Controversies Surrounding Androgen Deprivation for Prostate Cancer

Stephen G. Patterson, MD, Lodovico Balducci, MD, Julio M. Pow-Sang, MD

Disclosures

Cancer Control. 2002;9(4) 

In This Article

Intermittent vs Continuous Hormonal Therapy

Intermittent hormonal therapy only became feasible when medical castration became available. Advantages include reduction of side effects from therapy such as the physiological changes associated with castration, reduction of cost, and potentially delayed emergence of hormone refractoriness. Some studies have investigated the use of intermittent rather than continuous hormonal suppression. The intended goals include prolonging the initial hormone-sensitive period, achieving suppression of tumor growth at testosterone levels above those achieved by castration, and allowing sexual function during the interval between active androgen suppression. Experiments involving hormone-dependent breast cancer in the Noble rat model revealed that with a moderate reduction of the hormone level, tumor growth diminished and emergence of the hormone-independent state was delayed. Castration in the same rat model actually accelerated the progression to the hormone-independent state and hastened the death of the animal.[76] The results suggested that a delay in progression to hormone independence can be achieved using intermittent androgen suppression.[77]

Laboratory evidence suggests that intermittent androgen blockade improves outcome by delaying the onset of hormonal resistance,[78] but currently there are no clinical data available to verify this hypothesis. Serial serum PSA determinations make intermittent androgen suppression possible by providing an easy method for early determination of tumor growth during periods of no treatment. The important question of whether intermittent hormonal therapy improves survival can be accurately addressed only in a randomized trial.

Intermittent hormonal therapy consists of an initial active androgen suppression period, usually between 6 and 9 months, followed by a corresponding length of time where no active therapy is undertaken. Patients are then followed at regular intervals off therapy, and when laboratory values meet threshold criteria for reactivation of disease, active androgen suppression is reinitiated until maximal effect is again observed. Each period of active treatment followed by treatment cessation is referred to as one cycle of treatment. Ordinarily, patients who respond to an initial cycle will be observed to respond by objective criteria to a second initiation of androgen suppression. The key results of five trials investigating intermittent hormonal therapy are summarized in Table 2 . A variety of reversible medical modalities have been used to induce testosterone suppression intermittently.[79,80,81,82,83,84] Most of the reported phase II clinical trials have utilized approximately 8 months of androgen blockade followed by a period of no treatment when serial PSA is followed. Treatment is usually restarted after the PSA crosses a threshold of approximately 10 ng/mL. There are some anecdotal observations in the reported trials that the inability of a patient to reach normal levels of PSA with initiation of therapy could be considered a poor prognostic indicator.

Significant findings consistent among all five studies were recovery of libido during time off treatment in men who had normal libido prior to initial antihormonal therapy, effectiveness of reinstitution of hormonal suppression in prior responders, and subjective improvement in overall sense of well-being during time between active hormonal suppression. SWOG 9346, a multicenter randomized trial, is currently underway comparing intermittent vs continuous suppression. Assessed endpoints include quality of life and survival.

Intermittent androgen suppression may not only allow a reduction of the harmful side effects observed in patients who are treated with continuous androgen suppression, but also provide intervals of potency and regained libido during the intervals without androgen suppression. Investigators have theorized improved outcomes with intermittent hormonal therapy. To date, no randomized trial results have been reported that support such theory.

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