title: A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma.
abstract: BACKGROUND
  Preoperative radiotherapy (RT) is commonly used to treat localised soft-tissue sarcomas (STS). Hypoxia is an important determinant of radioresistance. Whether antiangiogenic therapy can 'normalise' tumour vasculature, thereby improving oxygenation, remains unknown.
  
  
  METHODS
  Two cohorts were prospectively enrolled. Cohort A evaluated the implications of hypoxia in STS, using the hypoxic tracer (18)F-azomycin arabinoside (FAZA-PET). In cohort B, sunitinib was added to preoperative RT in a dose-finding phase 1b/2 design.
  
  
  RESULTS
  In cohort A, 13 out of 23 tumours were hypoxic (FAZA-PET), correlating with metabolic activity (r(2)=0.85; P<0.001). Two-year progression-free (PFS) and overall (OS) survival were 61% (95% CI: 0.44-0.84) and 87% (95% CI: 0.74-1.00), respectively. Hypoxia was associated with radioresistance (P=0.012), higher local recurrence (Hazard ratio (HR): 10.2; P=0.02), PFS (HR: 8.4; P=0.02), and OS (HR: 41.4; P<0.04). In Cohort B, seven patients received sunitinib at dose level (DL): 0 (50 mg per day for 2 weeks before RT; 25 mg per day during RT) and two patients received DL: -1 (37.5 mg per day for entire period). Dose-limiting toxicities were observed in 4 out of 7 patients at DL 0 and 2 out of 2 patients at DL -1, resulting in premature study closure. Although there was no difference in PFS or OS, patients receiving sunitinib had higher local failure (HR: 8.1; P=0.004).
  
  
  CONCLUSIONS
  In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates.
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] The University of Melbourne, St Vincent's Hospital Campus, Fitzroy, Victoria, Australia.
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authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] The University of Melbourne, St Vincent's Hospital Campus, Fitzroy, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] Department of Orthopaedics, St. Vincent's Hospital, Fitzroy, Victoria, Australia [3] Department of Surgery, The University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
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authors.lastname: Powell
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] Department of Orthopaedics, St. Vincent's Hospital, Fitzroy, Victoria, Australia [3] Department of Surgery, The University of Melbourne, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: P F M
authors.initials: PF
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authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
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authors.initials: SA
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authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
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authors.initials: MG
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
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authors.lastname: Fox
authors.affiliation: The University of Melbourne, St Vincent's Hospital Campus, Fitzroy, Victoria, Australia.
authors.forename: J
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authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia [2] The University of Melbourne, St Vincent's Hospital Campus, Fitzroy, Victoria, Australia [3] The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, New South Wales 2010, Australia.
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mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D049268:Positron-Emission Tomography; D011446:Prospective Studies; D011758:Pyrroles / Q000008:administration & dosage*; D018714:Radiotherapy, Adjuvant; D012509:Sarcoma / Q000188:drug therapy* / Q000532:radiotherapy*; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib