Phase III trials

Studies of chemopreventive agents in randomized Phase III design require to be very large and very lengthy. For instance, a study of smokers randomized to retinoids needs to recruit thousands of smokers for a follow-up period of up to twenty years to detect any impact on lung cancer rate or survival. As it is impossible to afford, in terms of time or money, to test each new agent with the classical Phase II design, two solutions are being tested. One is the concentration on high-risk groups of individuals and the other is the development of intermediate biomarkers. Individuals can be at high risk because of a genetic predisposition or a previous treatment or by having had a previous cancer.

The Euroscan trial was designed to be cost-effective, as it tested patients who had been cured of one smoking-related cancer either in the lung, head, or neck. The primary endpoint was the appearance of a second smoking-related cancer, genotypically different from the first, anywhere in the aerodigestive tract. 'Ex-patients' were randomized to receive retinol or n-acetyl cysteine.

Retinol induces differentiation and inhibits malignant transformation. It acts at the promotion stage of carcinogenesis and there is evidence that it antagonizes a number of growth factors. It is an immune stimulant and it may actually be cytotoxic (transretinoic acid has been shown to be effective in the treatment of acute myelo-monocytic leukaemia). N acetyl cysteine has been used widely in chronic bronchitis in Europe and works in a totally different way from retinol. It is a potent anti-oxidant and increases intracellular glutathione. It has been shown in laboratory animals to be an anti-carcinogen.

In order to test the possible advantages in combining two chemo-preventive agents, which have different mechanisms of action, the third arm of the Euroscan trial includes both agents and the fourth arm, neither. This allows two questions to be answered with half the number of patients by analysis of the data at the end of the study by factorial methods. As second primary tumours are seen within seven years in 15% of this cohort, the study only requires 2500 individuals to be randomized.

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