Tumor Hypoxia Predicts Biochemical Failure following Radiotherapy for Clinically Localized Prostate Cancer

Abstract

Purpose: Tumor hypoxia is an important determinant of outcome in many human malignancies and is associated with treatment resistance and metastases. The aim of this study was to determine the effect of hypoxia in patients with prostate cancer treated with radiotherapy.Experimental Design: Tumor hypoxia was measured in 247 patients with clinically localized prostate cancer before radiotherapy, with or without hormonal therapy. The median pO 2 was 6.8 mm Hg and the median hypoxic percentage less than 10 mm Hg (HP 10 ) was 63%. The median follow-up was 6.6 years.Results:The 5-year biochemical relapse-free rate (bRFR) was 78%. Prostrate-specific antigen and Gleason score were both associated with biochemical relapse and formed a baseline clinical model. The effect of hypoxia was found to vary with the duration of patient follow-up. HP 10 , when added to the clinical model, was an independent predictor of early bRFR (P ¼ 0.019). The relationship between hypoxia and early bRFR was more pronounced when the analysis was restricted to 142 patients with bulk tumor at the site of the oxygen measurements (P ¼ 0.004). Hypoxia was the only factor predictive of local recurrence in 70 patients who had biopsies conducted during follow-up (P ¼ 0.043), again with the effect being greatest early after completing treatment.Conclusions: This is the largest clinical study of prostate cancer hypoxia with direct measurement of tumor oxygen levels. It shows that hypoxia is associated with early biochemical relapse after radiotherapy and also with local recurrence in the prostate gland.

Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

“…The proportional hazards assumption was checked for each variable by looking at the Schoenfeld residuals. As the proportional hazards assumption was found to be violated for metformin use, a Cox regression model was used to model metformin as a time-varying coefficient, adjusting for clinical T-category (T1 vs. T2þ), Gleason score (6 vs. 7 vs. 8þ), pretreatment PSA (continuous), and the use of hormonal treatment (Y vs. N) as previously described (2). All analyses were done using SAS version 9.2 and R version 2.12.1.…”

“…The presence of tumor hypoxia is a negative prognostic factor in tumors treated with curative intent by radiotherapy across multiple sites, including squamous cell carcinoma of the head and neck (1) and prostate carcinoma (2). Tumor cells located further than approximately 150mm from vessels experience "diffusion-limited" hypoxia as oxygen is consumed by the tumor cells more proximal to the vessels (3).…”

Defining normoxia, physoxia and hypoxia in tumours—implications for treatment response

“…24,27,87 Estimation of oxygenation in the prostate provides an additional problem, since the tumour often infiltrates throughout the gland, which may affect measurement of "normal" oxygen levels. It has been reported that the "normal" tissue is not significantly different in oxygen level from tumours; 26,88 however, it is possible that the normal tissue is influenced by the presence of tumour. In one study, the normal prostate was assessed in two patients prior to surgery for bladder cancer and they showed a mean of 3.4% oxygen (26.2 mmHg).…”

Hypoxia in prostate cancer

“…Median p02 was 6.8 mm Hg and the median percentage of hypoxia was less than 10 mm Hg [47]. Their findings show that hypoxia is associated with early biochemical recurrence and local recurrence in prostate after radiotherapy or radiotherapy associated with hormone therapy.…”