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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 18F-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 (r2=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).Conclusion:In STS, hypoxia is associated with adverse outcomes. The combination of sunitinib with preoperative RT resulted in unacceptable toxicities, and higher local relapse rates.

Type Journal
ISBN 1532-1827 (Electronic) 0007-0920 (Linking)
Authors Lewin, J.; Khamly, K. K.; Young, R. J.; Mitchell, C.; Hicks, R. J.; Toner, G. C.; Ngan, S. Y.; Chander, S.; Powell, G. J.; Herschtal, A.; Te Marvelde, L.; Desai, J.; Choong, P. F.; Stacker, S. A.; Achen, M. G.; Ferris, N.; Fox, S.; Slavin, J.; Thomas, D. M.:
Garvan Authors Prof David Thomas
Publisher Name BRITISH JOURNAL OF CANCER
Published Date 2014-01-01 00:00:00
Published Volume 111
Published Issue 12
Published Pages 2254-2261
URL http://www.ncbi.nlm.nih.gov/pubmed/25321190
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?12585_13046/2014-Lewin-Br J Cancer.pdf