Hypoxic radiosensitizers in radical radiotherapy for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated radiotherapy, carbogen, and nicotinamide

Abstract

Background: In animal models carbogen (normobaric 95% oxygen, 5% carbon dioxide) provides significant enhancement of local tumor control with fractionated radiotherapy. This approach to radiosensitization has been evaluated in the treatment of patients with bladder carcinoma using radical radiotherapy.

Methods: Sixty-one patients with locally advanced bladder carcinoma were treated using a Phase II trial delivering radiotherapy to the bladder (50-55 Grays in 20 daily fractions over 4 weeks) with inhalation of carbogen alone in 30 patients and the addition of oral nicotinamide (80 mg/kg) prior to radiotherapy with carbogen in 31 patients. The results from these 61 patients were compared with those from two earlier attempts at hypoxic sensitization: the second Medical Research Council (MRC) hyperbaric oxygen trial in patients with bladder carcinoma and a Phase III trial of misonidazole with radiotherapy in patients with bladder carcinoma performed at Mount Vernon Hospital.

Results: Although there was no difference between the hyperbaric oxygen and misonidazole trials, when compared with the two earlier series there was a large, statistically significant difference in favor of those patients receiving carbogen with or without nicotinamide for local control (P = 0.00001), progression free survival (P = 0.001), and overall survival (P = 0.04).

Conclusions: Although the advantage for the carbogen group may be explained in part by changes in radiotherapy practice over the period of the three studies the improvement in local control is sufficiently great to support the hypothesis that hypoxia is important in modifying the control of bladder carcinoma using radiation therapy. Further evaluation of accelerated radiotherapy, carbogen, and nicotinamide in patients with bladder carcinoma is needed in a Phase III trial.