A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma
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.
|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.:|
|Responsible Garvan Author||Prof David Thomas|
|Publisher Name||British Journal of Cancer|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25321190|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12585|