Intermittent hormone therapy and its place in the contemporary endocrine treatment of prostate cancer

Abstract

Castration results in dangerous and disabling side effects. Deferred hormone therapy has been shown to be associated with decreased survival. Intermittent hormone therapy (IHT) was attempted initially to reduce morbidity of treating metastatic prostate cancer with stilboestrol. Preclinical work using castrate mice with hormone sensitive prostate tumours demonstrated that pulses of testosterone delayed the onset of androgen independent growth and PSA production in these mice. This led to development of clinical treatment protocols for use in phase II trials by a number of centres in a variety of clinical scenarios. These phase II trials demonstrated apparent safety of this approach, prompting several large scale RCTs. Thus far no difference in survival has been demonstrated between IHT and continuous hormone therapy despite large numbers and prolonged follow-up. Quality of life has been proven to improve with stopping hormone therapy. A recent meta-analysis and multivariate analysis of phase II studies provides a unique opportunity to identify features of the various published IHT protocols which engender treatment success and allow the following recommendations to be made which may guide the clinician in devising their own IHT protocol. A PSA nadir below 1 ng/ml has been shown to be the best determinant of when it is safe to stop treatment. It can be achieved after as little as three months in patients with local disease. Patients with metastatic disease should be treated for at least eight months. Restarting treatment when the PSA rises to 15 ng/ml prolongs survival. MAB or LHRH monotherapy should be the standard of care in all patients with possible exception of recurrent disease after radiotherapy or prostatectomy where anti-androgen monotherapy may be appropriate. Initial PSA and the level of the PSA nadir achieved enable definition of prostate cancer patients in whom this approach may define a subgroup of local disease patients in whom it may be safe to avoid radical therapy. Preclinical and clinical data from a phase II trial demonstrating that addition of finasteride prolongs the off treatment period and provide the impetus for a randomized controlled trial (RCT) to prove this.