ABSTRACT
The idea of intermittent cycling of endocrine therapies arose through a realization that treatment resistance emerges from a Darwinian interplay of genetic and epigenetic factors and selective pressures of treatment. Early observations that prostatic involution after castration is an active process involving rapid elimination of most epithelial cells led to the postulate that replacement of androgens, even in small amounts, would have a conditioning effect on surviving cells and allow them to conserve or regain desirable traits of differentiation.6,7 In the case of tumors, several lines of evidence obtained by Foulds7 and Noble8 implied that long periods of hormone deprivation simply accelerated progression towards autonomous growth and thus were better avoided. Although, no practical method of countering progression by hormonal means emerged from this work, the subsequent demonstration that consecutive episodes of testosterone-induced regeneration of involuted prostate completely restored the susceptibility of the epithelium to further androgen withdrawal,9 was an incentive to try similar experiments on tumors. The potential benefits of intermittent, rather than continuous, therapy include improved quality of life through reduced therapy-induced side effects, decreased costs, and possibly improved control over progression to androgen-independence. However, IAS is a feasible treatment option only if immediate hormone therapy is superior to delayed, and if adaptive mechanisms help mediate androgen-independent progression. The following section will review evidence that supports this rationale.
