Androgen Withdrawal in Patients Reduces Prostate Cancer Hypoxia: Implications for Disease Progression and Radiation Response

Abstract

Hypoxia is a feature of many human malignancies, and leads to aggressive clinical behavior and recurrence after treatment. Here, we show for the first time that androgen withdrawal reduces prostate cancer hypoxia in patients. Oxygen measurements were done in 248 patients with clinically localized prostate cancer prior to radiotherapy, and showed hypoxia of potential biological and clinical significance. In 22 of these patients, prostate oxygen levels were measured both before and after 30 to 145 days of the androgen antagonist bicalutamide. There was a significant reduction in tumor hypoxia with androgen withdrawal (P=0.005). The median pO(2) increased from 6.4 to 15 mm Hg, and the hypoxic proportion decreased from 40% to 31%. However, the response was heterogeneous, with improvement in 12 patients, stable oxygen readings in 9 patients and worsening hypoxia in 1 patient. Among the responding patients, the median pO(2) increased from 4.9 to 33 mm Hg, and the hypoxic proportion decreased from 51% to 23%. There was no apparent relationship between the change in oxygenation and baseline prostatic volume, T category, Gleason score, prostate-specific antigen levels, the duration of treatment with bicalutamide, or the change in prostate-specific antigen levels with bicalutamide. These results might, in part, explain the improved patient outcome that has been observed in clinical trials of radiotherapy and hormones, and suggest a role for novel therapeutic agents that block the molecular response to hypoxia in prostate cancer either alone or in combination with other established treatments.