size, tumour site, the presence of anaemia, fever and pathological fracture at the time of diagnosis, were pretherapeutic variables analysed for their prognostic value (Table III). EFS was significantly influenced by fever, anaemia, and the serum LDH. Tumour size also showed a tendency towards significance. EFS was also significantly related to the histological response to chemotherapy (Table IV). In order to investigate the effect of surgical margins, we used the log-rank test to compare the four groups. The results were highly significant, probably because both patients with radical and intralesional margins relapsed. If we compare the largest groups (patients with wide and marginal margins) no significant difference is observed (p = 0.16). The five-year and ten-year EFS (Fig. 1) was 44% (95% CI 23 to 64) for the 23 patients treated only by radiotherapy, 59% (95% CI 46 to 72) and 56% (95% CI 42 to 70), respectively, for the 54 patients treated only by surgery, and both 62% (95% CI 35 to 88) for the 13 patients treated by surgery and radiotherapy. This difference is not statistically significant (p = 0.49), perhaps because of the small number of patients. For the patient who was treated only by chemotherapy, the tumour was under apparent control for 88 months, but then recur-red locally. The limb was amputated, but the patient developed lung and bone metastases six months later, and died 98 months after the beginning of treatment.

The median time to local recurrence was 24.5 months (7 to 98). Local recurrence-free survival was significantly related to the serum LDH concentration. Tumour size and fever also showed a tendency towards significance (Table III). No patient treated by surgery plus radiotherapy had a local recurrence, while the five-year local recurrence-free survival probability was 85% for patients treated by surgery alone and 59% for patients treated by radiotherapy alone (Table IV). The probability of local recurrence-free survival was significantly higher (p = 0.01) in patients who had been treated by surgery, with or without radiotherapy (88%; 95% CI 79 to 96), than for patients who had radiotherapy alone (59%; 95% CI 37 to 81).

Survival after relapse. The 39 patients who relapsed received different therapies, 18 patients at the authors' institution, and 21 patients at other centres. The treatment of local recurrence was an amputation in seven patients (six originally treated with radiotherapy and one with surgery) and only palliative treatments in the remaining nine. Lung metastases were treated by thoracotomy in six patients. The patients treated in other institutions had different chemotherapeutic regimes or only palliative treatments. Of the 39 patients who relapsed, 35 died from their tumour six to 98 months from the beginning of treatment (mean 31 months), three are alive and free from disease one, eight and 17 years after treatment for their relapse, and one patient is alive with uncontrolled disease 13 months after relapse. Each of the 16 patients with a local recurrence died from their tumour. The three patients presently alive and free from disease relapsed with lung metastases 36, 48 and 60 months after the beginning of treatment and were treated only by metastasectomy. The five-year and ten-year overall survival rates were 64% (95% CI 54 to 74) and 57% (95% Cl 47 to 68), respectively. Depending upon the type of treatment, the corresponding values were 67% (95% CI 54 to 79) and 65% (95% CI 52 to 78) for patients locally treated by surgery, 69% (95% CI 44 to 94) and 62% (95% CI 35 to 88) for those treated by surgery plus radiotherapy, and 57% (95% CI 36 to 77) and 44% (95% CI 23 to 64) for the 23 patients who received only radiotherapy (p = 0.33). Combining those patients treated by surgery, with or without radiotherapy, the five- and ten-year overall survival rates were both 64% (95% CI 52 to 76). If we compare them with those treated by radiotherapy alone, there was no significant difference (p = 0.14).

Other events. Two patients died four and 12 months after the beginning of treatment because of chemotherapy-related toxicity, one (REN- 1 protocol) due to doxorubicin cardiomyopathy and the other (REN-3) to a septic episode during chemotherapy.

Two other patients, both treated with chemotherapy (REA-2) and locally with radiotherapy (60 Gy), developed a radiation-induced osteosarcoma five and ten years after the beginning of treatment. The first, a 20-year-old man, had the secondary tumour treated by amputation and further chemotherapy with methotrexate and ifosfamide. In spite of this treatment he developed lung metastases and died two years later. The second, a 17-year-old girl, was treated with two cycles of high-dose methotrexate (12 g/m^sup 2^) and a high dose of ifosfamide (15 g/m^sup 2^ for a continuous 5-day infusion), surgery (limb salvage and prosthesis), and chemotherapy again (as applied preoperatively). She is alive and free from the disease three years after her last operation.

The major complications of local treatment after radiotherapy were four pathological fractures, each in patients treated by the adjuvant protocol (REA-2). There were no pathological fractures in the 12 patients treated by the three neoadjuvant protocols (p = 0.09). The four pathological fractures were treated by internal fixation. In two patients, because of nonunion, it was necessary to resect the affected bone and reconstruct with a prosthesis.

Other major complications were ankylosis in two patients, cutaneous ulcer of the leg in one patient, and radiation dermatitis in six. Of the 67 patients treated surgically, 16 underwent further surgery for major complications. Six were treated twice, eight three times and two had four operations.

Complications which required surgery were successfully managed both by sparing the involved limb and without removal of the prosthesis. The exception was a patient with a deep infection who required an amputation after three prosthetic reconstructions. The functional results according to Enneking's criteria,20 were only assessed in 46 patients. Of the 38 patients treated only by surgery, one had an excellent result, 32 a good result and five a poor result. Of eight patients treated by surgery followed by radiotherapy, five had 'good' and three 'poor' results.

Discussion

Historically, radiotherapy has been the standard local treatment for Ewing's sarcoma of bone. Before the introduction of chemotherapy, surgery (usually amputation) was considered to be too radical for a tumour with such a poor prognosis (more than 90% of the patients died within a few months from early metastases), while radiotherapy was apparently effective in controlling local disease until death.21-23 These early deaths did not allow a reliable assessment to be made of the efficacy of radiotherapy. In the 1970s, multiagent chemotherapy dramatically increased not only the rate of cure of Ewing's sarcoma but also the survival of patients who relapsed with systemic dissemination. This large number of long-term surviving patients highlighted the limits of radiotherapy as a local treatment. Local treatment with radiotherapy was followed by a high incidence of local recurrence, functional impairment, and the development of radiationinduced sarcoma.1,2,5,6,11,24-29 For these reasons, several institutions started extending the use of surgery, alone or combined with radiotherapy, for the local treatment of Ewing's sarcoma of bone.

The results of these series were conflicting. While the retrospective analyses of some studies indicated that surgery, or surgery combined with radiotherapy, provided survival rates which were better by five years than those after radiotherapy alone, others did not show significant improvement or showed improvement only in local control.1-3,5,6,8,11,12 It must be remembered that no study was randomised and that retrospective comparisons are selection-biased. Moreover, it is well known that the outcome of Ewing's sarcoma may differ according to the anatomical site. Patients with a surgically resectable tumour usually have lesions which are located in sites with a better prognosis (such as the limbs) regardless of the type of local treatment. Patients treated by radiotherapy usually have their tumour in a site which is associated with a worse outcome such as the pelvis or spine.

In order to determine the best local treatment for Ewing's sarcoma, assessment should therefore be made of tumours which are located at the same sites. For Ewing's sarcoma of a limb there are only a few reports which focus on specific sites. For the femur, which is the bone most frequently associated with Ewing's sarcoma, Ozaki et al,14 when assessing 69 patients treated in the multicentre Cooperative Ewing's Sarcoma Study, concluded that the survival of patients after radiotherapy alone was significantly worse (p = 0.005) than for patients who had received surgery with or without radiotherapy. Meanwhile, Terek et a115 assessed 32 patients who had been treated in four different centres and did not find a statistically significant difference between the various types of local treatment.

In our study, we retrospectively assessed 91 patients with Ewing's sarcoma of the femur who had been treated with four different protocols of chemotherapy and locally by surgery, with or without radiotherapy. The main strength of our review is that it involves a homogeneous group of patients who were treated at the same institution by the same team of surgeons, radiotherapists, and oncologists. The main shortcoming is that patients were not randomised for local treatment and that the study was carried out over a 20-year period with different protocols of chemotherapy.

The five-year EFS was 56%. This rate is the same as that achieved in the same period with the same protocols of chemotherapy for 227 patients with a tumour located in the limbs (five year EFS, 62%; 95% CI 57 to 67) and for 118 patients with a tumour located in the central bones (five-year EFS, 47%; 95% CI 39 to 55).1,2 Despite improvements in radiotherapeutic techniques, surgical reconstruction, and chemotherapy regimens during the 20 years of this review, the prognosis of patients who were treated in the most recent years was no better than for those who were treated at the beginning of the study (EFS, 66% for the first protocol REA2 and 60% for the last REN-3).

Of the variables assessed, the histological response to preoperative chemotherapy in patients treated with neoadjuvant chemotherapy and surgery was of great prognostic significance (p = 0.002). So, too, was the presence of fever, anaemia, and elevated values of serum LDH. This confirms our previous results and the findings of other authors.2,5,13,19,30 Based upon the type of local treatment, the five-year EFS was slightly better for patients treated by surgery (59%) or surgery and radiotherapy (69%) than for patients treated only by radiotherapy (52%). This difference is not statistically significant.

In terms of oncological outcome, there was no significant differences between patients treated surgically or those treated by radiotherapy, although in the group treated by radiotherapy alone there were two late radio-induced sarcomas and four pathological fractures. This is important for two reasons. First, radio-induced sarcomas can have a very long latent period, and some patients may still develop such neoplasms. Secondly, some authors have reported that pathological fractures may not unite.11,12 This occurred in two of four patients in our series. Irradiated bones lack osteogenic potential, as observed in this series, as well as in other studies.24,25,31

The probability of local recurrence-free survival was significantly higher in patients who were treated by surgery, with or without radiotherapy, than in those who received radiotherapy alone. No local recurrences were seen in the 13 patients who were treated by surgery and radiotherapy. A similar difference has been reported in two other papers dealing with Ewing's sarcoma of the femur. In 32 patients studied by Terek et al,15 the rate of local recurrence for patients treated by surgery with or without radiotherapy, or only by radiotherapy, was 50% and 5%, respectively. The 68 patients reported by Ozaki et alto showed the same, with results of 40% and 3% (p = 0.001). Unfortunately we do not have sufficient data in order to compare the functional results of patients according to the type of local treatment used.

Our study does not demonstrate significantly better results in patients treated only by surgery when compared with patients treated only by radiotherapy. Better local control was seen in patients who were treated by surgery with or without radiotherapy. This suggests that the best local treatment for Ewing's sarcoma of the femur is surgical resection of the involved femur and an appropriate reconstruction with local radiotherapy at reduced doses. The advantages of this approach are a potentially lower risk of local recurrence, elimination of the risk of pathological fracture through heavily irradiated host bone and a reduced risk of secondary malignancies. According to a recent review, no radiation-induced sarcomata have been observed in patients treated with less than 48 Gy, while for patients irradiated with 60 or more Gy the risk of second malignancy was 18%.29

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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23. Wang CC, Schultz MD. Ewing's sarcoma: a study of fifty cases treated at the Massachusetts General Hospital. N Engl J Med 1953;248:571-6. 24. Springfield DS, Pagliarulo C. Fractures of long bones previously treat

ed for Ewing's sarcoma. J Bone Joint Surg [Am] 1985;67-A:477-81. 25. Tefft M, Lattin PB, Jereb B, et al. Acute and late effects on normal tissues following combined chemo- and radiotherapy for childhood rhabdomyosarcoma and Ewing's sarcoma. Cancer 1976;37:(2 Suppl) 120117.

26. Li P, Cassady JR, Jaffe N. Risk of second tumors in survivors of childhood cancer. Cancer 1975;35:1230-5.

27. Nicholson HS, Mulvihill JJ, Byrne J. Late effects of therapy in adult survivors of osteosarcoma and Ewing's sarcoma. Med Pediatr Oncol 1992;20:6-12.

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29. Kuttesch JF, Wexler LH, Marcus RB, et al. Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas. J Clin Oncol 1996;14:2818-25.

30. Wunder JS, Paulian G, Huvos AG, et al. The histological response to chemotherapy as a predictor of the ontological outcome of operative treatment of Ewing's sarcoma. J Bone Joint Surg [Am] 1998;80A:1020-33.

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G. Bacci, S. Ferrari, A. Longhi, M. Versari, C. Fomi, D. Donati, M. Manfrini, P. Trentani, E. Barbieri

From the Istituto Ortopedico Rizzoli, Bologna, Italy

G. Bacci, MD

S. Ferrari, MD

A. Longhi, MD

M.Versari, MA

C. Forni, RN

D. Donati, MD

Department of Chemotherapy

M. Manfrini, MD

P. Trentani, MD

5th Department of Orthopaedic Surgery

Istituto Ortopedico Rizzoli, Via Pupilli 1, 40136 Bologna, Italy.

E. Barbieri, MD

Department of Radiotherapy, Policlinico S. Orsola, Bologna, Italy.

Correspondence should be sent to Dr G. Bacci.

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