Benefit of radiotherapy dose escalation in localised prostate cancer with respect to expression of intrinsic markers of hypoxia


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Scott Morgan, Gerard McVey, Cathy Corbishley, Colin Cooper, Robert Huddart, Alan Horwich, David Dearnaley, Chris Parker

The Institute of Cancer Research, Sutton, UK

Abstract

Background
Dose escalation improves the efficacy of prostate cancer radiotherapy (RT) at the cost of increased toxicity. Tumor hypoxia causes radioresistance, so the benefit of RT dose escalation may be greater in more hypoxic cancers.

Method
Cases had localized prostate cancer treated with neo-adjuvant androgen deprivation and radical RT at the Royal Marsden in two randomized trials of dose escalation (64 vs 74Gy). Tumour expression of three markers (vascular endothelial growth factor (VEGF), hypoxia inducible factor-1α (HIF-1α), and osteopontin) was assessed immunohistochemically using a semi-quantitative scale by a uro-pathologist, and analyzed with respect to freedom from biochemical failure (FFBF) using the Phoenix definition. Expression of each marker was dichotomised about the median for analysis of the impact of dose-escalation on outcome.

Results
201 cases with a median follow-up of 7 years were evaluable. Seven-year FFBF was 67% vs 40% (HR: 0.42, 95% CI 0.26-0.7, p=0.001) for 74 Gy versus 64Gy, respectively, among cases with high osteopontin expression, and 70% vs 82% (HR: 1.41, 95% CI 0.53-3.76, p=0.49) for 74Gy vs 64Gy among cases with low osteopontin expression. The benefit of RT dose escalation was similar regardless of VEGF or HIF-1α expression.

Conclusion
These data generate the hypothesis that osteopontin expression could inform RT dose individualisation. If validated, patients with low tumor expression of osteopontin could elect to receive less toxic, standard dose RT.