Ewing’s Sarcoma: Radiotherapy Versus Surgery for Local Control

Solid Tumors in Children

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Ewing's Sarcoma Radiotherapy Versus Surgery for Local Control

Marc E. Horowitz, MD, * James R. Neff, MD, t and Larry E. Kun, MDt.

Ewing's sarcoma is the second most common malignant primary bone tumor of childhood. Although classically believed to originate in bone, Ewing's sarcoma arising in soft tissues has been noted. The annual incidence of Ewing's sarcoma in the United States is two to three cases per million white children less than 21 years of age; it is exceedingly rare in blacks. It is diagnosed during the second decade of life in 65% of patients and is distinctly uncommon before 5 and after 30 years of age. 27 As with many pediatric tumors there is a slight male predominance. Pain is the presenting symptom in most patients; two thirds have a palpable mass and approximately one fifth present with fever which occasionally leads to a mistaken initial diagnosis of osteomyelitis. 40 The primary tumor most commonly originates in the extremity; 40% arise in the central axis including the pelvis, vertebrae, and chest wall. Although only 20% of patients present with gross metastatic disease, the fact that the prechemotherapy era distant relapse rate was more than 80% suggests that the majority of patients have microscopic metastases at diagnosisY The common sites for metastatic disease include lung, bone, and bone marrow. Those with chest wall primaries often have a coexistent malignant pleural effusion. There is now considerable evidence indicating that Ewing's sarcoma is a tumor of parasympathetic nerve lineage. It shares specific cytogenetic and molecular genetic abnormalities with a more differentiated peripheral neuroectodermal tumor called peripheral neuroepithelioma or PNET, has neural antigens on its cell membrane, and makes acetylcholinesterase. 16. 24, 26 As pathologists are recognizing the neural lineage of Ewing's sarcoma, many are searching more diligently for evidence of neural differentiation *Senior Investigator, Pediatric Branch, National Cancer Institute, Bethesda, Maryland tProfessor of Orthopedic Surgery and Pathology, Department of Orthopedic Surgery, University of Kansas School of Medicine, Kansas City, Kansas :j:Chairman, Department of Radiation Oncology, St. Jude Children's Research Hospital; and Professor and Director, Section of Radiation Oncology, University of Tennessee College of Medicine, Memphis, Tennessee

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by light and electron microscopy and make the diagnosis of PNET in place of Ewing's sarcoma more frequently. Although there are studies suggesting that patients with tumors that have more extensive neural differentiation may have a poorer prognosis, these tumors respond to the same therapy as those with Ewing's sarcoma. It is important that these patients be treated on the same protocols so that the prognostic implications of the pathologic findings can be prospectively determined. 16 In 1921, James Ewing observed that "small cell sarcoma of bone" was, in contrast to osteosarcoma, responsive to a radium implant. 12 For the next half century, the treatment for Ewing's sarcoma employed local surgery or radiation therapy or both. Even when local control was effective over 90% of patients died, usually of metastatic disease. 13 Adjuvant chemotherapy has had a major impact on the cure of Ewing's sarcoma. The earliest trials, begun in the mid-1960s at St. Jude Children's Research Hospital and the National Cancer Institute, demonstrated that adjuvant chemotherapy had the potential to cure patients with Ewing's sarcoma. 18, 20 Progress in the multimodality therapy of Ewing's sarcoma over the past 25 years has resulted in the expectation that approximately 50% of patients with localized tumors can be cured. 27 Thus, successful treatment of the patient with Ewing's sarcoma requires both local control of the primary lesion and eradication of microscopic or overt metastatic disease. The systemic treatment of Ewing's sarcoma has recently been reviewed. 16, 27 This article focuses on the local control of Ewing's sarcoma of bone, a subject of growing controversy among those involved in the multidisciplinary treatment of this disease. Until recently it was generally held that, with few exceptions, radiotherapy was the local treatment of choice for the patient with Ewing's sarcoma. A number of recent developments have led some to consider a greater role for surgery in the approach to this problem. These developments include:

1. The recognition that the local failure rate is higher than initially believed-at least 15% to 25% in most studies with rates as high as 45% in certain high-risk patient groups.4, 15 This awareness of a higher local failure rate may represent recognition of local disease persistence or progression through careful evaluation of the primary site at the time of systemic failure using sensitive imaging techniques such as high-resolution CT scanning and magnetic resonance imaging and, in some protocols, by routine biopsy of the primary site. 2. Imaginative surgical techniques that have been successful in allowing limb salvage in osteosarcoma that are now being applied to other bone tumors. (See article by Meyer and Malawer elsewhere in this issue.) 3. The routine use of chemotherapy prior to radiotherapy (neoadjuvant), which usually results in a major reduction of the soft-tissue component of the tumor, improving the feasibility of a surgical resection. In order to explore the controversy regarding the optimal approach to the local control of Ewing's sarcoma, Larry E. Kun, MD, and James R. Neff, MD, independently explain their understanding of the problem and approach to these patients.

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RADIATION THERAPY IN THE MANAGEMENT OF EWING'S SARCOMA This section by Dr. Kun discusses the improvement in the outcome of Ewing's sarcoma that was the result of widespread use of multimodal therapeutic approaches to childhood cancer, beginning in the 1960s. The combination of local irradiation and systemic chemotherapy resulted in survival rates of 45% to 60%,5, 6, 17, 31 substantially beyond the 5% to 20% levels reported after radiation therapy or surgery alone. 2, 39 More recent analyses have focused on local tumor management: identifying disease parameters likely to affect primary tumor control following irradiation and identifying patients likely to benefit from the addition of surgery. The selection of radiation therapy for primary tumor treatment is based upon a balance of efficacy and potential late toxicities. Overall local tumor control following irradiation is 75% to 90% in major series reporting coordinated irradiation and systemic chemotherapy, as shown in Table 1. Both primary tumor control and toxicities depend upon the techniques of radiation therapy. Early reports stressed the likelihood of medullary cavity extension in Ewing's sarcoma, recommending irradiation to the entire bone for both long and Hat bones, 18, 31, 39 Data regarding radiation results largely relate to full-bone irradiation to 50 Gy in 5 to 6 weeks or shrinking-field techniques, delivering 45 to 50 Gy to the medullary cavity and 50 to 55 Gy to the primary tumor site (see Table 1). Functional results after radiation therapy generally have been excellent, although such therapy requires detailed attention to the treatment technique, dose, and interactions between irradiation and chemotherapy. 19 Computed tomography (CT) and magnetic resonance (MR) imaging now provide more accurate tumor definition, permitting more precise radiation therapy planning. With the use of simulated treatment fields that carefully address tumor volume and minimize the exposure of adjacent Table 1. Ewing's Sarcoma: Results of Radiation Therapy and Chemotherapy

SERIES

N

RELAPSE-FREE SURVIVAL

LOCAL FAILURE

(%)

(%)

COMMENTS

IESS-l (Nesbit)

333

47

15

IESS-2 (Burgert, Evans)

214 (nonpelvic)

65

9

Surgical resection in 43%; complete (Le" amputation or negative margins) in 27%

59 (pelvic)

55

12

Surgical resection in 33%; complete in 19%

NCI (Tepper)

94

44

17

Primary RT series

MSKCC (Rosen)

67

79

21-RT O-S

Selected surgical resection in 50%

MGH (Sailer)

45

50

21

Surgical resection in 6%

Surgical resection in 25%

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normal tissues (especially the soft tissues or joints in extremity irradiation or the bowel and bladder for primaries in the pelvic bone), one can provide local disease control with significantly less morbidity. Extremity function following such techniques has been normal or only minimally altered in 80% of surviving children. 19 Hyperfractionated irradiation, delivering two or more smaller doses daily to higher total doses, has been investigated with the goal of further improving disease control while diminishing the late effect of therapy. Early results show more than 90% local control in sizable Ewing's tumors without additional damage to the normal tissues. 25 Assessment of local tumor control may be difficult follOwing primary radiation therapy. In children developing metastatic disease, it is important to determine the presence or absence of tumor at the primary site in assessing treatment regimens. 37 The significance of residual bone or softtissue abnormalities on imaging studies is often unclear. MR imaging may be a more sensitive way to detect residual tumor, but accurate determination of local status requires histologic sampling. The frequency of local recurrence following radiation therapy in the two consecutive Intergroup Ewing's Sarcoma Studies 1 and 2 was 15% and 10%, respectively. 6. 11,30 The original National Cancer Institute (NCI) series indicated clinical evidence of local failure in only 17% of cases; with autopsy data, an ultimate local recurrence rate of 23% was reported. 37 Local recurrence in the NCI series and most subsequent reports correlates strongly with primary tumor site. 30, 34, 37 While distal extremity lesions exhibit local tumor control in 90% to 95% of cases, figures for pelvic tumors are less favorable: 85% following irradiation in Intergroup Ewing's Sarcoma Study-2 (IESS-2) and a range of 30% to 70% in single institution reports. s, 11, 34, 37 A possible explanation for these results relates to the fact that many of these studies were conducted prior to the routine use of the CT scan, U sing imaging modalities available at that time, the radiotherapist might have underestimated the size of a generous soft-tissue mass and the treatment field may have missed part of the lesion, It should be noted that the IESS-l and -2 did not show a benefit for the surgical resection of extremity lesions. 6 Tumor size also appears to be a factor affecting tumor control and survival. Series by Marcus and others 25 document a more frequent local failure in tumors over 8 cm in diameter: 30%, as compared with 10% in tumors less than 8 cm in diameter. IS, 25 The question of surgical resection has been highlighted by retrospective reviews indicating improved local control following complete or microscopically marginal resections, the latter combined with irradiation. 33, 40 The proportion of Ewing's sarcoma cases undergoing surgery increased from 6% in IESS-l to 43% in IESS-2,6,3O Disease control in nonpelvic Ewing's sarcoma was not affected by surgery in IESS-2 (63% 5-year relapse-free survival following biopsy only versus 65% after complete or partial resection). Despite improvement in local control for selected pelvic tumors, no benefit in survival has been noted in the lESS study or the Memorial Sloan-Kettering datay,33 The German Cooperative Group Study, which did show a difference favoring operative intervention (56% freedom from relapse after biopsy only versus 80% following complete or partial resection), included a high proportion of local failures that were related, in part, to

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inadequate radiation therapy techniques ,6, 21 Later improvement in treatment planning led to a substantial reduction in local failures, 14 Selection bias toward surgery in most reports from single institutions limits the ability to compare local management because of the high proportion of better-prognosis distal extremity and smaller tumors in the surgically treated groups. 5, 33, 40 It is paradoxical that claims for surgery rely upon improvement in the very lesions best controlled by itradiationsmaller, peripheral tumors for which radiation therapy achieves greater than 90% local tumor control. 6, 22, 30, 40 The functional results following irradiation of extremity tumors may in fact be superior to those after surgical resection,19,22 If there is a role for surgery it lies in the large, central lesions more difficult to control with radiation therapy alone. Coordinated use of initial chemotherapy, function-sparing surgery to resect residual tumor in patients with less than a complete response, and lower-dose postoperative irradiation may be effective in improving outcome in these "high-risk" cases. 10, 34 The question of secondary bone tumors, i. e., osteosarcoma, in survivors of Ewing's sarcoma is one that is fundamentally important in addressing the use of radiation therapy. Reports of second tumors implicate both irradiation and chemotherapy, indicating an excess of second neoplasms in series reflecting older radiation treatment techniques. 38 More recent series show a smaller risk. I, 25, 34 Although total resection obviating radiation therapy in some settings may reduce the radiation component of carcinogenesis, marginal resections requiring postoperative irradiation, even at reduced doses, will alter neither the risk of second tumors nor the functional outcome. Radiation therapy is the treatment of choice for most patients with Ewing's sarcoma. Exceptions may include (1) large tumors that fail to respond to initial chemotherapy or (2) lesions that can be resected with negative margins in expendable bones (e.g., rib, proximal fibula). It should be remembered that the usual reason for treatment failure is recurrence in lung or bone distant from the primary tumor. Surgical procedures that delay chemotherapy and therefore compromise dose intensity may result in the recurrence of metastatic disease, an event that is rarely survivable.

SURGICAL THERAPY IN THE MANAGEMENT OF EWING'S SARCOMA Here Dr. Neff discusses the controversial role of surgical therapy in the management of patients with nonmetastatic osseous Ewing's sarcoma. Historically, radiotherapy has been the major modality used to control the primary tumor. Recent reports summarized below indicate that an aggressive surgical approach will increase survival and improve the functional outcome for some patients with this disease. With neoadjuvant chemotherapy to reduce tumor bulk followed by innovative techniques for surgical resection and reconstruction, some lesions once considered unresectable can now be removed with wide margins without sacrificing the limb.28, 29

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Even when tumor-free margins are not achievable, the patient may benefit from resection followed by postoperative radiation therapy. The studies reporting the benefits of surgical treatment for Ewing's sarcoma are retrospective and therefore fraught with potential selection biases. However, the consistency with which these reports document a surgical advantage suggests that these data should not be disregarded. In order to understand the issue it is important that one understands surgical terminology relating to outcome as defined in Table 2. One of the earliest reports of benefit for the surgical treatment of Ewing's sarcoma was from the Mayo Clinic by Pritchard in 1975. 32 The results of treatment of 194 patients with nonmetastatic Ewing's sarcoma prior to the consistent utilization of adjuvant chemotherapy were retrospectively reviewed. Survival for the 70 patients whose primary tumor originated in the extremity was 44.7% following surgical treatment versus 13.1% for the 52 patients managed without surgery. In the IESS-1 and2, a surgical resection resulted in an improvement in prognosis for patients with pelvic primaries treated with surgery and radiotherapy (18% local failure) versus radiotherapy alone (28% local failure). All patients received full-dose radiotherapy regardless of the surgical margins achieved. For those patients presenting with primary lesions originating within the ilium, 8 of the 29 (28%) recurred locally after biopsy alone; the 7 patients undergoing complete resection were locally controlled. 10 In the Memorial Sloan-Kettering lO-year experience with 67 consecutive patients with nonmetastatic Ewing's sarcoma, 21% of the 34 patients receiving radiotherapy alone experienced local recurrence; no local relapses were reported among patients having amputation alone (13 patients, primarily distal lesions) or surgery in combination with radiotherapy (20 patients). The overall functional results were superior for the surgically managed patients. This lead to the recommendation that surgery be utilized whenever possible. 33 Bacci2 , 3 reported the results of the management of 124 patients with nonmetastatic Ewing's sarcoma at the Instituto Ortopedico Rizzoli, In contrast to the IESS-1 and -2 experience, patients with lesions presenting within the extremities or other bones, excluding the pelvis, did benefit from surgery; no local failures compared to a 30% local recurrence in the extremities and 18% at other sites among patients receiving radiotherapy alone, In this series patients with primary lesions of the pelvis did not Table 2. Definitions of Surgical Outcome Complete resection Incomplete resections

Wide amputation Marginal amputation

The plane of resection passes through absolutely normal nonreactive tissues in all dimenions, At least one plane of resection passes through either the reactive tissue zone of the pseudocapsule or through tumor tissue such as an incisional biopsy, Plane of resection passes through absolutely normal tissue, with a minimum of 5 cm of normal tissue margin, The plane of resection passes through reactive tissue or is contaminated with tumor tissue,

From Enneking WF, Spanier FF, Goodman MA: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106, 1980; with permission.

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significantly benefit from surgery (33% local failures witlI surgery and 43% witlIout surgery), Other reports demonstrating improved local control in surgically treated patients include those by Juergens et al21 from Germany and Sailer et al34 from Boston. In order to determine which patients are most at risk for local failure when treated witlI radiotherapy alone a number of studies have related the size of the tumor to tlIe local failure rate. Goebel and colleagues,14 reporting for the Cooperative Ewing's Sarcoma Study of the German Society of Pediatric Oncology, concluded tlIat a better prognosis for patients following radical surgery appeared to be in part due to a biased distribution of tumor volumes witlIin local tlIerapy groups, as more patients with smaller tumors were managed utilizing surgical therapy for local control. Marcus,25 Brown, 5 and Hayes 15 each independently note tlIe impact of size on treatment outcome, witlI significantly better survival in cases with tumors less tlIan 8 to 10 cm. It is quite possible that tumors oflimited size, equally controllable with surgery or irradiation, may benefit from eliminating radiotlIerapy. The long-term functional results in patients treated solely with radiotlIerapy appear to be related to multiple factors, including tumor site, volume of tissue irradiated, dose, age, involvement of a major joint, and presence of open epiphyses.23 In young patients with an immature skeleton, radiation treatment may result in tlIe subsequent development of a limb lengtlI inequality. Butler and coauthors 7 retrospectively reviewed 143 patients receiving radiotherapy for childhood tumors and surviving to tlIe age of skeletal maturity. Fifty-one patients (36%) had asymmetry of the chest and ribs with 50 (35%) developing scoliosis and 14 developing kyphosis. Of tlIe 14 patients witlI kyphosis, 1 patient required a laminectomy and spinal fusion. Twelve patients developed a limb lengtlI inequality and 8 of tlIe 12 patients were symptomatic. Twenty-tlIree patients (16%) complained of significant pain at tlIe radiation site. Three of 143 patients have developed secondary malignancies in irradiated sites. 7 WitlI modern techniques, however, a reduction in skeletal complications has been achieved through improved shielding of growtlI centers, symmetric field selection, decreased total radiation dose, and sequence changes in chemotlIerapy. There is concern about tlIe induction of a second malignancy in the irradiated site (see article by Carter elsewhere in tlIis issue). Chan reported tlIat 4 of 24 patients with primary Ewing's sarcoma of the pelvis surviving 5 years developed secondary malignancies within tlIe irradiated field. 8 Strong35 reported a cumulative risk of a secondary malignancy of 35% after 10 years. Five or more courses of chemotlIerapy further increase tlIe secondary malignancy rate. In an extensive study by Tuckei18 of 9170 patients treated for childhood cancer and surviving two or more years, 64 patients subsequently developed malignancies of bone after treatment. Patients who had received radiotherapy alone had a 2.7-fold risk of development of a secondary malignancy. There appeared to be a doseresponse relationship witlI a 40-fold increase of risk after radiotherapy doses to bone of more than 60 Gy. Treatment with alkylating agents also appeared to increase tlIe subsequent risk of developing secondary bone malignancies. In summary, while the historical data cited has acknowledged flaws Text continued on page 377

Figure 1. A, An anteroposterior (AP) roentgenogram of the right humerus of a 9-year-old boy who reported pain in the midportion of his arm during the past 2 weeks. A destructive process can be recognized in the lateral midshaft of the humerus. B, After completion of the primary chemotherapy program and radiographic staging studies confirming that the patient was otherwise free of disease, an MR image of the right humerus revealed that both the proximal and distal metaphyseal areas of the humerus had a normal marrow signal. C, The patient and family elected to proceed with local resection of the shaft of the humerus preserving both the proximal (left) and distal (right) epiphyses. The shaft was reconstructed using a right nonvascularized free-fibular graft. This intraoperative photograph shows the fibular graft with internal fixation and cerclage wires. A drain (white) can be seen to the left, and the radial nerve can be identified in the lower right side coursing beneath the fibular graft. Illustration continued on opposite page

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Figure 1 (continued). D, The wounds healed without complication and no neurologic deficit was experienced. Wide margins were achieved and no postoperative radiation therapy was given. This AP and lateral radiograph shows the incorporation of the fibular graft at 6 months while on adjuvant chemotherapy. The limb function remains normal at 2 years. E, This AP and lateral radiograph of the right leg shows regeneration of the proximal fibula at 18 months. The stabilizing screw has been removed, with no symptoms related to the right leg.

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Figure 2. A, This CT scan shows a mass projecting from the right ilium of a 14-year-old girl with pain in her right side over the past 4 months. The right ala of the sacrum is minimally involved. Additional staging studies indicated that the patient was otherwise free of disease. B, An open biopsy revealed tissue diagnostic of Ewing's sarcoma. After completing the neoadjuvant portion of the chemotherapy program, the patient elected to proceed with local resection of the ilium. The preoperative angiogram showed the distribution of the mass and a potential surgical margin through the supra-acetabular region of the ilium and through the right ala of the sacrum. C, View of the comprehensive incision necessary to expose and resect the right ilium and preserve vital structures and postoperative function. Illustration continued on opposite page

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Figure 2 (continued), D, Intraoperative view of the ilium resected with a threaded Steinmann pin immobilizing the supra-acetabular region of the hip (right) to the remaining portion of the right ala of the sacrum (left), The gluteal vessels can be seen coursing with the gluteus medias musculature. E, The resection was marginal and the patient received postoperative radiation therapy. This AP radiograph of the pelvis shows the patient 11 months after resection. At this time, the patient was ambulating with a cane. The patient remains free of disease 4 years after initiation of therapy.

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Cherne Figure 3. A proposed protocol to evaluate the efficacy of surgery in patients with Ewing's sarcoma is currently under development to compare the effects of surgery, surgery plus radiation therapy, and radiation therapy alone. Provisions have also been made to evaluate the effects of surgery either at the time of completion of radiation therapy (for those patients not having an initial surgical option) or after the completion of radiation therapy and adjuvant chemotherapy.

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Table 3. Surgical Procedure by Site Resection of expendable bones not necessitating extensive reconstruction: Rays of hands and feet, proximal four fifths of the fibula, wing of ilium, sacrum (S3 and below), ribs, distal four fifths of the clavicle, body of the scapula Sites of possible complete resection (without radiotherapy) but requiring reconstruction: Intraosseous diaphyseal lesions of long bones with spared epiphyses and joints; extracompartmental diaphyseal lesions of long bones involVing one potentially expendable muscle compartment (Le., region of the thigh) but preserving the joint, and, where possible, neurovascular structures and the epiphysis Sites for possible marginal resections followed by radiotherapy, with or without prosthetic reconstruction: Ilium with neurovascular deviation, pubis with soft tissue extension, proximal femur and acetabulum (requires prosthetic or allograft/prosthesis hybrid reconstruction); proximal humerus with soft tissue extension, glenoid of the scapula with soft tissue involvement, isolated small lesions of the spine and sacrum with soft tissue extension

one can conclude that (1) the local failure rate is as high as 35% to 45% with radiotherapy and therefore a major cause of treatment failure, (2) many series demonstrate an advantage for surgical treatment, and (3) radiation treatment carries with it the risk of functional deficits and secondary malignancies. Acknowledging this, the majority of current multimodal Ewing's sarcoma protocols have provisions for surgery in an effort to provide improved local control and to avoid the late effects of radiation therapy. Surgical procedures are often limited to the resection of expendable bones including the rays of the hands and feet, the proximal four fifths of the fibula, the pubis and wing of the ilium, ribs, distal four fifths of the clavicle, the body of the scapula, and other small, well-localized lesionsprocedures that do not require elaborate reconstruction. At the University of Kansas we have instituted the following surgical approach to Ewing's sarcoma. The patient first undergoes a preoperative restaging to detect metastatic disease and define the full extent of the primary, including bone scan and MR imaging to detect intraosseous skip lesions. 36 The goal of the surgical procedure is a wide resection. If the surgeon is considering either a custom prosthesis or an allograft for reconstruction, the anticipated margins of resection should be free of disease, thereby eliminating the need for postoperative radiation therapy. Supplementary autogenous bone graft can be used at the host-allograft junctures to facilitate incorporation of the allograft and will not be confused with recurrent disease, as could occur with bone-forming tumors such as osteosarcoma. Surgical procedures providing less than a wide surgical margin require postoperative radiation and should be limited to anatomic locations where only soft-tissue or prosthetic and flap reconstruction can be performed. Procedures requiring bone graft reconstructive techniques are contraindicated when radiation therapy will be used because graft incorporation may be diminished. Table 3 lists our surgical approach to primary tumors of various sites. The surgical resections outlined for expendable bones are well accepted by most musculoskeletal oncologic surgeons. The other procedures are under investigation at several centers in the United States and throughout the world and should not be undertaken prior to

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careful consideration of the potential hazards of surgery or subsequent failure of the reconstructive procedure. Figures 1 and 2 provide examples of complete and incomplete resections, respectively. Proposal for a Clinical Trial Consideration must be given for a prospective randomized study to determine the role of surgery in the management of patients with Ewing's sarcoma. Figure 3 illustrates one proposed study that is under evaluation. It will require a significant collaborative effort to provide sufficient data to answer these difficult, but pertinent, questions. The stlldy concept is as follows: Patients with localized Ewing's sarcoma would complete aggressive neoadjuvant chemotherapy and then be re-evaluated. The oncology team (consisting of the orthopedic surgeon, pediatric oncologist, and radiation oncologist) would determine the response of the tumor to therapy and consider whether the lesion is operable. If the patient is believed to have a surgical option, the patient would be randomized to have either surgery or radiation therapy. If the patient is randomized to surgery and the resection is complete, only adjuvant chemotherapy would follow. If, however, the surgical resection is incomplete, the patient would undergo external beam radiotherapy followed by adjuvant chemotherapy. Patients judged not to have a surgical option would be managed with external beam irradiation. Once radiotherapy had been completed the patient would be re-evaluated to determine whether the lesion was made operable. If the patient is believed to have a surgical option, the patient would be randomized to either surgical removal or observation of the treated primary tumor. It is not at all certain that a randomized study such as this is feasible. Physician bias may preclude the un selected accrual of patients in sufficient numbers within a reasonable period of time to address the study's questions. REFERENCES 1. Arai Y, Kun LE, Brooks M, et al: Ewing's sarcoma: Local disease control and patterns of failure following limited-volume radiation therapy (abstract). 32nd Annual Scientific Meeting of the American Society for Therapeutic Radiology and Oncology, Miami Beach, Florida, October 15-19, 1990 2. Bacci G, Pieci P, Gherlinzoni F, et al: Localized Ewing's sarcoma of bone: Ten years experience at the Instituto Ortopedico Rizzoli in 124 cases treated with multi-modality therapy. Eur J Cancer Clin Oncol 21:163, 1985 3. Bacci G, Toni A, Avella M, et al: Long-term results in 144 localized Ewing's sarcoma patients treated with combined therapy. Cancer 63:1477, 1989 4. Bader JL, Horowitz ME, Dewan R, et al: Intensive combined modality therapy of small round cell and undifferentiated sarcomas in children and young adults: Local control and patterns of failure. Radiother OncoI16:189, 1989 5. Brown AP, Fixsen JA, Plowman PN: Local control of Ewing's sarcoma: An analysis of 67 patients. Br J Radiol 60:261, 1987 6. Burgert EO, Nesbit ME, Garnsey LA, et al: Multimodal therapy for the management of non-pelvic, localized Ewing's sarcoma of bone: An Intergroup Study (lESS-II). J Clin Oncol 8:1514, 1990 7. Butler MS, Robertson WW, Rate W, et al: Skeletal sequelae of radiation therapy for malignant childhood tumors. Clin Orthop 251:235, 1990

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8. Chan RC, SutowWW, Lindberg RD, et al: Management and results oflocalized Ewing's sarcoma. Cancer 43:1001, 1979 9. Enneking WF, Spanier SS, Goodman MA: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106, 1980 10. Evans R, Nesbit M, Askin F, et al: Local recurrence, rate and site of metastases, and time to relapse as a function of treatment regimen, size of primary and surgical history in 62 patients presenting with non-metastatic Ewing's sarcoma of the pelvic bones. Int J Radiat Oncol BioI Phys 11:129, 1985 11. Evans RG, Nesbit ME, Gehan EA, et al: Multimodal therapy for the management of localized Ewing's sarcoma of pelvic and sacral bones: A report from the Second Intergroup Study (IESS-II). Int J Radiat Oncol BioI Phys, 1990 (submitted) 12. Ewing J: Diffuse endothelioma of bone. Proc N Y Pathol Soc 21:17, 1921 13. Falk S, Albert M: Five-year survival of patients with Ewing's sarcoma. Surg Gynecol Obstet 124:319, 1967 14. Goebel V, Jurgens H, Etspuler G, et al: Prognostic significance of tumor volume in localized Ewing's sarcoma of bone in children and adolescents. J Cancer Res Clin Oncol 113:187, 1987 15. Hayes FA, Thompson EI, Meyer WH, et al: Therapy for localized Ewing's sarcoma of bone. J Clin Oncol 7:208, 1989 16. Horowitz ME: Ewing's sarcoma: Current status of diagnosis and treatment. Oncology 3:101, 1989 17. Hustu HO, Pinkel 0, Pratt CB: Treatment of clinically localized Ewing's sarcoma with radiotherapy and combination chemotherapy. Cancer 30:1522, 1972 18. Hustu HO, Holton C, James 0, et al: Treatment of Ewing's sarcoma with concurrent radiotherapy and chemotherapy. J Pediatr 73:249, 1968 19. Jentsch K, Binder H, Cramer H, et al: Leg function after radiotherapy for Ewing's Sarcoma. Cancer 47:1267, 1981 20. Johnson RE, Pomeroy TC: Integrated therapy for Ewing's sarcoma. Am J Roentgenol Radium Ther Nucl Med 114:532, 1972 21. Juergens H, Exner U, Gadner H, et al: Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer 61:23, 1988 22. Kinsella TJ, Lichter AS, Miser J, et al: Local treatment of Ewing's sarcoma: Radiation therapy versus surgery. Cancer Treat Rep 68:695, 1984 23. Lewis RJ, Marcove RC, Rosen G: Ewing's sarcoma: Functional effects of radiation therapy. J Bone Joint Surg 59A:325, 1977 24. Lipinski M, Brallam K, Philip I, et al: Neuroectoderm-associated antigens on Ewing's sarcoma cell lines. Cancer Res 47:183, 1987 25. Marcus RB, Grallam-Pole JR, Springfield OS, et al: High-risk Ewing's sarcoma: Endintensification using autologous bone marrow transplantation. Int J Radiat Oncol BioI Phys 15:53, 1988 26. McKeon C, Thiele CJ, Ross RA, et al: Indistinguishable patterns of protooncogene expression in two distinct but closely related tumors: Ewing's sarcoma and neuroepithelioma. Cancer Res 48:4307, 1988 27. Miser JS, Triche TJ, Pritchard OJ, et al: Ewing's sarcoma and the nonrhabdomyosarcoma soft tissue sarcomas of childhood. In Pizzo PA, Poplack DG (eds): Principles and Practices of Pediatric Oncology. Philadelphia, Lippincott, 1989 28. Neff JR: Non-metastatic Ewing's sarcoma of bone: The role of surgical therapy. Clin Orthop 204:111, 1986 29. Neff JR: The current role of surgical therapy in Ewing's sarcoma. In Ryan JR, Baker LO (eds): Recent Concepts in Sarcoma Treatment. Boston, Kluwer, 1988, p 210 30. Nesbit ME, Gehan EA, Burgert EO, et al: Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: A long-term follow-up of the first Intergroup Study. J Clin Oncol 8:1, 1990 31. Pomeroy TC, Johnson RE: Prognostic factors for survival in Ewing's sarcoma. AJR 123:598, 1975 32. Pritchard OJ, Dalllin DC, Dauphine RT, et al: Ewing's sarcoma: A clinicopathological and statistical analysis of patients surviving five years or longer. J Bone Joint Surg [Am] 57:10,1975

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