Details

Autor(en) / Beteiligte

• Lewin, J
• Khamly, K K
• Young, R J
• Mitchell, C
• Hicks, R J
• Toner, G C
• Ngan, S Y K
• Chander, S
• Powell, G J
• Herschtal, A
• Te Marvelde, L
• Desai, J
• Choong, P F M
• Stacker, S A
• Achen, M G
• Ferris, N
• Fox, S
• Slavin, J
• Thomas, D M

Titel

A phase Ib/II translational study of sunitinib with neoadjuvant radiotherapy in soft-tissue sarcoma

Ist Teil von

• British journal of cancer, 2014-12, Vol.111 (12), p.2254-2261

Ort / Verlag

London: Nature Publishing Group UK

Erscheinungsjahr

2014

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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). 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.