2001 CTOS Annual Meeting Posters— Surgery

AN OVERVIEW OF TREATMENTS RESULTS IN OSTEOSARCOMA: IS THERE A NEED FOR A GLOBAL COLLABORATION?
Sigbjørn Smeland
Norwegian Radium Hospital

METHODS: Review the literature of treatment results in high-grade osteosarcoma. Published results from prospective phase II studies including more than 100 patients and randomized studies are included in this analyses.

RESULTS: High-grade osteosarcoma are rare tumors that make up approx. 0.1 % of all malignant tumors. Introduction of intensive chemotherapy has significantly improved the prognosis for patients with non-metastatic disease and most patients with extremity localized tumors are currently operated with limb saving procedures. However, there have been no major improvements in outcome for the last 15 years and subgroups of patients still harbor a very poor prognosis. Most progress is osteosarcoma treatment is obtained from prospective phase II studies in patients with non-metastatic extremity localized tumors in patients aged < 40 years (classical osteosarcoma). The best centers report a 5-year overall survival of 70% and currently more than 80% of the patients are operated with a limb saving approach. Poor prognostic factors at time of diagnosis include presence of metastatic disease, axial localization and large tumor volume. Age is not a consistent prognostic factor in osteosarcoma. Surgical margins, tumor necrosis and treatment duration are important treatment related factors. Due to difference in post-operative therapy the true impact of tumor necrosis is hard to assess; in large randomized trials with similar post-operative therapy to good and poor responders the differences in event-free survival are in the range from 25 to 40%. Most centers agree that a three-drug combination with methotrexate, doxorubicin and cisplatinum should be given up-front to all patients and several groups also include ifosfamide to all or subgroups of patients in primary treatment. The schedule of therapy is still being investigated and important issues yet to be answered are the optimal use ifosfamide and comulative dose of doxorubicin. Such answers are likely only to be obtained in randomized trials. The lack of progress in treatment of osteosarcoma for the last 15 years justify the introduction of novel treatment approaches and specially to patients with an inherently poor prognosis. Candidate agents include interferon- and the immunostimulator, muramyl-tripeptide. For relapsed patients the prognostic factors important for outcome are in addition to surgical remission, extent of and time to relapse and application of adequate second-line chemotherapy. The benefit of radiotherapy for patients with inoperable disease/intralesional surgery is debated and needs further elucidation. Even with maximal doses of chemotherapy, the prognosis for patients with primary metastatic disease is dismal and there is no support in current literature for the use of myeloablative chemotherapy. In the Scandinavian Sarcoma Groups database containing 485 patients with osteosarcoma, 30% of the patients belongs to a heterogeneous group of patients with non-extremity localized tumors and/or secondary osteosarcomas and/or age> 40 years, that up to date have been excluded from most (inter)national trials. The treatment principles are based on data obtained from trial conducted on mainly classical osteosarcomas assuming a similar biology for the whole group of patients.

CONCLUSION: The rarity of osteosarcoma strongly argue for international collaboration to obtain further progress in treatment and insight in the biology of the disease. In primary treatment randomized trails are needed both to optimize the scheduling of the currently known active drugs and to test out novel treatment agents. For non-classical osteosarcomas and relapsed patients international prospective phase II studies are needed to test out treatment regimens and to identify prognostic factors in these patients.