Delayed onset of castration resistance with serum T-based LHRH agonist regimens

A new paper just published online in Urology suggests that intermittent and testosterone (T)-based LHRH regimens are less likely to be associated with early onset of castration resistance than traditional, continuous, calender-based regimens.

It has been suggested for years by a subset of physicians, patients, and advocates that non-traditional forms of LHRH agonist therapy — and more complex forms of androgen deprivation therapy (ADT) based on LHRH agonist therapy — might have beneficial long-term outcomes compared to continuous, calendar-based LHRH agonist and ADT regimens.

Blumberg et al. evaluated data from 1,617 patients with prostate cancer who were treated with LHRH agonist monotherapy in the Kaiser Permanente Southern California Cancer Registry between January 2003 and December 2006. Only patients who received LHRH agonist monotherapy as their first-line treatment were eligible for inclusion in the analysis (i.e., any patient who had previously received surgery and/or radiation therapy was ineligible).

Patients were categorized into one of three groups according to how their LHRH dosing was managed:

  • Group A: Calendar-based dosing regimens (in which patients were continuously dosed every 3, 4 or 12 months, depending on the specific formulation of the LHRH agonist being used)
  • Group B: Intermittent dosing regimens (in which patients with low, stable PSA levels might come off the LHRH agonist therapy for significant periods of time, and then go back on therapy when their PSA levels started to rise again)
  • Group C: T-based dosing regimens, in which LHRH dosing was based on the idea that serum T levels should be consistently  maintained at or below a predefined level and that LHRH agonist therapy was given to accomplish that goal.

This study is based on a retrospective analysis of data from 692 patients who met the study criteria. Here is what the authors found:

  • The numbers of patients in each group were
    • Group A: n = 325
    • Group B: n = 115
    • Group C: n = 252
  • Patients in Group C showed a significantly lower relative risk of treatment failure (hazard ratio [HR] = 0.65, P = 0.02) compared to those in Group A.
  • Patients in Group B demonstrated a trend toward a lower relative risk treatment failure (HR = 0.80, P = 0.3) compared to those in Group A, but it was not statistically significant.
  • Among the other variables analyzed, only a Gleason score > 8 (HR = 2.05, P = 0.01) and a pretreatment PSA level > 20 ng/ml (HR = 2.00, P < 0.01) were associated with a higher risk of treatment failure.

The authors conclude that, “During the time period studied, T-based and intermittent dosing regimen of LHRH agonist had lower rates of early castrate resistance compared with standard calendar dosing, based on measurements for early androgen resistance” Unfortunately, the abstract to this paper does not give precise details regarding time on therapy broken down by group or the methods used to assess castration resistance. We are requesting a copy of the full text of this paper from the authors and will post a follow-up report once we receive this.

Fundamentally, however, this paper would appear to support the idea that the use of LHRH agonist monotherapy, and potentially the use of ADT, should be based on serum T levels, which would allow for intermittent use of LHRH agonist monotherapy and ADT in men with stable T levels below a defined level (ideally 20 ng/dl).

It is clear to The “New” Prostate Cancer InfoLink that these data require the urgent development of a prospective, randomized clinical trial to confirm the results of this study by Blumberg and his colleagues.

One Response

  1. Aside from the vagaries of a retrospective, uncontrolled study, something is amiss here. The most obvious reason that T-based dosing would be better than calender dosing is that a portion of men on the calender schedule have testosterone escape and other uncontrolled studies suggest that is a bad thing. By monitoring testosterone regularly and adjusting the treatment, the T can be kept in the proper range. Of course that is entirely inconsistent with only treating when the PSA rises because those men will have greater fluctuations in the T level. The bottom line — only a randomized study can tell which is best.

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