symposium article

Osteosarcoma
J. Ritter1 & S. S. Bielack1,2*

Annals of Oncology 21 (Supplement 7): vii320vii325, 2010 doi:10.1093/annonc/mdq276

1 tsklinikum Mu diatrische Ha matologie und Onkologie, Mu Universita nster, Klinik und Poliklinik fu r Pa nster, Germany; 2Klinikum Stuttgart, diatrie 5 (Onkologie, Ha matologie, Immunologie), Stuttgart, Germany Zentrum fu r Kinder- und Jugendmedizin-Olgahospital, Pa

symposium article

The successful treatment of patients with osteosarcoma requires close cooperation within an experienced multidisciplinary team including pediatric or medical oncologists, surgeons, pathologists and radiologists. Therefore, therapy should be performed in specialized centers able to provide access to the full spectrum of care. As in other rare malignancies, treatment should be administered within prospective multicenter trials. Therapy must include complete surgical removal of all detectable tumor sites as well as multiagent chemotherapy. The chemotherapy regimen should include several or all of the following four drugs: doxorubicin, high-dose methotrexate with leukovorin-rescue, cisplatin and ifosfamide. Preoperative (neoadjuvant) plus postoperative (adjuvant) polychemotherapy should be preferred, because it allows preparation for safe surgery and preparation of the appropriate prosthesis for the individual patient. The choice of the postponed denitive surgical procedure should be inuenced by the anatomical site of the primary tumor, its relationship to neighboring structures, such as vessels and nerves, age and growth potential of the patient, and probably also by the response of the tumor to preoperative chemotherapy. A major, as yet unsolved, problem is the dismal prognosis for patients with unresectable or relapsed osteosarcomas. Novel approaches are needed in order to improve their prognosis. Key words: follow-up, limb salvage, multidisciplinary treatment, osteosarcoma, preoperative (neoadjuvant) chemotherapy, surgical techniques

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2013

introduction
Osteosarcomas are derived from primitive mesenchymal cells. They originate from bone and only rarely from soft tissue. Untreated, they run a dismal course with local and often metastatic disease progression. Before the introduction of polychemotherapy >90% of patients with osteosarcoma died from pulmonary metastases [1]

epidemiology
Osteosarcoma, the most frequent primary solid malignancy of bone, is dened by the presence of malignant mesenchymal cells which produce osteoid and/or immature bone [13]. The incidence of osteosarcoma in the general population is 23/million/year, but is higher in adolescence, in which the annual incidence peaks at 811/million/year at 1519 years of age. Osteosarcomas account for 15% of all solid extracranial cancers in this age group. Males are affected 1.4 times more frequently than females [4, 5].

growth spurt and the sites of maximum growth suggest a correlation with rapid bone proliferation. A minority of osteosarcomas are caused by radiation exposure. Exposure to alkylating agents may also contribute to osteosarcoma development. The incidence of osteosarcoma is increased in several well-dened hereditary disorders associated with germline alterations of tumor suppressor genes such as hereditary retinoblastoma [1] and the LiFraumeni cancer family syndrome [6].

diagnosis and staging

Local pain, followed by localized swelling and limitation of joint movement, are the typical signs and symptoms of osteosarcoma. In rare cases, particularly in patients with osteolytic tumors, a pathological fracture can be the rst sign of disease. Approximately 15% of patients present with radiographic metastases, most commonly to the lung, but metastases can also develop in bone and rarely in lymph nodes [7]. Although osteosarcoma can occur in any bone, it is most common in the metaphyses of long bones. The most common primary sites are the distal femur, the proximal tibia, and the proximal humerus, with 50% originating around the knee [3, 7, 8]. About 10% develop in the axial skeleton, most commonly the pelvis [9]. The evaluation of a patient with suspected osteosarcoma begins with a full history, physical examination, and plain radiographs [10]. Plain radiography is helpful to describe

etiology and pathogenesis

In most patients, the etiology of osteosarcoma remains obscure. The predilection of osteosarcoma for the age of the pubertal
*Correspondence to: Dr S. S. Bielack, Cooperative Osteosarkomstudiengruppe (COSS), diatrie 5 (Onkologie, Ha matologie, Immunologie), Klinikum Stuttgart-Olgahospital, Pa Bismarckstr. 8, D-70176 Stuttgart, Germany, Tel: +49-711-2787-2461; Fax: +49-711-2787-2462; E-mail: coss@olgahospital-stuttgart.de

The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Annals of Oncology

symposium article
studies. True-cut needle biopsy may also be used, provided that sufcient material can be obtained, while ne-needle biopsies are not appropriate. The biopsy specimen should be forwarded to the specialized pathologist without prior xation. The hallmark of diagnosis is the proliferation of malignant mesenchymal tumor cells and the production of osteoid and/or bone by these tumor cells. The amount of osteoid and/or bone production varies greatly between tumors and within an individual tumor. Thus, identication of diagnostic osteoid may require extensive sampling. Chondroid and brous matrix may also be present, reecting the mesenchymal origin of the malignant cells. The current World Health Organization (WHO) classication [1] recognizes three major subtypes of conventional osteosarcoma: osteoblastic, condroblastic and broblastic, reecting the predominant type of matrix within the tumor. In addition to classical osteosarcoma, the WHO classication recognizes additional histological variants, including telangiectatic osteosarcoma, small cell osteosarcoma, parosteal and periosteal osteosarcomas, as well as low grade central and high grade surface osteosarcomas [1]. The classical central subtypes are nearly always WHO grade III high malignant tumors, whereas surface osteosarcomas are mostly low grade I or intermediate grade II tumors. The current TNM (tumornodemetastasis) classication of osteosarcomas is shown in Table 2.

osseous changes: osteosarcomas can present with osteoblastic, osteolytic or mixed appearance. They often have a soft tissue component in which patchy calcications resulting from new bone formation or spiculae may be observed. A triangular area of periosteal calcication in the border region of tumor and healthy tissue is known as a Codman triangle, which is considered typical for osteosarcomas. Magnetic resonance imaging (MRI) is the best modality to assess the soft tissue component, its relationship to surrounding tissues, vessels and nerves, and its intramedullary extension, which is essential for safe denitive surgery. MRI has to include the whole involved bone as well as the neighboring joints, so as to not miss skip lesions, i.e. intramedullary tumor foci without direct contact with the primary lesion [11, 12]. A metastatic work-up is essential at presentation and includes a (spiral) CT scan of the thorax and a 99mTc bone scan (Table 1). Osteosarcomas lack specic tumor markers; however, an elevation of lactate dehydrogenase or, more frequently, alkaline phosphatase levels in serum is found in some patients. Both have been associated with inferior outcomes. Since polychemotherapy for osteosarcoma can result in cardiac and auditory dysfunction and signicant kidney and liver toxicity, patients should have baseline assessments including echocardiography, an audiogram, and liver and kidney function test (Table 1).

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2013

histopathology
The diagnosis of osteosarcoma must always be veried histologically. Because of the broad spectrum of histological appearances and the rarity of the tumor, it is strongly recommended that biopsies should be performed in specialized centers, so that appropriate biopsy techniques and appropriate histological examination of the obtained material are guaranteed, including genetic evaluation where necessary. Open biopsy is considered the most suitable technique to obtain sufcient material for histological evaluation and additional
Table 1. Recommended diagnostic work-up for osteosarcoma patients

Table 2. TNM classication of bone sarcoma [2]

Tx T0 T1 T2 T3 NX N0

Primary tumor X-ray Magnetic resonance imaging Metastases 99m Tc bone scan Computed tomography Organ function Heart Hearing Kidney

Tumor localization in two planes Whole extremity p/a Whole extremity/tumor region Whole skeleton Chest Echocardiogram, electrocardiogram Audiogram Creatinine (including estimated clearance) Tubular function tests Liver function tests

N1 MX M0 M1 M1a M1b Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IVA Stage IVB

Liver Other laboratory Alkaline phosphatase i.S. Lactate dehydrogenase i.S. i.S., in serum.

Primary tumor cannot be assessed No evidence of primary tumor Tumor 8 cm in greatest dimension Tumor >8 cm in greatest dimension Discontinuous tumors in the primary bone site Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Distant metastases cannot be assessed No distant metastases Distant metastases Lung Other distant sites T1 T2 T1 T2 T3 Any T Any T Any T

N0 N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M1a Any M M1b

(low grade) (low grade) (high grade) (high grade) (any grade) (any grade) (any grade) (any grade)

Volume 21 | Supplement 7 | October 2010

doi:10.1093/annonc/mdq276 | vii321

symposium article
rationale for a multidisciplinary treatment approach
Local therapy alone is insufcient, as 8090% of all patients with seemingly localized disease will develop metastases, mostly in the lungs, and will die if chemotherapy is not included as part of the multidisciplinary treatment [3]. Early studies describing the efcacy of multiagent chemotherapy included those by Rosen et al. in North America [13] and by Winkler et al. in Europe [14]. Two randomized trials in North America proved the efcacy of chemotherapy [15, 16]. Current treatment regimens encompassing primary (preoperative; neoadjuvant) induction chemotherapy, followed by denite surgery and then postoperative (adjuvant) chemotherapy lead to cure in approximately two-thirds of patients with seemingly localized disease [3, 8]. The total duration of chemotherapy is usually at least 68 months.

Annals of Oncology

include total en bloc spondylectomy for vertebral tumors [23] and hip transposition for pelvic sarcomas [24].

radiotherapy Osteosarcoma was long considered a radioresistant tumor, thus the experience with radiotherapy in local treatment of osteosarcomas is limited [25]. However, recent data suggest that the administration of radiotherapy may be useful in patients treated with multiagent chemotherapy who are unable to undergo complete resection or who have microscopic residual tumor foci following attempted resection [22]. The use of targeted radiotherapy with Samarium-153-ethylendiame tetramethylene phosphonate may also be considered in selected situations, although the role of this treatment modality is not well dened and its denition would require further evaluation in controlled clinical trials [26, 27]. systemic therapy polychemotherapy. Currently, doxorubicin [28], cisplatin [29], high-dose methotrexate with leukovorin-rescue [30] and ifosfamide [31] are considered the most active agents against osteosarcoma, but the ideal combination remains to be dened. Most current protocols include a period of preoperative (neoadjuvant) chemotherapy, even though this has not proved to add a survival benet over postoperative (adjuvant) chemotherapy alone [32]. The extent of histological response to preoperative chemotherapy [33], however, offers important prognostic information. Current prospective trials evaluate whether altering postoperative chemotherapy in poor responders improves outcomes. The use of high-dose chemotherapy followed by retransfusion of autologous hematological stem cells has not led to improved outcomes [34]. immunomodulation. An early, uncontrolled Swedish series of single-agent treatment with a-interferon reported promising results [35]. The current EURAMOS 1 Intergroup Study is evaluating a-interferon maintenance after completion of chemotherapy in a randomized study [36]. Addition of the immunomodulator liposomal muramyl tripeptide phosphatidyl ethanolamine (MTP) to postoperative chemotherapy was reported to correlate with a statistically signicant advantage in overall survival and a non-signicant trend in event-free survival in a follow-up report of a recent randomized trial [37]. The studys design and associated statistical limitations have been criticized, leading several authors to recommend that the exact role, if any, of this new immunomodulatory treatment remains to be proven in further studies [38, 39]. supportive care Together with the therapeutic advances in osteosarcoma management with polychemotherapy, a number of agents have been developed to help reduce the chemotherapy-related toxicity. The introduction of serotonin antagonists [40] has dramatically reduced chemotherapy-induced emesis. Such agents alone or in combination with dexamethasone have become the standard of care with the use of highly emetogenic chemotherapy, especially cisplatin. Other agents used in

treatment
surgery The goal of osteosarcoma surgery must always be complete tumor removal. Margins should be at least wide according to Ennekings denition [17] (Table 3), meaning that the tumor including the biopsy scar has to be removed surrounded by an inviolated cuff of healthy tissue. Advances in imaging techniques and in biomedical engineering as well as positive effects of preoperative chemotherapy have led to a major shift away from amputation towards limb-salvage surgery [3, 6, 8, 18, 19]. Options for reconstruction after limb-sparing tumor resections are manifold and include endoprosthetic devices [1820], biological reconstruction, or a combination of both. Rotation-plasty, another well-established biological reconstruction method for tumors around the knee, can result in functional and psychological outcomes equal or even superior to endoprosthetic reconstruction [21], but is cosmetically challenging. Surgery of sarcomas of the axial skeleton remains particularly challenging, both because local recurrence poses a great hazard and because complications after reconstruction are frequent [19, 22, 23]. It is essential that surgeons are aware of all surgical techniques and implement the most appropriate one for each individual patient after consultation within the multidisciplinary osteosarcoma team. More recent advances

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2013

Table 3. Ennekings criteria for surgical margins in musculoskeletal tumors [17] Margin Intralesional Marginal Wide Dissection Within the lesion Through the pseudocapsule or reactive tissue Lesion (including biopsy scar), pseudocapsule and/or reactive zone, and an unviolated cuff of normal tissue completely surrounding the mass removed as a single block Entire anatomic compartment containing the tumor removed as one block

Radical

vii322 | Ritter & Bielack

Volume 21 | Supplement 7 | October 2010

Annals of Oncology

symposium article
Table 4. Suggestions for follow-up investigations after multimodal therapy for osteosarcoma Time Baseline Tumor directed X-ray chest and CT Late effects Echocardiogram, audiogram, liver and kidney function, hepatitis B/C and HIV serology

supportive care of osteosarcoma patients include opioids for tumor pain control and hematopoetic growth factors to decrease the incidence and duration of chemotherapy-induced severe granulocytopenia. The addition of granulocyte colonystimulating factor (G-CSF) to chemotherapy led to increased dose density of treatment and improved histologic response, but not to improved survival rates in a randomized trial by the European Osteosarcoma Intergroup [41].

treatment of metastatic disease and relapse

Curative treatment for primary metastatic osteosarcoma is identical to that of localized disease, with the mandatory addition of surgical removal of all know metastatic foci, usually by exploratory thoracotomy including palpation of the whole lung [42]. Approximately 30% of all patients with primary metastatic osteosarcoma and >40% of those who achieve a complete surgical remission can become long-term survivors [42]. Treatment for relapse, either locally or within the lungs, is primarily surgical. The prognosis is poor, with long-term postrelapse survival in <20%. Complete removal of all metastasis must be attempted, as the disease is otherwise almost universally fatal. In contrast, more than a third of the patients with a second surgical remission survive 5 years or more. Even patients with multiple recurrences may be cured as long as recurrences are resectable, and repeated thoracotomies are often warranted [4345]. Overall, CT scans tend to underestimate the number of pulmonary metastases and may also fail to detect contralateral involvement in patients with seemingly unilateral pulmonary metastasis [46]. Thus, bilateral exploration by open thoracotomy including palpation of both lungs is recommended. The role of second-line chemotherapy for recurrent osteosarcoma is much less well dened than that of surgery, and there is no accepted standard regime. Choice may take into account the prior free interval and disease resectability, and often includes ifosfamide, etoposide and/or carboplatin [4346].

Years 1 and 2

X-ray and (CT)/MRI primary site X-ray chest every 612 weeks X-ray primary site every 4 months X-ray chest every6 24 months X-ray primary site every 4 months X-ray chest every 6 monthsb (Few) relapses reported as late as two decades after treatment. Discuss with patient whether to continue chest X-ray every 612 months

Years 3 and 4

Echocardiogram every 12 years, audiograma, livera and kidney function Echocardiogram every 12 years

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2013

Years 510 Thereafter

Echocardiogram every 24 years Echocardiogram every 24 years

Every visit should include detailed history and physical. Many institutions will add complete blood counts. Evaluate any site with unexplained pain or swelling. Chest CT scan is optional, but should always be performed if chest X-ray shows metastasis or is inconclusive. Add consultation with orthopedic surgery and physical therapy as indicated. Offer fertility testing for males. Additional investigations may be indicated. a Need not be repeated if normal at 1 year. b Some groups recommend annual radiographs of the primary site until year 10. CT, computed tomography, HIV, human immunodeency virus; MRI, magnetic resonance imaging.

outlook
While surgical reconstruction techniques have improved considerably over the past decades, allowing limb salvage in most patients, chemotherapy still relies on the same drugs as in the early 1980s, and survival rates have not improved since then. Translational research is required to identify targets for novel treatment modalities. Due to the rarity of disease, pivotal trials evaluating the addition of innovative therapies to conventional regimens will require multicenter, multinational, often intergroup collaboration. The activation of any clinical trial in a rare disease at centers which may see a patient a year or lessas is the case for most medical oncology institutions treating osteosarcomais cumbersome and associated with little or no nancial incentive. This should not deter us from trying to include as many young adults as possible in interdisciplinary trials of this cancer which so typically occurs at the pediatricadult interface.

follow-up and late effects of treatment

Follow-up intervals recommended in most trials are every 6 weeks to 3 months in years 1 and 2 after diagnosis, every 24 months in years 3 and 4, every 6 months in years 510 and every 612 months thereafter. Each visit should include a history and physical examination, and a chest X-ray (Table 4). Since late metastases may occur >10 years after diagnosis, there is no universally accepted stopping point for tumor surveillance. As in other childhood cancers, cured patients need lifelong follow-up [47]. Polychemotherapy of osteosarcoma may be associated with permanent alterations of cardiac [48], renal [49], auditory and reproductive function, orthopedic problems and other late effects including secondary malignancies [50]. Thus appropriate investigations to detect these late effects as early as possible should be included during regular follow-up (Table 4).

Volume 21 | Supplement 7 | October 2010

doi:10.1093/annonc/mdq276 | vii323

symposium article
disclosures
J. R., no potential conict of interest; S. B. consultant for IDM, Roche, Takeda Millennium and Advisory Board Membership of Merck & Co.

Annals of Oncology

references
1. Fletcher CDM, Unni KK. Pathology and genetics of tumours of soft tissue and bone. In Mertens F (ed): World Health Organization Classication of Tumours. Lyon, France: IARC Press 2002. 2. Sobin LH, Wittekind C. UICC-TNM Classicaton of Malignant Tumors.. New York: Wiley 2002. 3. Arndt CA, Crist WM. Common musculoskeletal tumors of childhood and adolescence. N Engl J Med 1999; 341: 342352. 4. Stiller CA, Bielack SS, Jundt G et al. Bone tumours in European children and adolescents, 19781997. Report form the Automated Childhood Cancer Infromation System project. Eur J Cancer 2006; 42: 21242135. 5. Stiller CA, Craft AW, Corazziari I. Survival of children with bone sarcoma in Europe since 1978: results form the EUROCARE study. Eur J Cancer 2001; 37: 760766. 6. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer and other neoplasms. A familial syndrome? Ann Intern Med 1969; 71: 747752. 7. Bielack SS, Kempf-Bielack B, Delling G et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1.702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002; 20: 776790. 8. Bielack S, Ju rgens H, Jundt G et al. Osteosarcoma: the COSS experience. Cancer Treat Res 2009; 152: 289308. 9. Ozaki T, Flege S, Liljenquist U et al. Osteosarcoma of the spine: experience of the Cooperative Osteosarcoma Study Group. Cancer 2002; 94: 10691077. 10. Meyer JS, Nadel HR, Marina N et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Childrens Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 2008; 51: 163170. 11. Wuisman P, Enneking WF. Prognosis of patients who have osteosarcoma with skip metastasis. J Bone Joint Surg 1990; 72A: 6068. 12. Kager L, Zoubek A, Kastner U et al. Skip metastases in osteosarcoma: experience of the Cooperative Osteosarcoma Study Group. J Clin Oncol 2006; 24: 15351541. 13. Rosen G, Marcove RC, Caparros B et al. Primary osteogenic sarcoma: the rationale for preoperative chemotherapy and delayed surgery. Cancer 1979; 43: 21632177. 14. Winkler K, Beron G, Kotz R et al. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J Clin Oncol 1984; 2: 617624. 15. Link MP, Goorin AM, Miser AW et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986; 314: 16001606. 16. Eilber F, Giuliano A, Eckardt J et al. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987; 5: 216. 17. Enneking WF, Soanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop Relat Res 1980; 153: 106120. 18. Gosheger G, Gebert C, Ahrens H et al. Endoprosthetic reconstrction in 250 patients with sarcoma. Clin Orthop 2006; 450: 164171. 19. Grimer RJ. Surgical options for children with osteosarcoma. Lancet Oncol 2005; 6: 8592. 20. Kotz RI, Windhager R, Dominkus M et al. A self-extending pediatric leg implant. Nature 2000; 406: 143144. 21. Hillmann A, Hoffmann C, Gosheger G et al. Malignant tumor of the distal part of the femur or the proximal part of the tibia: endoprosthetic replacement or rotationsplasty. Functional outcome and quality-of-life measurements. J Bone Joint Surg Am 1999; 81: 462468. 22. Ozaki T, Flege S, Kevric M et al. Osteosarcoma of the pelvis: experience of the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2003; 21: 334341.

23. Tomita K, Kawahara N, Murakami H et al. Total en bloc spondylectomy for spinal tumors: improvement of the technique and its associated basic background. J Orthop Sci 2006; 11: 312. 24. Hoffmann C, Gosheger G, Gebert C et al. Functional results and quality of life after treatment of pelvic sarcomas involving the acetabulum. J Bone Joint Surg Am 2006; 88: 575582. 25. Schwarz R, Bruland O, Cassoni A et al. The role of radiotherapy in osteosarcoma. Cancer Treat Res 2009; 152: 147165. 26. Franzius C, Bielack S, Flege S et al. High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin 2001; 40: 215220. 27. Franzius C, Schuck A, Bielack SS. High-dose Samarium-153 ethylene diamine tetramethylene phophonate: low toxicity of skeletal irradiation in patients with osteosarcoma and bone metastases. J Clin Oncol 2002; 20: 19531954. 28. Cortes EP, Holland JF, Wang JJ et al. Amputation and adriamycin in primary osteosarcoma. N Engl J Med 1974; 291: 9981000. 29. Ochs JJ, Freeman AI, Douglass HO et al. cis-Dichlorodiammineplatinum (II) in advanced osteogenic sarcoma. Cancer Treat Rep 1978; 62: 239245. 30. Jaffe N, Paed D, Farber S et al. Favorable response of metastatic osteogenic sarcoma to pulse high-dose methotrexate with citrovorum rescue and radiation therapy. Cancer 1973; 31: 13671373. 31. Harris MB, Cantor AB, Goorin AM et al. Treatment of osteosarcoma with ifosfamide: comparison of response in pediatric patients with recurrent disease versus patients previously untreated: a Pediatric Oncology Group study. Med Pediatr Oncol 1995; 24: 8792. 32. Goorin AM, Schwartzentruber DJ, Devidas M et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 2003; 21: 15741580. 33. Salzer-Kuntschik M, Brand G, Delling G. Bestimmung des morphologischen Regressionsgrades nach Chemotherapie bei malignen Knochentumoren. Pathologie 1983; 4: 135141. 34. Sauerbrey A, Bielack S, Kempf-Bielack B et al. High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCI) as salvage therapy for relapsed osteosarcoma. Bone Marrow Transpl 2001; 27: 933937. 35. Strander H, Bauer HC, Brosjo O et al. Long-term adjuvant interferon treatment of human osteosarcoma: a pilot study. Acta Oncol 1995; 34: 877880. 36. Marina N, Bielack S, Whelan J et al. International collaboration is feasible in trials for rare conditions: The EURAMOS experience. Cancer Treat Res 2009; 152: 339354. 37. Meyers PA, Schwartz CL, Krailo MD et al. Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival: a report from the s Oncology Group. J Clin Oncol 2008; 26: 633638. Children 38. Hunsberger S, Freidlin B, Smith MA. Complexities in interpretation of osteosarcoma clinical trial results (letter). J Clin Oncol 2008; 26: 31033104; author reply 31043105. 39. Bielack S, Marina N, Ferrari S et al. Osteosarcoma: the same old drugs or more? (letter). J Clin Oncol 2008; 26: 31023103; author reply 31043105. 40. Alvarez O, Freeman A, Bedros A et al. Randomized double-blind crossover ondansetrondexamethasone versus ondansetronplacebo study for the treatment of chemotherapy-induced nausea and vomiting in pediatric patients with malignancies. J Pediatr Hematol Oncol 1995; 17: 145150. 41. Lewis IJ, Nooij MA, Whelan J et al. Improvement in histologic response but not survival in osteosarcoma patients treated with intensied chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007; 99: 112128. 42. Kager L, Zoubek A, Potschger U et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols. J Clin Oncol 2003; 21: 20112018. 43. Ferrari S, Briccoli A, Mercuri M et al. Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term suvival. J Clin Oncol 2003; 21: 710715. 44. Kempf-Bielack B, Bielack SS, Ju rgens H et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol 2005; 20: 559568.

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2013

vii324 | Ritter & Bielack

Volume 21 | Supplement 7 | October 2010

Annals of Oncology

symposium article
48. Lipshultz SE, Lipsitz SR, Mone SM et al. Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 1995; 332: 17381743. dde A, Kleinebrand A et al. Unilateral nephrectomy and cisplatin as 49. Rossi R, Go risk-factors for ifosfamide-induced nephrotoxicity. Analysis of 120 patients. J Clin Oncol 1994; 12: 159165. 50. Aung L, Gurlick RG, Shi W et al. Second malignant neoplasms in long-term survivors of osteosarcoma: Memorial Sloan-Kettering Cancer Center Experience. Cancer 2002; 95: 17281734.

45. Bielack SS, Kempf-Bielack B, Branscheid D et al. Second and subsequent recurrences of osteosarcoma: presentation, treatment, and outcomes of 249 consecutive Cooperative Osteosarcoma Study Group patients. J Clin Oncol 2009; 27: 557565. 46. Carrle D, Bielack SS. Osteosarcoma lung metastases detection and principles of multimodal therapy. Cancer Treat Res 2009; 152: 165184. hr W, Paulides M et al. Prospective multicenter registration of major 47. Langer T, Sto late sequelae in sarcoma patients using the Late Effects Surveillance System (LESS). Klin Padiatr 2005; 217: 176181.

Downloaded from http://annonc.oxfordjournals.org/ by guest on March 26, 2013

Volume 21 | Supplement 7 | October 2010

doi:10.1093/annonc/mdq276 | vii325