Androgen deprivation therapy in advanced prostate cancer: is intermittent therapy the new standard of care?

Abstract

Purpose: Intermittent androgen deprivation is increasingly used as an alternative to continuous life-long androgen deprivation therapy for men with advanced or recurrent prostate cancer.

Recent findings: Two recent phase iii trials have clarified the benefits of intermittent therapy. The Canadian-led pr.7 trial in men with nonmetastatic disease and prostate-specific antigen recurrence after definitive local therapy showed that intermittent therapy resulted in survival equivalent to that with continuous therapy, with significant improvements in quality of life. Patients on intermittent therapy experienced improved bone health, fewer metabolic and hematologic disturbances, fewer hot flashes, and improved sexual function. In men with metastatic disease, the data are less clear. The long-awaited results of the Southwest Oncology Group 9346 trial, comparing intermittent with continuous therapy in metastatic disease, showed no difference in overall survival. Post hoc stratification analysis showed a worse outcome in patients with "minimal" metastatic disease, and no difference in those with widespread bone metastases. The significance of that observation is in dispute. The present review also addresses practical issues in the use of intermittent therapy, including patient selection, follow-up, and therapy cycling.

Summary: The recent results of randomized clinical trials now establish that intermittent androgen deprivation therapy is an approach that should be considered the standard of care in most patients with nonmetastatic prostate cancer requiring hormonal therapy and in selected patients with metastatic disease.

Key points: Level i evidence supports the oncologic equivalence of intermittent compared with continuous androgen blockade in men with biochemical failure.Compared with continuous androgen deprivation, intermittent therapy demonstrates improved quality of life and fewer side effects.Patient selection for intermittent therapy is important to maintain good oncologic results.Monitoring of prostate-specific androgen response and duration of off-treatment intervals allow for stratification of patients by risk of progression.

Keywords: Androgen deprivation therapy; prostate cancer; quality of life.

FIGURE 1

A three-cell-type model is consistent with the apparent conundrum of improved survival with low nadir testosterone on androgen deprivation therapy (adt) and noninferiority of intermittent adt, in which testosterone (T) returns to normal levels during the off-treatment interval. More effective adt, achieving serum T < 20 ng/mL, would result in cell death in both the androgen-sensitive and partially androgen-sensitive subpopulations. On repopulation, the result is a highly androgen-sensitive population of cells and a more prolonged time to castration resistance. Failure to adequately ablate T below 20 ng/mL could result in the persistence of a partially androgen-insensitive subpopulation, which repopulate upon re-treatment, accelerating progression to androgen-independence.