First 6 months of first off-therapy cycle may determine effectiveness of intermittent ADT

A new paper in Clinical Genitourinary Cancer provides some intriguing information about determining the likelihood of good and less good long-term responses to intermittent androgen deprivation therapy (ADT) among men with non-metastatic prostate cancer. Be warned: This is going to be a long post with a lot of data.

Kuo et al. conducted a study that enrolled 100 men with either locally advanced prostate cancer or progressive prostate cancer (after failure of first-line therapy) with the intent to study time to the onset of castration resistance (and  a number of other related factors). None of these patients had any evident metastatic disease at study entry.

All patients initially received 9 months of ADT with an LHRH agonist and the antiandrogen flutamide (250 mg three times a day). If the patients found the flutamide to be too toxic, they could be switched to bicalutamide. After 9 months on therapy, patients were taken off ADT and monitored if and only if their PSA level was ≤ 1 ng/ml and not rising.

Patients were then able to stay off ADT so long as:

  • Their PSA level stayed below 1 ng/ml (for the men who had had a prior radical prostatectomy)
  • Their PSA level stayed below 4 ng/ml (for the men who still had an intact prostate, even if they had had prior radiation therapy or other treatment)

Patients’ PSA levels were measured every month during the trial, and their serum testosterone (serum T) levels were measured every 3 months while they were on ADT and every month when they came off ADT.

All patients were scheduled to be cycled on and off ADT according to the above protocol until they showed clear evidence of castration-resistant prostate cancer (CRPC), defined as two sequential rises in PSA while on ADT and with a serum testosterone level < 50 ng/dl.

Here are the study findings as now reported by Kuo et al.:

  • 100 patients were enrolled in the trial between June 1996 and September 2006.
  • 62/100 patients were eligible for the current analysis.
  • For the 62 eligible patients, at original diagnosis
    • Average (median) age was 61.2 years at diagnosis (range, 48.3 to 74.8 years).
    • Average (median) PSA level was 9.7 ng/ml (range, 3.9 to 130.5 ng/ml).
    • Gleason scores ranged from 6 to 9.
  • Prior treatments included:
    • Radical prostatectomy (n = 47)
    • Definitive radiation therapy (n = 14)
    • Primary ADT (n = 1)
  • Average (median) time to biochemical recurrence after primary treatment was 3.3 years (range, 0.5 to 14.6 years).
  • At study entry
    • Average (median) age was 66.2 years (range (51.2 to 81.1 years).
    • Average (median) baseline PSA level was 3.9 ng/ml (range, 0.46 to 152.4 ng/ml).
    • Average (median) baseline serum T level was 350 ng/dl (range, 140 to 640 ng/dl).
    • 55/62 men had never had any ADT; 2/62 men had had neoadjuvant ADT; 5/62 men had had adjuvant ADT.
  • 52/62 men (84 percent) achieved a PSA level of < 0.1 ng/ml during their first treatment cycle.
  • For these 52 patients, during their first off-treatment period
    • The average (median) time to recovery of a serum T > 50 ng/dl was  3.1 months (range 0 to 5.1 months).
    • The average (median) time to PSA rise was 4.5 months (range, 0.9 to 92.3 months).
    • The median duration of the first off-treatment period was 9.5 months (range, 3.4 to > 47.5 months).
    • 5/52 patients (10 percent) were still in their first off-treatment cycle at the time of this analysis.
  • For the entire group of 62 patients
    • 22 (35 percent) have died.
      • 13/22 died of progressive CRPC.
      • 9/22 died of other causes.
    • 40 (65 percent) are still alive.
      • 23/40 are still on IAD.
      • 11/40 have CRPC.
      • 6/40 are off study.
  • For the 57 patients who are not still in their first off-treatment cycle
    • Average (median) time from the end of the first cycle of ADT to CRPC was 4.0 years (range, 0.5 to 8.6 years).
    • Average (median) time from the end of the first cycle of ADT to death was 6.6 years (range, 2.9 to 13.0 years).

Now it is clear from these data (in line with the many other studies of the use of ADT both intermittently and continuously) that there is an extremely wide range of responses to even just 9 months of ADT. Our understanding of precisely why this is the case is still limited. However, further analysis carried out by Kuo et al. was able to suggest the following:

  • Time to PSA rise and time to PSA rise after serum T reached a level > 50 ng/dl were each associated with time to CRPC.
  • Each 30-day increase in time to PSA rise was associated with a 21 percent reduction in risk for CRPC.
  • A time to PSA rise of ≥ 60 days after serum T reached a level of > 50 ng/dl was associated with a 71 percent reduction in risk for CRPC.
  • Time to first serum T > 50 ng/dl and PSA doubling time were not prognostic for progression to CRPC.
  • No time interval was prognostic for prostate cancer-specific mortality.

By using the first three indicators of good initial response to intermittent ADT, physicians and their patients may be able to make better decisions earlier about the value of remaining on intermittent ADT as opposed to initiating more aggressive forms of action (e.g., enrolling in clinical trials of newer agents).

Kuo et al. discuss the potential ramifications of their findings in great detail in the full text of this paper, and have noted that a retrospective analysis of comparable data from the much larger PR7 trial of intermittent androgen deprivation may help to clarify some of these implications. Support group leaders and others with an  intense interest in the application of intermittent ADT in the management of progressive and advanced forms of prostate cancer may want to seek out a copy of the full text of this paper.

[Editorial comment: The “New” Prostate Cancer InfoLink thanks Dr. Evan Yu, the senior author of the paper, for providing us with a full text copy of this article at a ridiculously early hour in the morning!]


8 Responses

  1. Do we know if any of these patients were using drugs such as Avodart in the “off season” of IHT?

  2. Jerry:

    There is no mention of sauch use of 5-alpha-reductase inhibitors in the full text of the paper, and I have no reason to beleive that this was the case.

  3. Thanks. … They were on ADT for 9 months. Do we know if the 9 months on therapy included time for it to leave the patient’s system? Meaning, with a 4-month Lupron shot, it probably takes 4 months to leave the system before serum T can even begin to recover. If it was in their system, it’s more like they were on for 13 months.

  4. Dear Jerry:

    While the paper does not say this explicitly, it seems to be very clear (based on the text and an image showing the trial design) that patients received three 3-month injections of leuprolide acetate at (approximately) days 0, 30, and 60 of the trial (with daily, oral antiandrogen therapy for 90 days), which would imply that they were, indeed, on therapy for 9 months and not the 12 that you suggest might be possible. And since all patients were being treated at a single center, there would seem to be no reason to think that this wasn’t the standard care for all the patients in this trial.

  5. “Time to PSA rise” is a crucial variable here. But how was that determined? For example, would a rise from 0.09 to 0.11 ng/ml be considered a PSA rise?

  6. Mike:

    You mention five men had adjuvant ADT; one would assume these were surgical patients. Does it mention for how long they received ADT and if they also had adjuvant radiation, or would that no longer be considered first-line therapy? The two who received neo-adjuvant ADT were likely radiation patients. How long did they receive hormone therapy first time around.

    Do you think these seven men contaminate the results at all?

  7. Rick:

    With respect to the use of ADT in the men considered eligible for evaluation, the paper reads as follows: “Patients could have received prior AD
    for neoadjuvant, adjuvant, or salvage settings as long as the duration of AD was ≤ 3 months and it was completed > 1 year before study entry.”

    It seems unlikely to me that inclusion of these patients would contaminate the results, but, as I wrote orginally, this was a small study sample and we really need to see data from a larger series of patients to be able to validate the conclusions drawn by Kuo et al. The authors themselves point this out.

  8. Dear TomT:

    A PSA rise in this study was defined as an increase in the patient’s PSA of a minimum of 0.1 ng/ml, so no, a rise from 0.09 to 0.11 ng/ml would not have been sufficient to meet the study criteria.

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