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Annals of Oncology20 (Supplement 4): iv137iv139, 2009

doi:10.1093/annonc/mdp154clinical recommendations

Osteosarcoma: ESMO Clinical Recommendations for

diagnosis, treatment and follow-up

S. Bielack1, D. Carrle1 & P. G. Casali2

On behalf of the ESMO Guidelines Working Group*1Cooperative Osteosarcoma Study Group, Department of Pediatric Oncology and Hematology, Olgahospital, Stuttgart, Germany; 2Department of Cancer Medicine,

Istituto nazionale dei Tumori, Milan, Italy

incidence

Osteosarcoma is the most frequent primary cancer of bone(incidence: 0.23/100 000/year). The incidence is higher inadolescents (0.811/100 000/year at age 1519), where itaccounts for >10% of all solid cancers. The male:female ratio is1.4. It usually arises in the metaphysis of a long extremitybone, most commonly around the knee. Involvement of theaxial skeleton or craniofacial bones is observed primarilyin adults.

diagnosis

Typical signs and symptoms are: history of pain, followed bylocalized swelling and limitations of joint movement andtypical findings on X-rays. Definitive diagnosis requireshistological examination of tumor material, which is generallyobtained by open biopsy. Patients with findings suggestive ofosteosarcoma should be sent to a reference center before biopsy

[IV, C], as inappropriate techniques can irrevocablycompromise chances for limb salvage or even cure.

By definition, the malignant cell population must produceosteoid for a tumor to be classified as osteosarcoma.Conventional osteosarcoma, a high-grade malignancy, accountsfor 8090% of all osteosarcomas. Its most frequent subtypes areosteoblastic, chondroblastic, and fibroblastic. Other high-gradetypes are teleangectasic, small cell osteosarcoma, and high-grade surface osteosarcoma. Low-grade central osteosarcomaand paraosteal osteosarcoma are low-grade malignancies, whileperiosteal osteosarcoma is an intermediate-gradechondroblastic osteosarcoma. Secondary osteosarcoma isa generally high-grade malignancy occurring in bone affectedby pre-existing abnormalities, mainly Paget disease and

radiation-therapy-induced changes. Confirmation of diagnosisby a pathologist with particular expertise in bone tumors isrecommended [IV, C].

staging and risk assessment

The primary tumor must be evaluated by plain radiographs intwo planes, which are mainly helpful to describe osseouschanges, complemented by cross-sectional imaging, ideallymagnetic resonance imaging (MRI), both of which should beperformed before biopsy. MRI is considered the most usefultool to evaluate an osteosarcomas intramedullary and softtissue extension and its relation to vessels and nerves. Theregion assessed by MRI should include the whole involved boneas well as the neighboring joints, so as to not miss skiplesions (intramedullary tumor foci without direct contact withthe primary lesion).

Systemic staging must focus on the lungs and the skeleton, inwhich the majority of metastases arise, and should include chest

X-rays, a CT scan of the thorax (preferably using a spiraltechnique performed with 5 mm collimation and obtainedduring a single breathhold) and a radionuclide bone scan,complemented by X-rays and/or MRI scans of affected areas.Appropriate imaging must be repeated before surgery of theprimary tumor or of known metastases.

For many years, the Musculoskeletal Tumor Society stagingsystem, which distinguishes between two grades of malignancy(low versus high) and intra- and extracompartmental extension,has been the one most widely used. There, the vast majority ofosteosarcomas are classified as stage IIB. The current 6th editionof the UICC-TNM is an advancement of this system.

There are no specific laboratory tests for osteosarcoma,

alkaline phosphatase (AP) and lactate dehydrogenase (LDH)are non-specific. Elevated levels correlate with adverse outcomes.A variety of laboratory tests is required before

interdisciplinary treatment is started. These are directedtowards assessing organ function and general health.Recommended tests include a complete blood count anddifferential, blood group typing, a coagulation profile, tests forserum electrolytes including magnesium and phosphate, renaland liver function tests as well as hepatitis and HIV testing.Since chemotherapy treatment for osteosarcoma can result incardiac and auditory dysfunction, patients should also have

*Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L.

Taddei 4, CH-6962 Viganello-Lugano, Switzerland;

E-mail: clinicalrecommendations@esmo.org

Approved by the ESMO Guidelines Working Group: August 2002, last update

December 2008. This publication supercedes the previously published versionAnn

Oncol 2008; 19 (Suppl 2): ii94ii96.

Conflict of interest: Dr Bielack has not reported any conflicts of interest. Dr Carrle has

reported that she received a travel grant from IDM Pharma. Dr Casali has reported that

he is currently conducting research sponsored by Lilly.

The Author 2009. 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

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baseline assessment by echocardiogram or radionuclideventriculography as well as an audiogram. Sperm storage isrecommended for male patients of reproductive age.

Adverse prognostic factors include proximal extremity oraxial tumor site, large tumor volume, elevated serum AP orLDH, and foremost detectable primary metastases and poorhistological response to preoperative chemotherapy [III, B].

treatment planlocalized tumors

Patients with osteosarcoma should be treated in referencecenters able to provide access to the full spectrum of care orshared with such centers within reference networks [IV, C].There, therapy is usually given within the framework ofprospective, often collaborative, clinical studies, or establishedtreatment protocols.

Curative treatment for high-grade osteosarcoma consists ofsurgery and chemotherapy [Ib, A]. Compared with surgeryalone, multimodal treatment of high-grade osteosarcomaincreases disease-free survival probabilities from only 1020%

to>

60%.The goal of surgery is to safely remove the tumor and yetpreserve as much function as possible. Most patients should beconsidered candidates for limb salvage. Surgical margins at leastwide by Ennekings definition, implying complete removal ofthe tumor (including the biopsy tract) surrounded by anunviolated cuff of normal tissue, must be attempted, asnarrower margins are associated with an increased risk of localrecurrence [III, B]. Radiotherapy has a limited role and shouldbe reserved for inoperable situations [IV, C].

Currently, doxorubicin, cisplatin, high-dose methotrexatewith leucovorin rescue and ifosfamide are considered the mostactive agents against osteosarcoma [Ib, A], but the idealcombination remains to be defined. Effective regimens employ

several of the aforementioned drugs, usually over a period of 612 months. The use of growth factors either to allow doseescalation to maximal doses of all agents [III, C] or an increasein dose intensity [Ib, A] does not appear to improve survivalexpectancies further. Addition of the immune modulatormuramyl tripeptide (MTP) to postoperative chemotherapycorrelated with a statistically significant advantage in overallsurvival and a non-significant trend in event-free survival ina recently published randomized trial. Following its approval byEMEA, the addition of MTP to the standard regimens forlocalized osteosarcoma, outside clinical trials, is therefore anoption for a shared decision making with the patient inconditions of uncertainty.

Most current protocols include a period of preoperativechemotherapy, although this has not been proved to addsurvival benefit over postoperative chemotherapy alone [Ib, B].The extent of histological response to preoperativechemotherapy, however, offers important prognosticinformation [Ib, A]. Current prospective trials evaluate whetheraltering postoperative chemotherapy in poor respondersimproves outcomes. As yet, the benefit of such an approachremains to be proved.

The multimodal treatment principles detailed above weregenerated in children, adolescents and young adults with high-

grade central osteosarcoma, but also relate to adults at least upto the age of 60 [III, B] and to rarer variants of high-gradeosteosarcoma, such as high-grade surface, secondary [III, B].Low-grade central and parosteal osteosarcoma are variants withlower malignant potential which are treated by surgery only[III, B], and the exact role of chemotherapy has not beendefined for periosteal osteosarcoma, while craniofacialosteosarcoma may display a low or a high malignancy grade

and is generally approached accordingly [III, B].

metastatic disease and recurrent disease

Curative treatment for primary metastatic osteosarcoma issimilar or even identical to that of localized disease, with themandatory addition of surgical removal of all known metastaticdeposits [III, B], usually by exploratory thoracotomy includingpalpation of the lung. Approximately 30% of all patients withprimary metastatic osteosarcoma and >40% of those whoachieve a complete surgical remission become long-termsurvivors.

Treatment for recurrent osteosarcoma is primarily surgical.Prognosis is poor, with long-term post-relapse survival in

5 years. Even patients with multiplerecurrences may be cured as long as recurrences are resectable,and repeated thoracotomies are often warranted [III, B].

Overall, CT scans tend to underestimate the number ofpulmonary metastases and may also fail to detect contralateralinvolvement in patients with seemingly unilateral pulmonarymetastases [III, B]. Bilateral exploration by open thoracotomy,including palpation of both lungs, is therefore recommended[IV, C].

The role of second-line chemotherapy for recurrentosteosarcoma is much less well defined than that of surgery andthere is no accepted standard regimen. Choice may take intoaccount the prior free interval, and often includes ifosfamide 6etoposide 6 carboplatin, etc. In the two largest reported series,the use of second-line chemotherapy correlated with limitedprolongation of survival in patients with inoperable metastaticrecurrences, while a positive correlation in operable disease wasobserved in only one of the two. Radiotherapy to inoperablesites can be indicated for palliation and may be associated withlimited prolongation of survival.

follow-up

Follow-up intervals recommended in current multinational

trials are every 6 weeks to 3 months in years 1 and 2 afterdiagnosis, every 24 months in years 3 and 4, every 6 months in

years 510 and every 612 months thereafter. Each visit shouldinclude a history and physical examination and a chest X-ray[IV, C]. X-rays of the primary tumor site are recommendedevery 4 months until the end of year 4 [IV, C]. Late metastasesmay occur >10 years after diagnosis and there is no universallyaccepted stopping point for tumor surveillance.

Multimodal therapy of osteosarcoma may be associated withpermanent alterations of cardiac, renal, auditory andreproductive function, orthopedic problems and other late

clinical recommendations Annals of Oncology

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effects including secondary malignancies, and appropriateinvestigations should be included during regular follow-up[IV, C].

note

Levels of Evidence [IV] and Grades of Recommendation[AD] as used by the American Society of Clinical Oncology

are given in square brackets. Statements without grading wereconsidered justified standard clinical practice by the experts andthe ESMO Faculty.

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Annals of Oncology clinical recommendations

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