Low serum T and active surveillance: let’s look before we leap

A new report from a group of Italian researchers has suggested that circulating serum testosterone (T) levels in the blood may be a risk for upgrading and upstaging among men initially diagnosed with low-risk prostate cancer who are managed on active surveillance.

It has long been understood that there is an association between having a low serum T level and risk for clinically significant prostate cancer that is high grade and/or high stage. What has not ever been studied (as far as your sitemaster is aware) is whether there is any association between low serum T levels and risk for upgrading of men initially diagnosed with low-risk disease who are initially managed on active surveillance.

This new paper by Ferro et al. (available as a full-text article) is based on a retrospective assessment of data from > 300 patients who met low-risk criteria for inclusion on active surveillance protocols (clinical stage ≤ T2a; PSA < 10 ng/ml; two or fewer cores including any cancer; a Gleason score ≤ 6; PSA density < 0.2 ng/ml/cm3). All patients had also had their serum T level measured prior to their surgery. However, these patients were never put on active surveillance. Rather, they had all opted for immediate treatment by radical prostatectomy.

Here is what Ferro et al. report:

  • The total number of patients included in the cohort was 338.
  • 53/338 patients (15.7 percent) had a serum T level of < 300 ng/dl prior to surgery.
  • Of these 53 patients with a serum T level of < 300 ng/dl prior to surgery,
    • 33 (62 percent) were pathologically upstaged post-surgery, and represented 50 percent of the total of 66 patients who were upstaged.
    • 40 (75 percent) were pathologically upgraded post-surgery, and represented 27 percent of the 146 patients who were upgraded.
  • Low serum T levels of < 300 ng/dl prior to surgery were “significantly associated with upgrading, upstaging, unfavorable disease and positive surgical margins.”

The authors promptly conclude that:

… our results support the idea that total testosterone should be a selection criterion for inclusion of low-risk [prostate cancer] patients in AS programs and suggest that testosterone level less than 300 ng/dl should be considered a discouraging factor when a close AS program is considered as treatment option.

Now these data are certainly interesting, but they come from a study which is retrospective in nature and include no data at all from patients who have actually been placed on active surveillance (and who might just as easily have had low serum T levels at the time they were initially diagnosed with low-risk prostate cancer). We therefore need to treat these data with a great deal of caution.

Rather than rushing to judgment about the relevance of low serum T levels to risk for upgrading or upstaging, what we are going to need here will be data from a prospectively followed cohort of highly identified patients who were actually started on active surveillance to see whether having a low serum T level actually increased the probability of a later finding of elevated risk and subsequent need for treatment. Until we have such data, all we would be doing is maintaining the well-understood risk for over-treatment of men with low-risk disease who may never have risk for metastasis or prostate cancer-specific mortality.

Any man who is being placed on active surveillance should, in any case, be given a repeat biopsy (preferably under MRI/TRUS guidance) within at most 12 months of his initial diagnosis before he is formally placed on an active surveillance protocol. For obvious reasons, this never happened in this cohort of patients. It is perfectly possible that this step alone would have shown that many of the men — who this group of researchers actually define as having “very low-risk” prostate cancer according to the Prostate Cancer Research International: Active Surveillance (PRIAS) protocol — were not actually low risk at all. After all 146/338 or 43.2 percent of the men in this cohort apparently had a Gleason score of 4 + 3 = 7 or higher at time of surgery. This suggests that this cohort actually contained a high percentage of men who were by no means either low or very low risk!

Having stated that, it should also be pointed out (as Ferro and his colleagues do indeed do) that there are good reasons why total circulating serum T levels should be measured routinely in men who are being evaluated for risk of clinically significant prostate cancer or who are being monitored on active surveillance — at least in series of men like this who are being monitored and evaluated at tertiary academic medical centers.

One Response

  1. Although the confounding factor of low serum testosterone is problematic, this study will be passing its way into the scrapheap of bad urological science now that the era of mpMRI mapping for index lesions is upon us.

    Clearly these men were understaged, given the pathological findings. The key question is this: Had these men undergone mpMRI imaging and with index lesion targeted biopsies, would they still have been candidates for AS? I doubt it.

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