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© 2003 American Society for Clinical Oncology Osteosarcoma of the Pelvis: Experience of the Cooperative Osteosarcoma Study Group
From the Departments of Orthopaedic Surgery, Pediatric Haematology and Oncology, and Medicine/Hematology and Oncology, Westfälische Wilhelms-University, Münster; Department of Orthopaedic Surgery, University of Heidelberg, Heidelberg; Departments of Bone Pathology, Pediatric Oncology, and Radiotherapy, University Hospital Hamburg-Eppendorf, Robert-Rössle-Klinik, Berlin; Cancer Center, Ulm, Germany; Department of Orthopaedics, Balgrist, Department of Pathology, University Hospital of Zürich, Switzerland; and Department of Orthopedics, Institute of Pathological Anatomy, University of Vienna, Vienna, Austria. Address reprint requests to Toshifumi Ozaki, MD, Department of Orthopaedic Surgery, Okayama University Medical School, Okayama 700-8558, Japan; email: tozaki{at}md.okayama-u.ac.jp.
Purpose: To define patients and tumor characteristics as well as therapy results, patients with pelvic osteosarcoma who were registered in the Cooperative Osteosarcoma Study Group (COSS) were analyzed. Patients and Methods: Sixty-seven patients with a high-grade pelvic osteosarcoma were eligible for this analysis. Fifteen patients had primary metastases. All patients received chemotherapy according to COSS protocols. Thirty-eight patients underwent limb-sparing surgery, 12 patients underwent hemipelvectomy, and 17 patients did not undergo definitive surgery. Eleven patients received irradiation to the primary tumor site: four postoperatively and seven as the only form of local therapy. Results: Local failure occurred in 47 of all 67 patients (70%) and in 31 of 50 patients (62%) who underwent definitive surgery. Five-year overall survival (OS) and progression-free survival rates were 27% and 19%, respectively. Large tumor size (P = .0137), primary metastases (P = .0001), and no or intralesional surgery (P < .0001) were poor prognostic factors. In 30 patients with no or intralesional surgery, 11 patients with radiotherapy had better OS than 19 patients without radiotherapy (P = .0033). Among the variables, primary metastasis, large tumor, no or intralesional surgery, no radiotherapy, existence of primary metastasis (relative risk [RR] = 3.456; P = .0009), surgical margin (intralesional or no surgical excision; RR = 5.619; P < .0001), and no radiotherapy (RR = 4.196; P = .0059) were independent poor prognostic factors. Conclusion: An operative approach with wide or marginal margins improves local control and OS. If the surgical margin is intralesional or excision is impossible, additional radiotherapy has a positive influence on prognosis.
PELVIC OSTEOSARCOMAS are rare. They account for only 7% to 9% of all osteosarcomas.1–3 There are several reports on the treatment outcome of patients with pelvic osteosarcoma.1,4–7 The overall survival (OS) of patients with pelvic osteosarcoma is reported to be between 20% and 47%. This is far worse than that in extremity osteosarcoma.8 One of the reasons for the poor prognosis may be that pelvic osteosarcomas are often diagnosed in an advanced stage with a large tumor size after a delay in diagnosis.9 Instead of hindquarter amputation, internal hemipelvectomy10–12 with removal of the tumor and sparing of the lower extremity has frequently been done. However, the anatomy of the pelvis often makes it difficult to assess the exact tumor extension.13 Excision with adequate margins and reconstruction is technically demanding and associated with a high rate of local recurrence14 and complications.15,16 In recent years, the development of imaging techniques,17,18 chemotherapy,19–27 and surgical techniques11,28 has widened the indication of limb-salvage procedures in patients with pelvic sarcoma. The principal role of chemotherapy is to destroy microscopic tumor deposits. When it is possible to achieve shrinkage of the primary tumor, chemotherapy is sometimes beneficial in assisting the surgeon in carrying out an operation that has better margins or that preserves function better than could have been achieved without chemotherapy. However, patients with axial primary tumors are more likely to have an unfavorable degree of necrosis at the time of surgical resection than those with nonaxial primary tumors.27 Although there are a few reports on additional radiotherapy after tumor excision with inadequate margins,7,29 the effect of radiotherapy for local tumor control remains unknown. Osteosarcoma of the pelvis is currently one of the most challenging tumors for the orthopedic surgeon. To better define patient and tumor characteristics as well as therapy results, we analyzed the case histories of patients with osteosarcoma of the pelvis who entered into the neoadjuvant polychemotherapy protocols of the Cooperative German/Austrian Osteosarcoma Study Group (COSS) before 1999.
Patient Eligibility From the end of 1979 until December 1998, 1,982 patients with osteosarcoma were registered into the consecutive, prospective, neoadjuvant studies performed by the COSS. The site of origin of the tumor was recorded for all patients. This study focuses on patients with osteosarcomas of the pelvis (ilium, acetabulum, pubis, and ischium) while excluding osteosarcomas of the sacrum. Patients with tumors of the sacroiliac region were only included here if the radiological reports documented the finding that the major part of the tumor was located in the ilium. Eighty-three of 1,982 patients with osteosarcoma (4.2%) had a pelvic tumor. Of these 83, four patients who had a low-grade osteosarcoma, a parosteal osteosarcoma, a periosteal osteosarcoma, or an extraskeletal osteosarcoma were not included into the analysis. Five patients with relapsed tumor at registration were excluded. Seven patients were further excluded because of a follow-up of less than 24 months. The remaining 67 patients with a high-grade osteosarcoma were considered eligible for this analysis.
Diagnostic Staging
Chemotherapy All studies were accepted by the local ethics committee and/or the Protocol Review Committees of the German Ministry for Science and Technology or of the German Cancer Society. Informed consent was required from all patients or their legal guardians, depending on the patient’s age.
Surgery
Histologic Effect
Follow-Up and Statistics
Patient Characteristics Of 67 eligible patients, 27 patients were diagnosed in the 1980s and 40 patients in the 1990s. Patient age ranged from 10 to 63 years (median, 20 years; Fig 1  ). Forty-one patients were male, and 26 patients were female. The exact tumor sites were specified for 65 sarcomas (Table 1): 58 tumors were located in the ilium (I), 12 in the acetabulum (II), and seven in the pubis (III). Twenty tumors showed sacral infiltration, and eight tumors infiltrated into the fifth lumbar vertebra (four patients showed both sacrum and lumbar vertebra infiltration). In 58 tumors, the largest diameter was noted; 13 tumors were small (< 10 cm), and 45 tumors were large ( 10 cm). The histologic subtype was specified in 55 cases: 19 osteoblastic, 27 chondroblastic, two fibroblastic, two small cell, two giant cell rich, two sclerotic, and one malignant fibrous histiocytoma-like. The histologic diagnosis was made by the local pathologist from biopsy and/or resection material in all cases. Moreover, 53 tumor samples were reviewed for diagnosis by a member of the COSS pathology panel and/or at the principal author’s institution.
Fifty-two patients had no metastasis at diagnosis (stage IIB), and 15 patients had detectable primary metastases (stage IIIB).30 Before the occurrence of osteosarcoma, nine patients had a previous malignant disease (all either in or around the pelvis), one patient had a benign lesion (Langhans cell histiocytosis) of the ilium, and one patient had a phylloides tumor (borderline malignancy) of the breast. Two of these patients had Ewing’s sarcoma; both received chemotherapy and radiotherapy 8 and 12 years before the diagnosis of osteosarcoma. Four patients had had cervical cancer and received radiotherapy 10, 17, 19, and 20 years, respectively, before the diagnosis of osteosarcoma. Two patients had teratoma and seminoma of the testis 15 years before the diagnosis of osteosarcoma; both received 40 Gy of radiotherapy. One patient had a rhabdomyosarcoma around the hip joint and received chemotherapy and surgery 10 years before the diagnosis of osteosarcoma. One additional patient had received chemo- and radiotherapy for pelvic Langhans cell histiocytosis 6 years before the diagnosis of osteosarcoma. One patient with phylloides tumor underwent excision only. In 10 patients with information on the treatment of previous disease, excluding a patient with phylloides tumor, the median interval between treatment of the previous disease and diagnosis of osteosarcoma was 13.5 years (range, 6 to 20 years). Six of 10 patients who had osteosarcoma at age 40 years or greater had a previous malignant lesion. There were no patients with Paget osteosarcoma in this series.
Symptoms
Histologic Effect
Surgical Excision
Radiotherapy Eleven patients received irradiation to the primary tumor site for local control: four postoperatively and seven definitively (without surgery; Table 3 ). Four patients received irradiation after intralesional excision: two patients after limb-sparing excision (45 and 51 Gy) and two patients after hemipelvectomy (neutron beam therapy). Seven of the 17 patients without definitive surgery received conventional irradiation between 56 and 68 Gy (median, 61 Gy), and one patient received high-activity samarium (Sm)-153-ethylene diamine tetramethylene phosphonate (EDTMP; 150 MBq/kg body weight, total 8.1 GBq) with peripheral blood stem cell rescue in addition.
Local Failure The total local failure rate was 47 in all 67 patients (70%): 31 of 50 (62%) patients with definitive surgery, and 16 of 17 patients without surgery. Forty-six local failures developed within 3 years after diagnosis, and one local failure developed at 146 months after diagnosis (Fig 3 ). In 50 patients who underwent tumor excision, local failure developed in one of two (50%) patients with assumed radical margins, in 11 of 23 (48%) patients with wide margins, in seven of 10 (70%) patients with marginal margins, in 12 of 13 (92%) patients with intralesional margins, and in neither of two patients with unknown margins (Table 3 ). Of the 17 patients without surgery, only a single patient who had received high-dose Sm-153-EDTMP therapy in addition to definitive irradiation with 60 Gy remained alive without local progression at 39 months after diagnosis. Local failure developed in 10 of 17 (59%) patients who underwent definitive surgery in the 1980s and in 21 of 33 (64%) patients from the 1990s.
Metastases Thirty-four of 67 patients had metastases (51%); 15 patients had primary metastases at diagnosis and 19 patients had metastases after diagnosis. Of 19 patients with metastases developing after diagnosis, 17 patients had metastases within 38 months after diagnosis and two patients had metastases at 146 and 161 months after diagnosis.
Survival Analysis
Cumulative 5-year OS was 27%, and cumulative 5-year progression-free survival was 19% for all 67 patients (Fig 4
Osteosarcoma of the pelvis belongs to the group of tumors for which treatment success is most difficult to obtain. In general, successful treatment of osteosarcoma of the extremity involves excision of the tumor with an adequate surgical margin after effective chemotherapy.7,33 Effective chemotherapy can make an adequate surgical margin easier to achieve. In pelvic osteosarcomas, however, the tumor volume changes little because the response of pelvic osteosarcomas to chemotherapy is generally poor because of bulk primary lesions,4,7 which are difficult to resect without marked morbidity. Because of its rarity, there are only a few published series reporting on the oncologic outcomes and surgical treatments for pelvic osteosarcoma.1,4,7,34 In the experience of our group, large tumor size is a poor prognostic factor.35,36 Taylor et al37 also reported that patients who had osteosarcoma exceeding 15 cm in diameter had an unfavorable prognosis. Pelvic osteosarcomas, which have often progressed considerably until diagnosis, are most often quite large and have a comparatively high rate of metastases.9,37 In the current study, the median interval between symptoms and diagnosis was 3.7 months, much longer than the 1.9 months reported by the Pediatric Oncology Group for 350 pediatric patients38 or the 2.3 months in 1,136 COSS patients of all ages with osteosarcoma of all sites.36 Much of this seems to be the result of the fact that the diagnosis is often made late, even when symptoms are present. In recent years, internal hemipelvectomy with limb salvage has become more popular than classical hemipelvectomy.12 Hindquarter amputation is avoided if possible, particularly when the prognosis is believed to be poor. Patients who still undergo hindquarter amputation may have more advanced disease, for example, with involvement of great vessels or a major nerve. In the current study, OS did not differ significantly between patients with hemipelvectomy and limb salvage surgery. By applying hindquarter amputation, patients can be relieved of pain and may remain mobile, thereby maintaining independence in their lives.39 Considering the mortal risk after local recurrence and the mobility after hemipelvic amputation, hindquarter amputation should be selected in patients where limb-salvage surgery may be associated with a poorer surgical margin. In most of the pelvic osteosarcoma cases, incomplete resection of the tumor results in death, whereas complete tumor removal confers a reasonably good prognosis.4 Daw et al40 reported that four of 10 patients with hemipelvectomy survived a median 11.3 years after diagnosis. Unfortunately, surgery in pelvic sarcoma is associated with a high rate of local recurrence. In different series, the local recurrence rates were 72% (after excision with any margin);1 32% (13% in wide, 38% in marginal, and 80% in intralesional surgery);4 and 11% (excision with any margin).7 In this study, the local failure rate was 70% in all 67 cases and 62% in 50 patients with definitive surgery (50% in radical, 48% in wide, 70% in marginal, and 92% in intralesional). In the report by Fahey et al,1 several patients treated more than a quarter of a century ago were included; this may be one reason for their high local failure rate. Fifty-three percent of patients underwent tumor excision with an adequate margin in the report by Kawai et al,4 and this figure was 52% in the current study. In the report by Grimer et al,7 the local failure rate was low, even though 11 of 18 surgical margins were inadequate. These differences among studies may be explained by the surgical indications among institutes. Moreover, centralization of tumor patients to a large institute should be reconsidered because these rare tumors must be treated in special centers in which multidisciplinary treatment is possible.7 Especially in pelvic sarcomas, surgery is justified only when performed by an experienced surgeon. In previous reports, the most common sites of positive margins and also of local recurrence were in the residual sacrum, the lumbar spine, the pelvic vessels, the rectum, and at the bladder.1,41 In this study, adequacy of surgical margins and OS were not affected by sacral infiltration. It may be that sacral canal (epidural space) infiltration as opposed to sacral invasion is the factor limiting surgery as reported by Grimer et al.7 Several authors1,4–7 have noted a high incidence of vascular invasion, particularly in chondroblastic lesions. Careful imaging of the association of the tumor with the great veins is mandatory to excise tumors more safely.7 Pelvic sarcoma is often associated with poor response. First, the median age (20 years) of patients with pelvic osteosarcoma is higher than that of patients with extremity osteosarcoma, so chemotherapy dose intensity may be lower in patients with pelvic sarcoma than in patients with extremity sarcoma. Second, the biologic characteristics of pelvic and extremity osteosarcomas may differ (eg, in chemosensitivity). Unexpectedly, poor chemotherapy response did not appear to influence outcome in our series, a finding that may reflect statistical bias resulting from the small sample size with very few good responders and an ouverwhelming effect of poor local control rather than tumor biology. Some surgically demanding osteosarcomas may respond to radiotherapy;29 however, it is performed on a case-by-case basis, and there is no clear information on the effect of radiotherapy on pelvic osteosarcoma.4 In the selected cases with intralesional or no surgery, the OS for patients receiving adjunctive radiotherapy to the primary tumor site was better than that for patients without this radiotherapy. These results indicate that unresectable osteosarcomas or those operated with inadequate margins should be treated by a regimen including radiotherapy. In recent years, targeted internal radiotherapy with high-dose Sm-153-EDTMP has emerged as an additional treatment option for inoperable osteosarcomas.42–44 The effect of this treatment seems to be attractive, but its contribution to local control and survival remains to be determined. In conclusion, an operative approach with wide or marginal margins improves local control and survival of patients with pelvic osteosarcoma. Our results indicate that additional radiotherapy may improve the outcome in cases where adequate surgical margins cannot be achieved.
The patients reported in this study were registered from the following institutes: Johaniter Kinderklinik (2), St. Augstin; Kantonsspital, Abteilung Onkologie (2), Basel; Robert-Rössle-Klinik (4), Virchow-Klinikum, Kinder- und Jugendmedizin (2), Berlin; Universitäts-Kinderklinik Bonn (2); Medizinische Klinik (1), Evangelisches Diakonie-Krankenhaus, Onkologie (1), Bremen; Klinik und Poliklinik für Kinderheilkunde, Abteilung Onkologie (1), Technische Universität Dresden; Zentrum für Kinderheilkunde, Abteilung Hämatologie und Onkologie (2), Düsseldorf; Universitäts-Kinderklinik, Abteilung Immunologie/Onkologie (2), Erlangen; Universitäts-Kinderklinik, Abteilung Hämatologie/Onkologie (1), Essen; Universitäts-Kinderklinik, Abteilung Hämatologie/Onkologie (2), Frankfurt/M.; Universitäts-Kinderklinik, Hämatologie/Onkologie (1), Freiburg; Universitäts-Kinderklinik (1), Göttingen; Medizinische Universitätsklinik, Abteilung Hämatologie/Onkologie (1), Graz; Universitäts-Kinderklinik, Abteilung für pädiatrische Hämatologie und Onkologie (1), und II. Med. Universitätsklinik, Hämatologie/Onkologie (2), Hamburg; Medizinische Poliklinik/Onkologie (2) der Medizinischen Hochschule, Hannover; Universitäts-Kinderklinik, Abteilung Onkologie/Hämatologie (2) und Medizinische Klinik & Poliklinik V (1), Heidelberg; Städtsiches Krankenhaus (1), Hohenems (Austria); Orthopädische Universitäts-Klinik (1) und Universitäts Kinderklinik, Abteilung Hämatologie/Onkologie (1), Innsbruck; St. Vincentius-Krankenhaus, II. Medizinische Abteilung (1), Karlsruhe; Medizinische Klinik, Abteilung Hämatologie/Onkologie (1) des Städtischen Klinikums Kassel; Universitäts-Kinderklinik, Abteilung Onkologie (1), Köln; Kinderklinik der Städtischen Krankenanstalten (1), Mannheim; III. Medizinische Klinik, Abteilung Hämatologie/Onkologie (1), Rechts der Isar der Technischen Universität, München, Kinderpoliklinik der Universität, Pettenkoferstr. (1), München; Universitäts-Kinderklinik (2) und Medizinische Universitätsklinik A (3), Münster; Pius-Hospital, Abteilung Hämatologie/Onkologie (1), Oldenburg; Krankenhaus Barmherzige Brüder (1), Regensburg; Universitäts-Kinderklinik, Abteilung Hämatologie/Onkologie (1), Tübingen; Universitäts-Kinderklinik (1) und Tumorzentrum (3), Ulm; St. Anna Kinderspital (1) and Orthopädische Universitäts-Klinik (9), Wien; Orthopädische Universitäts-Klinik Balgrist (3), Zürich.
Supported in part by a grant from the Alexander von Humboldt Foundation. The Cooperative Osteosarcoma Study Group studies are supported by Deutsche Krebshilfe.
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44. Anderson PM, Wiseman GA, Dispenzieri A, et al: High-dose samarium-153 ethylene diamine tetramethylene phosphonate: Low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol 20:189–196, 2002 Submitted January 29, 2002; accepted September 30, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test with or without Fisher’s correction. The Mann-Whitney U test evaluated differences of the mean rank between two groups. The cumulative probability of survival was calculated using the Kaplan-Meier method using the biopsy day as the starting point of the follow-up. As 15 of 67 patients had metastases at diagnosis and 17 patients did not have definitive surgery, interpretation of results of progression-free survival was often difficult; overall survival (OS) was used in most survival analyses in the current study. Tests of difference between survival curves were carried out using the log-rank test. Values, which were significant in the univariate analysis, were entered and reanalyzed in the multivariate method with a stepwise regression test. The statistical software used was StatView (version 5.0, SAS Institute, Cary, NC). 
