osteosarcoma (jurnal inggris)

Annals of Oncology 21 (Supplement 7): vii320–vii325, 2010

doi:10.1093/annonc/mdq276symposium article

Osteosarcoma

J. Ritter1 & S. S. Bielack1,2*1Universitatsklinikum Munster, Klinik und Poliklinik fur Padiatrische Hamatologie und Onkologie, Munster, Germany; 2Klinikum Stuttgart,

Zentrum fur Kinder- und Jugendmedizin-Olgahospital, Padiatrie 5 (Onkologie, Hamatologie, Immunologie), Stuttgart, Germany

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 definitive surgical procedure should be

influenced 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

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 oftenmetastatic disease progression. Before the introduction ofpolychemotherapy >90% of patients with osteosarcoma diedfrom pulmonary metastases [1]

epidemiology

Osteosarcoma, the most frequent primary solid malignancyof bone, is defined by the presence of malignantmesenchymal cells which produce osteoid and/or immaturebone [1–3]. The incidence of osteosarcoma in the generalpopulation is 2–3/million/year, but is higher in adolescence, inwhich the annual incidence peaks at 8–11/million/year at15–19 years of age. Osteosarcomas account for 15% of all solidextracranial cancers in this age group. Males are affected1.4 times more frequently than females [4, 5].

etiology and pathogenesis

In most patients, the etiology of osteosarcoma remains obscure.The predilection of osteosarcoma for the age of the pubertal

growth spurt and the sites of maximum growth suggesta correlation with rapid bone proliferation. A minority ofosteosarcomas are caused by radiation exposure. Exposure toalkylating agents may also contribute to osteosarcomadevelopment. The incidence of osteosarcoma is increased inseveral well-defined hereditary disorders associated withgermline alterations of tumor suppressor genes such ashereditary retinoblastoma [1] and the Li–Fraumeni cancerfamily syndrome [6].

diagnosis and staging

Local pain, followed by localized swelling and limitation of jointmovement, are the typical signs and symptoms of osteosarcoma.In rare cases, particularly in patients with osteolytic tumors,a pathological fracture can be the first sign of disease.Approximately 15% of patients present with radiographicmetastases, most commonly to the lung, but metastases can alsodevelop 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 commonprimary sites are the distal femur, the proximal tibia, and theproximal humerus, with �50% originating around the knee[3, 7, 8]. About 10% develop in the axial skeleton, mostcommonly the pelvis [9].The evaluation of a patient with suspected osteosarcoma

begins with a full history, physical examination, and plainradiographs [10]. Plain radiography is helpful to describe

sym

po

siu

ma

rtic

le

*Correspondence to: Dr S. S. Bielack, Cooperative Osteosarkomstudiengruppe (COSS),

Klinikum Stuttgart-Olgahospital, Padiatrie 5 (Onkologie, Hamatologie, Immunologie),

Bismarckstr. 8, D-70176 Stuttgart, Germany, Tel: +49-711-2787-2461;

Fax: +49-711-2787-2462; E-mail: [email protected]

ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

All rights reserved. For permissions, please email: [email protected]

by guest on March 26, 2013

http://annonc.oxfordjournals.org/D

ownloaded from

http://annonc.oxfordjournals.org/

osseous changes: osteosarcomas can present with osteoblastic,osteolytic or mixed appearance. They often have a soft tissuecomponent in which patchy calcifications resulting from newbone formation or spiculae may be observed. A triangular areaof periosteal calcification in the border region of tumor andhealthy tissue is known as a Codman triangle, which isconsidered typical for osteosarcomas. Magnetic resonanceimaging (MRI) is the best modality to assess the soft tissuecomponent, its relationship to surrounding tissues, vessels andnerves, and its intramedullary extension, which is essential forsafe definitive surgery. MRI has to include the whole involvedbone as well as the neighboring joints, so as to not miss skiplesions, i.e. intramedullary tumor foci without direct contactwith 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 specific tumor markers;however, an elevation of lactate dehydrogenase or, morefrequently, alkaline phosphatase levels in serum is found insome patients. Both have been associated with inferioroutcomes. Since polychemotherapy for osteosarcoma can resultin cardiac and auditory dysfunction and significant kidney andliver toxicity, patients should have baseline assessmentsincluding echocardiography, an audiogram, and liver andkidney function test (Table 1).

histopathology

The diagnosis of osteosarcoma must always be verifiedhistologically. Because of the broad spectrum of histologicalappearances and the rarity of the tumor, it is stronglyrecommended that biopsies should be performed in specializedcenters, so that appropriate biopsy techniques and appropriatehistological examination of the obtained material areguaranteed, including genetic evaluation where necessary. Openbiopsy is considered the most suitable technique to obtainsufficient material for histological evaluation and additional

studies. True-cut needle biopsy may also be used, provided thatsufficient material can be obtained, while fine-needle biopsiesare not appropriate.The biopsy specimen should be forwarded to the specialized

pathologist without prior fixation. The hallmark of diagnosis isthe proliferation of malignant mesenchymal tumor cells and theproduction of osteoid and/or bone by these tumor cells. Theamount of osteoid and/or bone production varies greatlybetween tumors and within an individual tumor. Thus,identification of diagnostic osteoid may require extensivesampling. Chondroid and fibrous matrix may also be present,reflecting the mesenchymal origin of the malignant cells. Thecurrent World Health Organization (WHO) classification [1]recognizes three major subtypes of conventional osteosarcoma:osteoblastic, condroblastic and fibroblastic, reflecting thepredominant type of matrix within the tumor. In addition toclassical osteosarcoma, the WHO classification recognizesadditional histological variants, including telangiectaticosteosarcoma, small cell osteosarcoma, parosteal and periostealosteosarcomas, as well as low grade central and high gradesurface osteosarcomas [1]. The classical central subtypes arenearly always WHO grade III high malignant tumors, whereassurface osteosarcomas are mostly low grade I or intermediategrade II tumors. The current TNM (tumor–node–metastasis)classification of osteosarcomas is shown in Table 2.

Table 1. Recommended diagnostic work-up for osteosarcoma patients

Primary tumor

X-ray Tumor localization in two planes

Whole extremity p/a

Magnetic resonance imaging Whole extremity/tumor region

Metastases99mTc bone scan Whole skeleton

Computed tomography Chest

Organ function

Heart Echocardiogram, electrocardiogram

Hearing Audiogram

Kidney Creatinine (including estimated

clearance)

Tubular function tests

Liver Liver function tests

Other laboratory

Alkaline phosphatase i.S.

Lactate dehydrogenase i.S.

i.S., in serum.

Table 2. TNM classification of bone sarcoma [2]

Tx Primary tumor cannot be

assessed

T0 No evidence of primary

tumor

T1 Tumor £8 cm in greatest

dimension

T2 Tumor >8 cm in greatest

dimension

T3 Discontinuous tumors in

the primary bone site

NX Regional lymph nodes

cannot be assessed

N0 No regional lymph node

metastasis

N1 Regional lymph node

metastasis

MX Distant metastases cannot

be assessed

M0 No distant metastases

M1 Distant metastases

M1a Lung

M1b Other distant sites

Stage IA T1 N0 M0 (low grade)

Stage IB T2 N0 M0 (low grade)

Stage IIA T1 N0 M0 (high grade)

Stage IIB T2 N0 M0 (high grade)

Stage III T3 N0 M0 (any grade)

Stage IVA Any T N0 M1a (any grade)

Stage IVB Any T N1 Any M (any grade)

Any T Any N M1b (any grade)

Annals of Oncology symposium article

Volume 21 | Supplement 7 |October 2010 doi:10.1093/annonc/mdq276 | vii321



ownloaded from


rationale for a multidisciplinarytreatment approach

Local therapy alone is insufficient, as 80–90% of all patientswith seemingly localized disease will develop metastases, mostlyin the lungs, and will die if chemotherapy is not included aspart of the multidisciplinary treatment [3]. Early studiesdescribing the efficacy of multiagent chemotherapy includedthose by Rosen et al. in North America [13] and by Winkleret al. in Europe [14]. Two randomized trials in North Americaproved the efficacy of chemotherapy [15, 16]. Currenttreatment regimens encompassing primary (preoperative;neoadjuvant) induction chemotherapy, followed by definitesurgery and then postoperative (adjuvant) chemotherapy leadto cure in approximately two-thirds of patients with seeminglylocalized disease [3, 8]. The total duration of chemotherapy isusually at least 6–8 months.

treatment

surgery

The goal of osteosarcoma surgery must always be completetumor removal. Margins should be at least wide according toEnneking’s definition [17] (Table 3), meaning that the tumorincluding the biopsy scar has to be removed surrounded by aninviolated cuff of healthy tissue. Advances in imagingtechniques and in biomedical engineering as well as positiveeffects of preoperative chemotherapy have led to a majorshift away from amputation towards limb-salvage surgery[3, 6, 8, 18, 19]. Options for reconstruction after limb-sparingtumor resections are manifold and include endoprostheticdevices [18–20], biological reconstruction, or a combination ofboth. Rotation-plasty, another well-established biologicalreconstruction method for tumors around the knee, can resultin functional and psychological outcomes equal or evensuperior to endoprosthetic reconstruction [21], but iscosmetically challenging.Surgery of sarcomas of the axial skeleton remains particularly

challenging, both because local recurrence poses a great hazardand because complications after reconstruction are frequent[19, 22, 23]. It is essential that surgeons are aware of all surgicaltechniques and implement the most appropriate one for eachindividual patient after consultation within themultidisciplinary osteosarcoma team. More recent advances

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

radiotherapy

Osteosarcoma was long considered a radioresistant tumor, thusthe experience with radiotherapy in local treatment ofosteosarcomas is limited [25]. However, recent data suggestthat the administration of radiotherapy may be useful inpatients treated with multiagent chemotherapy who are unableto undergo complete resection or who have microscopicresidual tumor foci following attempted resection [22]. The useof targeted radiotherapy with Samarium-153-ethylendiametetramethylene phosphonate may also be considered in selectedsituations, although the role of this treatment modality is notwell defined and its definition would require further evaluationin controlled clinical trials [26, 27].

systemic therapy

polychemotherapy. Currently, doxorubicin [28], cisplatin [29],high-dose methotrexate with leukovorin-rescue [30] andifosfamide [31] are considered the most active agents againstosteosarcoma, but the ideal combination remains to be defined.Most current protocols include a period of preoperative(neoadjuvant) chemotherapy, even though this has not provedto add a survival benefit over postoperative (adjuvant)chemotherapy alone [32]. The extent of histological response topreoperative chemotherapy [33], however, offers importantprognostic information. Current prospective trials evaluatewhether altering postoperative chemotherapy in poorresponders improves outcomes. The use of high-dosechemotherapy followed by retransfusion of autologoushematological stem cells has not led to improved outcomes[34].immunomodulation. An early, uncontrolled Swedish series ofsingle-agent treatment with a-interferon reported promisingresults [35]. The current EURAMOS 1 Intergroup Study isevaluating a-interferon maintenance after completion ofchemotherapy in a randomized study [36]. Addition of theimmunomodulator liposomal muramyl tripeptidephosphatidyl ethanolamine (MTP) to postoperativechemotherapy was reported to correlate with a statisticallysignificant advantage in overall survival and a non-significanttrend in event-free survival in a follow-up report of a recentrandomized trial [37]. The study’s design and associatedstatistical limitations have been criticized, leading severalauthors to recommend that the exact role, if any, of this newimmunomodulatory treatment remains to be proven in furtherstudies [38, 39].

supportive care

Together with the therapeutic advances in osteosarcomamanagement with polychemotherapy, a number of agents havebeen developed to help reduce the chemotherapy-relatedtoxicity. The introduction of serotonin antagonists [40] hasdramatically reduced chemotherapy-induced emesis. Suchagents alone or in combination with dexamethasone havebecome the standard of care with the use of highly emetogenicchemotherapy, especially cisplatin. Other agents used in

Table 3. Enneking’s criteria for surgical margins in musculoskeletal

tumors [17]

Margin Dissection

Intralesional Within the lesion

Marginal Through the pseudocapsule or reactive tissue

Wide 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

Radical Entire anatomic compartment containing the

tumor removed as one block

symposium article Annals of Oncology

vii322 | Ritter & Bielack Volume 21 | Supplement 7 |October 2010



ownloaded from


supportive care of osteosarcoma patients include opioids fortumor pain control and hematopoetic growth factors todecrease the incidence and duration of chemotherapy-inducedsevere granulocytopenia. The addition of granulocyte colony-stimulating factor (G-CSF) to chemotherapy led to increaseddose density of treatment and improved histologic response,but not to improved survival rates in a randomized trial by theEuropean Osteosarcoma Intergroup [41].

treatment of metastatic disease andrelapse

Curative treatment for primary metastatic osteosarcoma isidentical to that of localized disease, with the mandatoryaddition of surgical removal of all know metastatic foci,usually by exploratory thoracotomy including palpation of thewhole lung [42]. Approximately 30% of all patients withprimary metastatic osteosarcoma and >40% of those whoachieve a complete surgical remission can become long-termsurvivors [42].Treatment for relapse, either locally or within the lungs, is

primarily surgical. The prognosis is poor, with long-term post-relapse survival in <20%. Complete removal of all metastasismust be attempted, as the disease is otherwise almostuniversally fatal. In contrast, more than a third of the patientswith a second surgical remission survive 5 years or more. Evenpatients with multiple recurrences may be cured as long asrecurrences are resectable, and repeated thoracotomies areoften warranted [43–45]. Overall, CT scans tend tounderestimate the number of pulmonary metastases and mayalso fail to detect contralateral involvement in patients withseemingly unilateral pulmonary metastasis [46]. Thus, bilateralexploration by open thoracotomy including palpation of bothlungs is recommended.The role of second-line chemotherapy for recurrent

osteosarcoma is much less well defined than that of surgery,and there is no accepted standard regime. Choice may take intoaccount the prior free interval and disease resectability,and often includes ifosfamide, etoposide and/or carboplatin[43–46].

follow-up and late effects of treatment

Follow-up intervals recommended in most trials are every 6weeks to 3 months in years 1 and 2 after diagnosis, every2–4 months in years 3 and 4, every 6 months in years 5–10 andevery 6–12 months thereafter. Each visit should includea history and physical examination, and a chest X-ray (Table 4).Since late metastases may occur >10 years after diagnosis, thereis no universally accepted stopping point for tumorsurveillance. As in other childhood cancers, cured patients needlifelong follow-up [47].Polychemotherapy of osteosarcoma may be associated with

permanent alterations of cardiac [48], renal [49], auditory andreproductive function, orthopedic problems and other lateeffects including secondary malignancies [50]. Thusappropriate investigations to detect these late effects as early aspossible should be included during regular follow-up (Table 4).

outlook

While surgical reconstruction techniques have improvedconsiderably over the past decades, allowing limb salvage inmost patients, chemotherapy still relies on the same drugsas in the early 1980s, and survival rates have not improvedsince then. Translational research is required to identifytargets for novel treatment modalities. Due to the rarity ofdisease, pivotal trials evaluating the addition of innovativetherapies to conventional regimens will require multicenter,multinational, often intergroup collaboration. The activationof any clinical trial in a rare disease at centers which maysee a patient a year or less—as is the case for most medicaloncology institutions treating osteosarcoma—iscumbersome and associated with little or no financialincentive. This should not deter us from trying to include asmany young adults as possible in interdisciplinary trialsof this cancer which so typically occurs at the pediatric–adultinterface.

Table 4. Suggestions for follow-up investigations after multimodal

therapy for osteosarcoma

Time Tumor directed Late effects

Baseline X-ray chest and CT Echocardiogram, audiogram,

liver and kidney function,

hepatitis B/C and HIV

serology

X-ray and (CT)/MRI

primary site

Years 1

and 2

X-ray chest every

6–12 weeks

X-ray primary site

every 4 months

Echocardiogram every

1–2 years, audiograma,

livera and kidney function

Years 3

and 4

X-ray chest

every6 2–4 months


1–2 years

X-ray primary site

every 4 months

Years 5–10 X-ray chest every

6 monthsbEchocardiogram every

2–4 years

Thereafter (Few) relapses reported

as late as two decades

after treatment. Discuss

with patient whether to

continue chest X-ray

every 6–12 months


2–4 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.aNeed not be repeated if normal at 1 year.bSome groups recommend annual radiographs of the primary site until

year 10.

CT, computed tomography, HIV, human immunodefiency virus; MRI,

magnetic resonance imaging.





ownloaded from


disclosures

J. R., no potential conflict of interest; S. B. consultant for IDM,Roche, Takeda Millennium and Advisory Board Membership ofMerck & Co.

references

1. Fletcher CDM, Unni KK. Pathology and genetics of tumours of soft tissue and

bone. In Mertens F (ed): World Health Organization Classification of Tumours.

Lyon, France: IARC Press 2002.

2. Sobin LH, Wittekind C. UICC-TNM Classificaton 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: 342–352.

4. Stiller CA, Bielack SS, Jundt G et al. Bone tumours in European children and

adolescents, 1978–1997. Report form the Automated Childhood Cancer

Infromation System project. Eur J Cancer 2006; 42: 2124–2135.

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:

760–766.

6. Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer and other neoplasms.

A familial syndrome? Ann Intern Med 1969; 71: 747–752.

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: 776–790.

8. Bielack S, Jurgens H, Jundt G et al. Osteosarcoma: the COSS experience.

Cancer Treat Res 2009; 152: 289–308.

9. Ozaki T, Flege S, Liljenquist U et al. Osteosarcoma of the spine: experience of

the Cooperative Osteosarcoma Study Group. Cancer 2002; 94: 1069–1077.

10. Meyer JS, Nadel HR, Marina N et al. Imaging guidelines for children with Ewing

sarcoma and osteosarcoma: a report from the Children‘s Oncology Group Bone

Tumor Committee. Pediatr Blood Cancer 2008; 51: 163–170.

11. Wuisman P, Enneking WF. Prognosis of patients who have osteosarcoma with

skip metastasis. J Bone Joint Surg 1990; 72A: 60–68.

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: 1535–1541.

13. Rosen G, Marcove RC, Caparros B et al. Primary osteogenic sarcoma: the

rationale for preoperative chemotherapy and delayed surgery. Cancer 1979; 43:

2163–2177.

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:

617–624.

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: 1600–1606.

16. Eilber F, Giuliano A, Eckardt J et al. Adjuvant chemotherapy for osteosarcoma:

a randomized prospective trial. J Clin Oncol 1987; 5: 21–6.

17. Enneking WF, Soanier SS, Goodman MA. A system for the surgical staging of

musculoskeletal sarcoma. Clin Orthop Relat Res 1980; 153: 106–120.

18. Gosheger G, Gebert C, Ahrens H et al. Endoprosthetic reconstrction in 250

patients with sarcoma. Clin Orthop 2006; 450: 164–171.

19. Grimer RJ. Surgical options for children with osteosarcoma. Lancet Oncol 2005;

6: 85–92.

20. Kotz RI, Windhager R, Dominkus M et al. A self-extending pediatric leg implant.

Nature 2000; 406: 143–144.

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: 462–468.

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:

334–341.

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: 3–12.

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: 575–582.

25. Schwarz R, Bruland O, Cassoni A et al. The role of radiotherapy in osteosarcoma.

Cancer Treat Res 2009; 152: 147–165.

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: 215–220.

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: 1953–1954.

28. Cortes EP, Holland JF, Wang JJ et al. Amputation and adriamycin in primary

osteosarcoma. N Engl J Med 1974; 291: 998–1000.

29. Ochs JJ, Freeman AI, Douglass HO et al. cis-Dichlorodiammineplatinum (II) in

advanced osteogenic sarcoma. Cancer Treat Rep 1978; 62: 239–245.

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: 1367–1373.

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: 87–92.

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: 1574–1580.

33. Salzer-Kuntschik M, Brand G, Delling G. Bestimmung des morphologischen

Regressionsgrades nach Chemotherapie bei malignen Knochentumoren.

Pathologie 1983; 4: 135–141.

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: 933–937.

35. Strander H, Bauer HC, Brosjo O et al. Long-term adjuvant interferon treatment of

human osteosarcoma: a pilot study. Acta Oncol 1995; 34: 877–880.

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:

339–354.

37. Meyers PA, Schwartz CL, Krailo MD et al. Osteosarcoma: The addition of

muramyl tripeptide to chemotherapy improves overall survival: a report from the

Childrens Oncology Group. J Clin Oncol 2008; 26: 633–638.

38. Hunsberger S, Freidlin B, Smith MA. Complexities in interpretation of

osteosarcoma clinical trial results (letter). J Clin Oncol 2008; 26: 3103–3104;

author reply 3104–3105.

39. Bielack S, Marina N, Ferrari S et al. Osteosarcoma: the same old drugs or more?

(letter). J Clin Oncol 2008; 26: 3102–3103; author reply 3104–3105.

40. Alvarez O, Freeman A, Bedros A et al. Randomized double-blind crossover

ondansetron–dexamethasone versus ondansetron–placebo study for the

treatment of chemotherapy-induced nausea and vomiting in pediatric patients

with malignancies. J Pediatr Hematol Oncol 1995; 17: 145–150.

41. Lewis IJ, Nooij MA, Whelan J et al. Improvement in histologic response but not

survival in osteosarcoma patients treated with intensified chemotherapy:

a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl

Cancer Inst 2007; 99: 112–128.

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: 2011–2018.

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:

710–715.

44. Kempf-Bielack B, Bielack SS, Jurgens 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: 559–568.

symposium article Annals of Oncology

vii324 | Ritter & Bielack Volume 21 | Supplement 7 |October 2010



ownloaded from


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: 557–565.

46. Carrle D, Bielack SS. Osteosarcoma lung metastases detection and principles of

multimodal therapy. Cancer Treat Res 2009; 152: 165–184.

47. Langer T, Stohr W, Paulides M et al. Prospective multicenter registration of major

late sequelae in sarcoma patients using the Late Effects Surveillance System

(LESS). Klin Padiatr 2005; 217: 176–181.

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: 1738–1743.

49. Rossi R, Godde A, Kleinebrand A et al. Unilateral nephrectomy and cisplatin as

risk-factors for ifosfamide-induced nephrotoxicity. Analysis of 120 patients.

J Clin Oncol 1994; 12: 159–165.

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: 1728–1734.





ownloaded from


osteosarcoma (jurnal inggris)

Documents