AK-2123 (Sanazol) as a radiation sensitizer in the treatment of stage iii cancer cervix: Initial results of an IAEA multicentre randomized trial

Abstract

AK-2123, a nitrotriazole hypoxic cell sensitizer has reportedly improved results in head and neck cancers, uterine cervical cancers and other solid tumours when added to radical radiotherapy. A prospectively randomised trial was initiated by the International Atomic Energy Agency (IAEA) evaluating AK-2123 and radiotherapy in treatment of uterine cervical cancer stage IIIA and IIIB. A total of 333 patients were randomised between May 1995 and December 1998. Patients were randomised to either standard radical treatment (radiation therapy alone, RT) or standard radical radiotherapy and additional administration of AK-2123 (RT+AK-2123). The total dose of 45-50.8 Gy was delivered in 20 to 28 fractions over 4 to 5 1/2 weeks. The dose to the central disease was escalated to a radiobiologically equivalent dose of 70 Gy by external beam or brachytherapy, in accordance with each centres individual practice. In the study arm, patients received 0.6 g/sqm AK-2123 by intravenous administration before external beam radiotherapy, treating with AK-2123 on alternate days (e.g. Monday-Wednesday-Friday) during the entire course of external beam therapy. After a median follow up of 57 months (range 30-73 months) the rate of local tumour control was significantly higher in the group who received radiotherapy and additional administration of AK-2123. Local tumour control at the last follow up was 61% after combined radiotherapy and AK-2123 and 46% after radiotherapy alone (p = 0.005). AK-2123 neither increased gastro-intestinal toxicity nor gave any haematological toxicity. A mild peripheral neuropathy (Grade 1:11% and Grade 2:3%) was seen infrequently after AK-2123 administration and was usually completely reversible. Crude survival rates were 41% after radical treatment compared to 57% after combined therapy (p = 0.007). We conclude that the addition of AK-2123 to radical radiotherapy significantly increases response rates and local tumour control in advanced squamous cell cancer of the uterine cervix without any increase in major toxicity. Further analysis and follow up are needed to evaluate if this benefit will translate into prolonged survival. We strongly suggest that our initially very promising study should lead other centres to further studies of AK-2123 in randomised clinical trials.