Time Off Therapy After a First Cycle of Intermittent ADT

ProstateCancerInfoLink.net | 05.09.2010

A new report has suggested that, for men treated with intermittent androgen deprivation therapy (ADT) after biochemical relapse following surgery or radiation, the length of the first time-period off androgen deprivation therapy (ADT) may correlate with time to onset of castration-resistant prostate cancer (CRPC) and prostate cancer-specific mortality.

In this study by Yu et al., patients who had a rising PSA after radical prostatectomy or radiation therapy were started on intermittent androgen deprivation therapy (ADT) with leuprolide and flutamide. The first cycle on treatment lasted for nine months. ADT was then stopped and PSA levels were assessed once monthly during the off-treatment period. Patients were started on their second cycle of ADT when their PSA reached just 1 ng/ml for patients previously treated with radical prostatectomy or 4 ng/ml for patients previously treated with radiation therapy.

Patients were treated intermittently in this manner until CRPC, which was defined as at least two consecutive increasing PSA values while on ADT with castrate testosterone levels.

The results of this study were as follows:

•72/100 patients enrolled in the study met eligibility criteria for this particular analysis.
•A period of ≤ 40 weeks off-treatment in the first off-treatment cycle was associated with a briefer period of time to onset of CRPC (hazard ratio [HR] = 2.9) and death (HR = 3.8) after adjusting for age, stage, grade, and PSA at diagnosis.

Yu et al. conclude that, “In patients who completed the first cycle of [intermittent ADT], a duration of the first off-treatment interval of ≤ 40 weeks defines a subset of patients at higher risk of CRPC and death. Conversely, patients with an off-treatment interval of >40 weeks have a significantly better long-term prognosis.’

We don’t know the PSA levels of these patients at the time they first started ADT, but we assume it was no higher than 1 ng/ml for patients previously treated with radical prostatectomy or 4 ng/ml for patients previously treated with radiation therapy — and it may well have been lower.

The “New” Prostate Cancer InfoLink is concerned that starting intermittent ADT when PSA levels are as low as implied by this paper is, potentially, a problem – especially in patients who may not have any other signal for aggressive disease. Such use of ADT may even be stimulating early onset of CRPC because it may accelerate the growth of androgen resistant prostate cancer cells.

The “New” Prostate Cancer InfoLink would like to see more data from a larger patient set and with less aggressive criteria for the initiation of use of ADT before we accept the conclusions of this paper (which the authors themselves describe as an “exploratory” analysis).

There are certainly patients who fail first-line therapy with a low PSA doubling time (say < 6 months) and for whom early and aggresive use of intermittent ADT may be highly appropriate. There are other patients who fail first-line therapy with a much longer PSA doubling time (≥ 12 months) and for whom ADT may be appropriately deferred for a considerable period of time, because they will still respond well to such therapy at a later date. In these patients, the early use of ADT has a series of potentials for harm that may argue strongly in favor of deferring ADT in order to avoid the many side effects of androgen deprivation as well as the risk for early onset of CRPC.

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