Recovery of normal serum T levels after short-term ADT and radiation therapy

Two matters of concern to many prostate cancer patients who are considering radiation therapy as a treatment for their prostate cancer are : (a) Should I be having a short course of androgen deprivation therapy (ADT) along with the radiation therapy? (b) How well will I recover normal serum testosterone levels after such short-term treatment?

A newly published study by Inoue et al. in the journal Clinical Genitourinary Cancer has provided us with some initial answers to the second of these questions for patients with intermediate-risk prostate cancer, and their results may have implications with respect to the first question.

Now it needs to be appreciated that this is a small study in just 10 Japanese patients, so the degree that it may apply to other patients of other ethnicities must be considered with some caution, but this is the first study to address this question at all, so it is important (if “only” from a patient perspective).

Inoue et al. enrolled 10 men with intermediate-risk prostate cancer, all of whom were scheduled for treatment with radiation therapy + ADT. The ADT was executed using 4 months of treatment with degarelix (an LHRH antagonist).

The patients’ serum testosterone (T), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and PSA levels were all measured and Expanded Prostate Cancer Index Composite questionnaires were completed prior to receipt of any treatment (i.e., at baseline); at 1, 2, 3, and 4 months after the first injection of LHRH antagonist treatment; and every 2 months thereafter through 18 months.

Here are the core findings of the study:

  • The average (mean) age of the 10 patients was 69.9 years.
  • All patients received the full 4 months of neoadjuvant ADT followed  by external beam radiation therapy (EBRT).
  • Baseline levels of serum T prior to LHRH antagonist treatment were a mean of 14.2 mnol/l (409 ng/dl) and a median of 14.1 nmol/l (406 ng/dl).
  • All patients were followed for 15 months after the last injection of their LHRH antagonist
  • Patients’ serum testosterone levels were at castrate level at 1 month after the first LHRH antagonist injection.
  • 8/10 patients were treated with hypofractionated EBRT (54 Gy in 15 fractions)
  • 2/10 patients were treated with conventionally fractionated EBRT (70 to 76 Gy in 35 to 38 fractions) because they they were not good candidates for hypofractionation.
  • There were no cases of biochemical failure during the follow-up period.
  • At 5 months after the last injection of the LHRH antagonist
    • Serum T levels had returned to levels above the castrate level in 5/1o patients
    • Serum T levels had returned to “normal” (> 7.2 nmol/l or > 207 ng/dl) in 2/10 patients
  • The median time to recovery of  a “normal” serum T level (i.e., > 7.2 nmol/l or 207 ng/ml) was 7 months after the last LHRH antagonist administration.
  • At 9 months after the last injection of the LHRH antagonist
    • The mean level of serum T was 11.6 nmol/l (334 ng/dl)
  • Sexual function and hormonal bother subdomain scores, and sexual and hormonal domain scores, decreased after LHRH antagonist treatment but recovered thereafter (P < 0.05).
  • Patients’ body mass indexes (BMIs) were significantly higher at 18 months after the start of therapy than they were prior to therapy (i.e., at baseline).

Inoue et al. conclude that:

In most patients, the testosterone level had normalized within 9 months after the last LHRH administration. Sexual and hormonal function recovered after short-term LHRH antagonist administration for neoadjuvant therapy before EBRT.

However, what appears to be clear is that even by 15 months after the last injection of the LHRH antagonist, the patients’ serum T levels had generally not recovered to their original baseline levels. And there was evidence at that time of a long-term effect on the patients’ BMIs.

It is also important to acknowledge the wide range of what are considered to be “normal” serum T levels in otherwise health adult males (from 270 to 1,070 ng/ml or from 9 to 37 nmol/l according to the University of Rochester Medical Center).

Other studies have examined the rates and levels of recovery of serum T after ADT using a variety of different types of ADT in different scenarios. What is clear is the following:

  • There is considerable inter-patient variation in time to recovery of “normal” serum T levels after ADT.
  • Definitions of a “normal” serum T level vary, and this makes it difficult to compare the results of these types of study.
  • Most patients will see their serum T levels rise back up into the “normal” spectrum at 18 months after initiation of treatment, but …
  • No one seems to be suggesting that (at least within 18 months) patients should expect to recover the same level of serum T after even a short course of ADT as the level they had before their ADT.
  • The role of neoadjuvant ADT in combination therapy for intermediate-risk prostate cancer should probably be confined to those for whom it is essential (to whatever extent it is possible to define that necessity).

We would respectfully suggest to the research community that the appropriate primary endpoint for these types of study is really not the percentage of patients who recover a “normal” serum T level after coming off ADT. Rather, it is the percentages of patients who recover (a) a serum T level that is at least 75 percent of their individual baseline, pretreatment serum T level and better still (b) a serum T level that is at least 90 percent of their individual baseline, pretreatment serum T level. We suspect that these numbers would generally be low, but they would be far more informative for patients as a consequence.

Editorial note: The “New” Prostate Cancer InfoLink thanks Takahiro Inoue, MD, PhD, of Kyoto University Graduate School of Medicine, Kyoto, Japan, for kindly and promptly providing us with a full text copy of this article for our review.

3 Responses

  1. So, does this suggest that even a short course of ADT will result in a long-term, or possibly permanent, decrease in baseline (pre-treatment) testosterone level? If so, would testosterone supplementation be appropriate in some individual cases?

  2. Dear Michael:

    What I think this means is that assuming or expecting that one’s serum T levels will necessarily return to their pre-ADT treatment levels is not a very wise idea. However, it may well happen for some men.

    With regard to testosterone supplementation, we have known for years and years that this is appropriate in some men. What we don’t know in advance is which set of “some men” is the set in which it is appropriate. We also know it is highly inappropriate for some men … because they promptly get recurrent prostate cancer. Again, we have no clear indicators of which set of “some men” is the set in which it is appropriate, although the general assumption is that the higher your Gleason score at diagnosis the less appropriate you may be as a candidate for supplemental T (but that is an assumption).

  3. Thanks for your response, Mike. I discussed this with my radiation oncologist, and he advised waiting at least 3 years after completing treatment before considering testosterone replacement therapy. If you’d like the details of my case, for context, please let me know, and I’ll write up a brief summary. I was also informed, by my medical oncologist, that it might take 6 months to 1 year for T to return to whatever level it will. I will see this doctor in December, and plan to revisit this question with him then.

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