title: A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study.
abstract: OBJECTIVE
  After standard multimodal therapy, the prognosis of relapsed and unresectable high-grade osteosarcoma is dismal and unchanged over the last decades. Recently, mitogen-activated protein kinases were shown to be activated in osteosarcoma specimens, suggesting, therefore, they are suitable targets for the multikinase inhibitor sorafenib. Thus, we explored sorafenib activity in patients with relapsed and unresectable osteosarcoma.
  
  
  METHODS
  Patients > 14 years, progressing after standard treatment, were eligible to receive 400 mg of sorafenib twice daily until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) at 4 months. Secondary objectives were PFS, overall survival (OS), clinical benefit rate (CBR), defined as no progression at 6 months and safety. This nonrandomized phase II study used a Simon two-stage design. PFS and OS at 95% confidence intervals (95% CIs) were calculated by the Kaplan-Meier method. All tests were two sided.
  
  
  RESULTS
  Thirty-five patients were enrolled. PFS at 4 months was 46% (95% CI 28% to 63%). Median PFS and OS were 4 (95% CI 2-5) and 7 (95% CI 7-8) months, respectively. The CBR was 29% (95% CI 13% to 44%). We observed 3 (8%) partial responses (PRs), 2 (6%) minor responses (< 30% tumor shrinkage) and 12 (34%) stable diseases (SDs). For six patients (17%), PR/SD lasted ≥ 6 months. Noteworthy, tumor density reduction and [(18)F]2-fluoro-2-deoxy-d-glucose-positron emission tomography responses were observed among SD patients. Sorafenib was reduced or briefly interrupted in 16 (46%) patients and permanently discontinued in one (3%) case due to toxicity.
  
  
  CONCLUSIONS
  Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.
authors.affiliation: Medical Oncology Unit, Institute for Cancer Research and Treatment, Candiolo, Italy. giovanni.grignani@ircc.it
authors.forename: G
authors.initials: G
authors.lastname: Grignani
authors.forename: E
authors.initials: E
authors.lastname: Palmerini
authors.forename: P
authors.initials: P
authors.lastname: Dileo
authors.forename: S D
authors.initials: SD
authors.lastname: Asaftei
authors.forename: L
authors.initials: L
authors.lastname: D'Ambrosio
authors.forename: Y
authors.initials: Y
authors.lastname: Pignochino
authors.forename: M
authors.initials: M
authors.lastname: Mercuri
authors.forename: P
authors.initials: P
authors.lastname: Picci
authors.forename: F
authors.initials: F
authors.lastname: Fagioli
authors.forename: P G
authors.initials: PG
authors.lastname: Casali
authors.forename: S
authors.initials: S
authors.lastname: Ferrari
authors.forename: M
authors.initials: M
authors.lastname: Aglietta
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009536:Niacinamide / Q000031:analogs & derivatives; D012516:Osteosarcoma / Q000188:drug therapy* / Q000628:therapy; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib