title: Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup.
abstract: BACKGROUND
  A previous trial by the European Osteosarcoma Intergroup (EOI) suggested that a short intensive chemotherapy regimen with doxorubicin and cisplatin might produce survival of operable, non-metastatic osteosarcoma similar to that obtained with complex and longer-duration drug regimens based on the widely used T10 multi-drug protocol. We undertook a randomised multicentre trial to compare these two approaches.
  
  
  METHODS
  407 patients with operable, non-metastatic osteosarcoma were randomly assigned the two-drug regimen (six cycles [18 weeks] of doxorubicin 25 mg/m2 on days 1-3 and cisplatin 100 mg/m2 on day 1) or a multi-drug regimen (preoperatively vincristine, high-dose methotrexate, and doxorubicin; postoperatively bleomycin, cyclophosphamide, dactinomycin, vincristine, methotrexate, doxorubicin, and cisplatin; this protocol took 44 weeks). Surgery was scheduled for week 9 for the two-drug group and week 7 for the multi-drug group. Analyses of survival and progression-free survival were by intention to treat.
  
  
  RESULTS
  Of 407 randomised patients, 391 were eligible and have been followed up for at least 4 years (median 5-6 years). Toxic effects were qualitatively similar with the two regimens. However, 188 (94%) of 199 patients completed the six cycles of two-drug treatment, whereas only 97 (51%) of 192 completed 18 or more of the 20 cycles of the multi-drug regimen. The proportion showing a good histopathological response (> 90% tumour necrosis) to preoperative chemotherapy was about 29% with both regimens and was strongly predictive of survival. Overall survival was 65% at 3 years and 55% at 5 years in both groups (hazard ratio 0.94 [95% CI 0.69-1.27]). Progression-free survival at 5 years was 44% in both groups (hazard ratio 1.01 [0.77-1.33]).
  
  
  CONCLUSIONS
  We found no difference in survival between the two-drug and multi-drug regimens in operable, non-metastatic osteosarcoma. The two-drug regimen is shorter in duration and better tolerated, and is therefore the preferred treatment. However, 5-year survival is still unsatisfactory and new approaches to treatment, such as dose intensification, are needed to improve results.
authors.affiliation: University College London Medical School, UK.
authors.forename: R L
authors.initials: RL
authors.lastname: Souhami
authors.forename: A W
authors.initials: AW
authors.lastname: Craft
authors.forename: J W
authors.initials: JW
authors.lastname: Van der Eijken
authors.forename: M
authors.initials: M
authors.lastname: Nooij
authors.forename: D
authors.initials: D
authors.lastname: Spooner
authors.forename: V H
authors.initials: VH
authors.lastname: Bramwell
authors.forename: R
authors.initials: R
authors.lastname: Wierzbicki
authors.forename: A J
authors.initials: AJ
authors.lastname: Malcolm
authors.forename: A
authors.initials: A
authors.lastname: Kirkpatrick
authors.forename: B M
authors.initials: BM
authors.lastname: Uscinska
authors.forename: M
authors.initials: M
authors.lastname: Van Glabbeke
authors.forename: D
authors.initials: D
authors.lastname: Machin
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D002648:Child; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D004317:Doxorubicin; D002945:Cisplatin