In this issue of Clinical Cancer Research, Crokart et al.(1) report that glucocorticoids increase tumor oxygenation by decreasing oxygen consumption rate. The magnitude of the improvement in pO2 is sufficient to cause a 70% prolongation of tumor growth time when given before a single large dose of 25 Gy. This effect occurs despite the fact that this treatment decreases perfusion. The results of this paper highlight the complexity of oxygen transport deficiency in tumors, which is the subject of this commentary.

It has been recognized for well over half a century that hypoxic cells are more radioresistant than normoxic cells. Many clinical studies have shown that the prognosis for patients who have hypoxic tumors is consistently worse than for those who have well-oxygenated ones (2). Many methods have been tested to improve tumor oxygenation in attempts to improve radiation response; the majority have focused on improving oxygen delivery. Augmented delivery strategies tested in phase III trials have included hyperbaric oxygen (3), agents that right shift the hemoglobin saturation curve in combination with oxygen breathing (4), carbogen (95% oxygen+ 5% carbon dioxide)+ nicotinamide (a vasoactive vitamin B analogue) in a trial referred to as ARCON (accelerated radiotherapy with carbogen and nicotinamide), and erythropoietin (5, 6). Although the hyperbaric oxygen trials successfully improved local tumor control following radiotherapy, this modality is cumbersome and impractical for daily use with modern radiotherapy practice (3). Phase III trials of ARCON in invasive bladder (7) and head and neck cancer (6) are currently enrolling patients. A phase III trial radiotherapy F epoetin h in head and neck cancer patients tested the hypothesis that the maintenance of hemoglobin concentration above a threshold would improve treatment outcome. Tumor oxygenation was not measured, but amelioration of tumor hypoxia via prevention/correction of anemia was implicit in the study design. Administration of erythropoietin in this study did in fact result in higher hemoglobin concentrations, but survival was unexpectedly worse in the experimental group (5). The value of using blood transfusions for anemic patients to improve radiotherapy outcome is also doubtful (8). Presently, there is no level 1 evidence supporting the value of any method of improving tumor oxygenation.